pyrimidinones and Dyslipidemias

Darunavir, previously known as TMC-114, is a new protease inhibitor (PI) with a high affinity for the HIV-1 protease and strong ability to inhibit its action, even in mutated forms. Consequently, this drug is considered to have great intrinsic potency and a high genetic barrier. At the time of writing, data on the tolerability and safety of darunavir come mainly from studies of late rescue therapy (POWER, DUET), which have included more than 1,600 patients. Recent data, relating to shorter time periods, are also available from studies in early treatment-experienced patients (TITAN) and in treatment-naïve patients (ARTEMIS), increasing experience to a further 600 patients. Lastly, more than 4,000 patients who have received darunavir through the Expanded Access Program have allowed the drug's generally good safety and tolerability profile to be defined. In the studies performed to date, darunavir has been well tolerated, with a better profile than that of the PIs used in control groups in terms of adverse effects such as diarrhea, gastrointestinal tolerability and lipid alterations. Moreover, to date, no unexpected severe adverse effects have been reported.

Topics: Adult; Chemical and Drug Induced Liver Injury; Clinical Trials, Phase III as Topic; Darunavir; Drug Therapy, Combination; Dyslipidemias; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; Humans; Incidence; Lopinavir; Male; Multicenter Studies as Topic; Pyrimidinones; Randomized Controlled Trials as Topic; Ritonavir; Salvage Therapy; Sulfonamides

Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals.. HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2.. A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant.. In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.

Topics: Adenine; Adipose Tissue; Adult; Anti-HIV Agents; Blood Glucose; Carbamates; Confidence Intervals; Drug Administration Schedule; Drug Combinations; Dyslipidemias; Furans; HIV Infections; HIV-1; Humans; Insulin; Insulin Resistance; Lamivudine; Lipids; Lopinavir; Male; Organophosphates; Organophosphonates; Pyrimidinones; Ritonavir; Sulfonamides; Tenofovir

The ARTEMIS study compared the efficacy of darunavir/ritonavir at once-daily doses of 800/100 mg versus once- or twice-daily doses of lopinavir/ritonavir, together with 300 mg of tenofovir and 200 mg of emtricitabine, both in once-daily doses, in treatment-naive patients. The results at 48 weeks show that darunavir/ritonavir is not inferior to lopinavir/ritonavir; the increase in CD4 count observed with both regimens was similar. Darunavir/ritonavir was superior to lopinavir/ritonavir in patients with high viral loads (>100,000 copies/mL). The use of darunavir/ritonavir was associated with a lower proportion of grades 2-4 adverse effects, especially gastrointestinal effects such as diarrhea and with a lower frequency of lipidic adverse effects, such as increased triglyceride and total cholesterol levels. Once-daily darunavir/ritonavir may be an option in first-line antiretroviral therapy, with the added advantage of a reduced dose of ritonavir and high efficacy in patients with elevated viral loads.

Topics: Adult; CD4 Lymphocyte Count; Darunavir; Drug Therapy, Combination; Dyslipidemias; Female; Gastrointestinal Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Ritonavir; RNA, Viral; Sulfonamides; Viral Load

Topics: Adult; CD4 Lymphocyte Count; Cholesterol; Cohort Studies; Drug Therapy, Combination; Dyslipidemias; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Pyrimidinones; Retrospective Studies; Ritonavir; Treatment Outcome; Triglycerides; Viral Load

Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease.

Topics: Acetyl-CoA Carboxylase; Animals; Dyslipidemias; Enzyme Inhibitors; Fatty Liver; Female; Hep G2 Cells; Humans; Insulin Resistance; Male; Molecular Docking Simulation; Obesity; Protein Multimerization; Pyrimidinones; Rats, Sprague-Dawley; Rats, Zucker; Structure-Activity Relationship; Thiophenes

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Dyslipidemias; Fluorobenzenes; HIV Infections; HIV-1; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lopinavir; Male; Middle Aged; Pyrimidines; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Ritonavir; Rosuvastatin Calcium; Sulfonamides; Treatment Outcome