DRUG-SUPPLEMENT INTERACTIONS IN LYME DISEASE

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DRUG-SUPPLEMENT INTERACTIONS IN LYME DISEASE

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Leo Galland M.D.

Foundation for Integrated Medicine

133 East 73 Street

New York, N.Y. 10021

 

 

Interactions between prescription or over the counter drugs and

nutritional supplements are common and often not well known. In creating the

Drug-Nutrient Workshop (_www.NutritionWorkshop.com_

(http://www.NutritionWorkshop.com) ), a professional database of interactions

between drugs and dietary

supplements, nutrients, and food or food components, I found that over 400

drugs commonly used in the U.S. deplete specific nutrients and almost 500

drugs have their efficacy or side effects influenced by various foods. I also

identified about a thousand adverse interactions between drugs and dietary

supplements and several hundred beneficial interactions, in which specific

dietary supplements may enhance the efficacy or decrease the side effects

of specific drugs.

 

 

People with Lyme and related diseases are usually administered prolonged

therapy with antibiotics, often combined with Prilosec or other proton pump

inhibitors (drugs that greatly reduce stomach acid), sometimes in

conjunction with Plaquenyl (an immune modulator) or anti-parasitic drugs for

treatment of babesiosis. Some potential interactions (negative and positive)

between these drugs and dietary supplements are described below. Information on

drug/food interactions is usually available from the pharmacist and

included in the patient-package insert. This should be checked for each

individual

drug being taken, because the dosage form (sustained-release vs. regular,

for example) may influence the effect of food on drug absorption. Patients

with chronic tick-borne infections may also be taking antidepressants and

pain relievers, each of which may have its own interactions with

nutritional supplements and nutritional status.

 

 

Drugs may interact with food or supplements through the following

mechanisms:

 

 

(1) The food or supplements may interfere with drug absorption. This is

especially important for tetracycline or quinolone antibiotics. {Although

quinolones like Levaquin are not used for Lyme disease, they are the primary

drugs for treatment of bartonellosis, a common co-infection). Both groups

of antibiotics form insoluble complexes with minerals, especially calcium,

magnesium or iron. This process, called chelation, inhibits absorption of

both the antibiotic and the mineral. Not only are most tetracyclines (with

the sole exception of doxycycline) and all quinolones better absorbed away

from food (especially mineral-rich foods like meat and dairy products), they

must be taken several hours apart from any nutritional supplements

containing minerals. Two hours of separation may not be enough. Several herbs,

including fennel, dandelion, and Sanguisorba, have a high enough mineral

content that their consumption has been shown to interfere with quinolone

absorption.

 

 

Penicillins may have their oral absorption impaired by fiber or by food,

although this is more likely for penicillin V and ampicillin that for

amoxacillin. Food causes the drug to be retained in the stomach, where the

presence of acid causes the drug to decompose. Psyllium has been shown to bind

oral penicillin, decreasing its absorption.

 

 

(2) The drug may increase the requirement for certain nutrients, because

it causes depletion of the nutrient from the body. The normal

gastrointestinal bacterial flora synthesize B vitamins, biotin and vitamin K,

which are

absorbed and utilized by humans. Depletion of these bacteria by prolonged

antibiotic therapy may produce vitamin deficits. Bleeding caused by vitamin K

deficiency has occurred as a result of intravenous therapy with

cephalosporin antibiotics[1], a group that includes Rocephin and Claforan. High

dose

penicillin therapy causes increased excretion of potassium by the

kidneys[2]. When combined with antibiotic-induced diarrhea or poor appetite,

this

effect may cause potassium deficiency, with fatigue and muscle weakness as

primary symptoms. Proton pump inhibitors like Prilosec, used to enhance

antibiotic absorption and cellular penetration, decrease formation of stomach

acid, permitting overgrowth of bacteria and/or yeast in the stomach and upper

gastrointestinal tract. Microbial overgrowth may be associated with

gastrointestinal symptoms like diarrhea and bloating[3] and may cause

malabsorption of nutrients. Prolonged use of PPIs has been associated with

decreased

absorption of vitamin B12, zinc, and carotene and may create a need for

supplementation[4].

 

 

(3) Drugs, supplements and food may interact by inhibition or stimulation

of enzymes involved in drug transport or metabolism.

 

 

The cytochrome P450 (CYP) system is extensively involved in drug

metabolism and may be strongly inhibited or stimulated by drugs, foods or

dietary

supplements. CYP enzymes are most active in the liver, intestines, lungs and

kidneys. Humans have over 20 different CYP enzymes, all of which contain

iron and which all use oxygen to change the structure and function of the

drugs they metabolize. The most important CYP's for drug metabolism are

designated CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. This

classification system is not based upon biological function but upon similarity

of amino

acid sequences in the structure of the enzyme. CYP oxidation of drugs may

produce metabolites that are less active or more active than the parent

compound. The exact effect of inhibiting or stimulating any CYP enzyme will

therefore depend upon the specific clinical circumstances and cannot

necessarily be predicted from experiments done in a test tube.

 

 

Another important aspect of drug metabolism is transport into and out of

cells. Some drugs are ejected from cells by a transport system referred to

as P-glycoprotein (P-gp). In the intestine, P-gp limits the absorption of a

variety of unrelated drugs, many of which are also metabolized by the

intestinal form of CYP3A4. Inhibition of P-gp and/or CYP3A4 by grapefruit juice

or other natural substances can increase absorption of drugs that are P-gp

or CYP3A4 substrates, raising their concentration in blood. This effect is

only important for drugs that are slowly absorbed in the intestine to begin

with. Drugs that pass through the intestinal lining rapidly are absorbed

too quickly for inhibition of CYP or P-gp enzymes in the intestine to affect

drugs levels. St. John's wort is one of the few products that stimulate

intestinal P-gp and CYP3A4. Taking St. John’s wort can decrease the plasma

concentration of those same drugs and underlies many of the adverse drug

interactions reported for this herb.

 

 

Some important interaction of drugs used in treating tick-borne diseases

and the CYP system are listed below:

 

 

CYP2C9 is increased by rifampin (an antibiotic sometimes used to treat

Bartonella) and inhibited by fluconazole (Diflucan, an anti-fungal).

 

 

CYP2C19 is increased by rifampin and artemisin (a derivative of the herb

Artemisia annua, a natural anti-malarial herb that may be used in the

treatment of Babesiosis). CYP2C19 is decreased by Prilosec and ketoconazole

(Nizoral, an anti-fungal).

 

 

CYP3A4 is increased by St. John's wort and rifampin and inhibited by

grapefruit juice, Seville orange juice, the anti-fungal drugs ketoconazole

(Nizoral) and itraconazole (Sporanox), and the macrolide antibiotics

azithromycin (Zithromax), clarithromycin (Biaxin) and telithromycin (Ketek).

The

effect of grapefruit juice occurs only in the intestines, not in the liver, so

it can--at high levels of consumption--increase absorption of some drugs

without affecting their internal metabolism. Artemisinin is metabolized by

intestinal CYP3A4, and its absorption appears to be enhanced by grapefruit

juice[5]. The herb Echinacea, used for immune stimulation, inhibits

intestinal CYP3A4 but stimulates the liver's CYP3A4, so it may increase or

decrease

the levels of a co-administered drug, depending upon the drug's rate of

absorption and the extent to which it is metabolized by CYP3A4.

 

 

Milk thistle, an herb used to support liver function, contains a group of

bioflavonoids called silymarin. Silymarin may inhibit intestinal P-gp and

liver CYP3A4. Surprisingly, concomitant administration of milk thistle

significantly decreased the absorption of metronidazole (a drug used to treat

the spore form of Borrelia).[6] This interaction could not have been

predicted from knowledge of the herb's effects on drug metabolizing enzymes.

Moreover, vitamin C (500 mg/day) and vitamin E (400 units/day) decreased the

effectiveness of metronidazole in treating H. pylori infection of the

stomach.[7] The mechanism of this interaction is unknown but suggests that

anti-oxidants should not be used with metronidazole therapy.

 

 

Quercetin, a bioflavonoid used as an anti-oxidant and for relief of

allergic symptoms, competes with quinolone antibiotics for binding sites on

bacteria. No interaction between quercetin and antibiotics has yet been

demonstrated outside a test tube, but it would be prudent for people taking

quinolone antibiotics to refrain from the use of quercetin and perhaps other

bioflavonoids.

 

 

Beneficial effects of dietary supplements for people taking antibiotics

have been described. The most consistent benefits have been demonstrated for

probiotics (living organisms) that can counter the gastrointestinal side

effects of antibiotics. The best studied are Saccharomyces boulardii (a

yeast, dubbed " yeast against yeast " in France)[8], Lactobacillus rhamnosis

GG[9], Lactobacillus plantarum and Lactobacillus sporogenes[10].

 

 

Proteases are enzymes that digest protein. When taken by mouth on an empty

stomach some of the preparation is absorbed intact and may be active in

the body. Oral proteases have been shown to relieve pain and inflammation in

patients with arthritis[11], may break down circulating complexes of

antigen and antibody (these have been described in so-called " post-Lyme

syndrome " ) and may breakdown blood clots that form as a result of

inflammation.

Although research on proteases as adjuncts to antibiotic therapy is minimal, a

study done in animals found that bromelain (a protease-containing extract

of pineapple stem), increased penetration of tetracyclines into the

tissues[12].

 

 

 

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[1] Alitalo et al. Hypoprothrombinaemia and bleeding during administration

of cefamandole and cefoperazone. Ann Clin res 1985; 17: 116-9. Shimada et

al. Bleeding secondary to vitamin K deficiency in patients receiving

parenteral cephem antibiotics. J Antimicob Chemother 1984; 14 (Suppl B):

325-330

 

 

[2] Gill et al, Hypokalemic metabolic alkalosis induced by high-dose

ampicillin sodium. Am J Hosp Pharm 1977; 34: 528-31

 

 

[3] Lewis et al, Altered bowel function and duodenal bacterial overgrowth

in patients treated with omeprazole. Alimentary Pharmacol Ther 1996; 10:

557-61.

 

 

[4] Bradford & Taylor, Omeprazole and vitamin B12 deficiency. Ann

Pharmacother 1999; 33: 641-43. Bellou et al, Cobalamin deficiency with

megaloblastic anemia in one patient under long-term omeprazole therapy. J

Intern Med

1996; 240: 161-4. Marcuard et al, Omeprazole therapy causes malabsorption of

cyanocobalamin. Ann Int med 1994; 120: 211-15. Tang et al, Gastric acidity

influences the blood response to a beta-carotene dose in humans. Am J Clin

Nutr 1996; 64: 622-26.

 

 

[5] van Agtmael et al, Grapefruit juice increases bioavailability the

bioavailability of artemether. Eur J Clin Pharmacol 1999; 55: 405-410.

 

 

[6] Rajnarayana et al, Study on the influence of silymarin pretreatment on

metabolism and disposition of metronidazole. Arzneimittelforschung 2004;

54: 109-13.

 

 

[7] Chuang et al, Vitamin C and E supplements to

lansoprazole-amoxacillin-metronidazole triple therapy may reduce the eradication

rate of

metronidazole-sensitive Helicobacter pylori infection. Helicobacter 2002; 7:

310-16.

 

 

[8] Surawicz et al, Prevention of antibiotic-associated diarrhea by

Saccharomyces boulardii: A prospective study. Gastroenterol 1989; 96: 981-88

 

 

[9] Vanderhoof et al, Lactobacillus GG in the prevention of

antibiotic-associated diarrhea in children. J Pediatr 1999; 135: 564-48. Armuzzi

et al,

The effect of oral administration of Lactobacillus GG on

antibiotic-associated gastrointestinal side effects during helicobacter pylori

eradication

therapy. Aliment Pharmacol Ther 2001; 15: 163-69.

 

 

[10] LaRosa et al, Prevention of antibiotic-associated diarrhea with

Lactobacillus sporogens and fructo-oligosaccharides in children. A multicentre

double-blind vs placebo study. Minerva Pediatr 2003; 55: 447-52.

 

 

[11] Leipner et al, Therapy with proteolytic enzymes in rheumatic

disorders. BioDrugs. 2001;15(12):779-89.

 

 

[12] Luerti & Vignali, Influence of bromelain on penetration of

antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978, 4: 45-48.

 

 

 

This article is provided for general educational purposes only and is not

intended to constitute (i) medical advice or counseling, (ii) the practice

of medicine or the provision of health care diagnosis or treatment, (iii)

the creation of a physician--patient relationship, or (iv) an endorsement,

recommendation or sponsorship of any third party product or service by the

sender or the sender's affiliates, agents, employees, or service providers.

If you have or suspect that you have a medical problem, contact your doctor

promptly.

 

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