Muscular and haematopoietic toxicities of zidovudine in adult albino rat. Evaluation of the possible role of some antioxidants

ABSTRACT

Zidovudine, a potent inhibitor of retroviral replication was the first drug approved for the treatment of Acquired Immunodeficiency Syndrome [AIDS]. Long term use of Zidovudine in patients with AIDS is frequently associated with periods of dose reduction or discontinuation of therapy due to the development of muscular and haematopoietic toxicities. Zidovudine toxicity is thought to be mediated through its action on mitochondria with increased reactive species and oxidative DNA damage. Some antioxidants [Vitamin C, Zinc and N-acetyl Cysteine] were tried in this work aiming to evaluate their possible protective effects on zidovudine - induced muscle and haematopoietic toxicities. One hundred and eighty adult albino rats of both sexes were used in this study divided equally into the following groups Group I was considered as -ve control group. Group II animals received distilled water orally Group III in which animals received vitamin C orally at a dose of 175 mg/day. Group IV included animals which received Zinc Oxide orally at a dose of 6 mg/day. Group V in which animals received N-Acetyl Cysteine [NAC] orally at a dose of 18 mg/day. The drugs used in Group III, IV, V were given for 50 consecutive days. Group VI included animals which receive Zidovudine [AZT] in a dose of [10.8 mg/rat] oraly for 35 consecutive days. Group VII comprise animals which were pretreated with vitamin C for 15 days, then vitamin C was given concomitant with AZT for 35 consecutive days at the same previously given dose and route for each. Group VIII In which animals received Zinc Oxide before AZT for 15 days then Zinc Oxide concomitant with AZT for 35 consecutive days at the same previously given dose and route for each. Group IX comprised animals which received NAC for 15 consecutive days before then concomitant with AZT for 35 consecutive days at the same previously given dose and route for each. At the end of the experiment blood samples used for blood count were collected. Aliquots of the samples were centrifuged and the plasma was used for determination of serum malondialdehyde [MDA] level. Animals were sacrificed and the heart and gastrocnemius muscle with related bone were prepared for histological examination. In AZT group there was marked decrease in total WBC count, RBC count and platelet count with significant increase in serum MDA level. The L/M examination of skeletal and cardiac muscle sections revealed focal areas of necrosis with complete loss of architecture together with mononuclea; cellular infiltration. Skeletal muscles of the same group showed focal depletion of sarcoplasmi, PAS positive material and mitochondrial content together with increase in collagen fiber deposition. E/M examination of cardiac myocytes showed abundant sarcoplasmic vacuolation and myofibrillar loss. Their mitochondria showed different grades of degenerative changes. The bone marrow sections of AZT group showed marked hypercellularity, decrease bone marrow vacuolar spaces, dilated congested blood sinusoids. In AZT and vitamin C group [VII] and AZT with Zinc group [VIII] there was marked elevation of all blood count with marked drop in the level of serum MDA compared with AZT group. Also nearly complete normalization of the histological profile of skeletal and cardiac muscle was obtained in the same groups. The bone marrow sections of AZT and vitamin C group was nearly similar to - ve control group while that of AZT + Zinc group still showed changes. Whereas there was mild improvement of the skeletal, cardiac muscle and bone marrow AZT - induced histological and biochemical changes was detected in AZT and NAC group [IX]