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Volume 22, Number 8, January 2012

Online Submission

Advisory Bodies

IJCP Group of PublicationsDr Sanjiv Chopra

Prof. of Medicine & Faculty Dean Harvard Medical SchoolGroup Consultant Editor

Dr Deepak ChopraChief Editorial Advisor

Dr KK AggarwalCMD, Publisher, Group Editor-in-Chief

Dr Veena AggarwalMD, Group Executive Editor

Anand Gopal BhatnagarEditorial Anchor

Heart Care Foundation of India

Non-Resident Indians Chamber of Commerce & IndustryWorld Fellowship of Religions

FROM THE DESK OF GROUP EDITOR-IN-CHIEF

CLINICAL STUDY

REVIEW ARTICLE

ORIGINAL STUDY

369 Avoid these Foods for a Healthier Heart KK Aggarwal

371 Tuberculous Pericardial Effusion GS Sainani, Rajesh G Sainani

377 Vildagliptin – A New Prospect in Management of Type 2 Diabetes

Satish Babu

387 Polyherbal Formulation (Hairzone Solution) in the Management of Diffuse Hair Loss: Post Marketing Safety and Efficacy Study

J Prasad, Suprabha Hegde

392 Nasopharyngeal Foreign Bodies Sohit Kanotra, Mohd. Lateef, Showkat Ahmed

397 An Unusual Presentation of Churg-Strauss Disease (Allergic Angiitis and Granulomatosis)

A Bhatt, J Jain, OP Gupta, N Gangane

400 A Study of Performance of DOT Providers in Meerut District

Sanjay Gupta

CASE REPORT

ORIGINAL ARTICLE

IJCP Editorial BoardObstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj

ENT Dr VP Sood

Cardiology Dr Praveen Chandra Dr M Paul Anand, Dr SK Parashar

Paediatrics Dr Swati Y Bhave Dr Balraj Singh Yadav Dr Vishesh Kumar

Diabetology Dr Vijay Viswanathan Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty

Dentistry Dr KMK Masthan Dr Rajesh Chandna

Gastroenterology Dr Ajay Kumar

Dermatology Dr Hasmukh J Shroff

Nephrology Dr Georgi Abraham

Neurology Dr V Nagarajan

Editorial Policies

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article.

Note: Indian Journal of Clinical Practice does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

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EXPERT’S OPINION

MEDILAW

CONFERENCE CALENDAR

PHOTO QUIZ

405 Gastroesophageal Reflux Disease in Children: When is Surgery Indicated? What are the Long-term and Short-term Complications of Surgery?

Jyotsna M Kirtane

406 Insight on Medicolegal Sudhir Gupta

407 Conference Calendar

408 News and Views

409 Medicine revisited: Newer Drugs, Guidelines and recommendation

416 Acute Onset Vesicular rash

418 Lighter Side of Medicine

AROUND THE GLOBE

REVISITING 2011

LIGHTER READING

369IndianJournalofClinicalPractice, Vol. 22, No. 8, January 2012

Avoid these Foods for a Healthier HeartProcessed meats: Eat none or less than 2 servings (2-3 ounces) per week. Processed meats are those preserved using salts, nitrites or other preservatives. They include hot dogs, bacon, sausage, salami and other deli meats, including deli ham, turkey, bologna and chicken. Long-term observational studies have found that the worst types of meats for the heart are those that are processed.Highly refined and processed grains and carbohydrates: Eat none or at most 7 servings (1 ounce) per week. Studies have linked whole grain intake - in place of starches (like potatoes) and refined carbohydrates (like white bread, white rice and low-fiber breakfast cereals) - to a lower risk of heart disease, diabetes, and possibly stroke. Whole grains are also linked to lower weight gain over time. Whole grains lower blood pressure and cholesterol, and may improve blood vessel function and reduce hunger.

Refined or processed foods include white bread, white rice, low-fiber breakfast cereals, sweets and sugars, and other refined or processed carbohydrates.

High levels of processing remove many of the most healthful components in whole grains, such as dietary fiber, minerals, phytochemicals and fatty acids. High levels of processing also destroy the food’s natural structure. For example, eating a food made of finely milled oats (e.g., Cheerios) or grains (e.g., typically finely milled whole-grain bread) produces much higher spikes in blood sugar than less-processed versions such as steel-cut oats or stone-ground bread.

Moreover, processing often adds many ingredients that are less healthy, particularly trans fats, sodium and sugars. Also, some research shows that fructose is metabolized differently than other sugars, in a way that increases the liver’s production of new fat. Fructose represents about half of the sugar in sweeteners like high-fructose corn syrup or sucrose (found in cane sugar and beet sugar). That’s not to suggest that you never eat a slice of pie or white bread - just make them an occasional treat rather than a regular part of your diet.

Soft drinks and other sugary drinks: Drink none or at most seven 8-ounce servings per week (one 8-ounce serving per day). The examples are sodas, sweetened fruit drinks, and sports drinks. A 12-ounce can of soda contains the equivalent of 10 teaspoons of table sugar. Diet sodas are sugar-free or low in calories, but have no nutrients.

Sugary drinks have all the same ill effects on the heart as highly refined and processed carbohydrates. The body does not compute the calories you ingest in liquid form in the same way as it does the calories you take in from solid foods. So if you add a soda to your meal, you are likely to eat about the same amount of calories from the rest of your food as if you drank water instead. The soda calories are just ‘added on.’ In addition to the other harms of highly refined and processed carbohydrates, sugary drinks also increase your chances of weight gain.

(Source Harvard HEALTHbeat)

Dr KK AggarwalPadma Shri and Dr BC Roy National AwardeeSr. Physician and Cardiologist, Moolchand Medcity, New DelhiPresident, Heart Care Foundation of IndiaGroup Editor-in-Chief, IJCP Group and eMedinewSChairman Ethical Committee, Delhi Medical CouncilDirector, IMA AKN Sinha Institute (08-09)Hony. Finance Secretary, IMA (07-08)Chairman, IMA AMS (06-07)President, Delhi Medical Association (05-06)[email protected]://twitter.com/DrKKAggarwalKrishan Kumar Aggarwal (Facebook)

fromthedeskofgrouPedItor-In-ChIef


This is a common cause of chronic pericardial effusion particularly in Afro-Asian countries. It has become more common since occurrence

of HIV infection. It is relatively less common in well- developed countries. (USA, UK, Canada, Europe). Infection is either blood-borne or spread from neighboring structures like lymph nodes, lungs and bronchi. The patient presents with general features of tuberculosis such as low-grade fever, loss of appetite, loss of weight and fatigability, cough along with features of pericardial effusion.1

CLINICAL FEATURES OF PERICARDIAL EFFUSION

Symptoms vary according to the amount of pericardial fluid which may vary from 150 ml to 1,000 ml. Dyspnea is very common symptom and its severity will vary according to the quantity of fluid. The dyspnea is due to compression of the adjacent lungs and bronchi. Patient feels worse in lying down position and feels better in sitting and leaning forward as that posture reduces the compression of lungs and bronchi. Cough is another

Tuberculous Pericardial EffusiongssAInAnI,rAJeshgsAInAnI

Dept. of Medicine, Jaslok Hospital and Research Centre, Mumbai AddressforcorrespondenceDr GS Sainani 201, Buena VistaGen. Jagannath Bhosle Road, Mumbai - 400 021E-mail: [email protected]

ABSTRACT

Tuberculous pericardial effusion is common in Afro-Asian countries. Since, the introduction of HIV infection, the incidence of tuberculous pericardial effusion has increased not only in Afro-Asian countries but also the world over. It presents with the usual features of tuberculous infection (low grade fever, loss of appetite, loss of weight) along with features of pericardial effusion (dyspnea, cough and enlarged heart). The salient features of pericardial effusion are low volume pulse or even pulsus paradoxus, raised jugular venous pressure Kussmaul’s sign, congestive hepatomegaly, ascites and edema over legs. In massive pericardial effusion, patient may go into cardiac tamponade when patient is breathless, restless with poor volume pulse (typical paradoxus), engorged neck veins, sinus tachycardia, fall in blood pressure. Urgent pericardial paracentesis is warranted to reverse the hemodynamic changes with improvement in symptoms and signs. Laboratory tests reveal raised absolute lymphocyte count, raised ESR, cardiomegaly on X-ray chest, low voltage and sinus tachycardia on ECG, Echo-free space seen between two pericardial layers on 2D-echo with heart floating in pericardial sac. Diagnostic pericardial paracentesis shows that pericardial fluid is lymphocytic exudate, with elevated ADA and IFN-g levels. Tubercle bacilli may be isolated on culture, guinea pig inoculation and nowadays by PCR technique. For management of tuberculous pericardial effusion, antituberculous treatment with four standard drugs is started. Pericardial paracentesis with needle or even open drainage is useful in relieving symptoms and rapid recovery. Adjunctive corticosteroids are useful for rapid recovery and for prevention of development of constrictive pericarditis.

keywords:Nasopharynx, foreign bodies, sewing needle

common symptom and is attributable to compression of bronchi. Rarely, one may encounter hoarseness of voice or difficulty in swallowing due to pressure on recurrent laryngeal nerve or esophagus (seen in massive pericardial effusion).

On physical examination, patient looks, thin, emaciated, febrile, dyspneic and usually in propped up position. Pulse is small in volume or may have typical pulsus paradoxus (poor volume in inspiration and slightly better volume in expiration). Blood pressure is on lower side. There may be distension of neck veins with presence of Kussmaul’s sign (Jugular venous pressure rising during inspiration and lower during expiration). There may be tender hepatomegaly and in some chronic cases there is free fluid in abdomen (ascites). There is invariably pitting edema over both legs.2

Precordial examination may show slight bulging (fullness of intercostal spaces), cardiac impulse and other pulsations usually not visible. Apex beat may be just palpable. On percussion heart borders are enlarged. On left side, one may get dull percussion note beyond apex beat; on right side, one gets dull percussion note on right side of the sternum particularly in 5th intercostal space (Rotch’s sign). One may be able to demonstrate shifting dullness in left second space which is dull in recumbent position and becomes less dull in sitting position due to shifting of fluid down. In some cases

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372 IndianJournalofClinicalPractice, Vol. 22, No. 8, January 2012

of massive pericardial effusion, one can demonstrate Ewart’s sign (Dull note along with bronchial breathing and egophony over left infrascapular region due to compression of the lower lobe of left lung by pericardial fluid). On auscultation, heart sounds are distant. Rarely, one may hear a pericardial rub.2

In massive pericardial effusion, patient may drift into cardiac tamponade, which should be recognized and managed, on emergent basis. The clinical features of tamponade are due to impaired diastolic filling leading to low cardiac output due to increased intrapericardial pressure. It should be stressed that presentation of cardiac tamponade is due to rapidity with which the fluid collects rather than total quantity of fluid. If fluid starts collecting gradually over a long period, the heart adopts and cardiac tamponade does not develop. But if fluid collects rapidly, ventricular filling is impaired which leads to increase in diastolic pressure resulting in rise in atrial pressure, fall in stroke volume and cardiac output. That is reflected in compensatory sinus tachycardia and fall in systolic blood pressure. Increase in atrial pressures leads to rise in jugular venous pressure. Patient gets severe breathlessness in recumbent position (orthopnea) and he finds some comfort in sitting position and leaning forward. He may develop cyanosis. Heart sounds are distant and one may hear III heart sound. Pericardial paracentesis (preferably under echocardiographic guidance) is urgently warranted to reverse the hemodynamic alterations.1,2

INVESTIGATIONS

Blood: Total leukocyte count is usually normal with lymphocyte predominance. Absoute lymphocyte count is raised, erythrocyte sedimentation rate (ESR) is raised.X-ray: Chest shows enlarged cardiac shadow. In massive effusion, heart looks funnel shaped. The contours due to chambers and blood vessels are lost. One can assess the thickness of pericardium by injecting air in pericardial cavity after aspirating some fluid (which results in hydropneumo-pericardium).MRI: Hayashi et al3 reported a patient in when gadolinium enhanced magnetic resonance imaging (MRI) provided useful information. The incidence of tuberculous pericarditis has decreased but early diagnosis and treatment are critical because constrictive pericarditis is a serious complication which has a poor prognosis.4 MRI has recently been used to evaluate suspected pericardial heart

disease5 and few reports on MRI findings in tuberculous pericarditis are available.6,7

ECG: There is low voltage and sinus tachycardia, T waves are usually inverted.Echocardiography: This is most useful and confirmatory as one sees echo-free space between two pericardial layers. In massive pericardial effusions, one would see heart floating in pericardial sac.2

Cardiac catheterization: Before the advent of 2D-echo, cardiac catheterization and ventricular angiography used to be done to confirm and evaluate the severity of pericardial effusion.2

Diagnostitic pericardial paracentesis: Pericardial paracentesis for diagnositic and therapeutic purposes are carried out under echocardiographic scanning. On aspiration, the fluid is straw colored or sometimes blood tinged. The fluid is sent for cytology, biochemistry, Ziehl-Neelson stain and culture for tubercle bacilli. Guinea pig inoculation may confirm tuberculous etiology. The fluid is lymphocytic exudate. (Proteins are increased and there is predominance of lymphocytes). For therapeutic purposes, it is carried out in cardiac tamponade to relieve dyspnea, palpitation.2

Gibbs et al8 in their survey of 10 years experience of patients of pericardial effusion (who were managed by percutaneous paracentesis) had 46 patients of pericardial effusion. Amongst these, they documented 12 cases of tuberculous pericarditis, nine were Indo-Asian and three were of Afro-carribean origin. Fever, night sweats and weight loss were common among these patients. Pulsus paradoxus was the most important sign (100%) for the presence of echocardiographic features of tamponade. According to them pericardiocentesis remains an effective measure for immediate relief of symptoms of cardiac tamponade.

Reuter et al9 have stressed on laboratory tests for diagnosing tuberculous pericarditis. Definitive diagnosis of tuberculous pericarditis requires isolation of the tubercle bacillus from pericardial fluid, but isolating the organism is difficult. The authors studied 233 consecutive cases of pericardial effusion who underwent a predetermined diagnostic work-up. This included (i) Clinical examination (ii) pericardial fluid tests: Biochemistry; microbiology, cytology, differential white blood cell (WBC) counts, gamma-interferon (IFN-g), adenosine deaminase (ADA) levels, polymerase chain reaction (PCR) testing for mycobacterium tuberculosis (iii) HIV (iv) sputum smear and culture (v) blood biochemistry and (vi) differential WBC count.

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These results showed that fever, night sweets, weight loss, serum globulin (>40 g/l) and peripheral blood leukocyte count (<10 x 109/l) were independently predictive. Pericardial fluid IFN-g ≥50 pg/ml concentration, had 92% sensitivity, 100% specificity and a positive predictive value (PPV) of 100% for diagnosis of tuberculous pericarditis. Pericardial fluid ADA ≥40 U/l had 87% sensitivity and 89% specificity. A diagnositic model including pericardial ADA, lymphocytic/neurtophic ratio, peripheral leukocyte count and HIV status had 96% sensitivity and 97% specificity; substituting pericardial IFN-g for ADA yielded 98% sensitivity and 100% specificity. They concluded that pericardial IFN-g is the most useful diagnostic test. Alternatively they propose a prediction model that incorporates ADA and differential WBC counts

Burgess et al10 have stressed that traditional diagnostic tests for tuberculous pericarditis are insensitive and often require long culture periods. Hence, newer tools such as pericardial ADA and IFN-a were investigated by Burgess et al and they concluded that pericardial fluid levels of ADA and IFN-a are useful in the diagnosis of tuberculous pericarditis.

Mathur et al11 carried out study on 120 cases of serosal effusion (50 pleural, 50 peritoneal and 20 cases of pericardial effusion). ADA was found significantly raised with a mean value of 100 U/l, 92 U/l and 90 U/l in tubercular pleural, peritoneal and pericardial effusion respectively with overall 100% sensitivity and 94.6%, specificity and cut-off value of 40 U/l.

Cherian12 in his review article has suggested the following criteria for diagnosis of tuberculous etiology of pericardial effusion:

Culture of Mycobacterium tuberculosis from pericardial fluid or tissuePericardial tuberculous granuloma with acid-fast bacilliPericardial tuberculous granuloma + positive tuberculin skin testTuberculous granuloma in scalene node or peripheral lymph node or pleura with positive tuberculin test.Active tuberculosis elsewhere in the bodyMediastinal lymph nodes (matted with central necrosis) on CT chest/abdomenResponse to specific antitubular therapy.

Mishra et al13 in their study of 31 tuberculous (20 pleural, 8 ascites and 3 pericardial) and 24 nontuberculous

(10 transudative ascites, 8 pyopericardium) effusions evaluated PCR, ADA activity and absolute lymphocyte count (ALC). Their results showed that fluid PCR for M. tuberculosis was positive in 74% of tuberculous effusions, where as it was falsely positive in 13% of the nontuberculous group. The mean fluid ADA and ALC values were significantly higher in tuberculous effusions than in nontuberculous effusions (p < 0.001). The sensitivity and specificity of PCR, ADA and ALC were 74% and 88%, 81% and 75%, and 90% and 83%, respectively in diagnosing tuberculous effusions. They concluded that fluid PCR should not be relied on as a single test; rather, combined analysis with ADA or ALC could be more useful in the diagnosis of tuberculous effusions in children.

DIAGNOSIS

The diagnosis is confirmed by history of low-grade fever, malaise, loss of appetite, loss of weight, cough, dyspnea and clinical signs of pericardial effusion. X-ray chest, EKG and 2D-echo confirm the diagnosis of pericardial effusion. Examination of pericardial fluid would differentiate the other etiological causes of pericardial effusion. One should rule out viral, rheumatic, purulent and collagen disorders as causes of pericarditis. For confirmation of tuberculous aetiology, one should do culture of M. tuberculosis, do pericardial fluid PCR, estimate ADA and IFN-g levels in pericardial fluid. Raised ESR, elevated absolute lymphocyte count, lymphocytic exudative nature of pericardial fluid, fluid PCR for M. tuberculosis, elevated ADA and IFN-a or g help in confirming the tuberculous etiology of pericardial fluid.

TREATMENT

Antituberculous treatment with primary four drugs (rifampicin, isoniazid, pyrizinamide and ethambutol) is given for first two months. Later pyrizinamide is omitted and the remaining three drugs are given. Total 9-12 months of treatment is recommended with periodic follow-up of symptoms and signs of pericardial effusion, ESR, X-ray chest, ECG and 2D-echo till the complete disappearance of fluid and other clinical features.2

Strang et al14 in their 10-year follow-up concluded that in the absence of specific contraindication, corticosteroid should be prescribed in addition to antituberculous chemotherapy in the treatment of tuberculous pericardial effusion. The ability of prednisolone to prevent complication of constrictive pericarditis and thus reduce the need for pericardiectomy is important. Standard treatment for pericardial effusion is

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pericardiocentesis which is safe, especially under echo guidance. However, open drainage on admission, in their experience, proved to be more effective and it virtually eliminated the need for repeat pericardiocentesis.

According to Wragg and Strang,15 tuberculous pericarditis is increasing in sub-Saharan Africa where tuberculosis is the most common opportunistic infection complicating HIV infection. Adjunctive prednisolone is beneficial in HIV seronegative patients with TB pericardial effusion, reducing the risk of recurrent tamponade, death from pericarditis and constriction.16 Benefit from similar treatment in HIV seropositive patient is encouraging, particularly where the absence of antiretroviral drugs worsens the prognosis. Adjunctive prednisolone in Hakim’s study17 resulted in significant improvement in clinical condition and faster resolution of physical signs of pericardial effusion.

Trautner and Darouiche18 reported their experience of 10 cases of tuberculous pericarditis. They addressed four specific topics: (1) The importance of tissue for diagnosis (2) The optimal surgical management; (3) The role of corticosteroids and (4) The impact of HIV infection on the management of the disease. They concluded from their experience of 10 cases and review of literature that the optimal management should include an open pericardial window with biopsy both for the diagnosis and to prevent reaccumulation of fluid. Corticosteroids offer benefit in preventing fluid reaccumulation and preventing development of constrictive pericarditis. Patients with HIV seropositive also had an excellent response to open drainage, corticosteroids and antituberculous therapy. They stress that pericardial tissue specimens should be obtained to provide the best chance of definitive diagnosis.

Mayosi et al19 searched MEDLINE (Jan 1966 to May 2005) and the Cochrane Library to review and summarize the literature on the pathogenesis, diagnosis and management of tuberculous pericarditis. A ‘definite’ diagnosis of tuberculous pericarditis is based on the demonstration of tubercle bacilli in pericardial fluid or on histological section of the pericardium; a ‘probable’ diagnosis of tuberculous pericarditis is based on the proof of tuberculosis elsewhere in a patient with pericardial effusion, raised ADA levels with lymphocytic pericardial fluid exudate and/or response to anti-Koch’s treatment with four primary drugs.

According to their review, role of adjunctive corticosteroid in preventing progression to constrictive pericarditis or reducing mortality is still not clear. The timing of pericardiectomy is not clear but majority

workers recommend a trial of medical therapy and surgery in those who do not respond after six months medical therapy.

Reuter et al20 in their study of 57 patients of tuberculous pericarditis with adjunctive corticosteroids concluded that intrapericardial and oral corticosteroids were well-tolerated but did not improve the clinical outcome. In their experience, standard 4-drug treatment for six months was effective even in HIV-positive patients. They could not demonstrate, in their 3-year study, the significant benefits from adjunctive corticosteroids in tuberculous pericarditis.

CONCLUSION

Tuberculosis is an important etiological cause of pericardial effusion in Afro-Asian countries. Now with spread of HIV infection, the incidence of tuberculous pericardial effusion has increased not only in Afro-Asian countries but also all over the world. Improved techniques for recovery of M. tuberculosis, the use of PCR technology, ADA levels, pericardial IFN-g, absolute lymphocyte count, detection of mediastinal lymphnodes on CT and more clearly defined observations on 2D-echo have improved the percentage of proper diagnosis. For management, apart from antibuberculous regime, pericardial parocentosis or open drainage and corticosteroids (oral and/or intrapericardial) have improved the morbidity, mortality and reduced the sequalae of constrictive pericarditis.

REFERENCES1. Fowler NO. Tuberculous pericardiatis. JAMA

1991;266(1):99-103.2. Sainani GS. Pericarditis with effusion. API Text Book of

Medicine. Sainani GS, (Ed.), published by Association of Physicians of India Mumbai 2001:430-4.

3. Hayashi H, Kawamata K, Machida M, Kumuzaki T. Tuberculous pericarditis: MRI features with contrast enhancement. Br J Radiol 1998;71(846):680-2.

4. Desai HN. Tuberculous pericarditis. A review of 100 cases. S Afr Med J 1979;55(22):877-80.

5. Stark DD, Higgins CB, Lanzer P, Lipton MJ, Schiller N, Crooks LE, et al. Magnetic resonance imaging of the pericardium: normal and pathological findings. Radiology 1984;150(2):469-74.

6. D’Silva SA, Nalladaru M, Dalvi BV, Kale PA, Tendolkar AG. MRI as guide to surgical approach in tuberculous pericardial abscess. Case report. Scand J Thorac Cardiovasc Surg 1992;26(3):229-31.

7. Clifford CP, Davies GJ, Scott J, Shaunak S, Sarvill J, Schofield JB. Tuberculous pericarditis with rapid progression to

Cont’d on page 415...


Type 2 diabetes mellitus (T2DM) is a hetero-geneous disease with multiple underlying pathophysiological processes characterized by

hyperglycemia due to a progressive insufficiency of pancreatic β-cells in maintaining adequate regulatory levels of insulin secretion against backdrop of insulin resistance. Till recently, T2DM was primarily considered to be a disease affecting middle and elderly age group, but with the rising prevalence of obesity-associated T2DM, the disease has lately made its presence felt in adolescents and children,1, 2 presenting major health and socioeconomic challenges globally.

According to latest figures from International Diabetes Federation (IDF), the number of people with diabetes mellitus is projected to rise from 366 million in 2011 to 552 million by the year 2030. In 2011, IDF estimates that India alone has 61.3 million people living with diabetes, placing India second to China.3 T2DM is perceived to account for nearly 85-95% of all reported cases of diabetes globally.4

Vildagliptin – A New Prospect in Management of Type 2 DiabetessAtIshBABu

Consultant Endocrinologist and Diabetologist, BangaloreAddressforcorrespondenceDr Satish BabuConsultant Endocrinologist and DiabetologistNo. 313/D, 9th ‘A’ Main, 6th Block, Jayanagar, Bangalore - 560 041E-mail: [email protected]

ABSTRACT

Type 2 diabetes mellitus (T2DM) is a heterogeneous disease with multiple underlying pathophysiological processes and primarily affects the middle-aged and the elderly. However, recently the disease has been detected in adolescents due to the rising prevalence of obesity. The quality-of-life in these patients is characterized by chronic hyperglycemia, daily ordeal of self-management and life-long need for multiple medications. Despite availability of many antidiabetic therapies, optimizing glycemic control continues to be a challenge due to the progressive nature of the disease, which the existing oral antidiabetics (OADs) often fail to address. Also, the associated adverse effects limit their optimal use. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) have been focus of research in the last decade. These hormones regulate the release of insulin and glucagon from the pancreas, through a process termed as the incretin effect. Vildagliptin is a potent, selective and orally active dipeptidyl peptidase-4 (DPP-4) inhibitor, which prevents inactivation of incretin hormones by inhibiting DPP-4. It has been shown to be an effective and safe option for better glycemic control in a wide range of T2DM patients and has demonstrated HbA1C lowering potential when given as monotherapy or in combination with other OADs, without weight gain and minimal hypoglycemia.

keywords:Type 2 diabetes mellitus, incretins, dipeptidyl peptidase-4, vildagliptin, tolerability

The disease is characterized by chronic hyperglycemia, daily ordeal of self-management and life-long need for multiple medications; despite this, a large proportion of T2DM patients develop microvascular and macrovascular complications in due course of time,5 eventually affecting their quality-of-life.

With 90% T2DM patients being overweight/obese at diagnosis,6 therapeutic modalities beside lifestyle modification involve, reducing body weight preferably with loss of central adiposity, increasing insulin availability and decreasing insulin requirements.7 Clinicians today have accessibility to wide range of oral antidiabetic drugs (OADs) for management of T2DM, with each medication class diverse in its mode of action (Table 1). Despite the availability of antidiabetic therapies, achieving optimal glycemic control, keeping in mind efficacy, safety and tolerability profile and not to forget cost of medication, continues to be a challenge. However, each of this drug class is associated with one or more adverse effects.8 Drugs like sulfonylureas (SUs), meglitinides and insulin are associated with weight gain and hypoglycemia; thiazolidinediones (TZDs) causes weight gain and possibly peripheral edema. Metformin and a-glucosidase inhibitors are associated with gut-related side effects (seen in ~50% of treated patients). Moreover, with the possible exception of the TZDs, glycemic control gradually worsens over time

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with most treatments.9,10 Concerns about the safety and tolerability (notably weight gain) have often limited the optimal application of SUs and TZDs. Additionally, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has recently come under scrutiny.11

Among the OADs, TZDs till recently were increasingly used to treat T2DM and drug in initial years showed promising effect. But a decade after the launch of first TZDs, concerns have been expressed over the cardiovascular (CV) risks associated with TZDs. In a retrospective cohort study of 4,73,483 newly diagnosed T2DM patients, rosiglitazone monotherapy was found to be associated with higher risk for any CV event, than those receiving metformin monotherapy. Overall, add-on rosiglitazone and pioglitazone were associated with comparable CV risk.12 In addition, therapy with TZDs can cause weight gain of an extent similar to that observed with older SUs.13 TZDs, alone or in combination with other agents, may cause fluid retention. Because of this, patients with heart failure should be observed for signs and symptoms of worsened cardiac status; patients with New York Heart Association class III or IV cardiac status should not be prescribed TZDs.14 A recently identified additional safety concern with TZDs therapy is an increased risk of fractures; data suggest that treatment with TZDs contributes to bone loss and the effect being most prominent in postmenopausal women.15 A study in Scotland assessed the relationship between TZDs exposure and fracture in 2,12,000 patients and found increased risk for hip fracture associated with TZDs use, in both men and women alike.16

Though, existing OADs are usually effective in attaining short-to-medium term treatment goals in T2DM, but disease being progressive in nature, traditional treatment algorithms often fail to address this issue. Also, dysfunction of a-cells that is also present in T2DM has been overlooked all these years, primarily because of want of therapeutic options. The necessity to tackle issue of fundamental islet cell deficit led to a search for therapeutic alternatives, leading to rediscovery of the incretin hormones and their role in glucose homeostasis. Better understanding of their potential has in turn led to the development of incretin analogs and incretin enhancers for treatment of T2DM.17-19

DIABETES AND THE INCRETIN HORMONES

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) that stimulate insulin secretion are secreted from the gastrointestinal tract during food intake. They regulate insulin and glucagons release from the pancreas, through a process termed as the incretin effect.20 GLP-1 has also been shown to suppress glucagon secretion, slow gastric emptying and reduce food intake and body weight.21-24 But T2DM patients have reduced incretin effect, combined with constant decline in pancreatic α- and β-cell function, leading to progressive loss of glycemic control.This manifests as diminishing of glucose-dependent insulin release and progression to unregulated glucagon production, respectively.20,25,26 Since, GLP-1 secretion is lower than normal in T2DM and increasing GLP-1 decreases glycemia, it was theorized that reducing GLP-1 degradation may compensate for its reduced

Table 1. Mechanisms of Action of OADs for the Treatment of Hyperglycemia in T2DMAgent Mechanism of action HbA1C reduction IndicationMeglitinides Stimulate insulin secretion (more rapid onset

and shorter duration of action than SUs)0.6-2% Monotherapy

Combination with metforminMetformin Counters insulin resistance (especially

decreases hepatic glucose output) 1-2% Monotherapy

Combination with SUs, other insulin secretagogue, TZDs, insulin

Sulfonylureas Stimulate insulin secretion 1-2% MonotherapyCombination with metformin, TZDs, α-glucosidases inhibitor, insulin

Thiazolidinediones Increase insulin sensitivity (especially increase peripheral glucose utilization)

1-2% MonotherapyCombination with metformin, SUs ,insulin (pioglitazone only in combination with insulin)

α-Glucosidases inhibitors

Reduce rate of carbohydrate digestion 0.5-1% MonotherapyCombination with SUs

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secretion in T2DM, since, despite impaired GLP-1 secretion its effects are preserved and GIP secretion remains normal but with reduced insulinotropic effect.26 The actions of incretins on the deficiencies in glucose metabolism, pancreatic function and energy intake in T2DM patients are shown in Table 2.The major therapeutic drawback to using native incretins is their very short half-life (<2 min) following exogenous administration leading to rapid inactivation by dipeptidyl peptidase-4 (DPP-4), a circulating bioactive and synthetic peptide, resulting in loss of their insulinotropic activity.18 To counter this, GLP-1 mimetics have been developed, which maintain the physiologic effect of native GLP-1 and are not degraded by DPP-4. Another approach is to inhibit the enzyme DPP-4, thereby increasing levels of GLP-1 as well as its duration of action on target tissue, called ‘Incretin Enhancers’.27-29 The continuance endogenous GLP-1 and GIP effect produced by DPP-4 inhibition has several advantages compared with conventional therapies and newer GLP-1 analogs and gives it a unique place in T2DM therapy. Moreover, DPP-4 inhibitors are small molecules that can be administered orally and have the ability to potentiate the actions of GLP-1 as well as GIP.30 DPP-4 inhibit as a treatment of diabetes was initially verified in animal studies, which demonstrated improved glucose tolerance and insulin

secretion.27 The final proof-of-concept study in humans was published in 2002, even though the study was of only four weeks duration, where A1C was lowered by 0.5%. The treatment was also highly tolerable and safe, suggesting that DPP-4 inhibition is a feasible approach for the treatment of T2DM.31

VILDAGLIPTIN

Vildagliptin is a potent, selective and orally active second generation DPP-4 inhibitor, with a reversible and competitive mechanism of action that binds and forms a complex with DPP-4, causing its inhibition. Structurally, vildagliptin is 1-([(3-hydroxy-1-adamantyl)amino] acetyl)-2-cyano-[S]-pyrrolidine (Fig. 1). Its molecular weight is around 303.41 gm. Vildagliptin is approved in Europe for the treatment of T2DM, as dual oral therapy in combination with metformin, SU and TZDs.

Pharmacologic Overview

Vildagliptin rapidly and inhibits the enzyme DPP-4 in a dose-dependent manner,32 in turn slowing inactivation of GLP-1 and GIP and resulting in their increased half-lives.33 This increases sensitivity of a- and β-cells, consequently improving glucose-dependent insulin secretion33,34 and glucose-appropriate glucagon release inhibition,35 respectively. This combined effect increases insulin: Glucagon ratio and decreases fasting plasma glucose (FPG) and postprandial glucose (PPG) levels, resulting in improved hyperglycemia. Table 3 describes the pharmacokinetics of vildagliptin.

Clinical Efficacy

Vildagliptin monotherapy

Monotherapy with vildagliptin was well-tolerated and improved glycemic control in diet-treated subjects with T2DM in a 12-week study, assessing the efficacy and Figure 1. Chemical structure of vildagliptin.

Table 2. Incretins Action in T2DM PatientsDeficiencies in T2DM Actions of incretinsImpaired glucose-stimulated insulin secretion and lack of postprandial biphasic response

Restoration of glucose-dependent insulinotropic effect and first-phase response

Hyperglucagonemia Suppression of glucagon secretion Defective hypoglycemia counter-regulation Glucagon secretion, and loss of insulinotropic effect, when plasma glucose is low Reduced β-cell mass and insulin content Increased synthesis of proinsulin, possible increased β-cell mass or

differentiation of islet precursor cells into β-cells Accelerated β-cell apoptosis Possible inhibition of toxin-induced β-cell apoptosis Normal, retarded or accelerated gastric emptying Slowing of gastric emptying Hypercaloric energy intake, obesity Suppression of appetite/increased satiety, weight loss

Source: Khoo J, Raytner CK, Jones KL, et al. Ther Clin Risk Manag 2009;5:683-98.

OH

NH

O

N

N

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tolerability of vildagliptin (25 mg b.i.d., n = 70) versus placebo (b.i.d., n = 28). A simultaneous improvement in β-cell function was also observed. Subjects who had higher baseline HbA1C levels showed greater response.40 In another multicenter, 52-week study with vildagliptin 50 mg o.d. in 306 drug-naive T2DM patients with mild hyperglycemia, the drug significantly reduced HbA1C, FPG and PPG and improved β-cell function without weight gain or hypoglycemia.39 Two 24-week, parallel-group studies conducted in 63442 and 35443 drug-naive T2DM patients, assessed efficacy and tolerability of vildagliptin (50 mg o.d. or b.i.d. or 100 mg o.d.), with primary objective of assessing change in baseline HbA1C levels (8.4%) to endpoint.42,43 HbA1C decreased modestly in patients receiving placebo (–0.3 ± 0.1%) and to a significantly greater extent in patients receiving vildagliptin 50 mg q.i.d. (–0.8 ± 0 .1%), 50 mg b.i.d. (–0.8 ± 0.1%), or 100 mg q.i.d. (–0.9 ± 0.1%, p < 0.01 for all groups vs placebo) from an average baseline of 8.4%.42 Similarly, between treatment difference (vildagliptin-placebo) in adjusted mean change (AMDelta) in A1C was 0.5 ± 0.2% (p = 0.011), –0.7 ± 0.2% (p < 0.001) and –0.9 ± 0.2% (p < 0.001) in patients receiving vildagliptin 50 mg o.d. or b.i.d. or 100 mg o.d., respectively.43 In both the studies vildagliptin monotherapy was well-tolerated in drug-naive T2DM patients with decreases in HbA1C levels without weight gain and minimal hypoglycemia. Pooled efficacy data from five double-blind, randomized, placebo/active-controlled trials of ≥24 weeks duration, comparing effects of vildagliptin 100 mg daily monotherapy in younger (<65 years, n = 1,231) with older (≥65 years, n = 238) patients, showed that vildagliptin monotherapy was effective and well-tolerated in treatment-naive elderly patients.44 Another pooled analysis of data from all double-blind, multicenter, randomized, placebo or active-controlled trials, conducted in drug-naive patients T2DM, receiving vildagliptin 50 mg o.d. or b.i.d. or 100 mg o.d. monotherapy (n = 1,855) or placebo (n = 347), proved that vildagliptin monotherapy consistently produced robust improvements in both fasting and

meal test-derived measures of β-cell function across a broad spectrum of drug-naive T2DM patients.45 In a dose-finding Japanese study, 12 weeks of vildagliptin treatment significantly decreased mean HbA1C levels from baseline (7.4%) of 0.53%, 0.67% and 0.92% in patients receiving vildagliptin 10, 25 or 50 mg b.i.d. (p < 0.001 vs placebo). Vildagliptin 50 mg b.i.d. was considered to be the most effective and well-tolerated dose.46

Vildagliptin monotherapy: Comparative efficacy

In a 24-week study with primary objective to demonstrate noninferiority of vildagliptin (100 mg daily, n = 169) versus metformin (titrated to 1,500 mg daily, n = 166) in reducing HbA1C in drug-naive elderly (≥65 years; baseline HbA1C 7-9%) T2DM patients, vildagliptin was as effective as metformin, improving HbA1C by –0.64 ± 0.07% and –0.75 ± 0.07%, respectively, meeting the predefined statistical criterion for non-inferiority. This demonstrated that vildagliptin is an effective and well-tolerated treatment option in elderly patients with T2DM, with similar improvement in glycemic control as metformin.47 In a 52-week extension of a multicenter, randomized, parallel-group study with aim to compare the efficacy and tolerability of vildagliptin and metformin in drug-naive T2DM patients over 104 weeks, the adjusted mean change from baseline to study endpoint was –1.0 ± 0.1% in vildagliptin-treated patients and –1.5 ± 0.1% in those receiving metformin (p < 0.001 vs vildagliptin); results were in conjunction to those reported after the 1-year core phase of the study, with both drugs providing clinically meaningful decreases in HbA1C over two years.48 Twelve-week vildagliptin 50 mg b.i.d. (n = 188) was shown to be more effective than voglibose 0.2 mg t.i.d. (n = 192) in reducing HbA1C in Japanese patients with a mean between-group difference of –0.6% (95% CI; –0.7, –0.5; p < 0.001) with vildagliptin providing a much greater response rate in achieving HbA1C levels of ≤6.5% versus voglibose (50.8% vs 24.2%; p < 0.001).49 The reduction from baseline mean HbA1C levels with vildagliptin

Table 3. Vildagliptin: PharmacokineticsTmax after oral administration: 1.5-1.7 hours36 Absolute bioavailability: 85%37

Unaffected by foodHalf-life: 90 min (maximum inhibition of DPP-4 activity seen at 30 minutes after drug dose and ≥50% inhibition of DPP-4 continuing for ≥10 hours, making it suitable for once- (o.d.) or twice-daily dosing (b.i.d.).38

Metabolism: Extensively metabolized, primarily in the liver by hydrolysis; minimally metabolized by the cytochrome P-450 (CYP) enzyme systemExcretion: Mainly in the urine; 18-22% of the excreted drug is unmetabolized.39

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50 mg b.i.d. in drug-naive T2DM patients was noninferior to that with acarbose 300 mg/day.50

Signorovitch JE et al evaluated comparative efficacy of vildagliptin and sitagliptin, through randomized trials of vildagliptin or sitagliptin in Japanese T2DM patients. The aim of the study was to compare 12-week glycemic control with vildagliptin 50 mg b.i.d. versus sitagliptin 50 or 100 mg o.d. in Japanese T2DM patients. Two trials of vildagliptin and three trials of sitagliptin were identified for Japanese patients, from literature. Across all included trials, a total of 264 patients were treated with vildagliptin 50 mg b.i.d., 235 were treated with sitagliptin 50 mg o.d. and 145 were treated with sitagliptin 100 mg o.d. After adjusting for baseline differences among trials of vildagliptin and sitagliptin, vildagliptin 50 mg b.i.d. was associated with significantly greater absolute HbA1C reduction by 0.28% compared with sitagliptin 50 mg o.d. (95% CI; 0.15, 0.41; p < 0.001) and by 0.35% compared with sitagliptin 100 mg o.d. (95% CI; 0.07, 0.62; p = 0.013). The authors concluded that vildagliptin 50 mg b.i.d. was associated with significantly greater HbA1C reduction than sitagliptin 50 mg or 100 mg o.d.51

Vildagliptin as add-on to metformin: Comparison to placebo

A total of 544 patients with inadequate glycemic control (HbA1C 7.5-11.0%; mean 8.3-8.4%) on a metformin regimen of ≥1,500 mg/d were randomized to vildagliptin 50 mg o.d. (n = 177) or 50 mg b.i.d. (n = 185) or placebo (n = 182) while continuing on metformin for 24 weeks; metformin in all patients was titrated upto ≥2,000 mg/day by study baseline and the mean study dose was 2,100 mg/day.52

HbA1C was reduced by a mean of 0.7% with the addition of vildagliptin 50 mg o.d. and by 1.1% with vildagliptin 50 mg b.i.d. compared with metformin/placebo (both p < 0.001). FPG (baseline 9.7-10.1 mmol/l) was reduced by 0.8 mmol/l (p = 0.003) and 1.7 mmol/l (p < 0.001), respectively, with vildagliptin 50 mg o.d. and b.i.d. HbA1C target of <7.0% was reached in 54% of vildagliptin 50 mg b.i.d. patients, 50% of vildagliptin 50 mg o.d. patients and 14% of metformin/placebo patients starting treatment with HbA1C >8.0% and in 31%, 22% and 13%, respectively, of those starting at HbA1C ≥8.0-8.5%.

In another 24-week placebo-controlled trial in patients inadequately controlled with metformin (HbA1C 7.5-11%), patients were randomized to vildagliptin 100 mg given in the morning, vildagliptin 100 mg given

in the evening or placebo. Change from baseline to study endpoint in adjusted mean (SE) HbA1C improved significantly with vildagliptin a.m. dosing (–0.66 [0.11] vs 0.17% [0.11] with placebo; p < 0.001).53 In both these trials, vildagliptin was well-tolerated and produced clinically meaningful dose-related decreases in FPG52 and HbA1C, 52,53 as add-on therapy in patients with T2DM inadequately controlled by metformin and was equally efficacious when given as either a morning or evening dose.52

Add-on to metformin: Comparison to pioglitazone

In a 24-week trial, 576 patients with inadequate glycemic control (HbA1C 7.5-11.0%; mean <8.4%) on stable metformin ≥1,500 mg/day were randomized to vildagliptin 50 mg b.i.d. (n = 295) or pioglitazone 30 mg o.d. (n = 281). When added to metformin, the efficacy of vildagliptin was noninferior to that of pioglitazone.54

When added to a stable dose of metformin, both vildagliptin and pioglitazone decreased HbA1C (AMDelta = –0.9 ± 0.1% and –1.0 ± 0.1%, respectively) from identical baseline values (8.4 ± 0.1%). The between-group difference in AMDelta A1C was 0.1 ± 0.1%, establishing the noninferiority of vildagliptin to pioglitazone at both 0.4% and 0.3% margins for upper limit of the 95% CI. Pioglitazone decreased FPG (AMDelta = –2.1 ± 0.1 mmol/l) to a greater extent than vildagliptin (AMDelta = –1.4 ± 0.1 mmol/l), but pioglitazone increased body weight (AMDelta = +1.9 ± 0.2 kg: between-group difference= –1.6 ± 0.3 kg, p < 0.001).

The additional 28-week extension of this 24-week core study assessed long-term safety, while also assessing mean change from baseline to study end in HbA1C, FPG and body weight. During these 28 weeks, comparable HbA1C decreases were recorded in both groups.

Overall adverse event (AE) rates were similar in both groups, though serious AEs occurred more frequently with pioglitazone group with a significant increase in body weight.55 These studies established that when added to metformin, vildagliptin provided additional HbA1C lowering than was achieved with metformin monotherapy and was comparable to that achieved with pioglitazone. The drug also showed favorable safety and tolerability profile over 1-year treatment period, with only pioglitazone causing weight gain.

Add-on to metformin: Comparison to glimepiride

When metformin monotherapy fails to maintain adequate glycemic control, addition of vildagliptin provides comparable efficacy to that of glimepiride

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after 52 weeks with a favorable AE profile. In a 52-week interim analysis of a large randomized, multicenter study, noninferiority of vildagliptin was demonstrated with a mean (SE) change from baseline HbA1C (7.3% in both groups) to week 52 endpoint of –0.44% (0.02%) with vildagliptin and –0.53% (0.02%) with glimepiride. A greater proportion of patients reached this target without hypoglycemia in the vildagliptin group (50.9 vs 44.3%; p < 0.01).

Vildagliptin significantly reduced body weight, with 10-fold lower incidence of hypoglycemia than glimepiride.56 Results of another trial evaluating add-on therapy to metformin with 50 mg vildagliptin b.i.d. compared with glimepiride upto 6 mg q.i.d. in T2DM established that vildagliptin therapy but not glimepiride improves postprandial a-cell function, which persists for at least two years.57

Add-on to metformin: Comparison to TZDs

The GALIANT trial compared efficacy and tolerability of vildagliptin 100 mg with TZDs (agent and dose at the investigators’ discretion) as add-on therapy to stable metformin dose (≥1,000 mg/day) in a primary care patient population with T2DM inadequately controlled HbA1C (7-10%). The mean change in HbA1C from baseline was –0.68 ± 0.02% and –0.57 ± 0.03% in vildagliptin and TZD group, respectively.

Between-groups difference was –0.11%, establishing the noninferiority of vildagliptin (p = 0.001) after three months of treatment.58

Combination with metformin

In patients with T2DM inadequately controlled with metformin upto 1,000 mg daily, the addition of vildagliptin 100 mg daily achieved greater HbA1C reduction with fewer GI events than with increasing the metformin dose. The change in HbA1C from baseline at the 24th week was –0.51% in the vildagliptin/metformin group (mean baseline HbA1C: 7.4%) and –0.37% in the metformin monotherapy group (mean baseline HbA1C: 7.3%). As noninferiority (margin of 0.4%) was achieved, a test for superiority was performed, which showed statistically significant superiority of the combination over monotherapy group (p = 0.002).59

Add-on to SU vs placebo

In patients with T2DM inadequately controlled with prior SU monotherapy, addition of vildagliptin (50 or 100 mg daily) to glimepiride (4 mg o.d.) improved glycemic control and was well-tolerated. In a 24-week, multicenter, randomized, placebo-

controlled study, 515 patients with inadequate glycemic control on SU monotherapy (HbA1C 7.5-11.0%; mean 8.5-8.6%) were randomized to vildagliptin 50 mg o.d. (n = 170) or 50 mg b.i.d. (n = 169) or placebo (n = 176) plus glimepiride 4 mg o.d. for 24 weeks. Between-group difference (vildagliptin-placebo) in AMDelta HbA1C was –0.6 ± 0.1% in patients receiving vildagliptin 50 mg daily and –0.7 ± 0.1% in those receiving 100 mg daily (p < 0.001 vs placebo for both). Greater efficacy was seen in patients ≥65 years of age (–0.7 ± 0.1% and –0.8 ± 0.2% for 50 and 100 mg daily, respectively) and in patients with baseline HbA1C > 9% (Delta = –1.0 ± 0.2% and –0.9 ± 0.2% for 50 and 100 mg daily, respectively). The study suggested that addition of vildagliptin to SU monotherapy may proved to be an attractive option for treatment of elderly T2DM patients.60

Add-on to pioglitazone vs placebo

Vildagliptin is effective and well-tolerated when added to a maximum dose of pioglitazone, without increasing the risk of hypoglycemia as shown in a 24-week, multicenter, double-blind, randomized, parallel-group study. The adjusted mean change (AMDelta) in HbA1C from baseline to endpoint was –0.8 ± 0.1% (p = 0.001 vs placebo) and –1.0 ± 0.1% (p < 0.001 vs placebo), respectively, in patients receiving vildagliptin 50 or 100 mg daily.

Relative to baseline, vildagliptin added to pioglitazone also reduced FPG (AMDelta FPG = –0.8 ± 0.2 mmol/l and –1.1 ± 0.2 mmol/l; not significant [NS] vs placebo) and PPG (AMDelta PPG = –1.9 ± 0.6 mmol/l and –2.6 ± 0.6 mmol/l [p = 0.008 vs placebo]) for 50 and 100 mg daily, respectively. Relative to placebo, both doses of vildagliptin significantly increased the insulin secretory rate/glucose by more than 3-fold.61

Combination with pioglitazone

A study compared efficacy and tolerability of initial combination therapy with vildagliptin/pioglitazone (100/30 mg q.i.d. or 50/15 mg q.i.d.) to component monotherapy in 607 drug-naive patients with T2DM given for 24 weeks.62

Changes in HbA1C were −1.1% and −1.4% with vildagliptin and pioglitazone alone, respectively, −1.7% with the 50 mg/15 mg combination (p < 0.05 vs pioglitazone alone) and −1.9% with the 100 mg/30 mg combination (p < 0.001 vs pioglitazone alone). Both low- and high-dose combinations were significantly more efficacious than pioglitazone alone (p = 0.039 and p < 0.001, respectively).

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Adjusted mean changes in FPG were –1.9 ± 0.2, –2.4 ± 0.2, –2.8 ± 0.2 and –1.3 ± 0.2 mmol/l, respectively and both combination groups were significantly more effective than pioglitazone monotherapy (p = 0.022 and p < 0.001, respectively). The incidence of peripheral edema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%).

The study concluded first-line treatment with vildagliptin/pioglitazone combination provided better glycemic control than either monotherapy component with minimal risk of hypoglycemia and good tolerability profile.62

Combination with insulin

Vildagliptin decreases HbA1C in T2DM patients poorly controlled with high doses of insulin. As add-on, it is also associated with reduced confirmed and severe hypoglycemia. In a multicenter, 24-week study, patients were randomized to receive vildagliptin (n = 144; 50 mg b.i.d.) or placebo (n = 152) while continuing insulin therapy. The change in insulin dose was +1.2 U in the vildagliptin group and +4.1 U in the insulin/placebo group. Changes in HbA1C were −0.5% and −0.2% with vildagliptin and insulin/placebo (p = 0.01), respectively; among patients aged ≥65 years (vildagliptin, n = 42; insulin/placebo, n = 41; baseline 8.4%), changes were −0.7% with vildagliptin add-on and −0.1% with insulin/placebo. Vildagliptin was associated with significant reductions in number of hypoglycemic episodes (113 vs 185, p < 0.001) and number of severe events (0 vs 6, p < 0.05).63

In an extension of this trial, 96 patients on vildagliptin 50 mg b.i.d. continued on treatment and 104 in the insulin/placebo group switched to vildagliptin 50 mg o.d. + ongoing insulin for an additional 28 weeks (total 52 weeks). During the extension phase, the average insulin dose increased by approximately 2 U. At 52 weeks, vildagliptin 50 mg b.i.d. maintained its efficacy in reducing HbA1C (−0.5%), the change between Week 24 and 52 was −0.4%. In patients ≥65 years receiving vildagliptin 50 mg b.i.d., change in HbA1C at 52 weeks was −0.9%, compared with −0.24% in younger patients, indicating that overall efficacy primarily reflected the effect in older patients.64

Tolerability

Vildagliptin has generally been well-tolerated in the trials discussed above; with majority of AEs being of

mild-to-moderate severity and transient in nature. The overall incidence of AE in mono- or combination therapy studies did not differ between vildagliptin and placebo or active comparator recipients.40-64 AEs such as headache, nasopharyngitis, cough, constipation, dizziness and increased sweating, had higher incidence rate with vildagliptin than with placebo or active comparator.42,43,54,61 In monotherapy trials, the overall incidence of hypoglycemia with vildagliptin was similar to placebo or metformin,40-51 with no incidence of hypoglycemia being reported from two trials.39,40 Hypoglycemic events were also rare (≤3.6%) in all combination therapy trials.52-60 In a combination study with insulin, hypoglycemic events were less common and less severe in patients receiving a vildagliptin plus insulin regimen.63,64 In another trial, no severe episode of hypoglycemia transpired with vildagliptin, compared to 10 episodes with glimepiride (p < 0.01), with 11 patients discontinuing treatment in glimepiride group versus none with vildagliptin.58

More frequent GI AEs were reported with metformin47 and acarbose50 than vildagliptin. No significant change in body weight has been observed with vildagliptin either as monotherapy or as combination therapy. The drug appears to be body weight-neutral. An exception to this is a comparator phase-III trial, where there was a significant difference between weight-neutral effect of vildagliptin to weight gain effect of pioglitazone.55 It is also important to mention here that vildagliptin therapy was not associated with any kind of weight loss generally seen with some of the OADs.

Peripheral edema was reported in 8.8% of vildagliptin 50 mg b.i.d. recipients and 6.8% pioglitazone 30 mg o.d. recipients as add-on therapy to metformin54 and in 8.2% and 7% of vildagliptin 50 mg o.d. or b.i.d. recipient versus 2.5% of placebo recipients, when added to pioglitazone 45 mg o.d.61 However, the frequency of peripheral edema was unrelated to vildagliptin dose and may have been a trial-specific artifact. Clinically significant CV and cerebrovascular AEs were reported in 0.7% of vildagliptin recipients versus 1.4% of pioglitazone recipients when added to metformin.54

VILDAGLIPTIN CURRENT STATUS AND ROLE IN T2DM THERAPY

The main goal of T2DM management is to control hyperglycemia and the vascular complications. But, optimal control is seldom achieved and maintained.65 In general, for every 1% decrease in HbA1C, the risk of developing microvascular diabetic complications

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reduced by 40%. Though available OADs are capable of controlling blood glucose initially, they lack ability to stop the decline in β-cell function and to achieve lasting glycemic control.

The advent of DPP-4 inhibitors symbolizes a key therapeutic advance in the management of T2DM. DPP-4 inhibitors are weight-neutral, not associated with fluid retention and do not cause any serious hypoglycemic events; beneficial effect seen with the lipid parameters makes them theoretically safe from point of view of any CV risk. These therapies have shown potential to improve glycemic control similar to existing OADs, with prospective improvement in CV and pancreatic β-cell function. In the new group of DPP-4 inhibitors, vildagliptin has shown to be an effective and safe option for better glycemic control in a wide range of T2DM patients and promises to address limitations of current T2DM therapies. It also has the advantage of oral administration for patients who are either not candidates for or are resistant to injectable therapies.

The American Association of Clinical Endocrinologists (AACE) currently advocates DPP-4 inhibitor monotherapy for T2DM patients with HbA1C 6% to 7%, or in combination with metformin or TZDs if target HbA1C (≤6.5%) is not achieved.66 There is clear evidence of improved glycemic control with vildagliptin compared with placebo, either as monotherapy or in combination with metformin, TZDs or SU. The frequency of hypoglycemia with vildagliptin treatment was low and when added to other OADs (metformin, TZDs and SUs), the risk of hypoglycemia did not aggravate. Vildagliptin has been shown to be weight-neutral unlike TZDs, SUs, insulin and does not significantly reduce appetite. T2DM is a progressive disease, resulting in need for polypharmacy having complementary mechanism of action in due course of time. Recent guidelines suggest that patients will require combination therapy much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted AEs, especially hypoglycemia.67

The multiplicity of pharmacodynamic mechanisms of existing antihyperglycemic agents available for T2DM management, allows a number of combination regimens to effectively control glucose levels. Adding SUs to metformin has been the conventional and the gold-standard combination therapy for decades. Though previous glycemic targets made this therapy quite attractive, but relative risk of hypoglycemia warranted need for more glucose-sensitive combination regimes.

Vildagliptin is indicated as second-line therapy as part of an oral combination therapy regimen in patients with T2DM for whom hyperglycemia levels are poorly-controlled with metformin, SUs or TZDs.35 It is particularly useful in combination with metformin and TZDs. The highly favorable risk-benefit profile of vildagliptin makes it an useful agent for combination across all existing OADs therapies to further enhance glycemic control. Combining vildagliptin with metformin has proved to be the most encouraging/interesting amalgamation in recent times. Combining metformin, principally targeting insulin resistance, with vildagliptin primarily targeting the β-cell is a rational approach. Vildagliptin also has the added advantage of also targeting the α-cell dysfunction that is evidently present in T2DM patients, with insufficient suppression of glucagon secretion leading to postprandial hyperglycemia.

The lack of GI AEs with vildagliptin compared to GLP-1 agonists and metformin and low-risk of hypoglycemia, makes it especially suitable for older T2DM patients, in whom polypharmacy required for glycemic control is often associated with increased risks of hypoglycemia and other AEs along with comorbidities such as CV and renal impairment. Vildagliptin is currently approved in the European Union for use in combination with metformin and TZDs. The recommended daily dose of vildagliptin is 50 mg, administered o.d. or b.i.d. When used in combination with SUs, the recommended dose of vildagliptin is 50 mg o.d. administered in the morning. Drug can be administered with or without meals. Routine liver function tests (LFTs) are recommended during therapy and treatment should be withdrawn if aminotransferase levels exceed 3 times the upper limit of normal.35 Data till date indicate that treatment with DPP-4 inhibitor vildagliptin effectively stimulates insulin secretion, suppresses glucagons release and improves glycemic control. It is well-tolerated with low rate of major AEs and hypoglycemia.

SUMMARY AND CONCLUSION

Vildagliptin is a potent and selective DPP-4 inhibitor that has shown consistent and sustained efficacy and tolerability in clinical trials with reduced HbA1C, FPG, PPG levels and prandial glucagon secretion, improved CV and β-cell function and possibilities of addressing number of limitations of current therapies for T2DM. The weight-neutrality of drug can limit the development of comorbidities including dyslipidemia, obesity and hypertension associated with disease. Since managing associated comorbidities is major cost factor in overall

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cost of managing T2DM, this will make vildagliptin a potential cost-effective option, superseding any probable economic impact of the agent. Overall, vildagliptin as mono- or combination therapy improved glycemic control in T2DM patients and has been suggested to slow down the progression of β-cell degeneration, placing it at the forefront of T2DM therapy and a useful option for use in combination with other OADs.

AcknowledgmentDr Satish Babu would like to thank MIS division of medONE Pharma Solutions, New Delhi, India, for content and editorial support provided during preparation of manuscript of this article.

DisclosuresDr Satish Babu has received Speaker honorarium fees for scientific activities (CMEs) from Novo Nordisk and Novartis.

REFERENCES

1. Fox CS, et al. Circulation 2006;113(25):2914-8.2. Booth GL, et al. Lancet 2006;368(9529):29-36.3. Press release. International Diabetes Federation. World

Diabetes Day 2011.4. Diabetes Atlas: Executive Summary. 3rd edition.

International Diabetes Federation.5. Nathan DM. N Engl J Med 1993;328(23):1676-85. 6. Link between diabetes and overweight. Available at:

http://ezinearticles.com/?Link-Between-Diabetes-And-Overweight&id=537123.

7. Chehade JM, et al. Drugs 2000;60(1):95-113.8. Inzucchi SE. JAMA 2002;287(3):360-72.9. Turner RC, et al. JAMA 1999;281(21):2005-12.10. Lancet 1998;352(9131):854-65 11. Krentz AJ, et al. Drugs 2008;68(15):2131-62.12. Hsiao FY, et al. Drug Saf 2009;32(8):675-90. 13. Kelly IE, et al. Diabetes Care 1999;22:288-93.14. Collins FM. Am J Manag Care 2002;8(16 Suppl):S460-71.15. Murphy CE, et al. Annals Pharmacother 2007;41(12): 2014-8.16. Colhoun HM, et al. The Scottish Diabetes Research

Network Epidemiology Group. Thiazolidinedione associated fractures are not limited to distal fractures and occur in men as well as women. Program and abstracts of the American Diabetes Association (ADA) 70th Scientific Sessions; June 25-29, 2010; Orlando, Florida. Abstract 0074-OR

17. Deacon CF, et al. Front Biosci 2008,13:1780-94.18. Deacon CF. Diabetes 2004;53(9):2181-9.19. Drucker DJ. Cell Metab 2006;3(3):153-65.20. Drucker DJ, et al. Lancet 2006;368(9548):1696-705.21. Naslund E, et al. Am J Physiol 1999;277(3 Pt 2):R910-6.22. Delgado-Aros S, et al. Am J Physiol Gastrointest Physiol

2002;282(3):G424-31.

23. Zander M, et al. Lancet 2002;359(9309):824-30.24. Holst JJ. Diabetes Metab Res Rev 2002;18(6):430-41.25. Ahren B, et al. Horm Metab Res 2004;36(11-12):867-76.26. Deacon CF, et al. Int J Biochem Cell Biol 2006;38(5-6):831-44.27. Ahrén B. Diabetes Care 2007;30(6):1344-50.28. Kendall DM, et al. Diabetes Technol Ther 2006;8(3):385-96.29. Triplitt C, et al. Pharmacotherapy 2006;26(3):360-74.30. He YL, et al. Clin Pharmacokinet 2007;46(7):577-88.31. Ahrén B, et al. Diabetes Care 2002;25(5):869-75.32. He YL, et al. J Clin Pharmacol 2007;47(5):633-41.33. Ahren B, et al. Int J Clin Pract Suppl 2008;62(Suppl. 159):

8-14.34. Wajchenberg BL. Endocr Rev 2007;28(2):187-218.35. Novartis Pharmaceuticals UK Ltd. Galvus 50 mg tablets

[on line]. Available from URL: http://www.emc.medicines.org.uk [Accessed 15th May 2010].

36. Croxtall JD, et al. Drugs 2008;68(16):2387-409.37. Pratley RE, et al. Br J Diabetes Vasc Dis 2006;6:150-6.38. Villhauer EB, et al. J Med Chem 2003;46(13):2774-89.39. Lauster CD, et al. Am J Health Syst Pharm 2007;64(12):

1265-73.40. Pratley RE, et al. Horm Metab Res 2006;38(6):423-8.41. Scherbaum WA, et al. Diabetes Obes Metab 2008;10(8):675-82. 42. Dejager S, et al. Horm Metab Res 2007;39(3):218-23.43. Pi-Sunyer FX, et al. Diabetes Res Clin Pract 2007;76(1):132-8. 44. Pratley RE, et al. Diabetes Care 2007;30(12):3017-22.45. Pratley RE, et al. Diabetes Obes Metab 2008;10(10):931-8. 46. Kikuchi M, et al. Diabetes Res Clin Pract 2009;83(2):233-40.47. Schweizer A, et al. Diabetes Obes Metab 2009;11(8):804-12.48. Göke B, et al. Horm Metab Res 2008;40(12):892-5.49. Iwamoto Y, et al. Vildagliptin versus voglibose

monotherapy in patients with type 2 diabetes mellitus: superior efficacy and tolerability with vildagliptin [abstract no. 561-P]. 68th Annual Scientific Sessions of the American Diabetes Association; 2008 Jun 6-10; San Francisco (CA).

50. Pan C, et al. Diabet Med 2008;25(4):435-41.51. Signorovitch JE, et al. Clin Drug Investig 2011;31(9):665-74.52. Bosi E, et al. Diabetes Care 2007;30(4):890-5. 53. Goodman M, et al. Horm Metab Res 2009;41(5):368-73. 54. Bolli G, et al. Diabetes Obes Metab 2008;10(1):82-90.55. Bolli G, et al. Diabetes Obes Metab 2009;11(6):589-95. 56. Ferrannini E, et al. Diabetes Obes Metab 2009;11(2):157-66.57. Ahrén B, et al. Diabetes Care 2010;33(4):730-2. 58. Blonde L, et al. Diabetes Obes Metab 2009;11(10):978-86. 59. Filozof C, et al. World J Diabetes 2010;1(1):19-26.60. Garber AJ, et al. Diabetes Obes Metab 2008;10(11):1047-56. 61. Garber AJ, et al. Diabetes Obes Metab 2007;9(2):166-74.62. Rosenstock J, et al. Diabetes Obes Metab 2007;9(2):175-85.63. Fonseca V, et al. Diabetologia 2007;50(6):1148-55. 64. Fonseca V, et al. Horm Metab Res 2008;40(6):427-30.65. Brown JB, et al. Diabetes Care 2004;27(7):1535-40.66. Nathan DM, et al. Diabetes Care 2008;31(12):1-11.67. Halimi S, et al. Vasc Health Risk Manag 2008;4(3):481-92.


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Scalp hair grows in cycles, with each hair follicle undergoing 10-30 cycles in its lifetime.1 Diffuse hair shedding is the result of a disruption of

one phase of the hair cycle,2,3 i.e., anagen (active hair growth), catagen (involution) or telogen (resting). The anagen phase can last 2-8 years.4 The catagen phase lasts 4-6 weeks, and the telogen phase lasts 2-3 months. The exogen phase (the release of dead hair) coincides with the end of the telogen phase. Most people have about 100,000 scalp hairs; normally 10-15% of these are in the telogen phase.5 Shedding of 100-150 telogen hairs per day is normal.4 Anagen hair loss is never normal.

The most common cause of diffuse hair loss is androgenetic alopecia (male-pattern alopecia). In men, androgenetic alopecia causes typical temporal recession (thinning of the hair around the temples) and thinning at the vertex (Hamilton patterns). In women,

*Consultant DermatologistBNR Skin Clinic, Near Garuda Mall, Bangalore**Research Associate, R&D CenterThe Himalaya Drug Company, Makali, BangaloreAddressforcorrespondenceDr Suprabha HegdeResearch Associate, R&D CenterThe Himalaya Drug Company, Makali, Bangalore - 562 123E-mail: [email protected]

Polyherbal Formulation (Hairzone Solution) in the Management of Diffuse Hair Loss: Post Marketing Safety and Efficacy StudyJPrAsAd*,suPrABhAhegde**

ABSTRACT

Hair loss is a common and distressing problem, affecting men and women of all the ages and ranging from a small bare patch to a more diffuse and obvious pattern. The purpose of this study is to evaluate the safety and efficacy of Hairzone solution in diffuse hair loss. Twenty-eight cases were included in the study according to the subject selection criteria. All the patients were advised to gently massage the solution into the scalp part by part, covering the whole area of the scalp and to rinse it in the morning. The response to therapy was evaluated at monthly intervals for a period of six months. The changes in various parameters from baseline values and the values at each visit for six months were evaluated statistically using Graph Pad Prism Version 4.03 for windows, Graph Pad Software, San Diego, California, United States. The criteria for evaluation were signs and symptoms such as reduction in hairfall by 1-minute combing test, reduction in associated symptoms like itching and overall impression. The study clearly demonstrated the beneficial effects of Hairzone solution in diffuse hair loss as evident by reduced hair fall by 1-minute combing test, in addition to decrease in itching. Hair loss was reduced in 21 of 28 patients. Further safety of the product was also substantiated by clinical parameters. Therefore, it can be concluded that Hairzone solution is safe and effective in the management of diffuse hair loss.

keywords:Hairzone solution, diffuse hair loss

a more diffuse alopecia is generally seen (Ludwig pattern). Other causes of diffuse hair loss include telogen effluvium, severe iron deficiency and protein deficiencies. These conditions cause thinning of hair over the whole scalp, in contrast to the frontovertical loss seen in androgenetic alopecia. They can also exacerbate the hair thinning of androgenetic alopecia.

Both hypothyroidism and hyperthyroidism can cause diffuse telogen hair loss that is usually reversible once the euthyroid state is restored.5,6 Chronic systemic disorders can cause telogen hair shedding. Telogen hair loss has also been reported in autoimmune diseases and in chronic infections.7,8 Poor protein intake, essential fatty acid deficiency and malabsorption are few other factors that cause diffuse hair loss.

When assessing diffuse hair loss, it is important to examine the scalp closely to exclude an inflammatory scalp disease or scarring alopecia. Assessment should also include: Detailed medical history, complete blood count, comprehensive metabolic panel, thyroid function tests, iron and ferritin levels, and zinc level to identify any underlying systemic disease, thyroid disease and nutritional deficiency. The hair shafts should be examined for length, diameter and breakage. Broken

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hairs can suggest trichotillomania, traction alopecia, tinea capitis or a trichodystrophy. Signs of hyperandrogenism such as acne, seborrhea and hirsutism should also be identified. Skin and nail examinations are important parts of the clinical examination. Hair pull tests can be also useful.9 The hair pull test will be positive where the hair is thinning, but negative away from the thinning areas. Certain species of fungi fluoresce green under a Wood’s lamp, and Malassezia (Pityrosporum) species, which cause seborrheic dermatitis, fluoresce orange.10 Bacterial and fungal cultures should be obtained if pustules or scales, respectively, are present on the scalp. Light microscopy of clipped hair can reveal hair-shaft abnormalities. A 4 mm scalp biopsy is helpful in most hair-loss conditions.9 If signs of androgen excess are present, an androgen screen is needed to exclude an androgen-secreting tumor or other endocrinopathy.11

Anagen hair loss is usually managed with observation and support. In men, medical treatment of androgenetic alopecia includes topical minoxidil (2% or 5%) and oral finasteride. Treatment with finasteride can cause decreased libido, impotence and ejaculation disorders.12 Finasteride may also induce depression.13 Women can also use topical minoxidil; A hyperandrogenic state may limit the success of treatment with minoxidil.14 In these women, spironolactone 100-200 mg daily may slow the rate of hair loss.15,16 Antiandrogens cause feminization of the male fetus; hence, all women of childbearing age should be on a reliable form of contraception.11

Women with evidence of a hyperandrogenic state requesting combined oral contraceptives would benefit from using antiandrogenic progesterones, such as drospirenone.17 Finasteride is ineffective in postmenopausal women with female pattern hair loss.18 Over-the-counter topical preparations, hair extensions, and hairpieces are available for women with poor response to treatment.

Hairzone solution, a polyherbal formulation is available in the market and is known to be beneficial in patients suffering from hair loss.

AIM OF THE STUDY

To evaluate the safety and efficacy of Hairzone solution in diffuse hair loss.

MATERIAL AND METHODS

This study was an open post marketing clinical trial conducted at BNR Skin Clinic, Bangalore, between June 2010 and March 2011. The study protocol, case report

forms, regulatory documents, product information and informed consent forms were approved by Independent Ethics Committee. A total of 28 patients of both sexes, in the age group of 18-40 years, who were suffering from diffuse hair loss, and who were willing to give informed written consent were enrolled in the study. Patients on immunosuppressive drugs, patients applying other topical therapy for diffuse hair loss, in the last two weeks prior to the initiation of the study, patients with evidence of skin infection and pregnant and lactating women were excluded from the study. Patients who were not willing to give informed written consent were excluded from the study.

Study Procedure

Each patient’s demographic medical history (especially local fungal infection, dandruff, pediculosis, trichotillomania, stress, diet, past illness and drugs), and treatment details were recorded. All the enrolled patients underwent a thorough clinical examination including scalp skin examination, which included the assessment of number of hairs lost in 1-minute combing test and the presence of alopecic patches. All the patients were advised to gently massage the solution into the scalp part by part, covering the whole area of the scalp and to rinse it in the morning. The response to therapy was evaluated at once a month for the period of six months. The criteria for evaluation were signs and symptoms like reduction in associated symptoms like itching, 1-minute comb test and overall impression.

Response for 1-minute comb test was evaluated as number of hair fall. Itching was evaluated on an Analog scale of 0-3 (0-Nil, 1-Moderate, 2-Good, 3-Excellent). The overall response was in turn correlated with response to the treatment as follows:

Grade 0: No improvement

Grade 1: Poor response <25% reduction

Grade 2: Moderate response 25-49% reduction

Grade 3: Good response 50-74% reduction

Grade 4: Excellent response >75% reduction

All the adverse events, either reported or observed by the patients, were recorded with information about severity, date of onset, duration and action taken regarding the study drug. Relation of adverse events to study medication was predefined as ‘Unrelated’ (a reaction that does not follow a reasonable temporal sequence from the administration of the drug), ‘Possible’ (follows a known response pattern to the suspected

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drug, but could have been produced by the patient’s clinical state or other modes of therapy administered to the patient), and ‘Probable’ (follows a known response pattern to the suspected drug that could not be reasonably explained by the known characteristics of the patient’s clinical state).

Patients were allowed to voluntarily withdraw from the study, if they had experienced serious discomfort during the study or sustained serious clinical events requiring specific treatment. For patients withdrawing from the study, efforts were made to ascertain the reason for dropout. Noncompliance (defined as failure to take <80% of the medication) was not regarded as treatment failure, and reasons for noncompliance were noted.

Primary and Secondary EndpointsThe predefined primary efficacy endpoint was a decrease in the symptom score for diffuse hair loss. The predefined secondary safety endpoints were acute and chronic safety, as assessed by the incidence of adverse events and patient compliance to therapy.

Statistical Analysis

Statistical analysis was done according to intention-to-treat principles. The changes in various parameters from baseline values and follow-up visits at once a month for six months were evaluated for hair loss in 1-minute comb test by repeated measures of ANOVA followed by Tukey’s multiple comparison test. Itching was analyzed by repeated measures of ANOVA using Friedman test followed by Dunnett’s multiple comparison test. Statistical analysis was performed using GraphPad Prism Version 4.03 for windows, GraphPad Software, San Diego, California, United States.

RESULTS

The demographic details of subjects included in the study are listed in Table 1. There were eight males and 20 females in the study. Duration of illness was 2.60 ± 1.99 years.

The number of hair loss in 1-minute comb test at the end of first month was 31.79 ± 10.02 (Table 2). It reduced with treatment to 26.79 ± 10.99 (p < 0.05) at the end of two months, to 20.36 ± 8.38 (p < 0.05) at the end of three months, which further reduced to 16.61 ± 9.34 (p < 0.001) at the end of four months, to 12.86 ± 10.04

(p < 0.001) at the end of five months and which further reduced to 9.82 ± 9.08 (p < 0.001) at six months; the significance values are as compared to the values in the first month.

Itching at the end of first month was 1.53 ± 0.70. It reduced with treatment to 1.21 ± 0.54 at the end of two months, which again reduced to 0.95 ± 0.62 at the end of three months, to 0.58 ± 0.61 (p < 0.01) at the end of four months, to 0.47 ± 0.51 (p < 0.01) at the end of five months and further reduced to 0.47 ± 0.51 (p < 0.01) at six months; all the significance values are as compared to the first month values (Table 3).

Assessment of overall response is listed in Table 4. At the end of the study, 4 (10.71%) cases reported marked improvement, 9 (35.71%) cases reported moderate improvement, 10 (35.71%) cases reported slight improvement and 5 cases reported no change (Table 4). Hair loss reduced in 21/28 patients (75%); 25% patients reported no change. The safety evaluation of the investigational product was also evaluated. It was found that there were no adverse effects on application of the product for the period of the study.

Table 1. Demographic Data of Patients on EntryNumber of patients 28Male: Female Male: 8; Female: 20Diet Vegetarian: 60 Mixed: 40Mean age (years) 34.07 ± 9.60 Weight in kg (mean ± SD) 62.40 ± 14.30H/o smoking (n) 8H/o alcohol consumption (n) 2Duration of hair loss (years) 2.60 ± 1.99

H/o: History of.

Table 2. Number of Hair Loss in 1-minute

Treatment period Hair loss Significance

1st month 31.79 ± 10.02 -

2nd month 26.79 ± 10.99 ap< 0.05

3rd month 20.36 ± 8.38 ap < 0.001, bp < 0.01

4th month 16.61 ± 9.34 a,bp < 0.001

5th month 12.86 ± 10.04 a,b,cp < 0.001

6th month 9.82 ± 9.08 a,b,c,dp < 0.001

aAs compared to first month, bas compared to second month, cas compared to third month, das compared to fourth month. Statistical analysis: Repeated measures of ANOVA following Tukey’s multiple comparison test.

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DISCUSSION

Various factors contribute to hair fall/loss. Genetic predisposition and hormonal factors predominantly contribute to the above. Disease states such as typhoid, malaria, jaundice, etc. and use of chemotherapeutic agents also cause hair fall. Hormone therapy, use of α-reductase inhibitors and vasodilators like minoxidil are widely used to reduce the hair fall/loss. The synthetic drug, minoxidil is a potent vasodilator appears safe for long-term treatment. Treatments available for the various forms of alopecia have limited success with unwanted adverse effects. New technologies in cosmetic transplant surgery and hair replacement systems are available that can be completely undetectable.

The present study shows that Hairzone solution is beneficial in the management of diffuse hair loss. Hairzone solution consists of potent herbs, namely Butea monosperma and Butea parviflora.

B. monosperma inhibits degeneration of hair follicles, extends the anagen phase of hair growth cycle and enhances proliferation and maturation of precursor epithelial cells of the final hair strand. It prevents the massive apoptosis in the proximal hair bulb and stimulates the multiplication of hair fiber cells with the stimulation of anagenic phase, and reduce the catagenic and telogenic phase.19

B. monosperma displays antifungal activity against Cladosporium cladosporioides;20 it also has a significant bactericidal effect21 and potential antiviral activities.22 B. monosperma has astringent action,23,24 which shrinks or constricts body tissues, usually locally after topical medicinal application. Externally, applied astringents cause mild coagulation of skin proteins, dry, harden and protect the skin. Mildly astringent solutions are used to alleviate minor skin irritations resulting from superficial cuts, allergies, insect bites or fungal infections. B. monosperma has potent free radical scavenging activity, and has proven effective in promoting the therapeutic activity of Hairzone solution.25

B. parviflora inhibits hair follicle degeneration and extends the anagen phase of hair growth cycle. It enhances proliferation and maturation of precursor epithelial cells of the final hair strand; it also prevents the massive apoptosis in the proximal hair bulb. B. parviflora stimulates the multiplication of hair fiber cells with the stimulation of anagenic phase, and reduces the catagenic and telogenic phase. It has antimicrobial action.26

The efficacy of Hairzone solution can be attributed to the synergistic effects of both these herbs, B. monosperma and B. parviflora.

CONCLUSION

This post marketing study clearly demonstrates the beneficial effects of Hairzone solution in diffuse hair loss. There was significant reduction in hair fall after two months of treatment, which further continued to show reduction until the end of the study. Similarly, itching also reduced with treatment and there was significant relief from four months until the end of the study. Hair loss reduced in 21 out of 28 cases treated with Hairzone solution. Further safety of the product was also substantiated by clinical parameters. Therefore, it can be concluded that Hairzone solution is safe and effective in diffuse hair loss.

REFERENCES1. Harrison S, Sinclair R. Telogen effluvium. Clin Exp

Dermatol 2002;27(5):389-5.2. Headington JT. Telogen effluvium. New concepts and

review. Arch Dermatol 1993;129(3):356-63.3. Kligman AM. Pathologic dynamics of human hair loss. I.

Telogen effluvium. Arch Dermatol 1961;83:175-98.4. Paus R, Cotsarelis G. The biology of hair follicles. N Engl J

Med 1999;341(7):491-7.

Table 3. Effect of Hairzone Solution on ItchingTreatment period Itching score Significance1st month 1.53 ± 0.70 -2nd month 1.21 ± 0.54 NS3rd month 0.95 ± 0.62 NS4th month 0.58 ± 0.61 ap < 0.015th month 0.47 ± 0.51 ap < 0.01, bp < 0.056th month 0.47 ± 0.51 ap < 0.01, bp < 0.05

aAs compared to first month, bas compared to second month.Statistical analysis: repeated Measures of ANOVA using Freidman fest followed by Dunnett’s multiple comparison test.

Table 4. Overall ImpressionOverall impression responseSymptoms become worse 0No change 5 (17.87%)Slight improvement 10 (35.71%)Moderate improvement 9 (35.71%)Marked improvement 4 (10.71%)Cured 0

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5. Rook A, Dawber R. Chapter 1. The comparative physiology, embryology and physiology of human hair. In: Diseases of the Hair and Scalp. Rook A, Dawber R (Eds.), Blackwell Science Publications: Oxford, UK 1982:p.1-17.

6. Sperling LC. Hair and systemic disease. Dermatol Clin 2001;19(4):711-26, ix.

7. Bergfeld WF. Chapter 9. Telogen effluvium. In: Hair and Scalp Diseases: Medical, Surgical, and Cosmetic Treatments. McMichael J, Hordin MK (Eds.), Informa Health Care: London, UK 2008:p.119-36.

8. Apache PG. Eczematous dermatitis of the scalp. In: The Science of Hair Care. Zviak C (Ed.), Marcel Dekker: New York, NY 1986:p.513-21.

9. Shapiro J. Clinical practice. Hair loss in women. N Engl J Med 2007;357(16):1620-30.

10. Elewski BE. Clinical diagnosis of common scalp disorders. J Investig Dermatol Symp Proc 2005;10(3):190-3.

11. Olsen EA, Messenger AG, Shapiro J, Bergfeld WF, Hordinsky MK, Roberts JL, et al. Evaluation and treatment of male and female pattern hair loss. J Am Acad Dermatol 2005;52(2):301-11.

12. Leyden J, Dunlap F, Miller B, Winters P, Lebwohl M, Hecker D, et al. Finasteride in the treatment of men with frontal male pattern hair loss. J Am Acad Dermatol 1999;40(6 Pt 1):930-7.

13. Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol 2006;6:7.

14. Vexiau P, Chaspoux C, Boudou P, Fiet J, Jouanique C, Hardy N, et al. Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized trial. Br J Dermatol 2002;146(6):992-9.

15. Sinclair R, Wewerinke M, Jolley D. Treatment of female pattern hair loss with oral antiandrogens. Br J Dermatol 2005;152(3):466-73.

16. Burke BM, Cunliffe WJ. Oral spironolactone therapy

for female patients with acne, hirsutism or androgenic alopecia. Br J Dermatol 1985;112(1):124-5.

17. Raudrant D, Rabe T. Progestogens with antiandrogenic properties. Drugs 2003;63(5):463-92.

18. Price VH, Roberts JL, Hordinsky M, Olsen EA, Savin R, Bergfeld W, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol 2000;43(5 Pt 1):768-76.

19. Rawal R, Kolhapure SA. Evaluation of the efficacy and safety of “Hair Loss Cream (PCPB Hair Cream)” in the management of telogen effluvium. Indian J Clin Pract 2005;16(5):19-26.

20. Bandara BM, Kumar NS, Samaranayake KM. An antifungal constituent from the stem bark of Butea monosperma. J Ethnopharmacol 1989;25(1):73-5.

21. Mehta BK, Dubey A, Bokadia MM, Mehta SC. Isolation and in vitro antimicrobial efficiency of Butea monosperma seed oil on human pathogenic bacteria and phyto-pathogenic fungi. Acta Microbiol Hung 1983;30(1):75-7.

22. Yadava RN, Tiwari L. A potential antiviral flavone glycoside from the seeds of Butea monosperma O. Kuntze. J Asian Nat Prod Res 2005;7(2):185-8.

23. Chopra RN, Nayar SL, Chopra LC. B. monosperma. Glossary of Indian Medicinal Plants. National Institute of Science Communication, 4th edition, New Delhi 1996: p.42.

24. Asolkar LV, Kakkar KK, Chakre OJ. B. monosperma. Glossary of Indian Medicinal Plants with Active Principles (second supplement). Part I (A-K), CSIR Publication, New Delhi 1992:p. 148.

25. Lavhale MS, Mishra SH. Evaluation of free radical scavenging activity of Butea monosperma Lam. Indian J Exp Biol 2007;45(4):376-84.

26. Asolkar LV, Kakkar KK, Chakre OJ. B. parviflora. Glossary of Indian Medicinal Plants with Active Principles (second supplement). Part I (A-K), CSIR Publication, New Delhi 1992:p. 149.


The otolaryngologic literature is abundant with case reports of unusual foreign bodies in the upper aerodigestive tract. Of these, nasopharyngeal

foreign bodies are rare. Only imagination limits the objects and circumstances that result in things getting stuck inside the nose. Sharp foreign bodies pose a greater problem as they can pierce the soft tissues of the nose and pharynx and lead to complications. The removal of such foreign bodies poses a challenge as damage to the surrounding structures can occur if these are not carefully tackled. On the other hand inert foreign bodies have been known to remain unsuspectingly in the nasopharynx for prolonged periods of time.1 Being a blind area which is difficult to examine, especially in children who are the usual victims, foreign bodies in the nasopharynx are likely to be missed. The use of nasal endoscopes has revolutionized the otolaryngologist’s ability to visualize not only the intranasal structures but also the nasopharynx, thus helping the surgeon to localize and remove foreign bodies not visible on anterior rhinoscopy. We present here three cases of nasopharyngeal foreign bodies, which illustrate some aspects of such foreign bodies.

CASE 1

A 4-year-old female child was brought with a history of having swallowed a match stick two hours before. The mother had seen the child gagging after putting the

Nasopharyngeal Foreign BodiessohItkAnotrA*,mohd.lAteef**,showkAtAhmed†

*Postgraduate Student**Professor and Head†RegistrarDept. of ENT, Head and Neck Surgery, Govt. Medical College, Srinagar AddressforcorrespondenceDr Sohit Kanotra, Postgraduate Student, Dept. of ENT, Head and Neck Surgery Govt. Medical College, Srinagar, KashmirE-mail: [email protected]

ABSTRACT

Nasopharyngeal foreign bodies are rare and are likely to be missed. A high index of suspicion is required for their diagnosis. While reporting three cases of nasopharyngeal foreign bodies, the problems in their diagnosis and management have been discussed.

keywords:Nasopharynx, foreign bodies, sewing needle

match stick in the mouth and unsuccessfully attempted to remove the same by putting her finger in the throat of the child. In the process the child had vomited. The child had been seen by an ENT specialist who had advised an examination under general anesthesia the next day.

On presentation, the child was uncomfortable and complained of pain in the throat. Oral cavity examination did not reveal any foreign body but as the patient gagged during examination, the tip of the match stick covered with mucoid secretions was seen behind soft palate. This was held with a hemostat and removed without anesthesia.

CASE 2

A 2-year-old child had put a plastic ring from a toy into the mouth and had an attack of choking. The mother had put her finger into her mouth to retrieve the foreign body but the child vomited and became comfortable. The child was taken to the ENT specialist who performed hypopharyngoscopy, esophagoscopy and bronchoscopy under gneral anesthesia the next day and ruled out any foreign body impaction. However, nasal endoscopy was not done due to nonavailability of the endoscope. Following this, the parents had noted that the child had started snoring heavily, and the ENT surgeon had attributed it to the presence of adenoids which was confirmed on X-ray of the nasopharynx. The child also had recurrent attacks of nasal obstruction with cough and cold which were treated with antibiotics and decongestants with partial relief.

One year after the incidence, the child suddenly sneezed and brought out the plastic ring from the mouth. After this, there was marked reduction in her snoring though she continues to have recurrent nasal obstruction due to adenoids over the past one year.

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CASE 3

An 18-year-old female presented in the ENT emergency with a history of accidental lodgment of a sewing needle in her right nasal cavity four hours back. She was trying to pierce her nostril when the needle accidentally slipped into her nose. The patient was quite uncomfortable and was complaining of severe pain on the right side of nose radiating to the whole of the face. There was no history of epistaxis or any other nasal symptom. Anterior rhinoscopy did not reveal any foreign body in the nasal cavity. Posterior rhinoscopy was also inconclusive with no evidence of the needle. An oropharyngeal examination did not reveal any postnasal bleed. An X-ray skull lateral view was taken and showed the presence of the needle (Fig. 1). The needle was seen lying along the floor of the nasal cavity extending to the nasopharynx with the pointed end placed anteriorly. The patient was planned for endoscopic retrieval of the foreign body. The nasal cavity was decongested by instillation of xylometazoline nose drops followed by 10% lignocaine spray. A 0° nasal endoscope revealed the presence of the sewing needle which had pierced the posterior end of the inferior turbinate with the blunt end lying freely in the nasopharynx. A Blakesley foreceps was passed along the endoscope and the foreign body gripped under vision. The needle (Fig. 2) was then disengaged from the posterior end of the inferior turbinate by pushing it posteriorly and removed via the anterior nares with no damage to the surrounding mucosa. A check endoscopy was done. There was no bleeding and the patient was discharged after an hour of observation.

DISCUSSION

Foreign bodies can reach the nasopharynx either through the nose or through the oropharynx and rarely a penetrating foreign body may lodge in the nasopharynx. Foreign bodies introduced into the nose are a common occurrence in children who out of curiosity or boredom want to explore the body orifices and thus any object small enough to enter the anterior nares has been removed from the nasal cavity. In adults, nasal foreign bodies are seen usually in mentally deranged individuals or may reach accidentally. Foreign bodies in the nose typically lodge near the floor of the nose below the inferior turbinate though these can be seen in any part of the nasal cavity. Attempts at removal of such foreign bodies by the patients themselves or those around can push them back into the pharynx and occasionally these may get lodged in the nasopharynx. Most of the foreign bodies entering the oral cavity pass into the esophagus

and some are inhaled into the trachea. It is unusual for a foreign body taken orally to reach the nasopharynx. Various reasons for such an occurrence include attempts at digital removal,2 regurgitation due to vomiting or coughing3 or if the foreign body is put into the mouth in lying down position with the neck extended making the nasopharynx-dependent.4 A large size of the foreign body has been cited as another factor.5 In addition, animate foreign bodies like leeches can reach the nasopharynx through the nose or a round worm can get lodged in the nasopharynx during vomiting. A high index of suspicion is required for the diagnosis of nasopharyngeal foreign bodies. Adults may localize the foreign body in the nasopharynx but children may not be able to do the same.

Posterior rhinoscopy where possible can be helpful. It is customary to take X-rays of the neck, chest and abdomen in children presenting with foreign body ingestion but it is important to take a lateral view of the nasopharynx also. If the foreign body cannot be found in the aerodigestive tract, a simple digital examination

Figure 1. Lateral X-ray nasopharynx showing the needle.

Figure 2. The sewing needle after removal.

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of the nasopharynx should be performed to rule out the presence of foreign body there. In a conscious child, digital examination of the nasopharynx can be a frightening and annoying experience but in the absence of nasal endoscope, this could easily detect the presence of a foreign body in the nasopharynx. However, this is best avoided in case of sharp foreign bodies. The second case is an example where digital examination would have diagnosed the presence of the nonradio-opaque foreign body in the nasopharynx even if the nasal endoscope was not available. In children with a history of foreign body insertion into the nose, when anterior rhinosocopy with a nasal speculum or an auroscope fails to reveal the foreign body, an endoscopic examination can be performed under general anesthesia or under local anesthesia in co-operative children. Apart from examination of the nasal cavities, nasopharyngoscopy should also be performed.

Regarding case No. 3, there are only a few reports in literature describing lodgment of sewing needles in nasal cavity although such foreign bodies do get impacted in the hypopharynx,6 albeit rarely. Sewing needles have got impacted in the nasopharynx of magicians7,8 and had to be removed under general anesthesia. An interesting case of a sewing needle reaching the maxillary antrum through a carious tooth has also been described.9

Various methods have been described for the removal of nasal foreign bodies like instrumental removal, positive pressure technique, use of Foley’s catheter or Fogarty balloon and even cyanoacrylate glue.10 But except for the first modality, the rest of the methods can not be used for removal of nasopharyngeal foreign bodies.

The basic principle in the removal of a foreign body is its adequate visualization. For nasopharyngeal foreign bodies, nasal endoscopy provides the only method of proper visualization especially for sharp foreign bodies whose retrieval can cause damage to the surrounding tissues. Perforation of the pharyngeal wall is a real threat and retropharyngeal abscess formation has been reported.7 Direct exposure of the nasopharynx by retraction of the soft palate with catheters could be helpful in large sized blunt foreign bodies. The sewing needle located in the nasopharynx in case No. 3 could

only be removed endoscopically since it could not be visualized otherwise. Use of fluoroscopy or a magnet can be other possible ways of removal of a sharp metallic needle.

CONCLUSIONS

One must keep in mind the nasopharynx as a site for lodgment while investigating cases of foreign body ingestion. Apart from taking X-rays of the neck, chest and abdomen, lateral view of the nasopharynx should be included in the films. In case of non-radio-opaque foreign bodies, digital palpation of the nasopharynx though annoying should be employed but should be avoided in case of sharp foreign bodies. Nasopharyngoscopy is extremely useful for diagnosis and removal of foreign bodies from the nasopharynx.

REFERENCES1. Ogut F, Bereketoglu M, Bilgen C, Totan S. A metal ring

that had been lodged in a child’s nasopharynx for 4 years - Brief Article. Ear Nose Throat J 2001;80(8):520-2.

2. Sangeeta MM, Greval RS, Singh D. Paediatric nasopharyngeal foreign bodies. Indian J Otolaryngol Head Neck Surg 1999;51 Suppl 1:80-2.

3. Ransome J. Foreign bodies in the nose: Scott-Brown’s Otolaryngology. 5th edition, Vol. 6, Kerr AG (Ed.), Butterworth: London 1987:276.

4. Majumdar PK, Sinha AK, Mookherje PB, Ganguly SN. An unusual foreign body (10 N.P. Coin) in nasopharynx. Indian J Otolaryngol Head Neck Surg 1999;52(1):93.

5. Sharma SC, Bano S. An unusual foreign body in nasopharynx. Indian J Otolaryngol Head Neck Surg 1992;1:42-3.

6. Shiv Kumar AM, Naik AS, Prashanth KB, et al. Foreign bodies in upper digestive tract. Indian J Otolaryngol Head Neck Surg 2006;58:63-8.

7. Onakoya PA, Adoga AA, Adoga AS, Galadima C, Nwaorgu OG. An unusual rhino-pharyngeal foreign body. West Afr J Med 2005;24(1):89-91.

8. Ahmed BM. Needles in the nose and pharynx: resulting from traditional magic in Maiduguri, Nigeria. Trop Doct 2005;35(1):39-40.

9. Domanskiz, Fuchs G. An unusual case of a foreign body in the maxillary sinus. Otolaryngol Pol 1997;51(4):414-7.

10. Cox RJ. Foreign Bodies Nose: e Medicine Oct. 6, 2005.


Churg-Strauss described allergic angitis and granulomatosis in 1951.1,2 It is a rare syndrome with reported annual incidence of 2.5 per million

per year in adults. It is a granulomatous vasculitis of multiple organ systems, particularly of the lung. It involves blood vessels of various types and sizes (including veins and venules), intra- and extravascular granuloma with eosinophilic tissue infiltration.

The cause of allergic angiitis and granulomatosis is not known. No data have been reported regarding the role of immune-mediated mechanism in the disease. Disease has strong association with severe asthma and peripheral eosinophilia. It is because of rarity of this disease, present case is reported.

CASE REPORT

A 45-year-old woman presented with a four days history of fever, swelling over all four limbs, joint pain, myalgia and rash over legs. There was no history of cough, breathlessness, chest pain, abdominal pain, vomiting, bleeding from any site, urinary symptoms or unconsciousness.

On examination, she was febrile with a heart rate of 90/minute, blood pressure of 140/90 mmHg. She was pale, had cervical lymphadenopathy, tender pitting edema overall four limbs and papular skin lesions over legs. Her systemic examination revealed bilateral lung fields having normal vesicular breath sounds, no cardiomegaly, abdomen soft with no ascites or

An Unusual Presentation of Churg-Strauss Disease (Allergic Angiitis and Granulomatosis)ABhAtt*,JJAIn*,oPguPtA*,ngAngAne**

*Dept. of Medicine **Dept. of PathologyMahatma Gandhi Institute of Medical SciencesSewagram, Wardha, Maharashtra

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ABSTRACT

We present a case of a 45-year-old female with history of four days of fever and rash with swelling over both limbs diagnosed on postmortem autopsy as Churg-Strauss disease and further give a brief overview of the disease.

keywords:Angiitis, granulomatosis

organomegaly. Central nervous system examination was unremarkable.

Based on the presentation and clinical findings, a provisional diagnosis of viral exanthema in evolution, sepsis and vasculitis were kept.

Her complete blood count and peripheral smear revealed total leukocyte count of 30,100/mm3 with 85% neutrophils, and hemoglobin of 7.8 g/dl. Her electrolytes, random blood sugar, urea, creatinine, CPK, chest X-ray, ECG, abdominal ultrasonography were normal.

The patient received systemic prednisolone and an antimicrobial empirically along with supportive treatment. On third day the patient developed acute onset breathlessness. The patient did not respond to medical treatment and died.

Autopsy was performed and histopathology report revealed Churg-Strauss syndrome involving intra-and extravascular granuloma with eosinophilic tissue infiltration of small, and medium-sized blood vessels with predominant involvement of coronary arteries with secondary myocardial infarction (Figs. 1 and 2). Small focus of dull cortical necrosis with sorrounding viable renal tissue and small vessel was seen in renal cortex (Figs. 3 and 4). Liver showed mixed inflammatory infiltrate of predominantly eosinophils in portal triad surrounded by normal hepatic parenchyma (Figs. 5 and 6).

DISCUSSION

Churg-Strauss disease causes a variety of nonspecific clinical symptoms and signs. It mimics many other systemic diseases like asthma, acute mesenteric ischemia, polyarteritis nodosa, Wegener’s granulomatosis, hypereosinophilic syndrome, leukocytoclastic vasculitis,

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Figure 1. Churg-Strauss syndrome involving intra- and extravascular granuloma with eosinophilic tissue infiltration of small and medium-sized blood vessels.

Figure 2. Predominant involvement of coronary arteries with secondary myocardial infarction.

Figure 3. Kidney: Small focus of dull cortical necrosis with surrounding viable renal tissue.

Goodpasture syndrome and eosinophilic pneumonia.Most patients with Churg-Strauss disease have a prodromal period of many years characterized by allergic rhinitis, nasal polyposis and late onset asthma that is often difficult to control.3 Among the early symptoms and signs, similar to that in our patient, are fever, weight loss, pain in viscera, or the musculoskeletal

Figure 4. Kidney: Small vessel vasculitis in renal cortex.

Figure 5. Liver: Inflammation in portal triad surrounded by normal hepatic parenchyma.

Figure 6. Lung: Mixed inflammatory infiltrate of predominantly eosinophils.

system. Striking and specific initial signs may relate to acute glomerulonephritis, polyneuritis and myocardial infarction. The typical presentation of Churg-Strauss syndrome is a triad of skin lesions (purpura or nodules), asymmetric mononeuritis multiplex and eosinophilia on a background of resistant asthma. Some times, patients might also present without both eosinipilia and asthma

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similar to our patient.4 Upto 50% of patients have abdominal symptoms due to mesenteric vasculitis.

Leukocytosis in more than 75% cases, eosinophilia, increased ESR. C-ANCA or P-ANCA is present in around 40% of cases. Pulmonary opacities in 26-77%, no abnormalities in 25%, pleural effusion in 5-30% of the patients on X-ray chest.5 Pleural and pericardial effusions due to serositis may also be seen.

The American College of Rheumatology has proposed six criteria for diagnosis of Chung-Strauss syndrome.6 The presence of four or more criteria yields a sensitivity of 85% and a specificity of 99.7%. These criteria are:

Asthma (wheezing, expiratory ronchi)Eosinophilia of more than 10% in peripheral smear Paranasal sinusitis Pulmonary infiltrates (may be transient)Histological proof of vasculitis with extravascular eosinophilsMononeuritis multiplex or polyneuropathy.

It is critically important to establish this diagnosis. A high index of suspicion remains the most important element in diagnosis. Diagnosis of Churg-Strauss disease is made by biopsy.7 The prognosis of untreated disease is poor; with a reported 5-year survival of 25%. The principal causes of death are myocarditis and myocardial infarction secondary to coronary vasculitis.8 Glucocorticoid therapy has been reported to increase the 5-year survival to more than 50%. Oral glucocorticoids in high dosage (prednisolone 1 mg/kg/daily) alone usually are adequate for treatment of Chung-Strauss syndrome. Cytotoxic drugs (oral cyclophosphamide 2 mg/kg/daily) are necessary in fewer than 20% of the cases of glucocorticoid failure.

In cyclophosphamide resistant cases plasma exchange daily and oral etoposide are required.

Major life-threatening organ involvement may require treatment with pulse doses of IV corticosteroids (I/V bolus methylprednisolone 10 mg/kg) as well as other agents (azathioprine, mycophenolate mofetil and IV immunoglobulins and interferon-a).

REFERENCES

1. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951;27(2):277-301.

2. Strauss L, Churg J, Zak FG. Cutaneous lesions of allergic granulomatosis: a histopathologic study. J Invest Dermatol 1951;17(6):349-59.

3. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome. Clinical study and long-term follow up of 96 patients. Medicine (Baltimore) 1999;78(1):26-37.

4. Sevinc A, Hasanoglu HC, Gokirmak M, Yildirim Z, Baysal T, Mizrak B. Allergic granulomatosis and angiitis in the absence of asthma and blood eosinophilia: a rare presentation of limited Churg-Strauss syndrome. Rheumatol Int 2004;24(5):301-4.

5. Saxena S, Joshi JM. Multiple pulmonary nodules. Indian J Chest Dis Allied Sci 2005;47(3):193-5.

6. Masi AT, Hunder GG, Lie JT, Michel BA, Block DA, Arend WP. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33(8):1094-100.

7. Lie JT. Histopathologic specificity of systemic vasculitis. Rheum Dis Clin North Am 1995;21(4):883-909.

8. Eustace JA, Nadasdy T, Choi M. Disease of the month. The Churg Strauss Syndrome. J Am Soc Nephrol 1999;10(9):2048-55.


Tuberculosis, the word, evokes feelings of fear, anxiety, stigma and despair, known for centuries, to afflict, deblitate, impoverish large section of

the population and even kill, continues to ravage the world. It is a worldwide health problem. For the control tuberculosis in 1962, Govt., of India launched National Tuberculosis Control Programme,1 but the program did not achieve the desired results. In 1992 Govt. of India, WHO and World Bank Revised National Tuberculosis Control Programme (RNTCP) with direct observation of swallowing of drugs by the patients and the objectives of achieving at least 85% cure rate through DOTS and case finding 70% of the estimated cases.2 This revised strategy was introduced in the country as a pilot project since 1992 in a phased manner and proposed to be expanded throughout the country by the year 2005.3 Studies have shown that treatment success under RNTCP has increased for all types of patients between 1995 and 1998.4 RNTCP being a switch over program from the previous NTCP, more and more operational

Associate ProfessorDept. of Community Medicine, Guru Gobind Singh Medical College, Faridkot, PunjabAddressforcorrespondenceDr Sanjay Gupta Associate Professor, Dept. of Community Medicine, Guru Gobind Singh Medical College Faridkot, PunjabE-mail: [email protected]

A Study of Performance of DOT Providers in Meerut DistrictsAnJAyguPtA

Table 1. Type of DOT CentersType of DOT Centers Number %NGOs/Volunteers 19 31.7Private practitioners 15 25Sub center 11 18.3PHC 4 6.7Dispensaries 4 6.7Others 7 11.6Total 60 100

ABSTRACT

The study has been conducted with the background that DOTS providers are the key persons in the implementation of the program at ground level. Performance at this level maximally affects the outcome of the program. It is a cross-sectional study conducted in the rural and urban population of Meerut District. A multistage random sampling from tuberculosis unit, Microscopy centers and DOTS centers were performed to cover one 8th of the district. Total of 60 DOTS centers and DOT providers were chosen for the study. A modified form of survey has been performed by three visits at each DOT center. A salient observation of the DOT centers and a face to face interview of the DOT providers have been performed by the observer and recorded on a pilot tested performa. The data collected, was coded manually, tabulated and analyzed. One-fifth (20.0%) of the DOT provides were found performing poorly, while the performance of 34 (56.7%) DOT providers was average. Only 12 (20%) and 2 (3.3%) were found to be good, and very good respectively in their performance. The study concluded that quality at DOT center level maximally affects the compliance and satisfaction which in turn affects the treatment and outcome. Increasing the quality at DOT center level will definitely give the desired results of treatment and outcome.

keywords:DOTS, DOT provider, performance, quality

researches are needed at this juncture when it is moving from one phase to another to know whether it is heading towards the right direction as far as pace and quality of implementation are concerned. DOTS is the strategy5 and heart of the program, so DOT providers have an equal importance. The performance of any program is judged by certain performance indicators related with them, results achieved and the patient satisfaction. Performance indicator may be of qualitative and quantitative type. WHO has defined certain qualitative and quantitative performance indicators at various levels of implementation of the program but none to evaluate the performance of the DOT providers. The present study is an attempt to evaluate the performance of DOT providers both qualitatively and quantitatively.

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MATERIAL AND METHODS

Meerut district has a population of 30 lacs (census 2001). From the point of view of implementation of the program, Meerut district has been divided into six sub district units known as Tuberculosis units (TU). Each TU covers a numbers of microscopic centers. Each microscopic center caters services to many DOT centers falling under its jurisdiction. DOT center is the basic unit providing medicine to the tuberculosis patients. A multistage random sampling was applied to cover the entire district. A total of 60 DOT centers from three tuberculosis units (which were catering 7 microscopic centers) were obtained by sampling those which were

catering 431 patients. A careful and salient observation was made by three visits on Monday, Wednesday and Friday at the DOT centers. Observations were recorded on a pilot tested proforma. At the same time DOT providers and patients were also interviewed and the information was recorded on a predesigned and pretested proforma. The data was collected, coded manually, tabulated and has been presented in the form of simple frequency tables and bivariate tables as and where required. The data was analyzed and statistically evaluated, wherever applicable, by appropriate tests of significance.

RESULTS AND DISCUSSION

A majority of the studied DOT centers (56.7%) were being operated by non-government agencies as 31.7% DOT centers were being operated by NGO/volunteers and 25.0% by private practitioners indicating, an active community participation (Table 1). Out of the 60 only 40 (66.6) DOT providers were found on the first visit and rest could be contacted in subsequent visits. Only 12 (20.0) exhibited good behavior as observed by the investigator, 40 (66.6) showed satisfactory response and eight (13.3) were found having rude behavior indicating largely a low commitment of DOT providers towards the program. All the DOT providers knew that cough of more than three weeks; weight loss and tiredness were the symptoms suggestive of

Table 2. Knowledge of DOT Providers Regarding the Suspects of TuberculosisKnowledge Number %Cough of more than 3 week 60 100Weight loss 60 100Tiredness 60 100Evening rising fever 47 78.3Loss of appetite 38 63.3Chest pain 32 53.3Night sweats 22 36.7Shortness of breath 21 35Coughing out of blood 20 33.3

Table 3. Performance of DOT Administration in the StudyQuality Yes No

N % N %Maintenance of treatment card 60 100 0 0Treatment schedule followed 60 100 0 0Direct observation of treatment 54 90 6 10Proper filling of treatment cards 52 86.7 8 13.3Delay in starting of treatment 4 86.7 56 93.3Administering proper category-wise treatment 60 100 0 0Educating patients about tuberculosis and DOTS 24 40 36 60Educating the patints about follow-up examination of sputum 48 80 12 20Visiting those patients not coming on proper scheduled day 24 40 36 60Using separate box for each patients 60 100 0 0Adequate amount of drugs 60 100 0 0Awareness about the drug reaction 32 53.3 28 46.7Knowledge regarding side effects of ATT 32 53.3 28 46.7Asking the patients about any side effect of ATT drugs 10 16.7 50 83.3Drugs in treatment box tallying with treatment card 49 81.7 11 18.3Proper collection of sputum 60 100 0 0

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tuberculosis. Other symptoms such as evening rise of temperature, loss of appetite, chest pain, night sweats, shortness of breaths and coughing out of blood were known to 78.3%, 63.3%, 53.3%, 36.7%, 35.0 and 33.3%, respectively (Table 2). Detection of sputum of pulmonary tuberculosis is sheet anchor of program and thus requires further strengthening of their knowledge. Treatment cards were maintained in all the DOT centers but proper recording was found only in 86.6% centers. Although treatment was being administered properly as per the category of patient in all the DOT centers but treatment was directly observed in 90.0% DOT centers, further emphasises the need to stress on DOT to fulfil the objective of program. Education about tuberculosis and DOTS to the patients was being imparted by 40%, whereas advice for follow-up of sputum examination was being given by 80.0% of the DOT providers including strengthening of IEC by DOT providers. Only 40.0% DOT providers were visiting those patients who were not coming on the schedule day which is an essential aspect to reduce the default. Hundred percent of the DOT providers were using separate box of medicine for each patient and the amount of drugs was adequate. Empty strips were being returned by the patients at 86.7% DOT centers at the time of drug collection, in continuation phase of treatment. 53.3% DOT providers were aware about the drug reactions and side effects of ATT and only 16.7% were asking about the side effects of drugs from the

patients (Table 3). This shows that there is need for further education of DOT providers for timely referral and proper counseling of patients. From the point of performance DOT providers were grouped into four categories based on the scores obtained by the used quality parameter earmarking a positive score for each desirable and negative score for each undesirable performance. It is evident from Table 4 that one-fifth (20.0%) of the studied DOT provides were found performing poorly, while performance of 34 (56.7%) DOT providers was average. Only 12 (20%) and 2 (3.3%) were good and very good, respectively in their performance.

CONCLUSION

DOT provider is the key person in the DOTS. There should be regular re-orientation training of DOT providers. It is a must for a new DOT provider especially nonhealth staff person. Training must be provided by the medical officer. Quality at DOT center level maximally affects the compliance and satisfaction which in turn affects the treatment and outcome. Increasing the quality will definitely give the desired results of treatment and outcome.

REFERENCES1. Park K. Text book of Preventive and Social Medicine. 6th

edition, Banarasi Das Bhanot, Jabalpur 1977:120-40.2. Park K. Text book of Preventive and Social Medicine. 16th

edition, Banarasi Das Bhanot, Jabalpur 2000:126-54.3. Editorial. Indian J Tuberculosis 1996;43:3. 4. Ninth Five Year Plan (1997-2002). Development goals,

strategy and politics. Planning Commission, Government of India, New Delhi, 1999:1.

5. WHO Research for action. Understanding and controlling tuberculosis in India. Regional Office for South East Asia, New Delhi; 2000.

Table 4. Performance of DOT ProvidersQuality Score Number %Poor <12 12 20Average 12-16 34 56.7Good 17-20 12 20Very good 21-23 2 3.3Total 60 100


exPert’soPInIon

Gastroesophageal Reflux Disease in Children: When is Surgery Indicated? What are the Long-term and Short-term Complications of Surgery?JyotsnAmkIrtAne

Source: 100 Clinical Questions in Medicine, Vol. 5.

ABSOLUTE INDICATIONS

Stricture of the esophagus or severe degree of esophagitis, hiatus hernia, near-miss sudden infant death syndrome (SIDS), repeated attacks of apneic and cyanotic spells and failure to respond to conservative treatment.

RELATIVE INDICATIONS

Infants who have been operated for esophageal atresia and tracheoesophageal fistula and have gastroesophageal reflux (GER) with life-threatening episodes of aspiration. Children with severe mental retardation who have GER are difficult to manage on conservative treatment and need to be operated upon early.

SHORT-TERM COMPLICATIONS

Early complications of surgery for gastroesophageal reflux disease (GERD) which were seen about 2-3 decades ago are rarely seen now. These are: Too tight a wrap (fundoplication) giving rise to dysphagia, excessive salivation; herniation of the plication en masse through the hiatus into the chest; wrap coming apart, with recurrence of symptoms. All the aforementioned complications are preventable and, with refinement of surgical techniques, are rare today.

LATE COMPLICATIONS

Adhesive intestinal obstruction is a complication seen after any laparotomy, however, small. It is also seen after laparoscopic surgery. An intestinal obstruction typically presents with bilious vomiting and abdominal distension. However, after an antireflux procedure, the baby cannot vomit. There is, therefore, a risk of not suspecting intestinal obstruction, with resultant complications such as perforative peritonitis. It is important to explain this to the parents and the referring doctor.

SUGGESTED READING1. Meyers WF, Roberts CC, Johnson DG, et al. Value of tests

for evaluation of gastroesophageal reflux in children. J Pediatr Surg 1985;20(5):515-20.

2. Irwin S, Zawacki JK, Curley FJ, et al. Chronic cough as the sole presenting manifestation of gastroesophageal reflux. Am Rev Respir Dis 1989;(5)140:1294-300.

3. Kennedy JH. ‘Silent’ gastroesophageal reflux: an important but little known cause of pulmonary complications. Dis Chest 1962;42(1):42-5.

4. Orenstein SR. Controversies in pediatric gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1992;14(5):338-48.

5. Orenstein SR, Orenstein DM. Gastroesophageal reflux and respiratory disease in children. J Pediatr 1988;112(6): 847-58.


I am a physiotherapist and have the following questions: a. In what manner do physiotherapists violate rules and regulations? b. Is physiotherapy an independent profession? Is it an aid to other systems of medicine? c. Can a doctor, who is not an expert in physiotherapy, prescribe a physiotherapeutic plan for his patient?

1. First of all, we need to be clear about the words physiotherapy and physiotherapist. I am relying on the definitions given in Section 2(o) of the Paramedical and Physiotherapy Central Councils Bill, 2007, (Bill No. 96 Of 2007), “(o) physiotherapy means medically directed therapy through physical agents including heat, cold, light, water, massage, electricity or manual exercises to persons with the aim of preventing or correcting any disability and includes occupational therapy;” From the perspective of law, I am not concerned with definitions that might be given by WHO etc.

2. Physiotherapists are known to indulge in following violations:

1. They illegally use the prefix ‘Dr’ to their name. The illegality is clear from the following:

1. Section 6-A of the Indian Medical Degrees Act, 1916, reads - ”no person shall add to his name any title, descriptions letters or abbreviations which imply that he holds a degree, diploma, licence or certificate as his qualification to practice any system of medicine unless, he actually holds such degree, diploma, licence or certificate;……………”.

2. On 25th August, 2008, the Executive Committee of the MCI issued a letter No. MCI–5(3)/2008–Med./ dated 25th August, 2008. This letter referred to the Indian Medical Degrees Act, 1916, and stated that “wherever any person found to be using the title of ‘Doctor’ as a prefix when such a person is holding a qualification in physiotherapy but not possessing any recognized medical qualification, he would be violating the provisions of Act of 1916 and as such he would expose himself for necessary action by filing or requiring the filing of a complaint in accordance with Section 7 of the 1916 Act for violation of Sections 6 and 6A of the extent applicable.

Insight on MedicolegalsudhIrguPtA

Additional ProfessorForensic Medicine and ToxicologyAIIMS, New Delhi

Q 3. A reading of the Delhi Council for Physiotherapy and Occupational Therapy Act, 1997, reveals that there is nothing in the Act to imply that those registered under the Act may use the prefix ‘Dr’ http://www.lawsofindia.org/pdf/delhi/1997/1997Delhi7.pdf

4. On 25-11-2003, the Ministry of Health and Family Welfare, Government of India issued an order No.R.14015/25/96–U&H(R)(Pt.) Government of India Ministry of Health & Family Welfare (Research Desk). This order states, inter alia, that— “the term “Doctor” should be used only by practitioners of Systems of Medicine recognized by the Government of India”. The full text of the order can be seen at http://164.100.24.208/lsq14/quest.asp?qref=63774

5. On 9-9-2009, the Government of Tamil Nadu Health and Family Welfare (Z1) Department issued an Annexure dated 9-9-2009 to the G.O. (Ms) No.338 Health and Family Welfare Department, dated 16.10.2008, wherein it was stated that in reference to Tamil Nadu State Council for Physiotherapy:

“Physiotherapist means a person who possesses recognized physiotherapy education and whose name has been entered in the Register of Physiotherapy Council. He shall not use ‘Dr’ before his name and prescribe drugs”. This may be viewed at–– http://iapchennai.org/annexure.php6. The Madras High Court has held that

physiotherapists cannot use the prefix ‘Dr’ as per the following news report “High court warns against use of ‘Dr’ without valid medical degree TNN Feb. 24, 2010, 01.44 am IST Chennai: Putting a pause to the tug–of–war between physicians and physiotherapists over the use of the prefix ‘Dr,’ the Madras High Court has asked the authorities to take action against persons who use the prefix in their prescriptions and advertisements without a valid medical degree. Passing orders on a writ petition filed by the Indian Medical Association’s Quackery Eradication Committee, the first bench comprising Chief Justice HL Gokhale and Justice KK Sasidharan said the IMA must furnish details of people prescribing allopathic medicines and administering allopathic treatment and using the prefix ‘Dr’ to the authorities. The IMA wanted the Court to consider its two representations to the government, and to initiate criminal prosecution against paramedical technicians, practitioners and physiotherapists who

A

medIlAw

Cont’d on page 407...


Conference Calendar

ConferenCeCAlendAr

PEDICON 2012 49th Annual National Conference of Indian Academy of PediatricsVenue: Leisure Valley Ground, Sector-29, Gurgaon Date: 18-22 January, 2012 Website: www.pedicon2012.org E-mail: [email protected]

Star FetUS 2012 CME and Workshop on Fetal Ultrasound and DopplerVenue: Stanley Medical College, Chennai Date: 21-22 January, 2012 Website: http://www.stanleyradiology.com/star-fetus-pg-primer—frcr-2012.html E-mail: [email protected]

eMedinewS Conference3rd eMedinewS Revisiting 2011Venue: Maulana Azad Medical College, New Delhi Date: Sunday, 22nd January 2012 Website: www.emedinews.in/

E-mail: [email protected]/[email protected]

Paeds Anaesthesia 2012 4th National Conference of Indian Association of Paediatric AnaesthesiologistsVenue: Hyderabad, Hyderabad Date: 11-12 February, 2012 Website: http://isahyd.org/PA%202012/aboutevent.htm E-mail: [email protected]

40th National Conference of the Indian Association of Dermatologists, Venereologists and LeprologistsPre-conference Workshop on Dermatosurgery and Cosmetic Dermatology on 8th February 2012 Venue: BM Birla Science and Technology Research Center, Jaipur Date: 9-12 February, 2012 Website: http://www.dermacon2012.in/ E-mail: [email protected], [email protected]

prescribed allopathic medicine and used the prefix ‘Dr’ The government pleader assured the Court that the authorities would take necessary action in accordance with law. The state government had passed an order last year that a physiotherapist cannot use the prefix ‘Dr’ and should not prescribe drugs. However, paramedics and physiotherapists have been maintaining that the use of the prefix ‘Dr’ is more a matter of courtesy rather than adherence to law.”

b. Physiotherapists sometimes prescribe medicines though they are not supposed to do so in terms of the Patna High Court judgment in Sri Sarjoo Prasad and Ors. vs The State Of Bihar And Ors., dated 21 February, 2003, reported as 2003 (51) BLJR 686. http://www.indiankanoon.org/doc/1012912/

3. It is undisputed that physiotherapy is not a system of medicine. It can obviously be only an aid to a system of medicine in the context of treating a patient. Physiotherapy cannot be an independent profession on the same footing as the recognised systems of medicine.

4. The responsibility for treating a patient lies with the physician. In order to discharge this responsibility, he may have to get the aid of disciplines that are not systems of medicine in themselves but are meant to aid such systems in the interest of patient care. Examples are clinical psychology, acupuncture, physiotherapy (including occupational therapy), etc. It is obvious that a physician, who is admittedly not an expert in physiotherapy can, at his discretion, follow any one of the following approaches:

i. Prescribe physiotherapy to the patient directly on his own without any reference to a physiotherapist.

ii. Prescribe a certain physiotherapeutic regimen and refer the patient to a physiotherapist for administering the same, subject to any modification in the regimen by the physiotherapist in view of his superior knowledge of physiotherapy.

iii. Refer the patient, after diagnosing and prescribing necessary medicines etc., to a physiotherapist for necessary assessment and planning a line of treatment as regards physiotherapy.

...Cont’d from page 406


VAGINAL PROGESTERONE CUTS PREMATURE BIRTHS

Women with a sonographically detected short cervix cut their risk for preterm birth in half with vaginal progesterone, according to a meta-analysis published online December 14 in the American Journal of Obstetrics and Gynecology. The report confirms results from several, prospective, randomized trials showing that progesterone was effective in preventing preterm births. (Source: Medscape Medical News)

AroundthegloBe

News and Views

FDA PANEL RECOMMENDS APPROVAL OF INHALED ANTIPSYCHOTIC

A US Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) has recommended approval of inhaled loxapine (Adasuve, Alexza Pharmaceuticals), as the first inhaled antipsychotic for agitation associated with schizophrenia and bipolar disorder (BD). The handheld, single-dose inhaler enables rapid drug delivery with greater comfort and convenience for patients who typically must be physically restrained and treated by injection. (Source: Medscape Medical News)

DIURETICS YIELD LONG–TERM SURVIVAL BENEFIT

Older patients with isolated systolic hypertension gained an extra day of life expectancy for every month of treatment with diuretic-based stepped care, according to long-term follow-up of a randomized trial. (Source: Medpage Today)

ENDOMETRIOSIS LINKED TO LATER INFLAMMATORY BOWEL DISEASE

Endometriosis is associated with an increased risk of developing inflammatory bowel disease (IBD), according to a large-scale, long-term study by Danish researchers published online December 19 in Gut. (Source: Medscape Medical News)

PCI WITH NO SURGEON ON STANDBY APPEARS SAFE

Percutaneous coronary intervention (PCI) without surgical back-up did not increase the risk of in-hospital mortality or need for emergency bypass surgery, according to a systematic review of published literature. (Source: Medpage Today)

BRAIN ATROPHY TIED TO COGNITION LOSS IN PARKINSON’S

Brain atrophy in Parkinson’s disease correlates with cognitive decline, which worsens with the degree of tissue shrinkage, investigators reported. (Source: Medpage Today)

AND NOW CPAP REBOUND

Obstructive sleep apnea (OSA) and its associated c o m p l i c a t i o n s recurred rapidly after discontinuation of continuous positive airway pressure (CPAP), results of a small randomized trial showed. After two weeks without CPAP, the number of arousal events per hour had more than tripled, and apnea-hypopnea events had increased 17-fold.

Both measures remained unchanged in patients who continued CPAP. By the end of the study, endothelial function had decreased significantly, and morning blood pressure, heart rate and urinary catecholamines all increased significantly compared with patients who remained on CPAP.

“We found that CPAP withdrawal was associated with a return of OSA by the first night,” Malcolm Kohler, MD, of University Hospital Zurich in Switzerland, and coauthors reported online in the American Journal of Respiratory and Critical Care Medicine. (Source: MedPage)


REVISITING DRUGS IN 2011

Labeling changes to glitazones were made in 2011. Rosiglitazone and all rosiglitazone-containing products now include information regarding a possible increased risk for heart attacks.The Food and Drug Administration (FDA) approved rivaroxaban, an oral factor Xa inhibitor, for prevention of deep venous thrombosis after knee or hip replacement surgery as well as to prevent stroke and systemic embolism in patients with nonvalvular atrial fibrillation.The FDA warned that simvastatin 80 mg (should not be used in new patients or in patients already taking lower doses due to risk for myopathy. The recommended dose for use with amiodarone was raised to 20 mg from the 10 mg originally recommended in June.The FDA warned that fenofibric acid may not reduce risk for heart attack or stroke. Linagliptin, a dipeptidyl peptidase-4 inhibitor, was approved on May 2 to improve blood glucose control in adults with type 2 diabetes. The glucagon-like peptide-1 receptor agonist exenatide received expanded approval as an adjunct to insulin glargine, with or without metformin and/or thiazolidinedione therapy, in patients with type 2 diabetes not controlled by insulin glargine alone.On March 1, once-daily, oral roflumilast was approved to decrease the frequency of chronic obstructive pulmonary disease (COPD) exacerbations.The antiplatelet agent, ticagrelor was approved after a protracted process. The approval comes with a boxed warning stating that use of ticagrelor with aspirin doses above 100 mg/day decreases the effectiveness of the medication. Rofflumilast is the first in a new class of drugs for COPD called phosphodiesterase type 4 inhibitors.In December, the combination of azilsartan medoxomil and chlorthalidone was approved for the treatment of hypertension.

Medicine Revisited: Newer Drugs, Guidelines and Recommendation

revIsItIng2011

ECG changes, including QT interval prolongation and torsade de pointes, have been reported in patients receiving ondansetron. Patients with congenital long QT syndrome should not receive ondansetron.

A Drug Safety Communication issued in July warned that coadministration of the antibiotic linezolid or the medicinal dye methylene blue (various) with serotonergic agents should be avoided. These combinations could result in serotonin syndrome, a serious condition characterized by confusion, hyperactivity, memory problems and other mental changes, fever, shaking, chills, diarrhea, trouble with coordination, and, rarely, death.

On August 10, the once-daily, triple-drug combination (emtricitabine/rilpivirine/tenofovir disoproxil fumarate;) was approved for HIV infection in treatment-naive adults. Rilpivirine, emtricitabine and tenofovir are nucleoside reverse transcriptase inhibitors.

The US FDA approved tadalafil to also treat the signs and symptoms of benign prostatic hyperplasia (BPH) as well as a combination of BPH and erectile dysfunction (ED) when the conditions coincide.

Topical benzocaine sprays, gels and liquids used as anesthesia during medical procedures and for analgesia from tooth and gum pain may cause methemoglobinemia, a rare but serious and potentially fatal condition, the US FDA announced on April 7.

An FDA review launched in the wake of a controversial 2010 meta-analysis by Dr Ilke Sipahi (University Hospitals Case Medical Center, Cleveland, OH) suggesting an increased risk of cancer among patients taking angiotensin-receptor blockers (ARBs) has concluded that the drugs do not pose a cancer risk to patients.

Zoledronic acid, an injectable bisphosphonate used to prevent and treat osteoporosis, is now contraindicated for patients with creatinine clearance below 35 ml/min or evidence of acute


renal impairment, according to a label change announced by the US FDA.

2011 GAME CHANGERS IN CARDIOLOGY

Eplerenone for mild heart failure: EMPHASIS-HF trial showed that aldosterone antagonist eplerenone produced large reductions in both the risk for death and the risk for hospitalization compared with placebo in patients with systolic heart failure and mild symptoms. Its role in moderate and sever heart failure is already known.COURAGE findings are not being implemented: In 2007, the landmark COURAGE study found that in patients with stable coronary artery disease, optimal medical therapy was just as good at preventing future events as receiving a stent on top of optimal medical therapy. Still cardiologists are not following it.FDA Approves rivaroxaban for stroke prevention in atrial fibrillation: Based on ROCKET-AF trial following dabigatran, rivaroxaban is the second in a surge of novel oral anticoagulants to go before the FDA’s advisors for the atrial fibrillation/stroke indication. AIM-HIGH: Results raise controversy over early eiscontinuation: The AIM-HIGH study showed that raising high-density lipoprotein (HDL) using extended-release niacin (1,500-2,000 mg) was not beneficial in patients who had been treated with statin therapy for elevated low-density lipoprotein cholesterol levels. There was also a small, unexplained increase in ischemic stroke in the niacin group. However, the final results of the trial that were presented at AHA 2011 and published in The New England Journal of Medicine suggest that the signal of increased ischemic stroke with niacin could have been the play of chance.The NICE hypertension guidelines: A Monitoring Revolution: The new NICE guidelines formally recommend ambulatory blood-pressure monitoring as a ‘key priority’ in diagnosing suspected hypertension, particularly if a clinic blood pressure reading is 140/90 mmHg or higher.PARTNER ohort A: TAVI noninferior to surgery: PARTNER cohort A, results showed that transcatheter valve replacements (TAVR) in severe aortic stenosis, is an acceptable alternative to aortic valve replacement in selected high-risk operable patients.

DOSE Trial Published: How to give intravenous diuretics in acute heart failure: The DOSE trial suggested that aggressive decongestion is a critical part of achieving good outcomes in acute decompensated heart failure. It may seem to come at the cost of transient worsening renal function, but that doesn’t seem to be a major problem, as long as it’s monitored carefully.STICH ‘hypothesis one’ supports coronary artery bypass graft (CABG) in heart failure: Results of NIH sponsored STICH showed that CABG was associated with an early risk of death as a result of the surgical intervention, but this disadvantage for surgery disappeared two years after the procedure. Over a median follow-up of 56 months, 41% of the medical therapy group and 36% of the CABG group died.STICH: Viability testing didn’t affect treatment outcomes: STICH published in The New England Journal of Medicine was a randomized comparison of CABG surgery and medical therapy alone in 1,212 patients with a left ventricular ejection fraction <35% and coronary artery disease amenable to CABG. The sub study found that overall, substantial viable myocardium evident at baseline imaging studies had no independent bearing on all-cause mortality over five years; and such viability didn’t influence the relative effectiveness of the 2 treatment strategies. It questions the value of assessing myocardial viability with perfusion scans or other functional imaging methods to predict benefit from coronary revascularization in such patients.Death rates diverge but no change in advice: SYNTAX: The SYNTAX results show that in LMCA/TVD bypass surgery was better than percutaneous coronary intervention (PCI) using Taxus drug-eluting stent at three years.

RSNA UPDATE 2011

Women who have extensive atherosclerosis may have a greater risk of cardiovascular events than men with similar hardening of the arteries, but type of plaque can alter the equation. The risk of a major adverse cardiac event was significantly higher for women who had plaque of any type in more than four coronary segments than for men with the same amount of blockage. (Dr John Nance Jr., of Johns Hopkins). Men with noncalcified plaques were at

revIsItIng2011


a significantly higher risk of events than women with noncalcified plaques.Patients referred for studies by physicians who owned their own scanning equipment had significantly more negative scans than those referred by doctors who did not have a financial interest in the scanners (42% vs 23%, p < 0.0001) (Dr Ben Paxton, of Duke University Medical Center).Eating fish at least once a week could help lower older patients’ risk of developing dementia. Those who ate baked or broiled - but not fried - fish on a weekly basis had a greater volume of gray matter in areas of the brain associated with Alzheimer’s disease than people who didn’t eat fish as often. (Dr Cyrus Raji, of the University of Pittsburgh).In a small functional magnetic resonance imaging (fMRI) study, men who took aim at video game characters for about 10 hours during one week had diminished activity in areas of the brain associated with control of aggressive behavior. (Dr Vincent Mathews of Indiana University in Indianapolis).Extreme dieting - cutting calories to just 500 kcal/day - may eliminate the need for insulin and improve heart function in some patients with type 2 diabetes. After four months of a calorie-restriction diet, obese diabetes patients were able to come off insulin, and 75% were able to remain insulin-free for more than a year, even though they returned to their regular diets. (Dr Sebastiaan Hammer, of Leiden University Medical Center).Soccer players who use their head to work the ball may be at risk for white matter abnormalities similar to those seen in traumatic brain injury. (Dr Michael Lipton, of the Albert Einstein College of Medicine in Bronx, NY).Women ages 40 to 49 with no family history of breast cancer have similar rates of invasive disease as those with familial risk. (Dr Stamatia Destounis, of Elizabeth Wende Breast Care in Rochester, NY).Children with attention deficit/hyperactivity disorder appear to have different patterns of activity in brain regions associated with attention processing. In a small fMRI study, kids with ADHD had greater involvement of the anterior cingulate cortex and diminished activity in the connections between the frontal and parietal lobes compared with controls. (Xiaobo Li, PhD, of Albert Einstein College of Medicine).

RHEUMATOLOGY UPDATE 2011 (ACR)

Treatment with hydroxychloroquine in SLE was significantly protective against the development (50%) of renal failure. (Dr Michele Petri, of Johns Hopkins University in American College of Rheumatology meeting 2011).Monotherapy with etanercept can keep some rheumatoid arthritis (RA) patients in long-term remission. Combination therapy with etanercept and methotrexate is considered standard of care for RA. (Dr Roy Fleischmann, of University of Texas Southwestern Medical School in Dallas at American College of Rheumatology annual meeting 2011).Treatment with the oral Janus kinase inhibitor tofacitinib resulted in statistically significant and clinically meaningful improvements in all RA patient-reported outcomes. (Dr Vibeke Strand, of Stanford University in Palo Alto, Calif.)Treatment of early RA with glucosteroids provides relief of symptoms, but the therapy comes with a price - worrisome changes in body fat composition that are significantly increased within the first year. (Dr Michael Nurmohamed, at Jan van Breemen Research Institute/Reade, in Amsterdam).Long-term treatment with the biologic agent etanercept reduces a rheumatoid arthritis patient’s risk of heart attack and malignancy, and may also reduce the risk of death, when compared with therapy using disease-modifying antirheumatic drugs. (Dr Duncan Porter, of the University of Glasgow in Scotland)RA patients try almost anything to relieve symptoms - including special jewelry, household oils and even homemade concoctions. Dr Ashutosh Tamhane, at University of Alabama at Birmingham, found that 76% of patients used store-bought lotions for treatment of RA, and 80% utilized heat treatments. About 21% of patients took fish oil supplements; 27% utilized jewelry such as copper chains; 19% tried garlic; and 4% took raisins soaked in vodka or gin for relief. (American College of Rheumatology 2011).A strategy of methotrexate-based tight control in early RA was more effective in preventing joint damage if the initial regimen also included low-dose prednisone. Among patients who received methotrexate plus prednisone, 78% were erosion-free at two years compared with 67% of those

revIsItIng2011


who received methotrexate plus placebo, reported Johannes WG Jacobs, MD, of University Medical Center Utrecht in the Netherlands, and colleagues.Even short courses of glucocorticoids in conditions such as lupus, RA and many other diseases can be associated with the development of osteonecrosis. (Steven C. Vlad, MD, of Boston University School of Medicine, at the annual meeting of the American College of Rheumatology 2011).Patients with RA who respond well initially to methotrexate monotherapy may be able to maintain a good outcome on that drug alone, with no radiographic progression. (Dr James R. O’Dell, of the University of Nebraska Medical Center in Omaha).

Source: Med Page

TOP CARDIOLOGY NEWS OF 2011

ARISTOTLE trial: New oral factor Xa inhibitor apixaban is better than warfarin in atrial fibrillation (AF) patients.British scientists have reported that it may be possible for the heart to repair itself after injury, and they have discovered a protein molecule that seems to stimulate this process. (Dr Peter Weissberg, medical director of the British Heart Foundation). The cells that are capable of this healing are already there in the epicardium. Cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib) raised HDL cholesterol levels without increasing blood pressure and without impairing endothelial function (dal-VESSEL trial).The FDA is recommending that physicians restrict prescribing high-dose simvastatin to patients, given an increased risk of muscle damage. The new FDA drug safety communication, states that physicians should limit using the 80 mg dose unless the patient has already been taking the drug for 12 months and there is no evidence of myopathy. Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug. The new label has warnings not to use the drug with various medications, including itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine and danazol. In addition, the 10 mg dose should not be exceeded in patients taking

amiodarone, verapamil and diltiazem, and the 20 mg dose should not be exceeded with amlodipine and ranolazine.New reports of two elderly women faring badly when taking the novel anticoagulant dabigatran for stroke prevention in AF have prompted more discussion about the caution needed with this drug when treating the very old or those with renal impairment.Sanofi-Aventis has sent US healthcare professionals a letter warning them about cases of rare but severe hepatic injury associated with use of the anti- arrhythmic drug dronedarone. The FDA has also issued a ‘safety communication’.A new Cochrane review has provoked controversy by concluding that there is not enough evidence to recommend the widespread use of statins in the primary prevention of heart disease. (Dr Fiona Taylor at London School of Hygiene and Tropical Medicine, UK).New data help shed light on the malpractice risk physicians face in clinical practice. Cardiologists have a higher-than-average risk of being sued, but these lawsuits are less likely to result in a financial payment to plaintiffs. The surgical specialties face the largest threat of litigation, with approximately 20% of neurosurgeons and cardiothoracic surgeons facing a malpractice claim each year. Pediatricians and psychiatrists had the lowest risk of being sued. (Dr Amitabh Chandra, Harvard University, Boston).Arrhythmia-free survival rates after a single catheter-ablation procedure are relatively low at five years, just 29%, but the long-term success increases to 63% when outcomes are measured after the last ablation procedure. (Dr Rukshen Weerasooriya Hôpital Cardiologique du Haut-Lévêque, Bordeaux-Pessac, France).

TOP HEALTH STORIES OF THE YEAR (CNN)

A congresswoman’s recovery: In Januray shots rang out in a grocery store in Tucson, Arizona. US Rep. Gabrielle Giffords, 40, had been shot in the head by a gunman. The bullet passed through the left side of Gifford’s brain, but she survived. Nuclear fears in Japan: An 9.0-magnitude earthquake, the most powerful one to hit Japan in recorded history, led to a tsunami that engulfed

revIsItIng2011


parts of Honshu. It also started a meltdown at the Fukushima Daiichi’s nuclear facility in northeast Japan. Subsequent tests have detected radiation in a sample of people who live around the power plant.

WHO warns of possible cancer risk from cell phones: While there are no definitive studies, the warning gave people pause about cell phone use.

Tainted fruit: A listeria outbreak in cantaloupe killed 29 people and sickened nearly 150 in the United States, making this year’s outbreak the deadliest for listeria.

Prostate cancer screening controversy: The question of whether prostate-specific antigen tests for prostate cancer do more harm than good stirred controversy this year. The US Preventive Services Task Force gave the PSA test a ‘D’ rating, meaning

it offers “no net benefit or that the harms outweigh the benefits.”Cancer’s toll: Cancer claimed the lives of several luminaries this year: Tech innovator Steve Jobs (pancreatic cancer), author Christopher Hitchens (esophageal cancer) and former heavyweight champion Joe Frazier (liver cancer).30 years of HIV/AIDS: The first report of the disease appeared on June 5, 1981, in the Center for Disease Control’s Morbidity and Mortality Weekly Report.Head injuries: The toll of repeated head blows and injuries loomed over football again. One former football player killed himself after leaving a message telling his family to get his brain to the NFL brain bank. An examination of his brain showed that he had signs of a brain disease found in athletes who have been exposed to repeated brain trauma.

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constriction. Prompt diagnosis and treatment are needed. BMJ 1993;307(6911):1052-4.

8. Gibbs CR, Watson RD, Singh SP, Lip GY. Management of pericardial effusion by drainage: a survey of 10 year’s experience in a city centre general hospital serving a multiracial population. Postgrad Med J 2000;76(902): 809-13.

9. Reuter H, Burgess L, Van Vuuren W, Doubell A. Diagnosing tuberculous pericarditis. QJM 2006;99(12):827-39.

10. Burgess LJ, Reuter H, Carstens ME, Taljaard JJ, Doubell AF. The use of adenosine deaminase and interferon-gamma as diagnostic tools for tuberculous pericarditis. Chest 2002;122(3):900-5.

11. Mathur P, Tiwari KK, Trikha S, Tiwari D. Diagnostic value of adenosine deaminase (ADA) activity in tubercular serositis. Indian J Tubercul 2006;53:92-5.

12. Cherian G. Diagnosis of tuberculous aetiology in pericardial effusion. Postgrad Med J 2004;80(943):262-6.

13. Mishra OP, Kumar R, Ali Z, Prasad R, Nath G. Evaluation of polymerase chain reaction and adenoside deaminase assay for the diagnosis of tuberculous effusions in children. Arch Dis Child 2006;91(8):985-9.

14. Strang JI, Nunn AJ, Johnson DA, Casbard A, Gibson DG, Girling DJ. Management of tuberculous constrictive

pericarditis and tuberculous pericardial effusion in Transke: results at 10 years, follow-up. QJM 2004;97(8): 525-35.

15. Wragg A, Strang JI. Tuberculous pericarditis and HIV infection. Heart 2000;84(2):127-8.

16. Strang JI, Kakaza HH, Gibson DG, Allen BW, Mitchison DA, Evans DJ, et al. Controlled clinical trial of complete open drainage and prednisolone in treatment of tuberculous pericardial effusion in Transkei. Lancet 1998;2(8614):759-64.

17. Hakim JG, Termouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double-blind randomized placebo-controlled trial of adjunctive prednisolone in the treatmnt of effusive tuberculous precarditis in HIV seropositive patients. Heart 2000;84(2):183-8.

18. Trautner BW, Darouiche RO. Tuberculous pericarditis: optimal diagnosis and management. Clin Infect Dis 2001;33(7):954-61.

19. Mayosi BM, Burgess LJ, Doubell AF. Tuberculous percarditis. Circulation 2005;112(23):3608-16.

20. Reuter H, Burgess LJ, Louw VJ, Doubell AF. Experience with adjunctive corticosteroids in managing tuberculous pericarditis. Cardiovasc J S Afr 2006;17(5):233-8.

...Cont’d from page 374


PhotoquIz

An 87-year-old woman presented with a mildly painful, nonpruritic rash that appeared one day earlier and was preceded by a tingling sensation.

Her hobbies included gardening.

No other residents at her nursing home had a similar rash. Physical examination revealed an erythematous rash on the left axilla, breast (Figure 1), and back (Figure 2).

QUESTION

Based on the patient’s history and physical examination, which one of the following is the most likely diagnosis?

A. Cellulitis.

B. Herpes zoster.

C. Pediculosis corporis (human body louse).

D. Scabies.

E. Urushiol exposure.

Acute Onset Vesicular Rash

Source: Adapted from Am Fam Physician. 2010;82(7):815-816.

Figure 1.

Figure 2. seethenextPAgefordIsCussIon...


DISCUSSION

The answer is B: herpes zoster.

Herpes zoster is caused by the reactivation of the varicella zoster virus and commonly occurs in persons who are older or immunocompromised.1 The diagnosis is made clinically, although laboratory testing (e.g., Tzanck smear, direct fluorescent antibodies, viral culture, serology, polymerase chain reaction) may be used to confirm the diagnosis. Treatment with an antiviral agent (valacyclovir or acyclovir) should not be delayed while awaiting laboratory confirmation if the clinical suspicion for herpes zoster is high. Possible complications of herpes zoster include postherpetic neuralgia, secondary infection, and central nervous system or visceral involvement.

History and physical examination findings are key in correctly diagnosing herpes zoster. The rash is often preceded by tingling or pain. The dermatomal pattern of the rash, which rarely crosses the midline, is a defining feature of the condition.

Cellulitis usually appears as a warm, tender area of erythema and is accompanied by a fever and leukocytosis with left shift. If present, intense edema

may lead to focal blistering, but not a clustering of vesicles as with herpes zoster.The classic lesions of pediculosis corporis (human body louse) are red, pruritic papules or vesicles with a central punctum. They are often clustered, but do not follow a dermatomal pattern. Inspection of the patient’s clothing may reveal adult lice.The primary lesions of scabies may appear as papules, crusted lesions, vesicles, or burrows. The lesions are intensely pruritic; often generalized; and commonly appear in the finger web spaces, wrists, waist, axillae, and genitals.Contact dermatitis from exposure to urushiol (oil in the leaves of the poison ivy plant) may produce a rash similar to that from herpes zoster. Although the patient’s hobby of gardening increases her risk of exposure to poison ivy, the rash would be intensely pruritic and in a geometric pattern corresponding to the areas of exposure.

REFERENCES1. Whitley RJ. A 70-year-old woman with shingles: review

of herpes zoster [published corrections appear in JAMA. 2010;303(8):734, and JAMA. 2009;302(17):1864.] JAMA. 2009;302(1):73-80.

Summary TableCondition CharacteristicsCellulitis Warm, tender area of erythema accompanied by fever and leukocytosis with left shiftHerpes zoster Grouped vesicles on an erythematous base; dermatomal pattern; rash rarely crosses midline and may be

preceded by tingling or pain; delay of treatment may increase risk of postherpetic neuralgiaPediculosis corporis Red, pruritic papules or vesicles with a central punctum; inspection of clothing may reveal adult liceScabies Intensely pruritic papules, crusted lesions, vesicles, or burrows; commonly appear in finger web spaces,

wrists, axillae, waist, genitalsContact dermatitis from exposure to urushiol

Intensely pruritic vesicles and bullae; geometric pattern corresponding to areas of exposure

PhotoquIz


Lighter Side of MedicinelIghterreAdIng

THE GIFT FROM GOD

It was a warm summer day when God placed it in her hands. She trembled with emotion as she saw how fragile it appeared. This was a very special gift that God was entrusting to her. A gift that would one day belong to the world. Until then, He instructed her, she was to be its guardian and protector. The woman said she understood and reverently took it home, determined to live up to the faith God had placed in her.An

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At first she barely let it out of her sight, protecting it from anything she perceived to be harmful to its well-being; watching with fear in her heart when it was exposed to the environment outside of the sheltered cocoon she had formed around it. But the woman began to realize that she could not shelter it forever. It needed to learn to survive the harsh elements in order to grow strong. So with gentle care she gave it more space to grow…enough to allow it to grow wild and untamed. One day she became aware of how much the gift had changed. It no longer had a look of vulnerability about it. Now it seemed to glow with strength and steadiness, almost as if it were developing a power within. Month after month she watched as it became stronger and more powerful, and the woman remembered her promise. She knew deep within her heart that her time with the gift was nearing an end.The inevitable day arrived when God came to take the gift and present it to the world. The woman felt a deep sadness, for she would miss its constant presence in her life. With heartfelt gratitude

she thanked God for allowing her the privilege of watching over the precious gift for so many years. Straightening her shoulders, she stood proud, knowing that it was, indeed, a very special gift. One that would add to the beauty and essence of the world around it. And the mother let her child go.

MAKE SUrEDuring MeDical Practice

A patient with acute chest pain died before reaching the hospital.

Make sure that at the onset of acute heart attack and chest pain, water-soluble aspirin is chewed to reduce chances of sudden death.

KK Aggarwal

Oh my God! Why was water–soluble aspirin not given?

©IJ

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CHLORIDE

Increased: Diarrhea, renal tubular acidosis, mineralocorticoid deficiency, hyperalimentation, medications (acetazolamide, ammonium chloride).

Decreased: Mineralocorticoid excess, vomiting, diabetes mellitus with ketoacidosis

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INDICATIONS OF ECG

The main indications are for the evaluation of The electric axis of the heart Heart rate monitoring Arrhythmias

Supraventricular arrhythmias Ventricular arrhythmias

Disorders in the activation sequence- AV conduction defects Bundle-branch block Wolff-Parkinson-White syndrome

Increase in wall thickness or size of the atria and ventricles

Atrial enlargement (hypertrophy) Ventricular enlargement (hypertrophy)

Myocardial ischemia and infarction Ischemia Infarction

Drug effect Digitalis Quinidine

Electrolyte imbalance Potassium Calcium

Carditis Pericarditis Myocarditis

Pacemaker monitoring

MöNCKEBERG’S ARTERIOSCLEROSIS

Ring-like calcifications within the media of medium-sized to small muscular arteries (femoral, tibial, radial and ulnar arteries, genital arteries), occurs almost exclusively in individuals over 50-year-old; doesn’t narrow lumen, distinct from atherosclerosis.

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Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter

– The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

– Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

– Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript– Three complete sets of the manuscript should be

submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

– The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

– All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title pageShould contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the

departments and institutions where the work was performed, name of the corresponding authors, acknowledgment of financial support and abbreviations used.– The title should be of no more than 80 characters and

should represent the major theme of the manuscript. A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary– The summary of not more than 200 words. It must

convey the essential features of the paper.– It should not contain abbreviations, footnotes or

references.

Introduction– The introduction should state why the study was carried

out and what were its specific aims/objectives.

Methods– These should be described in sufficient detail to permit

evaluation and duplication of the work by others.– Ethical guidelines followed by the investigations should

be described.

StatisticsThe following information should be given:– The statistical universe i.e., the population from which

the sample for the study is selected.– Method of selecting the sample (cases, subjects, etc.

from the statistical universe).– Method of allocating the subjects into different

groups.– Statistical methods used for presentation and analysis of

data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

– Confidence intervals for the measurements should be provided wherever appropriate.

results– These should be concise and include only the tables

and figures necessary to enhance the understanding of the text.

Information for Authors


Discussion

– This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

referencesThese should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses). At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.Examples of common forms of references are:

ArticlesPaintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes. Q. J. Expt. Physiol. 1955;40:89-111.

BooksStansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Articles in BooksStrong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

Tables– These should be typed double spaced on separate

sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends– These should be typed double spaces on a separate

sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

– The legend must include enough information to permit interpretation of the figure without reference to the text.

Figures– Two complete sets of glossy prints of high quality

should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

– The back of each illustration should bear the first author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

– Color illustrations will be accepted if they make a contribution to the understanding of the article.

– Do not use clips/staples on photographs and artwork.

– Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript:1. Classification (e.g. original article, review, selected

summary, etc.)_______________________________2. Total number of pages ________________________3. Number of tables ____________________________4. Number of figures ___________________________5. Special requests _____________________________6. Suggestions for reviewers (name and postal address) Indian 1. ___________Foreign 1. _______________ 2. ___________ 2. _______________ 3. ___________ 3. _______________ 4. ___________ 4. _______________7. All authors’ signatures________________________8. Corresponding author’s name, current postal and

e-mail address and telephone and fax numbers __________________________________________

For Editorial CorrespondenceDr KK AggarwalGroup Editor-in-Chief

Indian Journal of Clinical PracticeE-219, Greater Kailash, Part-1

New Delhi - 110 048. Tel: 40587513E-mail: [email protected] Website: www.ijcpgroup.com

Online Submission Also e- Issue @ www.ijcpgroup.com

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