Tetracyclines

Summary

drug class: Tetracyclines

trade names: Achromycin®, Sumycin®, Tetra-C®, Tetracyn®, Tetralyn®, Tetram®, Tropicycline®.

type of drug: Broad spectrum antibiotics.

used to treat: Bacterial and protozoal infections; acne.

overview of interactions:
• adverse drug effects: Probiotic Intestinal Flora

• nutrient affected by drug: Folate (Folic Acid) (Folic Acid) (Folic Acid)

• nutrient affected by drug: Vitamin A

• nutrient affected by drug: Vitamin B2 (Riboflavin) (Riboflavin) (Riboflavin)

• nutrient affected by drug: Vitamin B6 (Pyridoxine) (Pyridoxine) (Pyridoxine)

• nutrient affected by drug: Vitamin B12

• nutrient affected by drug: Vitamin C (Ascorbic Acid) (Ascorbic Acid) (Ascorbic Acid)

• nutrient affected by drug: Vitamin K

• nutrient affected by drug: Multivitamin formula

• nutrient affecting drug performance: Aluminum

• nutrient/diet affecting drug performance: Calcium and Milk-containing Foods and Milk-containing Foods and Milk-containing Foods

• nutrient affecting drug performance: Iron

• nutrient affecting drug performance: Magnesium

• nutrient affecting drug performance: Potassium

• nutrient affecting drug performance: Zinc

• herbal constituent affecting drug performance: Berberine, as in Berberis aquifolium (Oregon Grape), Berberis vulgaris (Barberry), and Hydrastis canadensis (Goldenseal)

Interactions

adverse drug effects: Probiotic Intestinal Flora

• adverse drug effects: During the course of eliminating disease-causing bacteria, antibiotics such as tetracycline usually also destroy normally-occurring beneficial bacterial flora that form an integral part of the healthy intestinal ecology and assist digestive and immune functions. Diarrhea and yeast infections, including vaginal yeast, are common side-effects of the disruption of intestinal ecology and the creation of an environment more susceptible to proliferation of pathogenic levels of opportunistic yeast. In more serious cases, this diminished state of intestinal health can permit overgrowth of C. difficile, a bacteria responsible for pseudomembranous colitis. Patients who develop pseudomembranous colitis as a result of antibiotic treatment can experience diarrhea, abdominal pain, fever, and sometimes even shock.

• nutritional support: Supplementation of beneficial probiotic bacterial flora, such as Lactobacillus acidophilus, Bifidobacterium bifidus and Lactobacillus cassei, preferably in the form of a varied, vigorous and abundant culture, will restore the healthy intestinal ecology and stabilize the mucosal lining of the gut. A supplemental dosage of at least one billion organisms per day is necessary to achieve the critical mass of bacterial restoration and successfully reinvigorate healthy intestinal ecology.

• nutritional concern: If an individual desires to initiate rebuilding probiotic cultures while still taking tetracycline a solution of the culture is preferable to yogurt. As discussed below, milk products, including yogurt, interfere with drug absorption.

nutrient affected by drug: Folate (Folic Acid)

• mechanism: Intestinal bacteria are a major source of folate in the body. The use of tetracycline can eliminate these probiotic bacteria and hence contribute to a depletion of folate. This drug-induced folic acid deficiency can, in turn, induce a deficiency of vitamin B12.
(Klipstein FA, Samloff IM. Am J Clin Nutr 1966 Oct;19(4):237-246; Klipstein FA, et al. Gastroenterology 1966 Sep;51(3):317-332; Holt GA. 1998, 256.)

• nutritional support: Most individuals who use tetracycline will suffer from loss of probiotic flora and disruption of the healthy intestinal ecology. This concern can be addressed by supplementing with vigorous cultures of Lactobacillus acidophilus, Bifidobacterium bifidus and other probiotic bacteria. Such support of friendly flora will reverse the cause of antibiotic-induced folate depletion. Individuals using tetracycline on a longer term basis, i.e., more than two weeks, may need to additionally supplement with folic acid. Although folic acid is essentially non-toxic, anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting folic acid supplementation. A moderate supplemental dose of folic acid is usually in the area of 400 mcg per day. These levels can also be obtained through a diet rich in beets, leafy green vegetables, beans, citrus, meat, and wheat germ.

nutrient affected by drug: Vitamin A

• interaction: The concurrent use of tetracycline and high doses of vitamin A has been associated with severe headaches. Such adverse interactions may be attributable to increased blood pressure in the brain (benign intracranial hypertension); this condition and pseudotumor cerebri have been associated with both hypervitaminosis A and tetracycline use independently. Vitamin A and tetracycline are both used in the treatment of acne vulgaris so their simultaneous use is not uncommon.
(Walters BN, Gubbay SS. Br Med J (Clin Res Ed) 1981 Jan 3;282(6257):19-20; Holt GA. 1998, 258; Lee AG. Cutis 1995 Mar;55(3):165-168.)

• nutritional concerns: Individuals using tetracycline and high doses of vitamin A at the same time should be aware of such possible side effects. Likewise, individuals taking tetracycline should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting to supplement vitamin A.

nutrient affected by drug: Vitamin B2 (Riboflavin)

• mechanism: Research indicates that tetracycline can interfere with the activity of vitamin B2.
(Holt GA. 1998, 258.)

• nutritional support: While depletion of riboflavin may not have clinical significance with short-term use of tetracycline, individuals using the drug for periods longer than two weeks may benefit from supplementation with riboflavin. Although vitamin B2 is essentially non-toxic, anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting riboflavin supplementation. A moderate supplemental dose of riboflavin is usually in the range of 20-25 mg per day, easily obtained through most multivitamin formulas. These levels can also be obtained through a diet rich in leafy green vegetables and whole grains.

nutrient affected by drug: Vitamin B6 (Pyridoxine)

• mechanism: Research indicates that tetracycline impairs vitamin B6 absorption.
(Holt GA. 1998, 258; Robinson C, Weigly E. 1984:46-54.)

• nutritional support: While depletion of vitamin B6 may not have clinical significance with short-term use of tetracycline, individuals using the drug for periods longer than two weeks may benefit from supplementation with pyridoxine. Anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting vitamin B6 supplementation. A moderate supplemental dose of pyridoxine is usually in the range of 20-25 mg per day, easily obtained through most multivitamin formulas. Sustained use of higher doses of B6 can result in side effects. Significant dietary sources of vitamin B6 include bananas, lentils, potatoes, raisin bran, turkey, and tuna.

nutrient affected by drug: Vitamin B12

• mechanism: Tetracycline impairs vitamin B12 absorption. B12 status is further compromised by drug-induced folic acid deficiency, which in turn induces a deficiency of vitamin B12.
(Robinson C, Weigly E. 1984:46-54; Holt GA. 1998, 258.)

• research: One study involving rats found that intramuscular injections of vitamin B12 exerted a protective effect against fatty liver and elevated triglycerides due to tetracycline.
(Mikhail TH, et al. Z Ernahrungswiss 1980 Sep;19(3):173-178.)

• nutritional support: While depletion of vitamin B12 may not have clinical significance with short-term use of tetracycline, individuals using the drug for periods longer than two weeks may benefit from supplementation. Compensatory levels of B12 can be easily obtained by eating foods of animal origin, including dairy, eggs, fish, meat, and poultry. However, vegans using tetracycline for extended periods of time would likely benefit from supplementation in the range of 2-3 mcg per day. Although vitamin B12 is essentially non-toxic, anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting supplementation with vitamin B12.

nutrient affected by drug: Vitamin C (Ascorbic Acid)

• mechanism: Research indicates that tetracycline can interfere with the activity of vitamin C.
(Montenero AS. Acta Vitaminol Enzymol 1980;2(1-2):27-45; Holt GA. 1998, 258.)

• research: Several studies have suggested that vitamin C can play a valuable role through its protective effect against tetracycline-induced kidney and liver damage.
(Naseer F, Alam M. JPMA J Pak Med Assoc 1987 Mar;37(3):73-75; Omray A, Varma KC. Hindustan Antibiot Bull 1981;23:33-37; Polec RB, et al. J Pharmacol Exp Ther 1971 Jul;178(1):152-158.)

• nutritional support: While depletion of vitamin C may not have clinical significance with short-term use of tetracycline, individuals using the drug for periods longer than two weeks may benefit from supplementation with vitamin C. Although vitamin C is essentially non-toxic, anyone using tetracycline for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting megadose vitamin C supplementation. A supplemental (or moderate therapeutic) dose of vitamin C is usually in the range of 2000-4000 mg per day.

nutrient affected by drug: Vitamin K

• mechanism: When antibiotics destroy all or most of the beneficial bacterial flora in the gut they eliminate the organisms that synthesize a high proportion of the body's vitamin K. Therefore, many antibiotics can indirectly cause a depletion of vitamin K.

• nutritional support: Anyone taking antibiotics for more than a few weeks would most likely benefit from supplemental vitamin K, even though it is rare that such a depletion of vitamin K would produce noticeable symptoms. Restoration of the healthy bacterial flora that normally produce the Vitamin K is generally advisable after the use of any antibiotics. Vitamin K1 supplementation, in the range of 65-80 mg per day, may be necessary and is available in some multivitamin formulas. Leafy green vegetables are the best dietary sources of vitamin K.

nutrient affected by drug: Multivitamin formula

• nutritional concerns: Many researchers have concluded that most individuals would do best to avoid taking multivitamin combinations while using tetracycline. There is no singular reason for avoiding such a supplement formula. However, while some vitamin constituents of a multivitamin formula might be depleted by tetracycline, the minerals often included in such formulations could have adverse interactions as discussed below.

nutrient affecting drug performance: Aluminum

• nutritional concerns: Aluminum is not usually consumed as a nutritional supplement. However, the aluminum, in the form of aluminum magnesium hydroxide, contained in many antacids, such as Pepto-Bismol, can decrease the absorption of tetracycline and reduce its effectiveness. Tetracycline is best taken on an empty stomach, with a full glass of water, one hour before or two hours after ingestion of any supplements, food, or other drugs. Nevertheless, tetracycline and antacids are often used together in combination therapies for Helicobacter pylori.

nutrient/diet affecting drug performance: Calcium and Milk-containing Foods and Milk-containing Foods and Milk-containing Foods

• mechanism: Absorption of tetracycline class drugs takes place mainly in the stomach and upper small intestine. Calcium, as well as food and dairy products containing high concentrations of calcium, may decrease the absorption of tetracyclines due to chelate formation in the gut. This binding of the drug to the mineral may also lead to growth retardation and pigmented teeth. Furthermore, tetracycline increases urinary calcium excretion. Thus, with prolonged use, tetracycline can adversely effect bone formation and contribute to calcium depletion.

The interaction between tetracycline and calcium-rich foods such as milk products exerts adverse effects on both and teeth that are well documented and widely recognized. Tetracyclines form a stable calcium complex in any bone-forming tissue. Unwanted pigmentation and other problems with tooth development due to tetracycline are well known to dentists and the general public. The tetracyclines also tend to localize in tumors, necrotic or ischemic tissue, liver and spleen and form tetracycline-calcium orthophosphate complexes at sites of new bone formation.

Tetracyclines are potent inhibitors of osteoclast function (i.e., anti-resorptive). Vernillo and Rifkin described the processes by which tetracyclines can affect several parameters of osteoclast function and consequently inhibit bone resorption: (1) altering intracellular calcium concentration and interacting with the putative calcium receptor; (2) decreasing ruffled border area; (3) diminishing acid production; (4) diminishing the secretion of lysosomal cysteine proteinases (cathepsins); (5) inducing cell retraction by affecting podosomes; (6) inhibiting osteoclast gelatinase activity; (7) selectively inhibiting osteoclast ontogeny or development; and (8) inducing apoptosis or programmed cell death of osteoclasts.
(Vernillo AT, Rifkin BR. Adv Dent Res 1998 Nov;12(2):56-62; Roe DA. 1989:87.)

• research: This effect on bone formation carries a significantly greater risk when growth and bone formation is most active, such as with infants and children. A decrease in the fibula growth rate has been observed in premature infants receiving oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.
(Jung H, et al. Biopharm Drug Dispos 1997 Jul;18(5):459-463; Roe DA. 1989:87; Drug Evaluation Subscription. Winter 1993; Hammarstrom L. Lakartidningen 1968 Jun 4;65:Suppl 2:89-96.)

• nutritional concerns: Calcium in the form of antacids, milk products, and supplements should be avoided while using tetracycline. If, after consultation with the prescribing physician, continued use of calcium supplements is deemed necessary, the calcium supplement should be taken several hours apart from ingestion of the drug.

nutrient affecting drug performance: Iron

• mechanism: Concurrent ingestion of iron significantly impairs gastrointestinal absorption and bioavailability of tetracycline and tetracycline derivatives (doxycycline, methacycline and oxytetracycline).
(Campbell NR, Hasinoff BB. Br J Clin Pharmacol 1991 Mar;31(3):251-255.)

• nutritional concerns: Iron in the form of supplements and iron-rich foods should be avoided while using tetracycline. If concurrent use cannot be avoided, iron should be taken at least three hours before or two hours after the tetracycline. The simultaneous use of tetracycline and iron should only be undertaken after consultation with the prescribing physician.

nutrient affecting drug performance: Magnesium

• mechanism: Magnesium interferes with tetracycline absorption and reduces its effectiveness by chelating the drug. This interaction occurs not only with supplemental magnesium but also with many antacids, such as Pepto-Bismol, which contain aluminum magnesium hydroxide. Furthermore, in vitro studies indicate that chelates of magnesium and tetracycline may play a role in the toxicity of tetracycline.
(Machado FC, et al. J Inorg Biochem 1995 Nov 15;60(3):163-173; Drug Evaluation Subscription. Winter 1993.)

• nutritional concerns: Magnesium in the form of supplements should be avoided while using tetracycline. Tetracycline is best taken on an empty stomach, with a full glass of water, one hour before or two hours after ingestion of any supplements, food, or other drugs. Nevertheless, tetracycline and antacids are often used together in combination therapies for Helicobacter pylori. Individuals taking tetracyline should only use magnesium supplements after consultation with the prescribing physician.

nutrient affecting drug performance: Potassium

• research: Tetracycline may interfere with the activity of potassium.
(Holt GA. 1998, 256-258.)

There have been case reports of self-limiting esophagitis associated with tetracycline, particularly in combination with potassium.
(Teplick JG, et al. Radiology 1980 Jan;134(1):23-25; Kobler E, et al. Schweiz Med Wochenschr 1979 Aug 25;109(32):1180-1182; Eng J, Sabanathan S. Am J Gastroenterol 1991 Sep;86(9):1127-1133.)

Other researchers have also expressed concern that tetracycline may cause hypokalemia due to its nephrotoxic side effects
(Mavromatis F. JAMA 1965 193:191.)

• nutritional support: Depletion of potassium may not have clinical significance with short-term use of tetracycline. Individuals using the drug for periods longer than two weeks may want to ask their prescribing physician and/or a nutritionally trained healthcare professional about possible benefits from increasing potassium intake. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Tetracycline is best taken on an empty stomach, with a full glass of water, one hour before or two hours after ingestion of any supplements, food, or other drugs.

nutrient affecting drug performance: Zinc

• mechanism: Zinc in food and supplements can interfere with tetracycline absorption and reduce its effectiveness by chelating the drug.
(Weismann K. Dan Med Bull 1986 Aug;33(4):208-211; Drug Evaluation Subscription. Winter 1993.)

herbal constituent possibly affecting drug performance: Berberine, as in Berberis aquifolium (Oregon Grape), Berberis vulgaris (Barberry), and Hydrastis canadensis (Goldenseal) (Oregon Grape), Berberis vulgaris (Barberry), and Hydrastis canadensis (Goldenseal) (Oregon Grape), Berberis vulgaris (Barberry), and Hydrastis canadensis (Goldenseal)

• research: Several herbs commonly used for their anti-bacterial activity contain the alkaloid berberine. Berberis aquifolium (Oregon Grape), Berberis vulgaris (Barberry) and Hydrastis canadensis (Goldenseal) are the most well known of these plants.

• research: In their study involving individuals with cholera Khin-Maung-U et al found a reduction in the efficacy of tetracycline when 100 mg of berberine and 500 mg of tetracycline were administered simultaneously four times daily. This data has been interpreted to indicate that berberine may cause decreased absorption of tetracycline. However, after a double-blind trial, Rabbani et al concluded that berberine did not interfere with tetracycline in cholera patients.
(Khin-Maung-U, et al. Br Med J (Clin Res Ed) 1985 Dec 7;291(6509):1601-1605; Khin-Maung-U, et al. J Diarrhoeal Dis Res 1987 Sep;5(3):184-187; Rabbani GH, et al. J Infect Dis 1987 May;155(5):979-984.)

• herbal concerns: Many medical herbalists would question the extrapolation of data derived from high dose administration of isolated berberine to the use of berberine-containing medicinal herbs. Reviewing the studies on concurrent administration of berberine and tetracycline, Snow concludes that the studies demonstrate that berberine is an effective anti-secretory and anti-diarrheal agent in conjunction with tetracycline in enterotoxigenic diarrhea.
(Snow J. Protocol J Bot Med 1997.2,(2) 25-28.)

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Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.


References

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Abstract: Four hundred adults presenting with acute watery diarrhoea were entered into a randomised, placebo controlled, double blind clinical trial of berberine, tetracycline, and tetracycline and berberine to study the antisecretory and vibriostatic effects of berberine. Of 185 patients with cholera, those given tetracycline or tetracycline and berberine had considerably reduced volume and frequency of diarrhoeal stools, duration of diarrhoea, and volumes of required intravenous and oral rehydration fluid. Berberine did not produce an antisecretory effect. Analysis by factorial design equations, however, showed a reduction in diarrhoeal stools by one litre and a reduction in cyclic adenosine monophosphate concentrations in stools by 77% in the groups given berberine. Considerably fewer patients given tetracycline or tetracycline and berberine excreted vibrios in stools after 24 hours than those given berberine alone. Neither tetracycline nor berberine had any benefit over placebo in 215 patients with non-cholera diarrhoea.

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Abstract: Hypervitaminosis A may be associated with benign intracranial hypertension. So far, the explanation for this phenomenon has remained obscure. A 17-year-old patient with benign intracranial hypertension, following chronic vitamin A intake of 150,000 units daily for acne vulgaris, is presented. Bilateral papilledema was present and bilateral obstruction of the transverse sinuses was demonstrated in the late venous phase of cerebral angiography. Discontinuation of vitamin A and acetazolamide treatment was followed by complete regression of the signs and symptoms of intracranial hypertension. Bilateral sinus obstruction with interference of cerebral sinus outflow is suggested as a critical factor in the pathogenesis of benign intracranial hypertension in vitamin A intoxication. Menstrual dysfunction and tetracycline therapy cannot be completely excluded as possible causative factors.

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Larvol, L, Monier, A, Besnier, P, Levecq, H. Liver abscess caused by Lactobacillus acidophilus. Gastroenterol Clin Biol 1996;20:193-195. [Article in French]

Lee AG. Pseudotumor cerebri after treatment with tetracycline and isotretinoin for acne. Cutis 1995 Mar;55(3):165-168. (Review)
Abstract: Tetracyclines and isotretinoin are widely used treatments for patients with acne. Although generally safe, the use of these agents has been associated with pseudotumor cerebri and combination therapy with these agents may increase the risk for pseudotumor cerebri. A 14-year-old boy presented with headaches and bilateral visual loss secondary to papilledema. He had been treated with tetracycline and isotretinoin for acne for three weeks prior to presentation and was subsequently diagnosed as having pseudotumor cerebri. He required long-term medical therapy and eventually underwent bilateral optic nerve sheath decompression. The literature regarding pseudotumor cerebri in association with tetracyclines and isotretinoin treatment for acne is reviewed. Dermatologists should be aware of the risk of pseudotumor cerebri in patients receiving tetracycline or isotretinoin treatment for acne and should be particularly cautious about using both agents simultaneously. ?

Levy J. Immunonutrition: the pediatric experience. Nutrition 1998 Jul;14(7-8):641-647.
Abstract: The health benefits of specific nutrients in the diet are reviewed as they pertain to the pediatric population and its unique needs. Secretory immunoglobulins, lysozyme, interferon, and growth factors, among others, are known to confer immunological advantages to breast milk. Inhibition of bacterial pathogens, as well as permissive growth of a protective colonic ecoflora occur as a result of various cellular and biochemical mechanisms at play. The immunomodulatory properties of minerals such as iron, zinc, and selenium, are presented and the newly recognized protective role of vitamin A and its importance in developing countries and in conditions of compromised nutrition are discussed. The review also covers the role of arginine, glutamine, and nucleotides in adaptive responses of the developing gut and in pathologic states such as necrotizing enterocolitis, short bowel syndrome, and inflammatory bowel disease. Probiotics (specific microbial feeds with potential benefits to the host), and prebiotics (dietary components such as complex carbohydrates able to change the colonic microenvironment fostering colonization with non-enteropathogens) are areas of current interest because they offer alternatives for the management of the growing problem of multiple antibiotic resistance and overwhelming infections in the hospitalized patient.

Leyden JJ. Absorption of minocycline hydrochloride and tetracycline hydrochloride. Effect of food, milk, and iron. J Am Acad Dermatol 1985 Feb;12(2 Pt 1):308-312.
Abstract: Serum concentrations of tetracycline hydrochloride and minocycline hydrochloride were compared when administered with water, milk, a meal, and 300 mg ferrous sulfate in two groups of eight volunteers. Absorption of both antibiotics was significantly decreased by administration with iron (77% inhibition with minocycline and 81% with tetracycline), milk (27% inhibition with minocycline, 65% with tetracycline), and food (13% inhibition with minocycline and 46% with tetracycline). The inhibitory effect on absorption with food and milk was significantly greater for tetracycline than for minocycline.

Loizeau E. [Can antibiotic-associated diarrhea be prevented]? Ann Gastroenterol Hepatol (Paris). 1993 Jan; 29(1): 15-18. [Article in French] (Review)

Machado FC, Demicheli C, Garnier-Suillerot A, Beraldo H. Metal complexes of anhydrotetracycline. 2. Absorption and circular dichroism study of Mg(II), Al(III), and Fe(III) complexes. Possible influence of the Mg(II) complex on the toxic side effects of tetracycline. J Inorg Biochem 1995 Nov 15;60(3):163-173.

Majamaa H, et al. Probiotics: a novel approach in the management of food allergy. J Allergy Clin Immunol. 1997 Feb; 99(2): 179-185.

Malin, M, Suomalainen, H, Saxelin, M, Isolauri, E. Promotion of IgA immune response in patients with Crohn's disease by oral bacteriotherapy with Lactobacillus GG. Ann Nutr Metab 1996;40:137-145.

Mavromatis F. Tetracycline nephropathy. Case reports with renal biopsy. JAMA 1965 193:191.

Mikhail TH, Ibrahim KM, Awadallah R, Mona E,. The effect of vitamin B12 on tetracycline-induced fatty liver. Z Ernahrungswiss 1980 Sep;19(3):173-178.
Abstract: The effect of vitamin B12 on the metabolic alterations due to tetracycline toxicity was studied experimentally on laboratory animals. Treatment of Sprague-Dawley rats with 120 or 250 mg tetracycline (i.p.) per kg per day for two or three days caused an accumulation of lipids, mainly triglycerides in the liver of 75% of animals studied, while phospholipid level tend to decrease. These doses are approximately twice and four times the recommended maximum dose for man. In the present work no direct relationship was observed between dose of tetracycline and hepatic accumulation of triglyceride, although livers of rats treated with 250 mg tetracycline/kg appeared uniformly pale yellow. Elevated serum triglyceride was found predominantly in rats treated with 120 mg/kg, while there was no obvious difference between serum triglyceride of rats treated with 250 mg tetracycline and control rats, indicating a block in the release of hepatic triglycerides. Where protection by vitamin B12 was studied, the vitamin was given i.m. (50 microgram/animal) 3 hours before the injection of 120 mg tetracycline per kg. There was a good evidence that lipid abnormalities caused by tetracycline improved by vitamin B12. Thus both hepatic and serum total lipid and triglycerides were significantly lower than those of rats treated with tetracycline, although hepatic total cholesterol was significantly increased as in case of tetracycline only.

Montenero AS. Drugs producing vitamin deficiencies. Acta Vitaminol Enzymol 1980;2(1-2):27-45.

Naseer F, Alam M. The protective effect of ascorbic acid on oxytetracycline induced nephrotoxicity and hepatotoxicity. JPMA J Pak Med Assoc 1987 Mar;37(3):73-75.

Omray A, Varma KC. Evaluation of pharmacokinetic parameters of tetracycline hydrochloride upon oral administration with vitamin C and vitamin B complex. Hindustan Antibiot Bull 1981;23:33-37.

Pecorella, G, Vasquez, E, Gismondo, MR, et al. The effect of Lactobacillus acidophilus and Bifidobacterium bifidum on the intestinal ecosystem of the elderly patient. Clin Ter 1992;140:3-10. [Article in Italian]

Perdigon, G, de Macias, ME, Alvarez, S, et al. Systemic augmentation of the immune response in mice by feeding fermented milks with Lactobacillus casei and Lactobacillus acidophilus. Immunology 1988;63:17-23.

Polec RB, Yeh SD, Shils ME. Protective effect of ascorbic acid, isoascorbic acid and mannitol against tetracycline-induced nephrotoxicity. J Pharmacol Exp Ther 1971 Jul;178(1):152-158.

Rabbani GH, Butler T, Knight J, Sanyal SC, Alam K. Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae. J Infect Dis 1987 May;155(5):979-984.
Abstract: To evaluate the antisecretory activity of berberine sulfate (BS), we studied 165 adult patients with acute diarrhea due to enterotoxigenic Escherichia coli (ETEC) and Vibrio cholerae in randomized controlled trials. In patients with ETEC diarrhea who received 400 mg of BS in a single oral dose, the mean stool volumes were significantly less than those of the controls during three consecutive 8-hr periods after treatment (P less than .05). At 24 hr after treatment, significantly more patients who were treated with BS and had ETEC diarrhea stopped having diarrhea as compared with the controls (42% vs 20%, P less than .05). In patients with cholera who received 400 mg of BS, the mean 8-hr stool volume during the second 8-hr period after treatment declined to 2.22 liters, which was significantly less than the 2.79 liters found in the controls (P less than .05). However, patients with cholera who received 1200 mg of BS plus tetracycline did not have significant reduction in stool output compared with patients who received tetracycline alone. No side effects of BS were noted. These results indicated that BS is an effective and safe antisecretory drug for ETEC diarrhea, whereas the activity against cholera is slight and not additive with tetracycline.

Reid, G, Bruce, AW, McGroarty, JA, et al. Is there a role for Lactobacilli in prevention of urogenital and intestinal infections? Clin Microbiol Rev 1990;3:335-344.

Ribush N, Morgan T. Tetracyclines and renal failure. Med J Aust 1972 Jan 8;1(2):53-55.

Ringsdorf WM Jr, Cheraskin E, Medford FH. Vitamin C and antibiotics. J Oral Med 1980 Jan-Mar;35(1):14-17.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: Macmillan, 1984:46-54.

Roe DA. Diet and Drug Interactions. New York, Van Nostrand Reinhold, 1989:87.

Sadowski DC. Drug interactions with antacids. Mechanisms and clinical significance. Drug Saf 1994 Dec;11(6):395-407

Salminen S, et al. Clinical uses of probiotics for stabilizing the gut mucosal barrier: successful strains and future challenges. Antonie Van Leeuwenhoek. 1996 Oct; 70(2-4): 347-358. (Review)

Snow J. Golden Seal Rhizome Monograph. Protocol J Botan Med. 1997. 2,(2) 25-28.

Surawicz, CM, Elmer, GW, Speelman, P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: a prospective study. Gastroenterology 1989;96:981-988.

Tannock GW. Probiotic properties of lactic-acid bacteria: plenty of scope for fundamental R and D. Trends Biotechnol. 1997 Jul; 15(7): 270-274. (Review)

Teplick JG, Teplick SK, Ominsky SH, Haskin ME. Esophagitis caused by oral medication. Radiology 1980 Jan;134(1):23-25.

Threlkeld DS, ed. Anti-Infectives, Tetracyclines. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Dec 1989.

Witsell, DL, Garrett, CG, Yarbrough, WG, et al. Effect of Lactobacillus acidophilus on antibiotic-associated gastrointestinal morbidity: a prospective randomized trial. J Otolaryngol 1995;24:230-233.

Vernillo AT, Rifkin BR. Effects of tetracyclines on bone metabolism. Adv Dent Res 1998 Nov;12(2):56-62.
Abstract: The anti-resorptive properties of tetracyclines (TCs) and their non-antimicrobial, chemically modified analogues (CMTs) have enormous therapeutic potential in medicine and dentistry. Osseous destructive diseases associated with excessive mammalian collagenase (matrix metalloproteinase) activity and collagen breakdown include malignancy, arthritis, and periodontitis. However, apart from the significant antimatrix metalloproteinase effects of TCs, TCs/CMTs are also potent inhibitors of osteoclast function (i.e., anti-resorptive). Thus, TCs can affect several parameters of osteoclast function and consequently inhibit bone resorption by (1) altering intracellular calcium concentration and interacting with the putative calcium receptor; (2) decreasing ruffled border area; (3) diminishing acid production; (4) diminishing the secretion of lysosomal cysteine proteinases (cathepsins); (5) inducing cell retraction by affecting podosomes; (6) inhibiting osteoclast gelatinase activity; (7) selectively inhibiting osteoclast ontogeny or development; and (8) inducing apoptosis or programmed cell death of osteoclasts. TCs/CMTs, as anti-resorptive drugs, may act similarly to bisphosphonates and primarily affect osteoclast function.

Vil'shanskaia FL, Shteinberg GB, Kats IZ, Pospelova VV, Krylova NF. [Dysbacteriosis of the intestine in persons exposed to tetracycline under conditions of production and their treatment with colibacterin]. Antibiotiki 1969 Nov;14(11):1043-1046. [Article in Russian]

Walters BN, Gubbay SS. Tetracycline and benign intracranial hypertension: report of five cases. Br Med J (Clin Res Ed) 1981 Jan 3;282(6257):19-20.
Abstract: Benign intracranial hypertension occurred in four young women taking tetracycline for acne; two were also taking vitamin A. In a fifth case a 14-year-old boy developed papilloedema after taking a short course of tetracycline for bronchitis. All symptoms disappeared soon after stopping the drugs, though in two cases the papilloedema persisted for many months. Benign intracranial hypertension should be sought in any young woman complaining of headache during treatment with tetracycline. Moreover, young women given vitamin A and tetracycline in combination for acne may be at special risk and should be kept under surveillance.

Weismann K. Chelating drugs and zinc. Dan Med Bull 1986 Aug;33(4):208-211.