Zidovudine

Brand Names: Retrovir

Clinical Names: AZT, Azidothymidine, ZDV, Zidovudine

Summary

generic name: Zidovudine

synonyms: AZT, Azidothymidine

trade name: Retrovir®

type of drug: Zidovudine is a potent inhibitor of the in vitro replication of some retroviruses including human immunodeficiency virus, HIV.

used to treat: Zidovudine is used in cases of HIV (Human Immunodeficiency Virus) infection, and/or AIDS (Acquired Immunodeficiency Syndrome) to delay disease progression in asymptomatic HIV-infected patients and to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV disease.

adverse effects: Bone marrow suppression, especially in patients who have bone marrow compromise as evidenced by granulocyte count; Myopathy and myositis; Lactic acidosis and severe hepatomegaly with steatosis.

overview of interactions:
• nutrient affecting drug toxicity: Vitamin B12

• nutrient affecting drug performance: Vitamin E (Alpha-tocopherol)

• nutrient affecting drug toxicity: Folate (Folinic Acid)

• nutrient affected by drug: Carnitine



Interactions

nutrient affecting drug toxicity: Vitamin B12

• research: In several placebo-controlled studies, macrocytosis, anemia and granulocytopenia were the most significant adverse effects associated with zidovudine use, especially among patients with advanced symptomatic HIV disease. Significant anemia most commonly occurred after four to six weeks of therapy and in many cases required dose adjustment, discontinuation of zidovudine and/or blood transfusions.

• nutritional support: Individuals undergoing zidvudine therapy may benefit from supplementation with vitamin B12 and folate. Frequent blood counts are strongly recommended in patients with advanced HIV disease taking zidovudine. For asymptomatic HIV-infected individuals and patients with early HIV disease, most of whom have better marrow reserve, blood counts may be obtained less frequently, depending upon the patient's overall status. If anemia or granulocytopenia develops, dosage adjustments may be necessary. Individuals using zidvudine who are concerned about potential vitamin B12 deficiency and its implications should consult their prescribing physician and/or a nutritionally trained healthcare professional. Vitamin B12 levels can be tested through standard laboratory tests. In the event that supplementation is determined to be necessary, a typical adult dose of 10-25 mcg per day, or 1000-1500 mcg monthly, might be beneficial.
(Snower DP, Weil SC. Am J Clin Pathol 1993 Jan;99(1):57-60; Falguera M, et al. Eur J Haematol. 1995 Aug;55(2):97-102.)

nutrient affecting drug performance: Vitamin E (Alpha-tocopherol)

• research: Test tube studies suggest that supplementation with vitamin E (alpha-tocopherol) may enhance the therapeutic efficacy of AZT.
(Gogu SR, et al. Biochem Biophys Res Commun. 1989 Nov 30;165(1):401-407; Gogu SR, et al. Exp Hematol. 1991 Aug;19(7):649-652; Odeleye OE, Watson RR. Prog Food Nutr Sci. 1991:15(1-2):1-19.)

• nutritional support: Supplementation of vitamin E at doses of 800 IU might provide nutritional support for patients taking zidovudine, even though no decisive evidence has emerged showing that the vitamin reduces drug toxicity or enhances its efficacy. Individuals on a regime including zidovudine should consult their prescribing physician and/or a healthcare professional trained in nutritional therapy before starting megadoses of any supplements.

nutrient affecting drug toxicity: Folate (Folinic Acid)

• research: In several placebo-controlled studies, macrocytosis, anemia and granulocytopenia were the most significant adverse effects associated with zidovudine use, especially among patients with advanced symptomatic HIV disease. Significant anemia most commonly occurred after four to six weeks of therapy and in many cases required dose adjustment, discontinuation of zidovudine and/or blood transfusions.
(Snower DP, Weil SC. Am J Clin Pathol 1993 Jan;99(1):57-60; Falguera M, et al. Eur J Haematol. 1995 Aug;55(2):97-102; Baum MK, et al. J Acquir Immune Defic Syndr. 1991;4(12):1218-1226; Cronkite E, et al. Stem Cells. 1993 Sep;11(5):393-397.)

• nutritional support: Individuals undergoing zidovudine therapy may benefit from supplementation with vitamin B12 and folate. Frequent blood counts are strongly recommended in patients with advanced HIV disease taking zidovudine. For asymptomatic HIV-infected individuals and patients with early HIV disease, most of whom have better marrow reserve, blood counts may be obtained less frequently, depending upon the patient's overall status. If anemia or granulocytopenia develops, dosage adjustments may be necessary. Although folic acid is essentially non-toxic, anyone using zidovudine 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.

• nutritional concerns: While folate is generally considered nontoxic, large doses of folic acid may precipitate clinical B12 deficiency, especially if vitamin B12 status was already impaired. Individuals taking zidvudine should consult their prescribing physician about assessment of their serum B12 levels and only undertake supplementation of folate under supervision. Furthermore, it might be noted that some supportive research was done with the vitamin's activated form, folinic acid (5-formyltetrahydrofolate), at doses of 15 mg daily; this could relevant to therapeutic efficacy since zidovudine may interfere with normal folic acid metabolism.

nutrient affected by drug: Carnitine

• mechanism: L-carnitine normally plays a major role in the transport of long chain fatty acids across the inner mitochondrial membrane and facilitates the beta-oxidation of fatty acids. Dalakas et al examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT-induced myopathic symptoms of varying severity. They described a pattern of "DNA-depleting mitochondrial myopathy" associated with zidovudine (AZT) use, which is "histologically characterized by the presence of muscle fibers with "ragged-red"-like features, red-rimmed or empty cracks, granular degeneration, and rods (AZT fibers)." This muscle cell damage caused by AZT results in accumulation of lipid droplets within the muscle fibers due to poor utilization of long-chain fatty acids. Reduced muscle carnitine levels, due to decreased carnitine uptake by the muscle, are associated with depletion of energy stores within the muscle fibers.
(Dalakas MC, et al. Ann Neurol. 1994 Apr;35(4):482-487.)

• research: Semino-Mora et al conducted similar research with muscle specimens and concluded that L-Carnitine, used concurrently with AZT, prevents the human myotubes from the AZT-associated destruction, preserves the structure and volume of mitochondria and prevents the accumulation of lipids.
(Campos Y, Arenas J. Ann Neurol 1994 Oct;36(4):680-681; Semino-Mora MC, et al. Lab Invest. 1994 Jul;71(1):102-112; Dalakas MC, et al. Ann Neurol. 1994 Apr;35(4):482-487.)

• nutritional support: Individuals undergoing zidovudine therapy may benefit from supplementation with L-carnitine. Although carnitine is essentially non-toxic, anyone using zidovudine for an extended period should consult with their prescribing physician and/or a nutritionally trained healthcare professional before starting supplementation. A typical therapeutic dosage of L-carnitine would be in the range of 1-3 grams per day.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

References

Baum M, Cassetti L, Bonvehi P, Shor-Posner G, Lu Y, Sauberlich H. Inadequate dietary intake and altered nutrition status in early HIV-1 infection. Nutrition 1994 Jan-Feb;10(1):16-20.
Abstract: Recent studies indicate that multiple nutritional abnormalities occur relatively early in the course of human immunodeficiency virus (HIV-1) infection. Decreased plasma levels of vitamins B6, B12, A, and E and zinc have been correlated with dietary intake and associated with significant alterations in immune response and cognitive function. To determine the level of intake consistent with normal plasma nutrient levels, we examined nutrition status in relation to food consumption and nutrient supplementation in HIV-1-seropositive (HIV+) and -seronegative (HIV-) homosexual men. The mean level of total intake (diet plus supplements) for all nutrients was significantly higher in HIV+ men. To achieve normal plasma nutrient values, the HIV+ men appeared to require intake in multiples of the recommended dietary allowance (RDA) for vitamins A, E, B6, and B12 and zinc. For the HIV+ men, a relatively high proportion of biochemical deficiency was associated with consumption of vitamin B6 and zinc at the RDA level. Because little evidence of deficiency was observed with elevated intake in both groups, an effective program of nutritional supplementation may be beneficial in maintaining adequate plasma nutrient levels.

Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, Szapocznik J, Eisdorfer C, Buring JE, Hennekens CH. Micronutrients and HIV-1 disease progression. AIDS. 1995 Sep;9(9):1051-1056.
Abstract: OBJECTIVE: To determine whether nutritional status affects immunological markers of HIV-1 disease progression. DESIGN: A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up. METHODS: Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model. RESULTS: Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005). CONCLUSIONS: These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.

Baum MK, Javier JJ, Mantero-Atienza E, Beach RS, Fletcher MA, Sauberlich HE, Feaster D, Shor-Posner G.  Zidovudine-associated adverse reactions in a longitudinal study of asymptomatic HIV-1-infected homosexual males. J Acquir Immune Defic Syndr. 1991;4(12):1218-1226.
Abstract: Chemotherapeutic regimens frequently interact with and may influence nutritional factors. To determine the possible effects of zidovudine (ZDV) treatment on nutrient status, this study examined and compared the nutritional, immunological, and hematological status of asymptomatic, CDC stage III, HIV-1-seropositive males (n = 15) provided with ZDV (500-1,200 mg/day) and 22 nontreated, CD4-matched HIV-1-seropositive subjects. Prior to ZDV administration, hematological and plasma nutrient levels were similar in both groups. Following ZDV treatment, drug-treated subjects demonstrated alterations in hematological and nutritional parameters. A large proportion of the ZDV-treated participants exhibited decreased levels of zinc and copper along with a significant increase in red cell folate. The level of plasma zinc appeared to be particularly important in maintaining immune function in the ZDV-treated group. Whereas ZDV-treated subjects with adequate zinc levels displayed a significant increase in the response of peripheral blood lymphocytes to mitogens, this enhancement was not demonstrated in zinc-deficient, ZDV-treated participants or in untreated individuals whose lymphocyte response significantly declined over time, despite adeqaute zinc status. The findings of this study reveal a zidovudine-induced effect on nutritional parameters, indicating the importance of monitoring nutritional status with drug therapeutic regimens.

Beach RS, Mantero-Atienza E, Shor-Posner G, Javier JJ, Szapocznik J, Morgan R, Sauberlich HE, Cornwell PE, Eisdorfer C, Baum MK. Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 1992 Jul;6(7):701-708.
Abstract: OBJECTIVE: To determine whether specific nutrient abnormalities occur in earlier stages of HIV-1 infection, thereby preceding the marked wasting and malnutrition that accompany later stages of the infection. DESIGN: A longitudinal investigation to determine biological, psychological and social factors thought to influence the progression and outcome of HIV-1 infection. Nutritional status was assessed using biochemical measurement of nutrient levels, dietary history, anthropometry and clinical examination for the signs and symptoms of nutritional deficiency or excess. SETTING: The study was performed on an outpatient basis at the University of Miami School of Medicine. PARTICIPANTS: One hundred homosexual men, aged between 20 and 55 years, who were asymptomatic other than persistent generalized lymphadenopathy (Centers for Disease Control stage III) and 42 age-matched homosexual men demonstrated to be free of HIV-1 infection at two 6-month intervals. MAIN OUTCOME MEASURES: Biochemical measurement of nutrient status, dietary history, anthropometry, clinical signs or symptoms of nutritional excess or deficiency were obtained for all participants. RESULTS: Despite few differences in mean blood levels of specific nutrients, prevalence of specific nutrient abnormalities was widespread among HIV-1-infected subjects, compared with non-infected male homosexual controls. Overtly and marginally low blood levels of vitamins A (18%), E (27%), riboflavin (26%), B6 (53%), and B12 (23%), together with copper (74%) and zinc (50%) were documented in HIV-1-seropositive subjects. With the exception of riboflavin, zinc, and copper, a similar prevalence of abnormalities among HIV-1-seronegative controls was not observed. CONCLUSION: Specific nutrient abnormalities occur with relative frequency in asymptomatic HIV-1 infection and may contribute to the rate and form of HIV-1 disease progression.

Campos Y, Arenas J. Muscle carnitine deficiency associated with zidovudine-induced mitochondrial myopathy. Ann Neurol 1994 Oct;36(4):680-681. (Letter)

Cronkite E, Bullis J, Honikel L. Partial amelioration of AZT-induced macrocytic anemia in the mouse by folic acid. Stem Cells. 1993 Sep;11(5):393-397.
Abstract: CBA/Ca mice being maintained on azidothymidine (AZT) in drinking water were given vitamin B12 and folate in an effort to ameliorate the macrocytic anemia associated with AZT administration. The B12/folate regimen was ineffectual, but higher doses of folate given daily resulted in an increase in RBC and a decrease in mean corpuscular hemoglobin (MCH) and polychromatophilic erythrocytes (PCE) while mean corpuscular volume (MCV) remained relatively constant. The implications of these findings on RBC production and hemoglobin synthesis are discussed.

Dalakas MC, Leon-Monzon ME, Bernardini I, Gahl WA, Jay CA. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Ann Neurol 1994 Apr;35(4):482-487.
Abstract: The use of zidovudine (AZT) for the treatment of acquired immunodeficiency syndrome (AIDS) induces a DNA-depleting mitochondrial myopathy, which is histologically characterized by the presence of muscle fibers with "ragged-red"-like features, red-rimmed or empty cracks, granular degeneration, and rods (AZT fibers). Because dysfunctioning muscle mitochondria may lead to defects of beta-oxidation of fatty acids, we examined the degree of neutral fat accumulation and muscle carnitine levels in the muscle biopsy specimens from 21 patients with AZT-induced myopathic symptoms of varying severity. Six patients with no AZT fibers had normal endomyofibrillar lipid deposits and muscle carnitine levels; 7 patients with fewer than 5 AZT fibers per field had a mild (+) to moderate (++) increase in lipid droplets, and reduced muscle carnitine levels (3 patients); and 8 patients with more than 5 AZT fibers had severe muscle changes, a ++ to marked ( ) increase in lipid droplets, and reduced muscle carnitine levels (6 patients). Serial sections showed lipid globules often within "cracks" or vacuoles of the abnormal muscle fibers. We conclude that the muscle mitochondrial impairment caused by AZT results in (1) accumulation of lipid within the muscle fibers owing to poor utilization of long-chain fatty acids, (2) reduction of muscle carnitine levels probably due to decreased carnitine uptake by the muscle, and (3) depletion of energy stores within the muscle fibers. The findings may have potential therapeutic implications in the treatment of AZT-induced myopathic symptoms using oral carnitine supplementation.

Falguera M, Perez-Mur J, Puig T, Cao G. Study of the role of vitamin B12 and folinic acid supplementation in preventing hematologic toxicity of zidovudine. Eur J Haematol. 1995 Aug;55(2):97-102.
Abstract: A prospective, randomized study was conducted to evaluate the role of vitamin B12 and folinic acid supplementation in preventing zidovudine (ZDV)-induced bone marrow suppression. Seventy-five human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts < 500/mm3 were randomized to receive either ZDV (500 mg daily) alone (group I, n = 38) or in combination with folinic acid (15 mg daily) and intramascular vitamin B12 (1000 micrograms monthly) (group II, n = 37). Finally, 15 patients were excluded from the study (noncompliance 14, death 1); thus, 60 patients (31 in group I and 29 in group II) were eligible for analysis. No significant differences between groups were found at enrollment. During the study, vitamin B12 and folate levels were significantly higher in group II patients; however, no differences in hemoglobin, hematocrit, mean corpuscular volume, and white-cell, neutrophil and platelet counts were observed between groups at 3, 6, 9 and 12 months. Severe hematologic toxicity (neutrophil count < 1000/mm3 and/or hemoglobin < 8 g/dl) occurred in 4 patients assigned to group I and 7 assigned to group II. There was no correlation between vitamin B12 or folate levels and development of myelosuppression. Vitamin B12 and folinic acid supplementation of ZDV therapy does not seem useful in preventing or reducing ZDV-induced myelotoxicity in the overall treated population, although a beneficial effect in certain subgroups of patients cannot be excluded.

Fogelman I, Lim L, Bassett R, Volberding P, Fischl MA, Stanley K, Cotton DJ. Prevalence and patterns of use of concomitant medications among participants in three multicenter human immunodeficiency virus type I clinical trials. AIDS Clinical Trials Group (ACTG). J Acquir Immune Defic Syndr 1994 Oct;7(10):1057-1063.
Abstract: Data on the prevalence and patterns of use of concomitant medications among participants in three large phase III clinical trials of zidovudine (ZDV) in human immunodeficiency virus type 1 (HIV-1) infection were analyzed. Overall, 2,801 patients reported 43,331 uses of concomitant medications. Over 85% of clinical trial participants used one or more concomitant medications at some point during the study. Patients with acquired immune deficiency syndrome (AIDS) used an average of 7.1 drugs per month. Patients with AIDS-related complex (ARC) or who were asymptomatic used relatively fewer drugs: 3.1 and 2.7 per month, respectively. Fourteen percent of patients with AIDS used more than 10 concomitant medications per month. The three most commonly utilized classes of drugs were antiinfectives (57%), analgesics or antipyretics (55%), and vitamins (47%). A total of 17% of patients overall and 30% of AIDS patients used acyclovir while on trial. Consumption of prescription drugs was greater, and "over-the-counter" drugs less, among AIDS patients. Reported use of agents not approved by the Food and Drug Administration or approved drugs used for off-label indications was infrequent. Overall use of concomitant medications did not differ across demographic subgroups when corrected for disease stage at the time of enrollment. White, non-Hispanic, homosexual and bisexual men consumed significantly more antivirals and vitamins than other trial participants. Women in all three protocols took more analgesics or antipyretics than did men.

Gogu SR, Beckman BS, Rangan SR, Agrawal KC. Increased therapeutic efficacy of zidovudine in combination with vitamin E. Biochem Biophys Res Commun. 1989 Nov 30;165(1):401-407.
Abstract: Antiviral activity and bone marrow toxicity of 3'-azido-3'deoxythymidine (Zidovudine; AZT) was evaluated in the presence of alpha-D-tocopherol acid succinate (ATS) in the MT4 cell line and in murine hematopoietic progenitor cells, respectively. At varying concentrations (.016 to .125 microM) of AZT, addition of ATS (5 to 15 micrograms/ml) showed a dose-dependent increase in anti-HIV activity. The ED90 of AZT in this test system was 0.37 microM, whereas in the presence of ATS (15 micrograms/ml) it was 0.06 microM, thus producing an approximately 6-fold increase in anti-HIV activity. In contrast, in murine bone marrow cells, ATS (4 micrograms/ml) showed significant protection (p less than 0.05) against AZT-induced toxicity as measured by CFU-E and CFU-GM assays. The IC50 values in the presence and absence of ATS for CFU-E were 3.7 and 1.5 microM, whereas for CFU-GM were 6.0 and 2.7 microM, respectively. Overall, these data suggest that AZT in combination with ATS has greater therapeutic efficacy against HIV-1.

Gogu SR, Lertora JJ, George WJ, Hyslop NE, Agrawal KC. Protection of zidovudine-induced toxicity against murine erythroid progenitor cells by vitamin E. Exp Hematol. 1991 Aug;19(7):649-652.
Abstract: The ability of vitamin E (alpha-tocopherol) to stimulate erythroid progenitor cells was investigated in an attempt to identify ways to ameliorate zidovudine (azidothymidine, AZT)-induced anemia. In vitro, alpha-tocopherol acid succinate (ATS), upon incubation with murine bone marrow cells at concentrations of up to 4 micrograms/ml, caused a dose-dependent increase in erythroid colony-forming unit (CFU-E)-derived colonies. This increase was equivalent to the effect demonstrated by 50 mU of recombinant human erythropoietin (rhEpo) or 200 U of recombinant interleukin 3 (rIL-3). For in vivo studies, anemia was produced in CD-1 male mice by administering AZT in drinking water (1.5 mg/ml). Treatment with vitamin E (50 mg/kg body weight) or Epo (0.4 U per mouse) was initiated 24 h later and continued for five consecutive days. Seventh day bone marrow cells from femurs were assayed for CFU-E-derived colonies. Both vitamin E and Epo significantly increased the number of CFU-E-derived colonies by 75% and 86% of control, respectively, indicating that these agents were approximately similar in protecting the bone marrow from AZT-induced toxicity.

Harakeh S, Jariwalla RJ. Ascorbate effect on cytokine stimulation of HIV production. Nutrition 1995 Sep-Oct;11(5 Suppl):684-687.
Abstract: We have recently shown that ascorbic acid (AA) suppresses the production of HIV in a latently infected T-lymphocytic cell line (ACH-2) following stimulation with the tumor promoter, PMA. To evaluate the effect of ascorbic acid on virus activation following treatment with inflammatory cytokine, we tested tumor necrosis factor alpha (TNF-alpha) whose levels are elevated in patients with HIV/AIDS. ACH-2 cultures, pretreated with various nontoxic concentrations of ascorbate or AZT were stimulated for 2 h with TNF-alpha, and incubated further with fresh supplements of ascorbate or AZT. At 24 to 48 h post-treatment, the RT activity released into culture supernatant was determined. Results showed that TNF-alpha alone caused approximately 13- to 16-fold stimulation in the level of extracellular RT. Pretreatment with ascorbic acid at 200 micrograms/ml caused a little more than about 2- to 4-fold reduction in extracellular RT levels. Most remarkably, exposure to 300 micrograms/ml ascorbate resulted in approximately 5- to 10-fold lowering of the extra-cellular RT titer. In contrast, no significant suppression in extracellular RT levels was seen with concentrations of AZT in the range of 1-5 micrograms/ml.

Odeleye OE, Watson RR. The potential role of vitamin E in the treatment of immunologic abnormalities during acquired immune deficiency syndrome. Prog Food Nutr Sci. 1991;15(1-2):1-19. (Review)

Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. Part I: L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994 Jul;71(1):102-112.
Abstract: BACKGROUND: Zidovudine (AZT) as used in the treatment of AIDS, causes a mitochondrial myopathy characterized by depletion of mitochondrial DNA, enzymatic defects in the respiratory chain system, and accumulation of lipid droplets. Most of these changes are also seen in normal human myotubes treated with AZT. Because L-carnitine plays a major role in the transport of long chain fatty acids across the inner mitochondrial membrane and facilitates the beta-oxidation of fatty acids, we examined the effect of L-carnitine in preventing the destructive effect of AZT on the mitochondria and the myotubes of human muscle in tissue culture. EXPERIMENTAL DESIGN: Myotubes, prepared from human muscle biopsies, were exposed to various concentrations of AZT for up to 3 weeks. One-third of the flasks were treated with AZT alone, another third with AZT plus L-carnitine and another third were untreated. The cultures were evaluated with: (a) immunocytochemistry counting the number of myotubes stained with antibodies to Leu-19; (b) enzyme histochemistry for NADH reaction and oil-red-O stain to assess mitochondrial enzymatic activity and lipid droplet accumulation; and (c) electron microscopy counting all the organelles within representative sections of the myotubes, at x24,000, and calculating the volumetric density of each organelle/unit volume of tissue. RESULTS: AZT, at concentrations 250 microM and above, caused depopulation of the Leu-19-positive myotubes, destructive changes in the mitochondria consisting of swelling, lamellar inclusions and multiple concentric cristae, accumulation of lipid droplets, and increase lysosomes. L-Carnitine increased the number of Leu-19-positive myotubes from 3.4 +/- 0.6 to 9.4 +/- 1.2, preserved the morphology of the mitochondria, increased their volumetric density from 2.5 +/- 0.4 to 6.0 +/- 0.7, and reduced the volumetric density of the lipid droplets from 12.2 +/- 4.9 to 1.4 +/- 0.7 and of the lysosomes from 15.6 +/- 3.6 to 3.9 +/- 1.4 (p < 0.001). CONCLUSIONS: L-Carnitine, used concurrently with AZT, prevents the human myotubes from the AZT-associated destruction, preserves the structure and volume of mitochondria and prevents the accumulation of lipids. The findings may have potential clinical implications in preventing the myotoxicity of AZT in patients with AIDS.

Snower DP, Weil SC. Changing etiology of macrocytosis. Zidovudine as a frequent causative factor. Am J Clin Pathol 1993 Jan;99(1):57-60.
Abstract: Macrocytosis is most commonly associated with vitamin B12 and folate deficiencies, followed by alcoholism, liver disease, and malignant neoplasms. Many laboratories have observed that in recent years macrocytosis increasingly has been associated with zidovudine treatment of acquired immune deficiency syndrome. One hundred consecutive inpatients in a large metropolitan urban hospital with mean corpuscular volumes greater than 110 fL were studied; 44% were patients with acquired immune deficiency syndrome being treated with zidovudine, 19% were alcoholics, and 12% had malignant neoplasms. Only 3% were folate deficient and just 4% were vitamin B12 deficient. This study suggests that zidovudine has become the most common cause of macrocytosis in the hospitalized urban patient population and that vitamin B12 and folate deficiencies have decreased in proportion.

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997, 248-249.