Vliv šesti antiretrovirotik (delavirdinu, stavudinu, lamivudinu, nelfinaviru, amprenaviru a lopinaviru/ritonaviru v kombinaci) na březí bílé krysy (Rattus norvegicus Albinus, Rodentia, Mammalia): biologický test


Autoři: M. U. Nakamura *;  Edward Araujo Júnior * ;  Simões M. J.+;  Oliveira Filho R. M.§;  L. Kulay Júnior *
Působiště autorů: Department of Obstetrics, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil +Department of Morphology, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil §Department of Pharmacology, São Paulo University (USP), São Paulo, SP, *
Vyšlo v časopise: Ceska Gynekol 2014; 79(4): 295-304

Souhrn

Cíl:
Srovnat chronické účinky antiretrovirotické léčby (lamivudin, stavudin, delavirdin, nelfinavir, amprenaviru a kombinace lopinaviru/ritonaviru) u březích potkanů albínů.

Typ studie:
Review.

Název a sídlo pracoviště:
Gynekologicko-porodnická klinika, Federal University of São Paulo (UNIFESP), Sao Paulo, SP, Brazílie.

Metodika:
Retrospektivní srovnávací studie se zabývala 18 skupinami po 10 březích samičkách potkanů, které byly téměř tři měsíce staré a vážily 200 gramů. Každé z nich byla denně aplikována léčba pomocí žaludeční sondy, zatímco kontrolní skupině byl aplikován 1 ml destilované vody. Studijní skupiny obdržely lamivudin (5, 15 a 45 mg/kg/den); stavudin (na 1, 3 a 9 mg/kg/den); nelfinavir (40, 120 a 360 mg/kg/den); amprenavir (na 46, 138 a 414 mg/kg/den); lopinavir/ritonavir (12.8/3.2, a 38.4/9.6 115/28.8 mg/kg/den) a delavirdin (20 a 60 mg/kg/den). To představuje jedno-, troj- a devítinásobek terapeutické dávky pro člověka, s výjimkou posledního léku, kde nebyla nejvyšší dávka podána. Byla hodnocena hmotnost samice, plodu a placenty, počet implantací a reabsorpcí, hlavní zevní malformace plodu a odumření samice nebo plodu. Pro statistické zpracování byly použity test Kruskalův-Wallisův a χ2 test.

Výsledky:
U všech tří dávek stavudin zvyšoval hmotnost samice (p = 0,001), zatímco lamivudin při trojnásobné a devítinásobné dávce hmotnost snižoval (p < 0,001). Amprenavir u všech dávek, a lopinavir//ritonavir u troj- a devítinásobné dávky zvyšoval úmrtnost samic (p < 0,001). Z hlediska plodů nebylo žádné z antiretrovirotik škodlivé, pokud jde o implantaci, reabsorpci, teratogenitu a úmrtnost (p > 0,05). Stavudin při všech dávkách snižoval hmotnost mláďat(p < 0,001); Nicméně lamivudin u trojnásobné, delavirdin u trojnásobné a amprenavir u trojnásobné dávky hmotnost mláďat zvyšoval (p < 0,001).

Závěr:
U březích samic jsme pozorovali letální toxicitu u krys, kterým byl aplikován amprenavir a ritonavir/lopinavir; hmotnost krys se měnila při užití lamivudinu a stavudinu . U plodů byly pozorovány nežádoucí účinky v souvislosti s hmotností mláďat u stavudinu, lamivudinu, amprenaviru a delavirdinu..

Klíčová slova:
březí krysy, antiretrovirotika, teratologie, biologický test


Zdroje

1. Ananworanich, J., Nuesch, R., Cote, HC., et al. Changes in metabolic toxicity after switching from stavudine/didanosine to tenofovir/lamivudine – a Staccato trial substudy.J Antimicrob Chemother, 2008, 61, p. 1340–1343.

2. Anderson, AM., Bartlett, JA. Fixed dose combination abacavir/lamivudine in the treatment of HIV-1 infection. Expert Rev Anti Infect Ther, 2005, 3, p. 871–883.

3. Barreto, RL., de Jesus Simões, M., Amed, AM., et al. Stavudine effects on rat pregnancy outcome. J Obstet Gynaecol Res, 2004, 30, p. 242–245.

4. Bongiovanni, M., Cicconi, P., Landonio, S., et al. Predictive factors of lopinavir/ritonavir discontinuation for drug-related toxicity: results from a cohort of 416 multi-experienced HIV-infected individuals. Int J Antimicrob Agents, 2005, 26, p. 88–91.

5. Carr, A., Ritzhaupt, A., Zhang, W., et al. Effects of boosted tipranavir and lopinavir on body composition, insulin sensitivity and adipocytokines in antiretroviral-naive adults. AIDS, 2008, 22, p. 2313–2321.

6. Casau, NC., Glesby, MJ., Paul, S., Gulick, RM. Brief report: efficacy and treatment-limiting toxicity with the concurrent use of lopinavir/ritonavir and a third protease inhibitor in treatment-experienced HIV-infected patients. J Acquir Immune Defic Syndr, 2003, 32, p. 494–498.

7. Centers for Disease Control and Prevention (CDC). Epidemiology of HIV/AIDS – United States, 1981–2005. MMWR Morb Mortal Wkly Rep, 2006, 55, p. 589–592.

8. Chappuy, H., Treluyer, JM., Jullien, V., et al. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Antimicrob Agents Chemother, 2004, 48, p. 4332–4336.

9. Chen, CH., Vazquez-Padua, M., Cheng, YC. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol, 1991, 39, p. 625–628.

10. Cohen, MS., Hellmann, N., Levy, JA., et al. The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. J Clin Invest, 2008, 118, p. 1244–1254.

11. Cooper, ER., Charurat, M., Mofenson, L., et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr, 2002, 29, p. 484–494.

12. Cressey, TR., Lallemant, M. Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: an update. Infect Genet Evol, 2007, 7, p. 333–342.

13. Cunha, AM. Action of delaverdine on albino pregnant rats. Biological assay. Dissertation. [MSD thesis]. São Paulo: Federal University of São Paulo, 2000.

14. Dube, MP., Parker, RA., Tebas, P., et al. Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides. AIDS, 2005, 19, p. 1807–1818.

15. Dube, MP., Qian, D., Edmondson-Melancon, H., et al. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin Infect Dis, 2002, 35, p. 475–481.

16. Evagelidou, EN., Kiortsis, DN., Bairaktari, ET., et al. Lipid profile, glucose homeostasis, blood pressure, and obesity – anthropometric markers in macrosomic offspring of nondiabetic mothers. Diabetes Care, 2006, 29, p. 1197–1201.

17. Figueiró-Filho, EA., Duarte, G., Silva, AA., et al. [Effects of antiretroviral drugs on fertility of Wistar rats]. Rev Bras Ginecol Obstet, 2002, 24, p. 647–652.

18. Gervasoni, C., Ridolfo, AL., Trifiro, G., et al. Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS, 1999, 13, p. 465–471.

19. Hamilton, JB., Wolfe, JM. The effect of male hormone substance upon birth and prenatal development in the rat. Anat Rec, 1938, 70, p. 433–440.

20. Healan-Greenberg, C., Waring, JF., Kempf, DJ., et al. A human immunodeficiency virus protease inhibitor is a novel functional inhibitor of human pregnane X receptor. Drug Metab Dispos, 2008, 36, p. 500–507.

21. Kobayashi, D., Ieiri, I., Hirota, T., et al. Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta. Drug Metab Dispos, 2005, 33, p. 94–101.

22. Kojima, K., Nagata, K., Matsubara, T., Yamazoe, Y. Broad but distinct role of pregnane x receptor on the expression of individual cytochrome p450s in human hepatocytes. Drug Metab Pharmacokinet, 2007, 22, p. 276–286.

23. Kosmiski, LA., Miller, HL., Klemm, DJ. In combination, nucleoside reverse transcriptase inhibitors have significant effects on 3T3-L1 adipocyte lipid accumulation and survival. Antivir Ther, 2006, 11, p. 187–195.

24. Kulay, L. Jr., Hagemann, CC., Nakamura, MU., et al. Administration of lopinavir/ritonavir association during rat pregnancy: maternal and fetal effects. Clin Exp Obstet Gynecol, 2013, 40, p. 151–154.

25. Lagathu, C., Eustace, B., Prot, M., et al. Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther, 2007, 12, p. 489–500.

26. Ma, X., Cheung, C., Krausz, KW., et al. A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4. Drug Metab Dispos, 2008, 36, p. 2506–2512.

27. Mao, Q. BCRP/ABCG2 in the placenta: expression, function and regulation. Pharm Res, 2008, 25, p. 1244–1255.

28. Marzolini, C., Rudin, C., Decosterd, LA., et al. Transplacental passage of protease inhibitors at delivery. AIDS, 2002, 16, p. 889–893.

29. Masuyama, H., Hiramatsu, Y., Mizutani, Y., et al. The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse. Mol Cell Endocrinol, 2001, 172, p. 47–56.

30. Mathias, CV., Mathias, CF., Simões, MJ., et al. Safety of nelfinavir use during pregnancy. An experimental approach in rats. Clin Exp Obst Gyn, 2005, 32, p. 163–165.

31. Mirochnick, M., Capparelli, E. Pharmacokinetics of antiretrovirals in pregnant women. Clin Pharmacokinet, 2004, 43, p. 1071–1087.

32. Mota, DR. Action chronic amprenavir on pregnant rats (Rattus norvegicus albinos, Rodentia, Mammalia). Biological assay. [MSD thesis]. São Paulo: Federal University of São Paulo, 2003.

33. Nguyen, A., Calmy, A., Schiffer, V., et al. Lipodystrophy and weight changes: data from the Swiss HIV Cohort Study, 2000–2006. HIV Med, 2008, 9, p. 142–150.

34. Pontes, RD., Amed, AM., Simões, RS., et al. A morphological and biochemical appraisal of the liver and renal effects of lamivudine on rat pregnancy. Clin Exp Obstet Gynecol, 2006, 33, p. 209–212.

35. Prot, M., Heripret, L., Cardot-Leccia, N., et al. Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice. Antimicrob Agents Chemother, 2006, 50, p. 3998–4004.

36. Public Health Service Task Force. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf. Accessed 20 April 2009.

37. Roberts, AD., Liappis, AP., Chinn, C., et al. Effect of delavirdine on plasma lipids and lipoproteins in patients receiving antiretroviral therapy. AIDS, 2002, 16, p. 1829–1830.

38. Rosenkranz, SL., Yarasheski, KE., Para, MF., et al. Antiretroviral drug levels and interactions affect lipid, lipoprotein, and glucose metabolism in HIV-1 seronegative subjects: a pharmacokinetic-pharmacodynamic analysis. Metab Syndr Relat Disord, 2007, 5, p. 163–173.

39. Sattler, FR. Pathogenesis and treatment of lipodystrophy: what clinicians need to know. Top HIV Med, 2008, 16, p. 127–133.

40. Scott, LJ., Perry, CM. Delavirdine: a review of its use in HIV infection. Drugs, 2000, 60, p. 1411–1444.

41. Stricker, RB., Goldberg, B. Weight gain associated with protease inhibitor therapy in HIV-infected patients. Res Virol, 1998, 149, p. 123–126.

42. UNAIDS and WHO. Report on the global HIV/AIDS epidemic 2008: executive summary. Available at:

43. van der Valk, M., Casula, M., Weverlingz, GJ., et al. Prevalence of lipoatrophy and mitochondrial DNA content of blood and subcutaneous fat in HIV-1-infected patients randomly allocated to zidovudine- or stavudine-based therapy. Antivir Ther, 2004, 9, p. 385–393.

44. Young, J., Rickenbach, M., Weber, R., et al. Body fat changes among antiretroviral-naive patients on PI- and NNRTI-based HAART in the Swiss HIV cohort study. Antivir Ther, 2005, 10, p. 73–81.

45. Zhou, SF. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab, 2008, 9, p. 310–322.

Štítky
Dětská gynekologie Gynekologie a porodnictví Reprodukční medicína

Článek vyšel v časopise

Česká gynekologie

Číslo 4

2014 Číslo 4

Nejčtenější v tomto čísle
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se