|
4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV22-25 September 2002, San Diego, CA, USA |
THE EFFECTS OF SINGLE AND COMBINATIONS OF ANTIRETROVIRAL DRUGS ON PLASMA LIPID AND GLUCOSE LEVELS IN APOE*3 LEIDEN TRANSGENIC MICE
Antiviral Therapy 2002; 7:L27 (abstract 39)
M den Boer1,2, JA Romijn2, P Reiss3, M van der Valk3, PJ Voshol1,2, LM Havekes1
1TNO Prevention and Health, Leiden; 2Department of Endocrinology, LUMC, Leiden; and 3Department of Infectious Diseases, AMC, Amsterdam, Netherlands
AIM: To study the effect of single and combinations of antiretroviral drugs on lipid and glucose metabolism.
METHODS: ApoE*3 Leiden transgenic mice have a humanised lipoprotein profile and are susceptible to diet-induced hypertriglyceridemia. Groups of 5 or 6 mice each received four escalating doses (chosen on the basis of standard doses in literature) of either indinavir, ritonavir, zidovudine, lamivudine, stavudine, abacavir or didanosine for 4 weeks, added to a western type diet. Subsequently, the effects of administration for 4 weeks of zidovudine or stavudine with either didanosine or lamivudine, as well as each of these nucleoside reverse transcriptase inhibitors (NRTIs) plus ritonavir or indinavir were investigated.
RESULTS: After administration of ritonavir for 2 weeks at 35 mg/kg/day, plasma triglycerides (TG), but not cholesterol, increased from 1.5 to 4.0 mmol/l (P=0.014). However, when compared to controls, hepatic VLDL-TG production was not increased after injection of Triton WR 1339. None of the other drugs given alone, including indinavir or stavudine, significantly altered plasma lipid or glucose levels. In the livers of ritonavir- or zidovudine-treated mice an increased TG content was found compared with controls (P=0.014 and P=0.018, respectively). Ritonavir, but not indinavir, when given in combination with either zidovudine, stavudine, didanosine or lamivudine caused an increase in plasma TG (P<0.05), and an average 27% rise in plasma cholesterol (P<0.05). Dual combinations of NRTIs did not significantly elevate plasma lipids. Plasma glucose increased after 4 weeks of administration of combinations of indinavir, but not ritonavir, with zidovudine or stavudine (P<0.05). A significantly impaired glucose tolerance was confirmed by intraperitoneal glucose tolerance test in mice treated for 6 weeks with the combination of indinavir+stavudine. Similar, but non-significant trends were observed with the combinations of indinavir+zidovudine and lamivudine+zidovudine.
CONCLUSIONS: Similar to what is seen in patients, a pronounced effect on plasma TG was observed in ritonavir-treated mice. This effect could not be explained by an increase in hepatic VLDL-TG production. Indinavir, but not ritonavir, caused impaired glucose tolerance in apoE*3 Leiden transgenic mice.
Presenting author: M den Boer
2002-09-22
39
Copyright © 2002 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.