pyrimidinones and Metabolic-Syndrome

In the current era of HIV treatment, the toxicity profiles of antiretroviral drugs have increasingly emerged as a basis for selecting initial antiretroviral regimens as well as a reason for switching therapy in treatment-experienced patients. In this respect, an intensive research effort involving clinical research as well as basic science research over the past six years, has focused on the cluster of metabolic and body composition abnormalities that have come to be termed the 'lipodystrophy syndrome'. These data have now provided a clear and clinically relevant understanding of the individual profiles of drugs within the nucleoside analogue reverse transcriptase inhibitor , HIV protease inhibitor and non-nucleoside analogue reverse transcriptase inhibitor drug classes, and have provided a rational basis for assessing and monitoring these adverse effects in clinical practice. In this review, current and emerging drug toxicities are considered with an emphasis on lipodystrophy complications.

Topics: Adenine; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Cardiovascular Diseases; Cyclopropanes; Drug Monitoring; Drug Therapy, Combination; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Kidney Diseases; Lopinavir; Metabolic Syndrome; Nevirapine; Organophosphonates; Oxazines; Pyrimidinones; Risk Factors; Tenofovir

It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function revealed that even the lowest dose of lopinavir/ritonavir caused significant cognitive impairment assessed in multi-unit T-maze, but did not affect motor functions assessed as rotarod performance. Collectively, our results indicate that repeated lopinavir/ritonavir administration produces cognitive as well as metabolic impairments, and suggest that the development of selective aspects of metabolic syndrome in HIV patients could contribute to HIV-associated neurocognitive disorders.

Topics: Animals; Cognition; Drug Administration Schedule; Drug Combinations; HIV; HIV Infections; HIV Protease Inhibitors; Lopinavir; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Motor Activity; Pyrimidinones; Ritonavir; Weight Loss

HIV protease inhibitors (HIV-PIs) are key components of highly active antiretroviral therapy, but they have been associated with adverse side effects, including partial lipodystrophy and metabolic syndrome. We recently demonstrated that a commonly used HIV-PI, lopinavir, inhibits ZMPSTE24, thereby blocking lamin A biogenesis and leading to an accumulation of prelamin A. ZMPSTE24 deficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease phenotypes. Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausible mechanism for some drug side effects. Here we show, with metabolic labeling studies, that lopinavir leads to the accumulation of the farnesylated form of prelamin A. We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24. We found that darunavir does not inhibit the biochemical activity of ZMPSTE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. This property of darunavir is potentially attractive. However, all HIV-PIs, including darunavir, are generally administered with ritonavir, an HIV-PI that is used to block the metabolism of other HIV-PIs. Ritonavir, like lopinavir, inhibits ZMPSTE24 and leads to an accumulation of prelamin A.

Topics: Animals; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Lamin Type A; Lipodystrophy; Lopinavir; Membrane Proteins; Metabolic Syndrome; Metalloendopeptidases; Mice; Mice, Knockout; Nuclear Proteins; Protein Precursors; Protein Processing, Post-Translational; Pyrimidinones; Ritonavir; Sulfonamides

To assess the presence of insulin resistance in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy.. Cross-sectional study in consecutive HIV-infected patients treated with regimens containing efavirenz, lopinavir/ritonavir or atazanavir. Insulin resistance was assessed by HOMA (Homeostasis Model Assessment).. We analyzed 47 patients, 18 on treatment with efavirenz, 17 with lopinavir/ritonavir and 12 with atazanavir. Patients treated with lopinavir/ritonavir had higher insulinemia than those treated with efavirenz (p = 0.007) or atazanavir (p = 0.020). The HOMA index was also higher in subjects treated with lopinavir/ritonavir than in those receiving efavirenz (p = 0.07) or atazanavir (p = 0.028). Insulin resistance was found in 5 (10.6%) patients, 4 among those receiving lopinavir/ritonavir, one among those treated with efavirenz and none among subjects receiving atazanavir (p = 0.065). In the logistic regression analysis, the antiretroviral regimen was associated with risk of insulin resistance.. A substantial number of patients on antiretroviral therapy may have insulin resistance according to the HOMA index. Alterations of the hydrocarbonated metabolism appear to be more likely to occur in patients receiving regimens with lopinavir/ritonavir.

Topics: Alkynes; Anti-HIV Agents; Atazanavir Sulfate; Benzoxazines; Cross-Sectional Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Metabolic Syndrome; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Ritonavir; Time Factors