GEORGE D. COMERCI, JR., MD,FACP, DAAPM

PROFESSOR OF INTERNAL MEDICINECO-DIRECTOR: PROJECT ECHO PAIN

HEADACHE CLINIC,UNM PAIN CONSULTATION AND

TREATMENT CENTER

Update in Outpatient Internal Medicine for the

Outpatientalist: 2013

Financial Disclosures

What to expect….

Discussion of New Studies pertinent to the internist

Update on New Disease Prevention Recommendations

New Drugs, New uses for old drugs, News about drugs

Objectives

Describe the clinical features of the H7N9 flu Discuss the relationship of statins to diabetesDiscuss the emerging knowledge of the

relationship of the human microbiome to disease

Describe the possible relationship of exercise on dementia prevention

Discuss the importance of mammographic breast density as this relates to mammography frequency

Describe the indications for the PCV-13 vaccineDiscuss new information about drugs

Clinical Findings in 111 Cases of Influenza A H7N9 [N Engl J Med.2013.368:2277-85]

•Novel avian-origin influenza virus appeared in China•Data on 111 cases evaluated•H7N9 virus identified by RT-PCR assay•Clinical Findings Lab Findings

• Pneumonia: 97.3 % lymphopenia• ARDS: 71.2% Inc. CK and AST

• Shock: 26.1%• Death: 27%

Origin of the Novel Avian Influenza A H7N9 Virus.

Morens DM et al. N Engl J Med 2013;368:2345-2348.

3 factors a pandemic make….

A substantial portion of the population should not be immune

The virus should be capable of causing human disease

Efficient human-human transmission*

Human Microbial Biosphere (Microbiota)

• The microbiota represents the communities of microorganisms that resides within (and on) us

10 times more microbial cells than human cellsThe microbiome is the genetic content of the

microbial communities and is far more complex than the human genetic content

Our symbiotic relationship to our microbial biosphere is usually commensal or of mutual benefit, but occasionally the relationship is pathologicWe Are One with our Microbiota!

The Human Microbiome [Nutr Clin Pract.2012;27:201-214]

The Microbiome is studied via gene sequencing techniques not by culture techniquesThe Microbiome is most similar in twins, differing some degree within family members and further differing amongst unrelated family membersInfant gut microbiota resembles that of an adult by three years of ageThe microbiota is dramatically influenced by environment, foods, antibiotics, etc.

Microbiota of different body surfaces [Harrisons Principles of Internal Medicine.18th ed. 2012]

Pharacometabonomic identification of a significant host-microbiome metabolic interaction affecting

human drug metabolism [PNAS.106.2009]

Can a host’s metabolic phenotype (their microbiota) influence drug metabolism?Acetaminophen Acet Sulfate

Acet GlucuronideAcet N Acetylcysteine

P-cresol is produced by certain gut microbes and competes for sulfation with acetaminophenPatients who were high producers of p-cresol had reduced sulfation and reduced metabolism of acetaminophen

Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome.

[Nature.2013;499:99-103]

Senescent cells develop a secretory profile consisting of inflammatory cytokines, chemokines and proteases (senescence associated secretory profile-SASP) Some of these SASP promote cell clearance but others promote

tumorigensis

Dietary changes that promote obesity change the gut of mice microbiota in such a way that production of deoxycholic acid (DCA) was increased which in turn increased SASP phenotype in hepatic cells favored tumorigensis and increased HCC

This effect was reduced by administration of vancomycin which reduced DCA production

Energy-balance studies reveal associations between gut microbes, caloric load and nutrient absorption in

humans. [AmJClinNutr.2011;94:58-65.]

Indigestible carbohydrates and proteins account for 10-30% of total ingested energy

The ability to “harvest” this energy is highly dependent upon the gut microbiota

The microbiota of obese individuals is different than that of lean individuals.

This study showed that a high caloric diet (3400 kcal/d) increased Firmicutes sp. and decreased Bacteriodetes sp. resulting in a net increased caloric absorption of 150Kcal/d

Duodenal Infusion of Donor Feces for Recurrent Clostridium dificile. [N Engl J Med.2013;368:407-414.]

Question: Is duodenal infusion of donor feces effective for the treatment of recurrent Clostridium dificile infection.

Methods: 43 patient who had failed a course of vancomycin for C dif colitis 17 received vancomycin 500qid x 4 D and subsequent

colon lavage followed by infusion of donor feces 13 received vancomycin 500 qid x 14 D with bowel

lavage 13 received vancomycin 500 qid x 14 D

Rates of Cure without Relapse for Recurrent Clostridium difficile Infection.

van Nood E et al. N Engl J Med 2013;368:407-415

Microbiota Diversity in Patients before and after Infusion of Donor Feces, as Compared with Diversity in Healthy Donors.

van Nood E et al. N Engl J Med 2013;368:407-415

We (our genome) and the microbiome are One!

Variations in gut microbiome are affected by our immediate surroundings, our diet and drugs.

Variations in gut microbiome can affect drug metabolism

Variations in the gut microbiome may increase the risk of certain cancers

Re-establishment of a damaged gut microbiome can eliminate disease

Meta-Analysis of Impact of Different Types and Doses of Statins on

New-Onset Diabetes Mellitus [Am J Cardiol2013;111:1123e1130]

Question: What is the specific the specific risk fordeveloping DM associated with one statin

compared with another and is there a relationship to dosage and DMMethods: •Meta-analysis of RCTs between 1994-2012•Studies need have >1000 patients who were followed for > 1 yearEndpoints•New onset DM

Meta-Analysis of Impact of Different Types and Doses of Statins on

New-Onset Diabetes Mellitus [Am J Cardiol2013;111:1123e1130]

Results:•17 studies:

• 14 compared statin to placebo• 3 compared high dose vs. moderate dose statin

•11,3394 patients representedRosuvastatin 20 mg/day: 25% relative increase in the risk for developing new-onset DM.Pravastatin 40 mg/day: lowest risk for DM, almost comparable with placebo treatment.Simvastatin 40 mg/day: approx. = Rosuvastatin 20 mg/day.

1 case of diabetes for every 4 cardiovascular events prevented.

[Circ.2012.126;e282-284]

The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort

Study [Ann Intern Med. 2013;158(3):162-168]

Question: Is there an association between midlife fitness and all cause dementia?Methods:Study Center: Cooper Center Longitudinal StudyStudy Cohort: 19,458 persons who had an exercise treadmill test between 1999-2009Exclusion Criteria: MI, stroke, chronic illness leading to disability, age>65.Fitness Level: quintiles according to METs on ETT

The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort

Study [Ann Intern Med. 2013;158(3):162-168]

Methods (cont.) Quintile 1: 8.1 METS Quintile 2: 9.4 METS Quintile 3: 10.4 METS Quintile 4: 11.3 METS Quintile 5: 13.3 METSAssessment at ages 70, 75, 80 and 85 years

Dementia identified ICD-9 codes (primarily for Alzheimer-type dementia but also for vascular dementia)

The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort

Study [Ann Intern Med. 2013;158(3):162-168]

Results: •Mean follow-up: 24 years•Hazard ratio: Quintile 5 compared to Quintile 1= 0.64•No significant effect of educational level (mean =15 yr.)•No significant difference in those with or without a history of stroke

Date of download: 10/8/2013

Copyright © The American College of Physicians. All rights reserved.

From: The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort Study

Ann Intern Med. 2013;158(3):162-168. doi:10.7326/0003-4819-158-3-201302050-00005

Dementia-free survival, according to midlife fitness level.

Figure Legend:

Chronic Opioid Use is associated with increased DNA Methylation correlating with increased clinical

pain. [Pain.2013;154.15-23]

Does chronic opioid therapy have pharmacoepigenetic effects which result in decreased opioid responsiveness?

The pain response to opioids varies amongst patientsMost patients develop tolerance to opioidsSome develop hyperalgesia with opioids

Chronic Opioid Use is associated with increased DNA Methylation correlating with increased clinical

pain. [Pain.2013;154.15-23]

MethodsCohort 1: Addicts on methadoneCohort 2: Matched controlsCohort 3: Pain patients on 115.8 MEDsCohort 4: Pain patients on no opioids

Quantitative Analysis:OPRM 1 (Mu receptor gene)LINE 1 (transposone on mu receptor

gene)

The Transposon

DNA Methylation

Comparison of global methylation and pain scores

Prevention

PCV13 Pneumococcal Conjugate Vaccine

The “classic” vaccine (PPV23) is a 23 valent vaccineIn use since 1983No anamnestic response, ergo, immunity wanesPCV 13 is a conjugate made of a protein + a polysaccharide capsular antigenLarge scale clinical trial data not yet available

Date of download: 10/1/2013Copyright © 2012 American Medical

Association. All rights reserved.

From: Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults With Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP)JAMA. 2013;309(4):334-336. doi:10.1001/jama.2012.31377

Figure Legend:

Breast Cancer Screening

JT is a 56 y/o female who presents for her yearly health exam. She has visited the Are You Dense website, wants to know her breast density “score” on her recent mammogram. She disagrees with your recommendation to have mammograms every 2 years and, furthermore, wants an MRI if her breasts are dense.Is breast density a risk for breast cancer?Does she need yearly mammograms if she has dense breasts?Should she have an MRI if her breasts are dense?

Breast Cancer Screening

Breast “density” correlates with the degree of fat replacement of breast tissue

Women with mammographically dense breast have a higher risk of invasive breast cancer

Are You Dense, a breast advocacy group, has pushed for laws mandating that women be informed of the degree of density of their breast on mammography and have more aggressive screening if their breasts are dense on mammography

[J Natl Cancer Inst;2013;105:1043–1049]

Outcomes of Screening Mammographyby Frequency, Breast Density, and PostmenopausalHormone Therapy [JAMA Intern Med. 2013;173(9):807-816.]

Purpose: To compare the benefits and harms of screening mammography frequencies according to age, breast density, and postmenopausal hormone therapy (HT) use.

Prospective study from data from the Breast Cancer Surveillance Consortium (BCSC) mammography registriesData collected January 1994 to December 2008

11,474 women with breast cancer and 922,624 without breast cancer

Outcomes of Screening Mammographyby Frequency, Breast Density, and PostmenopausalHormone Therapy [JAMA Intern Med. 2013;173(9):807-816.]

Women aged 40 to 49 years: biennial mammography vs. annual is associated

with increased risk of advanced-stage cancer (odds ratio [OR], 1.89 and large tumors (OR, 2.39).

Women age 50 to 74 years: biennial mammography was not associated with

increased risk of less favorable tumor characteristics regardless of breast density or HT usage.

Triennial mammography WAS associated with higher grade lesions only in women with extremely dense breasts

New Drugs, New uses of Old Drugs, News about Old

Drugs

Zolpidem

220% increase in ER visits due to toxicity (2005-2010)[JAMA.2013;309:2203]

Impaired driving, especially women and elderlyWomen: 5mg IR/ 6.25 mg XR Elderly: [JAMA.2013;309:646]

Increased risk of Hip Fracture in ElderlyOR = 1.66 for hip fracture in nursing home residents [JAMA Intern Med. 2013 May 13;173(9):754-61.]

[

Fake and Substandard Drugs

“falsified drug” misrepresents identify, source or both“substandard drug”: fails to meet accepted standards of manufacturing

production packaging distribution JAMA.2013.309.1693-1694

Fake and Substandard Drugs

Supplements Life style drugs

sildenafil Antimicrobials

TB medications Malaria medications HIV medication

Bull World Health Organ 2010;88: 247–248

Codeine

• A natural derivative of OpiumA weak analgesic nearly on the bottom of the WHO

pain ladderConverted to morphine by cytochrome P-450

enzyme 2 D6 (CYP2DR)CYP2DR activity exists as a spectrum of activity [slow metabolizers high

metabolizers]15% of Middle Eastern and Northern African

patients are high metabolizers Clin Pharm & Therap .2012; 91:323-326

N. Engl. J. Med.2009; 361, 827–828 (2009).

Fluoroquinolones

Severe neuropathy Usually during treatment Potentially irreversible

Severe fluctuations in glucose levels

http://1.usa.gov/17QhZK3

In summary….

The H7N9 influenzaThe increased risk of DM with rosuvastatin

and simvastatinThe complex role of the human microbiome in

disease and metabolismThe role of exercise in dementia preventionDNA methylation with chronic opioid usageBreast cancer screening and breast densityPCV-13 vaccineUpdates on Zolpidem, Codeine and Fake drugs

Thank You!