Effect of telcagepant on spontaneous ischemia in cardiovascular patients in a randomized study.

OBJECTIVE: The primary purpose of the study was to explore the safety and tolerability of telcagepant in patients with stable coronary artery disease. BACKGROUND: Triptans are effective acute anti-migraine drugs whose vasoconstrictive effects limit their use in patients at risk for adverse cardiovascular events. Telcagepant, a calcitonin gene-related peptide receptor antagonist, is being developed for the acute treatment of migraine. Antagonism of calcitonin gene-related peptide, which does not appear to cause vasoconstriction, may allow for treatment of migraine in patients with coronary artery disease. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients with documented stable coronary artery disease were assigned to 1 of 2 treatment sequences: telcagepant then placebo, or placebo then telcagepant. In each treatment period, patients received 2 doses of telcagepant 300-mg or placebo 2 hours apart. They remained in the research center for 24 hours after receiving the first dose of each period, during which time continuous 12-lead ambulatory electrocardiographic (Holter) monitoring was performed. RESULTS: Twenty-eight patients were enrolled; all patients completed the study and were included in all analyses. Telcagepant was generally well tolerated. No laboratory or serious adverse experiences were reported, and no patient discontinued due to an adverse experience. There were no consistent treatment-related changes in laboratory, vital signs or electrocardiogram safety parameters. Three patients (2 after receiving placebo and 1 after receiving telcagepant) experienced ST segment depression during the study; none of these patients reported chest pain. CONCLUSIONS: Two doses of 300-mg telcagepant, administered 2 hours apart, did not appear to exacerbate spontaneous ischemia and were generally well tolerated in a small cohort of patients with stable coronary artery disease. Results of this study support further evaluation of telcagepant in patients with stable coronary artery disease.

Effects of extended release niacin/laropiprant, laropiprant, extended release niacin and placebo on platelet aggregation and bleeding time in healthy subjects.

Laropiprant (LRPT) has been shown to reduce flushing symptoms induced by niacin and has been combined with niacin for treatment of dyslipidemia. LRPT, a potent PGD(2) receptor (DP1) antagonist that also has modest activity at the thromboxane receptor (TP), may have the potential to alter platelet function either by enhancing platelet reactivity through DP1 antagonism or by inhibiting platelet aggregation through TP antagonism. Studies of platelet aggregation ex vivo and bleeding time have shown that LRPT, at therapeutic doses, does not produce clinically meaningful alterations in platelet function. The present study was conducted to assess platelet reactivity to LRPT using methods that increase the sensitivity to detect changes in platelet responsiveness to collagen and ADP. The responsiveness of platelets was quantified by determining the EC(50) of collagen to induce platelet aggregation ex vivo. At 24 hours post-dose on Day 7, the responsiveness of platelets to collagen-induced aggregation was similar following daily treatment with extended-release niacin (ERN) 2 g/LRPT 40 mg or ERN 2 g. At 2 hours post-dose on Day 7, the EC(50) for collagen-induced platelet aggregation was approximately two-fold higher in the presence of LRPT, consistent with a small, transient inhibition of platelet responsiveness to collagen. There was no clinical difference between treatments for bleeding time, suggesting that this small effect on collagen EC(50) does not result in a clinically meaningful alteration of platelet function in vivo. The results of this highly sensitive method demonstrate that LRPT does not enhance platelet reactivity when given alone or with ERN.

Effect of rifampin, a potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir.

Raltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor that is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin (rifampicin). Two pharmacokinetic studies were performed in healthy subjects: study 1 examined the effect of administration of 600-mg rifampin once daily on the pharmacokinetics of a single dose of 400-mg raltegravir, and study 2 examined the effect of 600-mg rifampin once daily on the pharmacokinetics of 800-mg raltegravir twice daily compared to 400-mg raltegravir twice daily without rifampin. Raltegravir coadministered with rifampin resulted in lower plasma raltegravir concentrations: in study 1, the geometric mean ratios (GMRs) and 90% confidence intervals (90% CIs) for the plasma raltegravir concentration determined 12 h postdose (C(12)), area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), and maximum concentration of drug in plasma (C(max)) (400-mg raltegravir plus rifampin/400-mg raltegravir) were 0.39 (0.30, 0.51), 0.60 (0.39, 0.91), and 0.62 (0.37, 1.04), respectively. In study 2, the GMRs and 90% CIs for raltegravir C(12), AUC(0-12), and C(max) (800-mg raltegravir plus rifampin/400-mg raltegravir) were 0.47 (0.36, 0.61), 1.27 (0.94, 1.71), and 1.62 (1.12, 2.33), respectively. Doubling the raltegravir dose to 800 mg when coadministered with rifampin therefore compensates for the effect of rifampin on raltegravir exposure (AUC(0-12)) but does not overcome the effect of rifampin on raltegravir trough concentrations (C(12)). Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used, since raltegravir trough concentrations in the presence of rifampin are likely to be at the lower limit of clinical experience.

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.

BACKGROUND: Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. METHODS: We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. FINDINGS: In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. INTERPRETATION: This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

Advances in antifungal therapy.

The prevalence of invasive fungal infections (IFIs) has increased over the past three decades owing to the increasing numbers of immunocompromised hosts. These infections are associated with significant morbidity and mortality. Recent significant advances in antifungal therapy include the broad-spectrum triazoles (voriconazole and posaconazole) and a new class of antifungals, the echinocandins (caspofungin, micafungin, and anidulafungin). New treatment strategies, such as combination therapy and pre-emptive therapy, are being investigated. There have also been significant improvements in diagnostics; the galactomannan enzyme immunoassay and the beta-glucan test are now part of the EORTC/MSG criteria for diagnosis of IFI. Despite these advances, there remain a number of unanswered questions regarding optimal management of serious fungal infections, and research continues to discover and develop new therapies and evaluate new management strategies.

Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine.

OBJECTIVE: To assess virological and immunological responses and toxicity in subjects receiving combination antiretroviral therapy. DESIGN: Six-year follow-up of a single arm of a randomized study of combination antiretroviral therapy. METHODS: HIV-infected, zidovudine-experienced patients originally randomized to receive indinavir, zidovudine, and lamivudine had HIV RNA levels and CD4 cell counts assessed over 6 years. Information was collected by questionnaire from subjects who discontinued the study regimen before 6 years. Both on-study and post-study responses were assessed. RESULTS: Of 33 subjects, 16 (48%) discontinued before 6 years of follow-up. After 6 years, 16 (53%) and 14 (47%) of 30 contributing subjects had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline for 28 contributing subjects was 268 x 10(6) cells/l. Treatment-limiting nephrolithiasis occurred in four subjects. Of the 16 subjects who discontinued the study, 12 had post-study questionnaire data available and seven had HIV RNA < 500 copies/ml on a post-study regimen. In an exploratory analysis combining both on-study and post-study data at approximately 6 years, 26 (79%) and 19 (58%) of 33 had HIV RNA levels < 500 and < 50 copies/ml, respectively, and the median increase in CD4 cell count from baseline was 344 x 106 cells/l. CONCLUSIONS: Antiretroviral therapy with indinavir, zidovudine, and lamivudine suppressed HIV viremia and produced continued CD4 cell increases in a majority of subjects for 6 years. Most subjects who discontinued study medications had HIV RNA levels suppressed on post-study therapy. Though based on a small group, this study demonstrates the durable effects of antiretroviral therapy.