1

Blackmores Companions Research Summary

The Blackmores Companions range was developed to support the nutritional status of some people taking certain key prescription medicines.

For people who need to take medications for long periods of time, drug-nutrient interactions may lead to vitamin or mineral deficiencies, which may have a detrimental effect on health outcomes.

As treatment for many diseases becomes increasingly complex with multiple drug therapies prescribed and used at varying times, the need to identify clinically significant drug nutrient interactions is an important part of medication management. We believe that healthcare professionals play an important role in interpreting the available data and tailoring an approach to therapy that is compatible with each patient’s disease state, life stage, and dietary intake.

These formulations were developed based on a review of scientific literature and in consultation with leading healthcare professionals.

The Companion product claims, as listed on the Australian Register of Therapeutic Goods, have been formulated for communication to healthcare professionals who have the training and clinical experience to evaluate them and consider their relevance to their patients on a case-by-case basis. The range is neither designed nor recommended for routine, en masse supplementation.

The evidence was compiled in line with the Therapeutic Goods Administration’s Levels of Evidence Guidelines for listed products, and demonstrates that some prescription medicines may diminish nutrients and that supplementation can improve nutritional status.

In addition, evidence was sourced using two key resources identified by leading Australian professional bodies as having ‘tier one’ quality of information for complementary medicines: The Natural Standard Professional Database and the Natural Medicines Comprehensive Database.

2

Antibiotics and Lactobacillus reuteri Protectis®

There is clear evidence that antibiotics can indiscriminately reduce the number of beneficial bacteria in the gastrointestinal tract. In addition, antibiotics can upset the normal balance of gut microflora and allow pathogens to proliferate, which may result in antibiotic-induced diarrhoea of varying severity.

1,2

Probiotics such as Lactobacillus species may be used in cases when symptoms occur or might occur due to depleted normal flora. There is evidence to show that when taken during antibiotic treatment Lactobacillus reuteri Protectis

® may help to reduce antibiotic associated

diarrhoea as well as other gastrointestinal symptoms such as flatulence and bloating.4-6

Antibiotics disrupt healthy microflora

1. A 2001 Lancet review indicated that antibiotics indiscreetly reduce the number of beneficial bacteria in the gastrointestinal tract. In addition, antibiotics can upset the normal balance of gut microflora and allow pathogens to proliferate, which may result in antibiotic-induced diarrhoea. The review concluded that a balanced microflora is of importance to reduce the opportunities for pathogens to establish themselves and to prevent colonisation by resistant microbial strains.

1

2. A 2002 article in the New England Journal of Medicine reported that the frequency of antibiotic-associated diarrhoea varies among different antibiotics, and can affect up to 25 percent of patients receiving a particular antibiotic. Diarrhoea may occur in approximately 5 to 10 percent of patients prescribed ampicillin, 10 to 25 percent of those prescribed amoxicillin–clavulanate, 15 to 20 percent of those who receive a third generation cephalosporin and 2 to 5 percent of those who are prescribed other cephalosporins, azithromycin, clarithromycin, erythromycin, and tetracycline.

2

3. The Natural Medicine Comprehensive Database indicates that Lactobacilli are used therapeutically as probiotics, the opposite of antibiotics. They are considered "friendly" bacteria and are taken for the purpose of re-colonizing areas of the body where they normally would occur.

3

The human body relies on the normal flora for several functions including metabolizing foods and certain drugs, absorbing nutrients, and preventing colonization by pathogenic bacteria. Lactobacilli seem to provide nutritional benefits including inducing growth factors and increasing the bioavailability of minerals. Lactobacilli also stabilize the mucosal barrier and decrease intestinal permeability.

3

Probiotics such as lactobacillus are typically used in cases when a disease occurs or might occur due to depleted normal flora. For example, treatment with antibiotics can kill off pathogenic bacteria and also the normal flora of the gastrointestinal and genitourinary tracts. Altering the normal flora allows for potential colonization by pathogenic organisms, which can result in side effects such as diarrhoea, cramping, and less commonly pseudomembranous colitis caused by Clostridium difficile.

3

The theory is that taking lactobacillus probiotics during antibiotic treatment can prevent or minimize normal flora depletion and pathogenic bacteria colonization. There is some evidence to support this theory. When taken orally, lactobacilli pass through the gut and attach to the intestinal mucosa where they can persist for at least one week. When probiotic lactobacilli latch on to and colonize the intestinal and urogenital mucosa, it seems to prevent epithelial attachment by pathogenic bacteria. Lactobacilli seem to have

3

this effect by increasing epithelial mucus production and competing with pathogens for mucosal binding sites, possibly through steric hindrance. Lactobacilli also inhibit bacterial pathogens by producing lactic acid, and many lactobacilli also produce hydrogen peroxide.

3

Supplementing L. reuteri Protectis®

and colonisation of the human gastrointestinal tract

1. In a 2003 open clinical investigation, ten healthy adults and nine adults with ileostomy but without any signs of ongoing inflammation of the gut underwent gastroscopy or ileoscopy. Biopsy samples were taken from the stomach (corpus and antrum), duodenum and ileum at baseline and after supplementation with L. reuteri Protectis

® (4x10

8 colony forming

units (CFU)/day) for 28 days.

Colonisation of the gastrointestinal tract was shown by the FISH fluorescence probe method, which detects live L. reuteri at the time of biopsy. Ingestion of L. reuteri Protectis

® led to significant colonisation.

At baseline, a few subjects were naturally colonised by L. reuteri. By the end of the supplementation period L. reuteri Protectis

® had colonised the stomach, duodenum and

ileum of all subjects.4

Supplementing L. reuteri Protectis® reduces the incidence of antibiotic-associated

diarrhoea and gastrointestinal symptoms

1. A 2011 randomised, double-blind, placebo-controlled pilot study, investigated 31 hospitalised patients receiving antibiotics with L. reuteri (1x10

8 CFU twice daily) or an

identical placebo for 4 weeks. Stool frequency, consistency, and gastrointestinal symptoms were monitored during the 4-week treatment period and during a 2-week follow-up period. Patients treated with the probiotic had a significantly lower incidence of diarrhoea than patients receiving placebo; incidence of diarrhoea was 50 percent in the placebo group versus 7.7 percent in the probiotic group (p=0.02).

5

2. In a 2006 prospective, double-blind, placebo-controlled study, 40 dyspeptic adults with verified H. pylori infection were randomised to take either L. reuteri Protectis

® chewable

tablets (108 CFU) or placebo once daily for 28 days. Thereafter all patients received a

ten-day sequential therapy comprising of rabeprazole (20 mg twice/day) plus amoxicillin (1 g, twice/day) for 5 days followed by raprazole (20 mg twice/day) plus clarithromycin (500 mg, twice/daily) and tinidazole (500 mg, twice/day). After four weeks of treatment, L. reuteri Protectis

® significantly reduced stomach levels of

H. pylori by 13 percent (p<0.05) and stool levels by 15 percent (p<0.05). In comparison, stomach and stool levels of H. pylori increased by 3 and 10 percent respectively in subjects taking placebo. In patients receiving L. reuteri for four weeks, a significant decrease of Gastrointestinal Symptom Rating Scale (GSRS) was observed, compared to the pre-treatment value (7.9 versus 11.8; p<0.05) that was not present in those receiving placebo (9.7 versus 11.4; p=not significant), although a reduction was still noted. When the frequencies of the symptoms were evaluated by taking into account only the occurrence of new or worsened symptoms after treatment compared to baseline, it was found that patients receiving L reuteri experienced less frequent symptoms than those receiving placebo; abdominal distension (25 percent versus 55 percent; difference - 30 percent; p<0.05), disorders of defecation (10 percent versus 35 percent; difference; - 25 percent; p<0.05), and flatulence (5 percent versus 30 percent; difference; -25 percent; p<0.04) than those receiving placebo. No adverse events were reported.

6

4

3. A 2006 double-blind, placebo-controlled trial investigated whether daily supplementation with L. reuteri Protectis

® reduced antibiotic-associated side effects during and after H.

pylori eradication therapy (omeprazole + amoxycillin for five days, and omeprazole + clarithromycin + tinidazole for another five days). 40 children aged 3-18 years completed the study. They were randomly assigned to receive L. reuteri (1x10

8 CFU/day) or placebo

in addition to a 10-day course of eradication therapy and for another 10 days post-treatment. When probiotic-supplemented children were compared with those receiving placebo there was a significant reduction of GSRS score during the eradication therapy (4.1 versus 6.2; P < 0.01), which became more marked at the end of follow-up (3.2 versus 5.8; P < 0.009). When symptom frequency was evaluated by taking into account only the occurrence of new or aggravated symptoms during and after the eradication week relative to baseline, it was found that children receiving L. reuteri experienced less frequent epigastric pain during eradicating treatment (15 percent versus 45 percent; difference:- 30 percent; P < 0.04) and abdominal distension (0 percent versus 25 percent; difference: - 25 percent; P < 0.02), eructation (5 percent versus 35 percent; difference: - 30 percent; P < 0.04), disorders of defecation (15 percent versus 45 percent; difference: - 30 percent; P < 0.04) and halitosis (5 percent versus 35 percent; difference) – 30 percent; P < 0.04) thereafter. No adverse events were reported.

7

Safety

1. In a 1998 prospective, double-blind, placebo-controlled study, 39 HIV-positive subjects (including two women) aged 23–50, consumed L. reuteri at a daily dose of 1x10

10 CFU, or

placebo, for 21 days. No significant differences was observed in any of the parameters monitored (analyses of blood, serum and urine) or in regard to tolerance of L. reuteri intake. Colonisation of L. reuteri in the active group was verified. The authors concluded that daily consumption of L. reuteri at the dosage of 1 x 10

10 CFU for 21 days was safe

and without adverse effects for adults infected with HIV.8

2. In a 1995 prospective double-blind, placebo-controlled study, 30 healthy males, aged 18–75, consumed L. reuteri (1 x 10

11 CFU/day) or placebo, for 21 days. The subjects made a

daily note of gastrointestinal symptoms, and samples were taken on days 0, 7, 14, 21 and 28 for analysis of serum, blood, urine and stools. After one week, stool analyses demonstrated an increased colonisation rate by L. reuteri in the GI tracts of the active group in comparison to the control group. The colonisation persisted for at least one week after intake had stopped, with one individual remaining colonised for up to two months after the end of the L. reuteri intake period. No significant differences were shown in regard to blood and urine analyses or in regard to tolerance of bacterial intake. The only adverse effect noted was a tendency towards slightly increased gas formation, which was transient.

9

3. A 2006 prospective, randomised, double blind, placebo-controlled study evaluated the safety of two probiotic strains in healthy full-term formula-fed infants, aged 3-65 days at baseline.

Over a four week period, the infants consumed either humanised cow’s milk formula (control group, n=19), the same formula with Bifidobacterium lactis Bb-12 (n=20) or the same formula with L. reuteri (n=20). The mean daily intake of each of the probiotic strains was 1.2 x 10

9 CFU.

Physical examinations occurred at baseline and at four weeks. The parents filled out a daily questionnaire for seven days during the first and fourth week of the trial for documentation of feeding, behaviour and stool characteristics. The parents were also asked to report daily on every complaint or symptom.

5

No clinical adverse effects were seen during the trial. Growth, feeding, behaviour and stool characteristics were the same in all three groups. The authors concluded that both probiotic strains were well tolerated by these very young infants during the 4-week study.

10

4. As part of a larger double-blind, placebo-controlled, multicentre study in infants with a family history of allergy, a safety investigation was performed examining the levels of D(-)-lactic acid in the blood at the ages of 6 and 12 months. A sample group of 24 infants were randomly chosen from the total study population of 232 infants. They had been supplemented with L. reuteri or placebo for twelve months from birth. The daily dose of L. reuteri was 10

8 CFU, suspended in oil. 14 infants were supplemented with L. reuteri and

10 with placebo. All 24 infants had very low levels of D(-) lactic acid (range 0.020 – 0.130 mmol/L), and there was no difference between the infants ingesting L. reuteri and those receiving placebo. The highest level observed was well within the normal range seen in humans (0.020 – 0.250 mmol/L) and far below levels associated with D-lactic acidosis in humans (> 3 mmol/L). No symptoms were reported that would normally be associated with acidosis, and there were no safety problems in any of the participating children. Authors concluded that daily supplementation with L. reuteri was safe and did not have adverse effects on serum D(-)-lactic acid in healthy newborns during their first 12 months of life.

11

5. A 2001 randomised, double-blind, placebo-controlled study investigated the safety of L. reuteri in healthy newborn, full-term newborns. For 28 days from the day of birth children consumed either placebo (n=28) or L. reuteri in doses 10

5 CFU/day (n=12), 10

7 CFU/day (n=25) or 10

9 CFU/day (n=25).

The degree of L. reuteri colonisation, measured as the number of living cells in stool samples, was found to be related to the given dose. The occurrence of watery diarrhoea was significantly lower in children given L. reuteri. All dose levels of L. reuteri were well tolerated and the authors concluded that L. reuteri was safe to consume for healthy full-term newborns during their first four weeks of life, in doses up to 10

9 CFU/day.

12

6. A 1996 double-blind, randomised, placebo-controlled safety study was conducted on 72 healthy children, aged 12–36 months living in Mexico City, who consumed L. reuteri in a nutritional beverage containing a probiotic blend of three strains over a three week period. The children were randomised into four groups, three of which consumed the probiotic beverage containing L. reuteri in doses of 1x10

6, 1x10

8 and 1x10

10 CFU, and a control

group who consumed a placebo beverage. All dose levels of L. reuteri were well tolerated and no side-effects were noted. The authors concluded that daily consumption of L. reuteri, in doses up to 10

10 CFU over a three-week period were safe for healthy children

aged 12–36 months.13

6

Probiotic references

1. Sullivan A, et al. Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infectious Diseases 2001;1:101–14.

2. Bartlett JG. Antibiotic-associated diarrhoea. N Engl J Med 2002;346: 334-9.

3. Natural Medicines Comprehensive Database. Lactobacillus monograph. http://naturaldatabase.therapeuticresearch.com

4. Valeur N, et al. Colonization and immunomodulation by L. reuteri ATCC 55730 in the human gastrointestinal tract. Applied and Environmental Microbiology 2004;70(2):1176-81.

5. Cimperman L, et al. A randomized, double-blind, placebo-controlled pilot study of L. reuteri for the prevention of antibiotic-associated diarrhoea in hospitalized adults. J Clin Gastroenterol 2011;00:1-5

6. Francavilla R, et al. Inhibition of Helicobacter pylori infection in humans by L. reuteri ATCC 55730 and effect on eradication therapy: a pilot study. Helicobacter 2008;13:127-34

7. Lionetti E, et al. L. reuteri therapy to reduce side-effects during anti-Helicobacter pylori treatment in children: a randomised placebo controlled trial. Aliment Pharmacol Ther 2006;24:1461-8.

8. Wolf B, et al. Safety and Tolerance of L. reuteri Supplementation to a Population Infected with the Human Immunodeficiency Virus. Food and Chemical Toxicology 36 (1998) 1085-94.

9. Wolf BW, et al. Safety and tolerance of L. reuteri in healthy adult male subjects. Microb Ecol Health Dis 1995: 8:41-50.

10. Weizman Z, Alsheik A. Safety and tolerance of a probiotic formula in early infancy comparing two probiotic agents: a pilot study. J Am Coll Nutr 2006;25:415-9.

11. Connolly E, Abrahamsson T, Björkstén B. Safety of D(-)-lactic acid producing bacteria in the human infant. J Pediatr Gastroenterol Nutr 2005;41:489-92.

12. Karvonen A, Casas I, Vesikari T. Safety and possible antidiarrhoeal effect of the probiotic L. reuteri after oral administration to neonates. Clin Nutr 2001; 20(suppl 3):63: abstract 216.

13. Ruiz-Palacios G, et al. Tolerance and faecal colonization with L. reuteri in children fed a beverage with a mixture of Lactobacillus spp.Pediatr Res 1996: 39(4) part 2:184A, abstract 1090.

7

Proton Pump Inhibitors and Magnesium

There is evidence to sufficiently demonstrate that the long-term use of proton-pump inhibitors (PPIs) may lead to magnesium deficiency (hypomagnesaemia).

1-5 There is also evidence to

show that magnesium supplementation may help to treat or prevent magnesium deficiency.1,2

Because dietary magnesium intake of many older Australians may be low to begin with7, the

awareness of this interaction is even more important.

Individuals who are taking long-term PPIs should seek the advice of a healthcare professional to determine if they are at risk or are showing signs of magnesium deficiency and whether a magnesium supplement may be appropriate.

Magnesium levels may become disrupted while taking a proton pump inhibitor

1. In March 2011, the US Food and Drug Administration (FDA) issued a drug safety indication that hypomagnesaemia may be associated with long-term use (in most cases, longer than one year) of proton pump inhibitor (PPI) drugs.

1

In coming to this conclusion the FDA reviewed reports from the FDA Adverse Event Reporting System (AERS), medical literature, and periodic safety update reports for cases of hypomagnesaemia in patients undergoing prolonged treatment with PPI medications. FDA's review focused on 38 cases in AERS and 23 cases reported in the literature (which include at least eight of the identified AERS cases).

1

Treatment of hypomagnesaemia generally requires magnesium supplements. In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.

1

FDA recognises that hypomagnesaemia is likely under-recognised and under-reported and states that the available data are insufficient to quantify an incidence rate for hypomagnesaemia with PPI therapy.

1

In the USA, information about the potential risk of low serum magnesium levels from PPIs will be added to the warnings and precautions sections of the labels for all the prescription PPIs.

1

2. A 2011 review published in Current Opinion in Gastroenterology reported that hypomagnesaemia has been described with all PPIs. Several studies have documented recurrence when one PPI is substituted for another, so it is a true class effect. The mechanism responsible for hypomagnesaemia associated with long-term PPI use is unknown, however, long-term use of PPIs may be associated with changes in intestinal absorption of magnesium.

2

3. The Therapeutic Goods Administration (TGA) has issued a Medicines Safety Update warning of a potential association between the use of PPIs and hypomagnesaemia, which may not be easily corrected without magnesium supplementation. The TGA also recognise that there is no way to reliably predict those who may be at higher risk. Other medications (e.g. loop and thiazide diuretics) may cause or worsen hypomagnesaemia.

3

In several cases magnesium supplementation was only partially effective at correcting the hypomagnesaemia while PPIs were continued. TGA advises that prescribers should be vigilant to the potential risk of hypomagnesaemia in patients requiring long-term PPI treatment. Patients developing hypomagnesaemia may require PPI discontinuation.

3

4. Regarding the interaction between PPIs and magnesium, The Natural Standard Professional Database Magnesium Monograph indicates that in clinical research, case studies, and reviews, use of PPIs has been associated with decreased magnesium levels. Severe hypomagnesaemia has been reported in some cases.

4

8

5. Natural Medicines Comprehensive Database Magnesium Monograph indicates that taking a PPI long term, especially for durations over one year, has been linked to an increased risk of hypomagnesaemia in several reports. PPIs are thought to inhibit active transport of magnesium in the intestine. This appears to be a class effect as hypomagnesaemia has been reported with all PPIs.

5

Severe hypomagnesaemia can cause potentially serious effects including muscle spasm, tetany, arrhythmia, hypokalaemia, hypoparathyroidism, hypocalcaemia, and seizures. This reference recommends that patients who are likely to take a PPI long term should have serum magnesium levels checked at baseline and annually thereafter. A magnesium supplement may be necessary to treat or prevent magnesium deficiency. In some patients, magnesium supplementation alone may not be adequate to treat hypomagnesaemia. Case reports suggest that up to 25 percent of patients who developed hypomagnesaemia had to discontinue the PPI in order for magnesium levels to return to normal. In many cases, hypomagnesaemia recurred when the PPI was re-initiated.

6

In some reports, use of pantoprazole, in combination with a magnesium supplement, was effective for treating reflux and preventing magnesium loss. In another case, use of alternate-day dosing of pantoprazole (Protonix) three days per week and famotidine four days per week, in combination with a magnesium supplement, was also effective for treating symptoms and increasing magnesium levels. Some experts hypothesise that the magnesium depletion caused by PPIs could contribute to the increased risk of fracture seen in some patients taking PPIs long-term.

6

Natural Medicines Comprehensive Database Magnesium Monograph also advises that taking magnesium orally or parenterally is helpful for treating and preventing hypomagnesaemia.

6

Physiological role of magnesium

The Natural Medicines Comprehensive Database Magnesium Monograph reports that magnesium is important for normal bone structure, plays an essential role in more than 300 cellular reactions and is involved in ion movements across cell membranes. It is involved in protein synthesis and carbohydrate metabolism. Extracellular magnesium is critical to maintaining nerve and muscle electrical potentials and transmitting impulses across neuromuscular junctions.

5

Oral magnesium absorption

1. A 2003 randomised double-blind, placebo-controlled, parallel intervention study compared preparations of magnesium amino acid chelate, magnesium citrate and magnesium oxide at a daily dose of 300 mg elemental magnesium over 60 days.

6

Supplementation with the organic forms of magnesium (citrate and amino acid chelate) showed greater absorption (P ± 0.033) at 60 days than magnesium oxide, as assessed by 24-hour urinary magnesium excretion.

6

Magnesium citrate led to the greatest mean serum magnesium concentration compared to other treatments following both acute (P ± 0.026) and chronic (P ±0.006) supplementation.

6

Mean erythrocyte magnesium concentration showed no differences among groups, however chronic magnesium citrate supplementation resulted in the greatest (P ± 0.027) mean salivary magnesium concentration compared with all other treatments.

6

9

Safety

1. The Natural Medicines Comprehensive Database Magnesium Monograph identifies oral magnesium as being safe when used in doses below the tolerable upper intake level (UL) of 350 mg per day.

5

2. The Natural Standard Professional Database Magnesium Monograph indicates that reports of magnesium toxicity are rare, except in certain instances, such as renal failure and high-dose intravenous administration.

6

Magnesium is safe when used orally, intravenously, or intramuscularly in people with normal renal function. Oral magnesium has been given in doses of 600-1,200mg daily for four months without major adverse effects.

6

Magnesium references

1. U.S. Food and Drug Administration. FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs. http://www.fda.gov/Drugs/DrugSafety/ucm245011.htm#Data_Summary

2. Cundy T, Mackay J. Proton pump inhibitors and severe hypomagnesaemia. Curr Opin Gastroenterol. 2011;27(2):180-5.

3. TGA. Risk of hypomagnesaemia with proton pump inhibitors. Medicines Safety Update 2011 June; 2(3):81

4. Natural Standard. Magnesium monograph. www.naturalstandard.com

5. Natural Medicines Comprehensive Database. Magnesium monograph. http://naturaldatabase.therapeuticresearch.com/home.aspx

6. Walker AF, et al. Mg citrate found more bioavailable than other Mg preparations in a randomised, double-blind study. Magnesium Research, 2003;16(3):183-1.

7. Bannerman E et al. Evaluation of micronutrient intakes of older Australians: the National Nutrition Survey – 1995. The Journal of Nutrition, Health & Aging. 2001;5(4)

10

Statins, Coenzyme Q10 and Vitamin D3

The impact of the use of statins on the reduction of serum CoQ10 levels is well documented.

1-17 There is also evidence to demonstrate that supplementation with CoQ10 can increase

endogenous tissue levels and activity when tissue levels of CoQ10 are low. 4,16,18

In addition, evidence exists to demonstrate that CoQ10 supplementation does not affect the cholesterol-lowering effect of statins.

16,17

There are many health benefits of CoQ10 that may be related to its antioxidant effects and its role in the generation of adenosine triphosphate (ATP). The support of cardiovascular health may occur via reduction of free radicals, increased ATP synthesis and/or a protective effect on membranes.

16 Given the important role that CoQ10 plays in the human body, it is

important to ensure that adequate levels exist. In addition to CoQ10, evidence is emerging on the importance of maintaining adequate levels of vitamin D for people who use statin medications. While the link between statin use and vitamin D deficiency has not yet been demonstrated, supplementation may be warranted in patients taking statins who have deficient or reduced levels of vitamin D.

19

Vitamin D has been shown to play a role in muscle health and may reduce risk of falls and support muscle strength in older people with low levels of vitamin D. In population studies, low levels of vitamin D (below 15 ng/mL), have been associated with a greater risk of cardiovascular disease.

25,26

Serum Coenzyme Q10 levels may be disrupted whilst taking statins

1. From 1990-2004 at least 15 studies have been published that investigate the effect of statins on the body’s production of coenzyme Q10 (CoQ10).

1-15 A reduction in CoQ10

status as a result of statin treatment has been shown in 13 of those 15 studies. Decreases in serum CoQ10 range from 19 percent – 54 percent.

1-15

2. The Natural Standard Professional Database reports that based on clinical trials in hypercholesterolaemic patients, statins may reduce serum CoQ10 levels.

16

3. The Natural Medicines Comprehensive Database reports in the CoQ10 professional monograph that statins can reduce serum CoQ10 levels. They block the synthesis of mevalonic acid, which is a precursor of CoQ10. The effect of statins on CoQ10 appears to be dose-related; taking atorvastatin 10 mg/day or pravastatin 20 mg/day does not significantly decrease levels of circulating CoQ10 in healthy people, however taking atorvastatin 80 mg/day for 30 days reduces CoQ10 levels by 52 percent. The clinical significance of this statin-induced reduction of CoQ10 levels is unclear. For example, taking simvastatin 20 mg/day for four weeks reduces serum CoQ10 levels about 32 percent, but levels in muscle may actually increase, up to 47 percent according to one study.

17

CoQ10 is transported with low-density lipoprotein (LDL) cholesterol. Some evidence indicates that the statin-related decrease in CoQ10 levels is due to the statin's reduction of cholesterol levels. Some researchers have hypothesised that depletion of CoQ10 levels might result in statin-related adverse effects such as myopathy. However, to date there is no reliable evidence that CoQ10 depletion is the cause of statin adverse effects or that supplementation prevents or relieves the adverse effects of statins.

17

The Natural Medicines Comprehensive Database also states that CoQ10 does not affect the cholesterol-lowering effect of statins.

17

11

Function of CoQ10

1. Natural Medicines Comprehensive Database indicates that coenzyme Q10 is present in virtually all cells and that there are especially high concentrations in the heart, kidney, liver and pancreas.

17

2. The Natural Standard Professional Database notes that many of the health benefits of CoQ10 may be related to its antioxidant effects and its role in the generation of adenosine triphosphate (ATP). The support of cardiovascular health may occur via reduction of oxidation, reduction of free radicals, increased ATP synthesis and/or a protective effect on membranes.

16

Supplementing with CoQ10 increases serum CoQ10

1. A 2007 randomised double-blind, placebo-controlled study examined the effects of CoQ10 and placebo in hypercholesterolaemic patients treated by atorvastatin for 16 weeks. All patients took atorvastatin (10 mg/day). Half the patients also took CoQ10 (100 mg/day) and the other half took a placebo supplement. Patients in the placebo group showed a 42 percent reduction of plasma CoQ10. Patients supplemented with CoQ10 showed increases in plasma CoQ10 of 127 percent.

18

2. A 1994 controlled cross-over trial examined the effects of CoQ10 and simvastatin in outpatients with hypercholesterolaemia (IIa phenotype) for 180 days. Participants were treated with either simvastatin (20 mg/day) or simvastatin (20 mg/day) plus CoQ10 (100 mg/day) for 6 months. In the statin-only group, there was a marked decrease in plasma CoQ10 levels from 1.08 mg/dL to 0.80 mg/dL. In comparison, plasma CoQ10 levels in the group taking the statin plus CoQ10 increased from 1.20 to 1.48 mg/dL. The two groups experienced similar hypercholesterolaemic effects.

4

3. The Natural Standard Professional Database indicates that supplemental CoQ10 can increase endogenous tissue levels and activity of CoQ10 significantly when tissue levels are low.

16

4. The Natural Medicines Comprehensive Database indicates that taking CoQ10 orally seems to improve symptoms of CoQ10 deficiency. When tissue levels of CoQ10 are low, supplementation with CoQ10 can increase endogenous tissue levels and activity. This reference also states that coenzyme Q10 does not affect the cholesterol-lowering effect of statins.

17

Vitamin D and statins

There is no evidence to date to indicate that statins diminish body levels of vitamin D.

Statin-associated skeletal muscle complaints and vitamin D deficiency

1. A 2011 systematic review found preliminary data to suggest that vitamin D deficiency is associated with increased risk of statin-associated skeletal muscle complaints, but no definitive evidence that vitamin D contributes to statin myalgia or is effective in its treatment. The review suggests that some (but not all) statins increase 25-hydroxycholecalciferol (25(OH)D) levels.

19

Two cross-sectional studies have reported an association between vitamin D deficiency and statin-associated myalgias, and state that increasing vitamin D levels may reverse the myalgia.

19

Until more data becomes available, it remains unclear whether vitamin D supplementation reduces the incidence or severity of statin-associated muscle complaints in patients with normal vitamin D levels. However, supplementation may be warranted in patients taking statins who have deficient or reduced levels of vitamin D.

19

12

This review concluded that both statins and vitamin D affect skeletal muscle metabolism and function. Some cross-sectional studies suggest that vitamin D supplementation may reduce myalgic symptoms in some statin-treated patients, however, a placebo effect cannot be excluded.

19

Consequently, it is reasonable to determine vitamin D levels in statin-myalgic patients and provide vitamin D supplementation in doses of 400–2,000 IU to those with low vitamin D levels (<32 ng/mL) in advance of definitive clinical study data becoming available.

19

Vitamin D insufficiency is widespread in the Australian population

1. The National Health and Medical Research Council acknowledge that a significant number of Australians and New Zealanders may have lower than optimal vitamin D status, and have reflected this in the nutrient reference values for this nutrient.

20

2. The Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia, and Osteoporosis Australia 2005 position statement on vitamin D and adult bone health concludes that a significant number of Australians have low levels of vitamin D. Those at particularly high risk of vitamin D insufficiency include the elderly, those with dark skin and those with malabsorption syndromes.

21

A 2011 Clinical Practice Guideline by the Endocrine Society of Australia provides guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency. The guideline recognises that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D. The guideline recommends supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. Adults aged 50-70 and ≥ 70 years require at least 600 and 800 IU/day respectively, of vitamin D. To raise the blood level of 25(OH)D above 30 ng/mL may require at least 1,500-2,000 IU/d of supplemental vitamin D. This was based on the fact that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D.

22

Supplementing with Vitamin D can improve vitamin D status

1. A 2003 randomised controlled trial was undertaken to show human serum 25(OH)D changes in response to extended Vitamin D3 supplementation. Vitamin D3 was administered daily at doses of 0, 25 (1,000 IU), 125 and 250 µg. This study was conducted over 20 weeks during the winter in Omaha, USA. Results showed that serum 25 (OH)D levels changed in direct proportion to the dose.

23

2. A 2010 position statement by the International Osteoporosis Foundation estimates that the average vitamin D requirement in order for older adults to attain a serum 25(OH)D level of 75 nmol/L (30 ng/mL) is 20 to 25 µg/day (800 to 1,000 IU/day).

24

The repletion dose will vary among individuals according to their baseline levels, their BMI, their effective sun exposure, and other unidentified factors. An intake lower than 20 µg/day (800 IU/day) may be adequate for individuals with regular effective sun exposure.

24

Intake may need to be adjusted upward to as much as 50 µg/day (2,000 IU/day) in individuals who are obese, have limited sun exposure (e.g. due to being institutionalised or homebound), or who are affected by osteoporosis or malabsorption syndromes.

24

Additionally, people of some non-European origins have increased risk of vitamin D deficiency; this includes those from the Middle East and South Asia.

24

3. The Natural Standard indicates that Vitamin D supplementation can help prevent or treat vitamin D deficiency.

25

13

4. The Natural Medicines Comprehensive Database indicates that Vitamin D supplementation can help prevent or treat vitamin D deficiency.

26

Function of Vitamin D

1. The Natural Standard Professional Database indicates that the main physiological function of vitamin D is to maintain normal blood levels of phosphorus and calcium. Vitamin D assists the absorption of calcium. Research suggests that the vitamin D-receptor gene plays a role in regulating bone mineral density.

25

2. The Natural Medicines Comprehensive Database notes that vitamin D has been shown to play a role in muscle health and may reduce risk of falls and support muscle strength, in older people with low levels of vitamin D. These effects may be due to its effects on receptors on muscle cells. Vitamin D deficiency is associated with a greater risk of falls in older adult patients. In population studies, low levels of vitamin D (below 15 ng/mL), have been associated with a greater risk of cardiovascular disease.

26

14

Safety

CoQ10

1. From the Natural Standard:

Likely safe: When up to 3,000 mg is taken daily for up to eight months in healthy patients; when taken daily in recommended doses by patients with cardiovascular diseases, or prior to cardiac surgeries; and in patients with periodontitis, muscular dystrophies, Parkinson's disease, Alzheimer's disease, cancer, diabetes, or HIV/AIDS/ARC.

16

CoQ10 is also likely safe in an otherwise healthy population when taken in recommended doses for exercise performance.

16

Possibly unsafe: When used daily in high doses for long periods; doses greater than 300 mg daily may elevate liver enzymes (SGOT and LDH).

16

Secondary sources offer conflicting evidence regarding safety of CoQ10 when used with antihyperglycaemic, psychiatric or cardiovascular agents.

16

Likely unsafe: When taken by patients using warfarin or anticoagulants or by patients with liver diseases.

16

Note: Studies of long-term effects of moderate doses of CoQ10 have found that it is generally safe in otherwise healthy individuals, with only few or minor adverse effects reported.

16

2. The Natural Medicines Comprehensive Database indicates that CoQ10 is likely safe when used orally and appropriately. CoQ10 has been safely used in studies lasting up to 30 months.

17

Vitamin D

1. From the Natural Standard:

Oral and parenteral vitamin D is generally well tolerated in recommended doses.

Likely safe: When used at doses of 100 µg of vitamin D3 daily (4,000 IU).25

Possibly safe: When used at doses of 300,000 IU of vitamin D2 or D3 orally or intramuscularly three times a year for vitamin D insufficiency.

25

Possibly unsafe: When used in patients with liver disease (vitamin D is metabolised in the liver); when used in patients with diabetes or those using hypoglycaemic agents (vitamin D may lower blood glucose and increase the risk of hypoglycaemia); when used in patients with hypertension or those using antihypertensive agents (according to clinical review, vitamin D may lower blood pressure and increase the risk of hypotension). Use cautiously in patients with hyperparathyroidism, as vitamin D may increase calcium levels. When used in patients with renal disease, as vitamin D may increase calcium levels and the risk of arteriosclerosis. When used in patients with granulomatous disorders (sarcoidosis, tuberculosis, fungal granulomas, berylliosis, and lymphomas), which are associated with calcium metabolism disorder. Theoretically, concurrent use of high amounts of vitamin D in these patients may increase the risk of hypercalcemia and kidney stones. When used in mothers who are receiving vitamin D supplements and are breastfeeding, as, according to human research, vitamin D supplementation during breastfeeding may increase the risk of urinary tract infection, particularly in the first three months.

25

Likely unsafe: When used in individuals with known allergy to vitamin D or with vitamin D hypersensitivity syndromes. When used in patients with hypercalcemia;

15

theoretically, high amounts of vitamin D may cause this adverse effect and exacerbate this condition.

25

2. The National Health and Medical Research Council (NHMRC) sets the upper limit of intake for vitamin D at 80 µg/day (3,200 IU).

20

3. The Natural Medicines Comprehensive Database indicates that vitamin D is likely safe when used orally or intramuscularly and appropriately. Vitamin D has been safely used in a wide range of doses. When used orally long-term, doses should not exceed the tolerable upper intake level (UL) of 4,000 IU per day for adults.

26 In a study in which 16

people taking atorvastatin received either an additional multivitamin containing vitamin D, or an additional calcium plus vitamin D supplement. Levels of atorvastatin decreased by 55 percent during vitamin D supplementation, however total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol levels did not substantially change. The authors acknowledge that the combination of poor design and small subject numbers limit the ability to draw conclusions from this study.

26, 27

16

Coenzyme Q10 and vitamin D references

1. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA 1990;87:8931-4

2. Watts GF, Castelluccio C, Rice-Evans C, et al. Plasma coenzyme Q (Ubiquinone) concentrations in patients treated with simvastatin. J Clin Pathol 1993;46:1055-7

3. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double blind, placebo-controlled study. J Clin Pharmacol 1993;33:226-9

4. Bargossi AM, Grossi G, Fiorella PL, et al. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med 1994; 15 Suppl.:s187-93

5. Laaksonen R, Ojala J-P, Tikkanen MJ, et al. Serum ubiquinone concentrations after short and long-term treatment with HMG- CoA reductase inhibitors. Eur Clin Pharmacol 1994; 46:313-7

6. Laaksonen R, Jokelainen K, Sahi T, et al. Decreases in serum ubiquinone concentrations do not result in reduced levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995;57(1):62-6

7. De Pinieux G, Chariot P, Ammi-Said M, et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/ pyruvate. Br J Clin Pharmacol 1996;42:333-7

8. Laaksonen R, Jokelainen K, Laakso J, et al. The effect of simvastatin treatment on natural antioxidants in low-density lipoproteins and high-energy phosphates and ubiquinone in skeletal muscle. Am J Cardiol 1996;77:851-4

9. Davidson M, McKenny J, Stein E, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Am J Cardiol 1997;79:1475-81

10. Human AJ, Ubbink JB, Jerling JJ, et al. The effect of simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolemia. Clin Chim Acta 1997;263:67-77

11. Mortensen SA, Leth A, Agner E, et al. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspects Med 1997;18 Suppl.:137- 44

12. De Lorgeril M, Salen P, Bontemps L, et al. Effects of lipid- lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients. J Cardiovasc Pharma col 1999;33(3):473-8

13. Miyake Y, Shouzu A, Nishikawa M, et al. Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase in hibitors on serum coenzyme Q10 in diabetic patients. Arzneimittel Forschung 1999;49 (1): 324-9

14. Bleske BE, Willis RA, Anthony M, et al. The effect of pravasta tin and atorvastatin on coenzyme Q10. Am Heart J 2001; 142 (2):E2

15. Rundek T, Naini A, Sacco R, et al. Atorvastatin decreases the CoQ10 level in the blood of patients at risk for cardiovascular disease and stroke. Arch Neurol 2004;61:889-92

16. Natural Standard. Coenzyme Q10 monograph. www.naturalstandard.com

17

17. Natural Medicines Comprehensive Database. CoenzymeQ10 monograph. www.naturaldatabase.therapeuticresearch.com

18. Mabuchi H, et al. Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: A randomized double-blind study, Atherosclerosis, 2007; 195: 182-189

19. Gupta A, Thompson P. The relationship of vitamin D deficiency to statin myopathy, Atherosclerosis, 2011; 215: 23–29

20. National Health and Medical Research Council. Vitamin D http://www.nrv.gov.au/nutrients/vitaminpercent20d.htm

21. Working Group of the Australian and New Zealand Bone and Mineral Society, Endocrine Society of Australia and Osteoporosis Australia. Vitamin D and adult bone health in Australia and New Zealand: a position statement. MJA 2005;182(6):281-285

22. Holick MF, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011; 96: 1911-1930

23. Heaney RP, et al. Human serum 25-hydroxyxholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-10

24. Dawson-Hughes B, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporosis Int 2010;21:1151-1154

25. Natural Standard. Vitamin D monograph. www.naturalstandard.com

26. Natural Medicines Comprehensive Database. Vitamin D monograph. http://naturaldatabase.therapeuticresearch.com

27. Schwartz JB. Effects of vitamin D supplementation in atorvastatin-treated patients: A new drug interaction with an unexpected consequence. Clin Pharmacol Ther 2009;85:198-203.

18

Zinc and Angiotensin Converting Enzymes (ACE) Inhibitors, Angiotensin-II Receptor Antagonists and Thiazide Diuretics

There is clear evidence that the long term use of ACE inhibitors, thiazide diuretics and angiotensin II receptor antagonists can lead to low levels of zinc overtime in some individuals.

1-10

There is also clear scientific recognition that the intake of zinc is low in several groups of people within the Australian community who may also be taking some anti-hypertensive medications.

Low intake of zinc from the diet places individuals at risk of zinc deficiency.

14-16

It is important to recognise that the long term use of an ace inhibitor, thiazide diuretic or angiotensin II receptor antagonist along with low dietary intake of zinc may increase the risk of zinc deficiency. Individuals who are taking an ace inhibitor, thiazide diuretic or angiotensin II receptor antagonist should seek the advice of a healthcare professional to determine if they are at risk or are showing signs of zinc deficiency and whether a zinc supplement may be appropriate.

Chronic use of ACE inhibitors increases urinary excretion of zinc

1. A 1998 open label trial involved 42 patients newly diagnosed with essential hypertension. Zinc levels were assessed before and after six months therapy with either enalapril or captopril and compared to healthy controls. While serum zinc levels were unchanged after six months of treatment, patients treated with captopril exhibited significantly higher urinary zinc excretion and significantly decreased intracellular zinc levels compared to the control group. The results of this study demonstrate that chronic use of ACE inhibitors by hypertensive patients results in zinc depletion, as reflected by intramonocytic zinc levels.

1

2. In a controlled trial assessing zinc status and ACE inhibitors (enalapril and captopril), zinc concentrations in plasma, urine and red blood cells were assessed in eight patients with essential hypertension treated with captopril (25 mg/day), seven patients with essential hypertension treated with enalapril (20 mg/day), six untreated hypertensives, and nine healthy controls. Captopril-treated patients showed significantly increased 24-hour urinary zinc excretion compared to the other groups. The zinc:creatinine ratio in 24-hour urine was significantly increased in both the captopril- and enalapril-treated groups, but to a larger extent in the captopril group. Although plasma zinc concentrations were comparable in all groups, red blood cell (RBC) zinc values were significantly decreased in the captopril group compared to the other three groups. The researchers concluded that both captopril and enalapril produce renal zinc loss, however the loss is far greater in patients receiving captopril. Captopril administration for three months leads to depletion of RBC zinc.

2

3. A 1988 cohort study assessed taste acuity and measured plasma zinc levels and urinary zinc excretion in 31 hypertensive patients. Of these, 11 were long-term, high-dose captopril recipients (more than six months, 266 ± 34 mg/day), six were short-term captopril recipients (less than six months, 104 ± 40 mg/daily dose), and the remaining 14 served as non-captopril treated controls. Compared to controls, the long-term captopril group had significantly higher taste detection and recognition thresholds, lower plasma zinc, (91 ± 3 vs. 100 ± 3 µg/dL, P < 0.05) and higher urinary zinc excretion (1017 ± 89 vs. 609 ± 76 µg/day, P < 0.005. The short-term captopril group did not differ significantly from the non-captopril group except for higher taste-recognition thresholds for NaCl and sucrose (P < 0.05). Discontinuing captopril improved taste acuity and almost normalised zinc parameters in two patients on long-term captopril.

3

19

4. A 2007 case-controlled study investigated the effects of ACE inhibitors and furosemide on zinc metabolism in heart failure patients. Data were obtained from the 11 patients and 24 healthy controls matched for age and sex. Urine and serum zinc levels in a heart failure group, which has begun treatment with ACE inhibitors in the previous hours, were compared with those of a healthy control group. Zinc concentration was considered normal in serum in the range 55–150 µg/dL and urine zinc in the range 0.3–1 referred to as µg/g creatinine. Significant differences were observed between cases and controls for serum and urine zinc concentrations. Serum zinc levels were lower in the heart failure group (67.27 µg/dL versus 87.32 µg/dL) (p = 0.001) and the urine zinc excretion was significantly higher in the treated group (2.24 µg/g versus 0.21 µg/g) (p<0.001). The authors suggest that treating heart failure patients with ACE inhibitors may result in zinc deficiency.

4

5. The Natural Standard Professional Database states that based on human research, ACE inhibitors such as captopril and enalapril may increase urine zinc excretion, resulting in zinc deficiency. In human research, an effect of perindopril on salivary or plasma zinc levels was not observed.

5

6. The Natural Medicines Comprehensive Database states that some data suggest captopril increases urinary zinc excretion, possibly due to chelation of zinc by sulfhydryl groups. Some studies have found a link between captopril, low zinc levels, and taste loss which can be reversed with zinc supplements, while others have not. Differences may be due to dose and duration of captopril therapy - increased zinc losses seem more likely with high captopril doses (greater than 150 mg/day) taken for several weeks or months. Routine zinc supplements aren't necessary with captopril. Monitor for symptoms of zinc depletion in patients on high doses of captopril for prolonged periods, especially if they have other risk factors. Significant zinc depletion doesn't occur with enalapril, and is unlikely with other ACE inhibitors.

9

Thiazide diuretics increase urinary excretion of zinc

1. A 1980 crossover study investigated urinary zinc excretion during treatment with six diuretic drugs (bendroflumethiazide, bumetanide, chIolthalidone, furosemide, hydrochlorothiazide and triamterene). Eighteen patients with untreated arterial hypertension were divided into two groups and treated with equipotential doses of bendroflumethiazide, hydrochlorothiazide and chlorthalidone for two weeks and triamterene, furosemide and bumetanide for two weeks, with one week washout between each medication. During treatment with thiazides, urinary zinc excretion rose by 30 percent and the total amount of zinc excretion increased by 60 percent. In contrast, during treatment with the loop-diuretics, urinary zinc concentrations diminished and the total zinc excretions was much less than that of the thiazide diuretics.

6

2. A 1980 study assessing treatment with chlorthalidone showed a substantial increase in the urinary output of zinc. The study assessed tissue zinc in the liver, kidney and skeletal muscle tissue of 147 consecutive autopsies. In 90 of the cases muscle and aortic tissue were also studied. The values were correlated to previous duration of diuretic treatment. A lower liver zinc level was observed in the bodies of those who had been on diuretics for more than six months compared to the group without treatment, the difference being highly significant.

7

3. In 1987 Golik investigated serum zinc levels and urinary zinc excretion in medicated hypertensives. Fifteen patients with essential hypertension taking a combination of hydrochlorothiazide and amiloride chronically were compared to eight patients maintained with hydrochlorothiazide alone, and eight control subjects. Serum zinc values were statistically comparable in all three groups, however, urinary zinc excretion was abnormally elevated in both patient groups.

8

4. Natural Medicines Comprehensive Database indicates that there is moderate depletion associated with thiazide diuretics. It recommends monitoring for depletion and states that a supplement is needed in some patients. Thiazide diuretics increase urinary zinc excretion by 50 to 60 percent, and this is likely sustained during at least three years of

20

treatment. Decreased serum zinc levels sometimes occur, although they usually remain within the normal range, possibly due to compensatory mechanisms. However, prolonged thiazide therapy might deplete tissue zinc. It is suggested that this could contribute to the impotence sometimes seen with thiazides. Monitor patients on long-term thiazide therapy for symptoms of zinc deficiency. Amiloride is zinc-sparing and can counteract zinc losses caused by thiazides. Thiazides include chlorothiazide, hydrochlorothiazide, chlorthalidone, indapamide, metolozone, and others.

9

5. The Natural Standard Professional Database states that based on human evidence, loop and thiazide diuretics may increase urinary zinc excretion.

5

Zinc levels may be disrupted in the body with the use of angiotensin-II receptor antagonists

1. In 2005, mild to moderate hypertensive patients were studied in an open label trial. The treatment was using losartan (50 mg/day) for four weeks followed by a fixed combination of 50 mg losartan and 12.5 mg hydrochlorothiazide for an additional four weeks. Treatment resulted in a significant increase in urinary zinc excretion in all patients (P <0.001). Serum zinc concentrations gradually decreased (P <0.014 versus baseline) after treatment with losartan and further after losartan/hydrochlorothiazide (P <0.007 versus baseline). Thus treatment with an angiotensin-II receptor antagonist such as losartan can cause an increase in urinary zinc excretion and may induce zinc deficiency in patients with hypertension. Additive effects may occur when losartan is combined with hydrochlorothiazide.

10

Zinc status of Australians

1. Based on data from the National Nutrition Survey of 1995, and compared with the RDI (12mg/day), zinc intake in Australian women is low. Further, while information on zinc bioavailability is not readily available from the National Nutrition Survey, the high contribution of plant foods to the diet of Australians suggests that zinc bioavailability is low to medium. Thus, a considerable proportion of women are likely to be at risk of zinc deficiency.

14

The Australian National Nutrition Survey in 1995 estimated the mean intakes of zinc in male and female individuals to be 14.4 and 9.7 mg/day, respectively. A considerable proportion of men in the age range of 25–64 years were consuming zinc at levels below the RDI (14 mg/day), and men aged >65 years were consuming zinc levels that were consistently below the RDI.

15

Other groups at risk of zinc deficiency include the elderly individuals with hypochlorhydria, the elderly in residential aged care, individuals with diabetes and those with coeliac disease or other malabsorption syndromes.

16

Zinc assessment

1. Measuring zinc status is difficult and currently there is no universally accepted single method for this purpose.

17 Plasma levels of zinc are tightly regulated, although the signals

and processes involved in this regulation are not well understood. Plasma zinc levels are also affected by other factors, such as diurnal rhythm, stress, infection, starvation and plasma protein levels. As a consequence of its regulation and other common factors that can influence its distribution, plasma zinc levels are not considered an accurate reflection of dietary zinc intake or status.

17 Clinical presentation and response to zinc administration

provide one of the more accurate means of assessing zinc status and confirming deficiency.

17,18

As such, the diagnosis of marginal zinc deficiency relies to a considerable degree on the practitioners’ own clinical astuteness in determining the best course of action to be taken based on presentation of symptoms of insufficiency.

21

Physiological role of zinc

1. The Natural Standard Professional Database states that zinc is a trace mineral essential for the functioning of enzymatic and other cellular processes, including the regulation of gene expression, protein folding, and immunity.

1 Zinc is an essential mineral that serves

as the active centre of approximately 300 enzymes. Mild zinc deficiency may be overlooked, since symptoms are not always evident, but it may include, for example, loss of hair, appetite, weight, and the senses of taste and smell.

5

Solubility of zinc gluconate

1. Water-soluble mineral compounds are considered preferable because they are absorbed more efficiently. A number of studies have been conducted to assess the absorption of different forms of supplemental zinc (zinc acetate, aminoate, ascorbate, citrate, gluconate, histidine, methionine, oxide, picolinate and sulfate). Although results have been variable and sometimes conflicting in terms of their relative absorption, research seems to support water-soluble compounds, such as zinc acetate, zinc gluconate, and zinc sulfate, as are being more readily absorbable than compounds with limited solubility at neutral pH.

11

Zinc safety

1. The National Health and Medical Research Council (NHMRC) has set the upper limit of zinc at 40 mg/day for adults 19+ years.

25 The NHMRC upper limit is also in agreement

with the Institute of Medicine Dietary Reference Intakes (DRI) upper level.12

2. Medline Plus states that zinc is likely safe for most adults when taken by mouth in amounts not larger than 40 mg per day. However, routine zinc supplementation is not recommended without advice from a healthcare professional.

13

3. The Natural Medicines Comprehensive Database:

Likely safe: When used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 40 mg/day).

9

Possibly safe: When used orally and appropriately in doses higher than the tolerable upper intake level (UL). There is some concern that doses higher than the UL of 40 mg/day might decrease copper absorption and result in anaemia. However, there is some evidence that doses of elemental zinc as high as 80 mg daily in combination with copper 2 mg can be used safely for approximately six years without significant adverse effects.

9

Possibly unsafe: When used intranasally. Case reports and animal research suggest that intranasal zinc might cause permanent anosmia or loss of sense of smell. Several hundred reports of anosmia have been submitted to the US Food and Drug Administration (FDA) and the manufacturer of some intranasal zinc products. Advise patients not to use intranasal zinc products.

9

Likely unsafe: When taken orally in excessive amounts. Ingestion of 10-30 grams of zinc sulfate can be lethal in adults. Chronic intake of 450-1600 mg daily can cause sideroblastic anaemia, copper deficiency, and myeloneuropathies. This has been reported with use of zinc-containing denture adhesives in amounts exceeding the labelled directions (e.g. several times a day for several years). Advise patients to follow the label directions on denture adhesives.

9

22

Zinc references

1. Golik A, et al. Effects of captopril and enalapril on zinc metabolism in hypertensive patient.J Am Coll Nutr 1998; 17(1): 75-78.

2. Golik A, et al. Zinc metabolism in patients treated with captopril versus enalapril. Metabolism 1990; 39 (7):665-667

3. Abu-Hamdan DK, et al. Taste acuity and zinc metabolism in captopril-treated hypertensive male patients. Am J Hypertens 1988; 1: 303S-308S

4. Trasobares E, et al. Effects of angiotensin-converting enzyme inhibitors (ACEi) on zinc metabolism in patients with heart failure. Journal of Trace Elements in Medicine and Biology 2007; 21(S1):53-55

5. Natural Standard Zinc Monograph. 2011: accessed 30th September 2011

http://naturalstandard.com/databases/herbssupplements/zinc.asp

6. Wester PO. Urinary zinc excretion during treatment with different diuretics. Acta Med Scand. 1980;208(3):209-1220

7. Wester PO. Tissue zinc at autopsy--relation to medication with diuretics. Acta Med Scand. 1980; 208(4):269-71

8. Golik A. Hydrochlorothiazide – amiloride causes excessive urinary zinc excretion. Clin Pharm.Ther 1987;42:42-4

9. Natural Medicines Comprehensive Database. Zinc monograph. http://naturaldatabase.therapeuticresearch.com

10. Koren-Michowitz M et al.The Effect of Losartan and Losartan/Hydrochlorothiazide Fixed-Combination on Magnesium, Zinc, and Nitric Oxide Metabolism in Hypertensive Patients: A Prospective Open-Label Study. Am J Hypertension 2005; 18:358-363

11. Hotz C, Brown KH, et al. International Zinc Nutrition Consultative Group (IZiNCG) Technical Document #1: Assessment of the risk of zinc deficiency in populations and options for its control. Food and Nutrition Bulletin, 2004;25(1 Supp 2): S91-S204

12. NHMRC Nutrient Reference Values for Australia and New Zealand, Executive Summary. Zinc. National Health and Medical Research Council. 2006:19-32

13. Medline Plus access 30.09.11 http://www.nlm.nih.gov/medlineplus/druginfo/natural/982.html

14. Anon. Is zinc an important nutrient for women aged 40 and over? Med J Aust 2000; 173 Suppl 6 November: S98-S99

15. Samman S. Zinc. Nutrition & Dietetics 2007; 64(4): S131–S134

16. Gibson R, Heath AL. Population groups at risk of zinc deficiency in Australia and New Zealand. Nutrition & Dietetics 2011;68:97-108.

17. Wood RJ. Assessment of Marginal Zinc Status in Humans. J. Nutr. 2000;130:1350S—

1354S 18. Hambidge M. Biomarkers of Trace Mineral Intake and Status. J. Nutr. 2003;133: 948S–

955S