Abstract
Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo-fetal developmental toxicity and teratogenicity were studied in pregnant Sprague-Dawley rats after intragastric administration of Metacavir (200, 100, 50, 0 mg/kg body weight) during the first 6–15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6–20 pregnant days were significantly different (P < 0.01, P < 0.05). Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group (P < 0.05), while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/(kg·d) (i.e., 40 times the effective dose in rats), Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/(kg·d) there is no teratogenic side effects.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Mohamadnejad M, Malekzadeh R. Hepatitis B. N Engl J Med 2004; 350(26): 2719–2720
Chinese Society of Hepatology. Guidelines on the Prevention and Treatment of Chronic Hepatitis B. 2005
Telegdy L. Treatment of hepatitis B. Orv Hetil 2004; 145(45): 2293–2296 (in Hungarian)
Sagna T, Bisseye C, Kagone TS, Djigma FW, Ouermi D, Zeba MTA, Bazié VJT, Douamba Z, Moret R, Pietra V, Koama A, Pignatelli S, Gnoula C, Sia JD, Nikiema JB, Simpore J. PMTCT of HIV-1 in Burkina Faso: evaluation of residual vertical transmission by PCR, molecular characterization of subtypes and determination of antiretroviral drugs resistance. BMC Infect Dis 2014; 14(Suppl 2): 59 (Updated guidelines available at http://www.biomedcentral.com/1471-2334/14/S2/P59)
Report of the NIH Panel to Define Principles of Therapy in HIV. Infection and guidelines for the use of antiretroviral agents in HIVinfected adults and adolescents. MMWR Morb Mortal Wkly Rep 1998; 47(RR-5): 43–82 (Updated guidelines available at http://www.hivatis.org)
Rotjanee W, Nawaporn P, Panthong S, Doungnapa K, Peninnah O, Pannee S, Sakorn P. Hematological alterations and thymic function in newborns of HIV-infected mothers receiving antiretroviral drugs. Indian Pediatr 2013; 50(6):567–572
Lorenzi P, Spicher VM, Laubereau B, Hirschel B, Kind C, Rudin C, Irion O, Kaiser L. Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects: Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy Study, and the Swiss Neonatal HIV Study. AIDS 1998; 12(18): F241–F247
Tuomala RE, Shapiro DE, Mofenson LM, Bryson Y, Culnane M, Hughes MD, O’Sullivan MJ, Scott G, Stek AM, Wara D, Bulterys M. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002; 346(24): 1863–1870
Zhang P, Zhang L, Jiang Z, Xiong Y, Chen H, Tao Y, Hu M, Li Z. Evaluation of mitochondrial toxicity in Marmota himalayana treated with metacavir, a novel 2′,3′-dideoxyguanosine prodrug for treatment of hepatitis B Virus. Antimicrob Agents Chemother 2011; 55(5): 1930–1936
Chen ZY, Cheng AC, Wang MS, Xu DW, Zeng W, Li Z. Antiviral effects of PNA in duck hepatitis B virus infection model. Acta Pharmacol Sin 2007; 28(10): 1652–1658
Li Z, Huang X, Jiang Z, Xiao Y, Liu C, Zhang L, Shu B, Huang J, Li T, Wang T, Wang F. A sensitive and specific liquid chromatographymass spectrometry method for determination of metacavir in rat plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2008; 864(1–2): 9–14
Chen ZL, Zeng W, Cheng AC, Luo QH, Li Z, Peng X, Fang J, Pan KC, He M, Tang L. Six-month repeated dose toxicity of orally administered metacavir in rhesus monkeys. Exp Toxicol Pathol 2011; 63(4): 379–385
Zeng W, Cheng AC, Chen ZL, Luo QH, Sun YB, Li Z, Bi FJ. In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration. Acta Pharmacol Sin 2009; 30(12): 1666–1673
The Ministry of Science and Technology of the People’s Republic of China. Guidance Suggestions for the Care and Use of Laboratory Animals 2006
Wilson JC. Methods for administering agents and detecting malformations in experimental animals. In: Wilson JG, Warkany J. Teratology: Principles and Techniques. Chicago: University of Chicago Press, 1965; 262–277
Staples RE, Schnell VL. Refinements in rapid clearing technic in the KOH-alizarin red S method for fetal bone. Stain Technol 1964; 39: 61–63
Hung JH, Chu CJ, Sung PL, Chen CY, Chao KC, Yang MJ, Hung SC. Lamivudine therapy in the treatment of chronic hepatitis B with acute exacerbation during pregnancy. J Chin Med Assoc 2008; 71(3): 155–158
Watts DH. Management of human immunodeficiency virus infection in pregnancy. N Engl J Med 2002; 346(24): 1879–1891
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Luo, Q., Chen, Z., Cheng, A. et al. Reproductive toxicity study with a novel deoxyguanosine analogue (Metacavir) in pregnant SD rats. Front. Med. 9, 82–89 (2015). https://doi.org/10.1007/s11684-015-0376-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11684-015-0376-0