We compared bone mineral density (BMD) changes and their correlates, between men and women participating in two randomized trials of initial [antiretroviral therapy (ART)] regimens, with or without tenofovir disoproxil fumarate (TDF).
This chapter describes previously published nonintegrated pharmacokinetic-pharmacodynamic (PK/PD) approaches, as well as some current ones. It discusses current approaches to describe effect-time profiles of benzodiazepines. The chapter also discusses that the data obtained under conditions commonly used in benzodiazepine studies can be analyzed with an appropriate PK-PD model. Benzodiazepines are used extensively as sedative, hypnotic, and anxiolytic agents, as well as anesthetic medication. Single dosing of benzodiazepines is important in hypnotic, anesthetic, and anxiolytic therapy. By far the greatest use of benzodiazepines is in the treatment of anxiety and related conditions. Early studies have used nonintegrated PK/PD approaches for the evaluation of the clinical profile of benzodiazepines. One could argue that distribution phenomena are not likely to interfere substantially with the establishment of benzodiazepine plasma concentration-drug effect relationships, as the majority of these highly lipophilic compounds readily cross the blood-brain barrier.
Background Insomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated. Methods We examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, “Difficulty falling or staying asleep?,” with the following response options: “I do not have this symptom” or “I have this symptom and…” “it doesn’t bother me,” “it bothers me a little,” “it bothers me,” “it bothers me a lot.” Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval ( CI ). Results We observed no significant associations between insomnia symptoms and sCD14 or IL-6. For D-dimer, veterans in the “Bothers a Lot” group had, on average, 17% higher D-dimer than veterans in the “No Difficulty Falling or Staying Asleep” group in the demographic-adjusted model (exp[b] = 1.17, 95% CI = 1.01–1.37, p = .04). This association was nonsignificant in the fully-adjusted model (exp[b] = 1.09, 95% CI = 0.94–1.26, p = .27). Conclusion We observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted.
Eight healthy young males were administered single doses of lorazepam (4 mg), clonazepam (4 mg), alprazolam (2 mg) or placebo, and their performance on behavioral tasks was monitored for 7 h. Lorazepam and clonazepam impaired performance on subcritical tracking, a primarily neuromotor task, for 2–4 h longer than alprazolam. Although the duration of impairment of the digit symbol substitution task was less discrepant for the three drugs, clonazepam and lorazepam still affected performance for a longer period of time than alprazolam. The rapid development of acute tolerance was indicated by clockwise hysteresis curves for all the drugs on the SCT task and for clonazepam and alprazolam on the DSS task. The maximum effect, effect offset rate and duration of the drug effect are discussed in relation to molecular structure and receptor affinity.
A 45-year-old man infected with human immunodeficiency virus (HIV) developed abnormal fat accumulations that initially were believed to be caused by HIV lipodystrophy. Further clinical evaluation revealed, however, that the patient had developed exogenous Cushing syndrome, which presumably was caused by the inhibition of CYP3A4's metabolism of inhaled fluticasone by the protease inhibitor ritonavir. Clinicians should be aware that clinical clues may indicate conditions other than lipodystrophy that may cause abnormal fat accumulation and that fluticasone should be cautiously administered to patients who are receiving ritonavir.
