A brief peer gatekeeper suicide prevention training: Results of an open pilot trial.

OBJECTIVE: The purpose of the present study was to test a 1-hour peer suicide gatekeeper training for students from the broad college community in the context of an open pilot trial. METHOD: Two-hundred and thirty-one college students were recruited university-wide, Mage  = 20.7, 65.4% female, and completed a peer suicide prevention gatekeeping training program. Assessments were completed at pre-training and post-training as well as 3-month follow-up. RESULTS: This brief peer suicide gatekeeper training program was associated with increases in suicide prevention knowledge. It was also associated with an increase in the number of students who identified suicidal youth and made mental health referrals, as well as total number of referrals made, over the course of three months. Females reported greater improvement in suicide prevention skills and knowledge post-training than males. CONCLUSIONS: Offering peer suicide gatekeeper training to students from the general college population may hold promise in suicide prevention efforts.

Pharmacokinetics of a CCR5 inhibitor in rhesus macaques following vaginal, rectal and oral application.

OBJECTIVES: This study measured and compared the pharmacokinetics of CMPD167, a small molecule antiretroviral CCR5 inhibitor with potential as an HIV microbicide, following vaginal, rectal and oral administration in rhesus macaques. METHODS: A vaginal hydroxyethylcellulose (HEC) gel, a rectal HEC gel, a silicone elastomer matrix-type vaginal ring and an oral solution, each containing CMPD167, were prepared and administered to rhesus macaques pretreated with Depo-Provera. CMPD167 concentrations in vaginal fluid, vaginal tissue (ring only), rectal fluid and blood plasma were quantified by HPLC-mass spectrometry. RESULTS: CMPD167 concentrations measured in rectal fluid, vaginal fluid and blood plasma were highly dependent on both the route of administration and the formulation type. Although rectal and vaginal fluid concentrations were highest when CMPD167 was administered locally (via either gel or ring), lower concentrations of the drug were also measured in these compartments following administration at the remote mucosal site or orally. CMPD167 levels in the vaginal and rectal fluid following oral administration were relatively low compared with local administration. CONCLUSIONS: The study provides clear evidence for vaginal-rectal and rectal-vaginal drug transfer pathways and suggests that oral pre-exposure prophylaxis with CMPD167 may be less efficacious at preventing sexual transmission of HIV-1 than topically applied products.

Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques.

OBJECTIVES: To investigate the pharmacokinetics (PK) of maraviroc, a CCR5-targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model. METHODS: Maraviroc concentrations in vaginal fluid (Weck-Cel(®) sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single-dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003%-3.3% w/w) that test gels included both fully solubilized and predominantly dispersed formulations. The efficacy of the HEC gels against a single high-dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations. RESULTS: Maraviroc concentrations in vaginal fluid (range 10(4)-10(7) ng/mL), vaginal tissue (100-1200 ng/g) and plasma (<10(2) ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilized versus dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily through to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel. CONCLUSIONS: A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 10(7) ng/mL and 10(3) ng/g, respectively, are required for complete protection with this compound.

Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220.

OBJECTIVES: The non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques. METHODS: In vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H(2)O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1 week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT-SHIV162P3 once weekly for 4 weeks. RESULTS: SEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H(2)O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan-Meier analysis over 9 weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037). CONCLUSIONS: An MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1.

Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques.

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 µg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.

Pharmacokinetics of etoricoxib in patients with hepatic impairment.

The effect of hepatic insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was investigated following administration of single and multiple oral doses to mild hepatic insufficiency patients (Child-Pugh score of 5 to 6), multiple oral doses to moderate hepatic insufficiency patients (Child-Pugh score of 7 to 9), and single intravenous doses to both mild and moderate hepatic insufficiency patients. A trend of decreasing systemic clearance with increasing hepatic impairment was observed. Absorption of etoricoxib was unaffected by hepatic impairment. Binding of etoricoxib to plasma proteins was also found to be unaffected by hepatic disease. Etoricoxib was generally well tolerated by patients with mild and moderate hepatic insufficiency. Together, these results support a 60-mg once-daily dosing regimen for mild hepatic insufficiency patients and a 60-mg every-other-day dosing regimen for moderate hepatic insufficiency patients. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score > 9).

Pharmacokinetics of etoricoxib in patients with renal impairment.

The effect of renal insufficiency on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, was examined in 23 patients with varying degrees of renal impairment (12 moderate [creatinine clearance between 30 and 50 mL/min/1.73 m2], 5 severe [creatinine clearance below 30 mL/min/1.73 m2], and 6 with end-stage renal disease requiring hemodialysis) following administration of single 120-mg oral doses of etoricoxib. Even the most severe renal impairment was found to have little effect on etoricoxib pharmacokinetics. The low recovery of etoricoxib in dialysate (less than 6% of the dose) supports that hemodialysis also has little effect on etoricoxib pharmacokinetics, and binding of etoricoxib to plasma proteins was generally unaffected by renal disease. Single doses of etoricoxib were generally well tolerated by patients with renal impairment. Based on pharmacokinetic considerations, dosing adjustments are not necessary for patients with any degree of renal impairment. However, because patients with advanced renal disease (creatinine clearance below 30 mL/min/1.73 m2) are likely to be very sensitive to any further compromise of renal function, and there is no long-term clinical experience in these patients, the use of etoricoxib is not recommended in patients with advanced renal disease.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc.

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Absorption, metabolism, and excretion of etoricoxib, a potent and selective cyclooxygenase-2 inhibitor, in healthy male volunteers.

[(14)C]Etoricoxib (100 microCi/dose) was administered to six healthy male subjects (i.v., 25 mg; p.o., 100 mg). Following the i.v. dose, the plasma clearance was 57 ml/min, and the harmonic mean half-life was 24.8 h. Etoricoxib accounted for the majority of the radioactivity (approximately 75%) present in plasma following both i.v. and p.o. doses. The oral dose, administered as a solution in polyethylene glycol-400, was well absorbed (absolute bioavailability of approximately 83%). Total recovery of radioactivity in the excreta was 90% (i.v.) and 80% (p.o.), with 70% (i.v.) and 60% (p.o.) excreted in urine and 20% in feces after either route of administration. Radiochromatographic analysis of the excreta revealed that etoricoxib was metabolized extensively, and only a minor fraction of the dose (<1%) was excreted unchanged. Radiochromatograms of urine and feces showed that the 6'-carboxylic acid derivative of etoricoxib was the major metabolite observed (> or =65% of the total radioactivity). 6'-Hydroxymethyl-etoricoxib and etoricoxib-1'-N-oxide, as well as the O-beta-D-glucuronide conjugate and the 1'-N-oxide derivative of 6'-hydroxymethyl-etoricoxib, were present in the excreta also (individually, < or =10% of the total radioactivity). In healthy male subjects, therefore, etoricoxib is well absorbed, is metabolized extensively via oxidation (6'-methyl oxidation >1'-N-oxidation), and the metabolites are excreted largely in the urine.

Metabolism of rofecoxib in vitro using human liver subcellular fractions.

The metabolism of rofecoxib, a potent and selective inhibitor of cyclooxygenase-2, was examined in vitro using human liver subcellular fractions. The biotransformation of rofecoxib was highly dependent on the subcellular fraction and the redox system used. In liver microsomal incubations, NADPH-dependent oxidation of rofecoxib to 5-hydroxyrofecoxib predominated, whereas NADPH-dependent reduction of rofecoxib to the 3,4-dihydrohydroxy acid metabolites predominated in cytosolic incubations. In incubations with S9 fractions, metabolites resulting from both oxidative and reductive pathways were observed. In contrast to microsomes, the oxidation of rofecoxib to 5-hydroxyrofecoxib by S9 fractions followed two pathways, one NADPH-dependent and one NAD+-dependent (non-cytochrome P450), with the latter accounting for about 40% of total activity. The 5-hydroxyrofecoxib thus formed was found to undergo NADPH-dependent reduction ("back reduction") to rofecoxib in incubations with liver cytosolic fractions. In incubations with dialyzed liver cytosol, net hydration of rofecoxib to form 3,4-dihydro-5-hydroxyrofecoxib was observed, whereas the 3,4-dihydrohydroxy acid derivatives were formed when NADPH was present. Although 3,4-dihydro-5-hydroxyrofecoxib could be reduced to the 3,4-dihydrohydroxy acid by cytosol in the presence of NADPH, the former species does not appear to serve as an intermediate in the overall reductive pathway of rofecoxib metabolism. In incubations of greater than 2 h with S9 fractions, net reductive metabolism predominated over oxidative metabolism. These in vitro results are consistent with previous findings on the metabolism of rofecoxib in vivo in human and provide a valuable insight into mechanistic aspects of the complex metabolism of this drug.

The disposition and metabolism of rofecoxib, a potent and selective cyclooxygenase-2 inhibitor, in human subjects.

The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [(14)C]rofecoxib (125 mg, 100 micro Ci) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that the t(max) was achieved at 9 h postdose. After t(max), levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effective t(1/2) approximately equal 17 h). A similar result was obtained after oral administration of [(14)C]rofecoxib (142 mg, 100 micro Ci) to cholecystectomy patients equipped with an L-tube. In healthy subjects, radioactivity was recovered predominantly from the urine (71.5% of dose), with a small amount excreted in feces (14.2%). In patients with an L-tube, half the radioactive dose was recovered in feces, with a lesser amount excreted in urine (28.8%) and a negligible fraction in bile (1.8%). Rofecoxib underwent extensive metabolism in humans, and very little parent drug was recovered unchanged in urine (<1%). Products resulting from both oxidative and reductive pathways were identified by a combination of (1)H NMR and liquid chromatography-tandem mass spectrometry analyses, and included rofecoxib-3',4'-trans-dihydrodiol, 4'-hydroxyrofecoxib-O-beta-D-glucuronide, diastereomeric 5-hydroxyrofecoxib-O-beta-D-glucuronide conjugates, 5-hydroxyrofecoxib, rofecoxib-erythro-3,4-dihydrohydroxy acid, and rofecoxib-threo-3,4-dihydrohydroxy acid. Interconversion of rofecoxib and 5-hydroxyrofecoxib appeared not to be a quantitatively important pathway of rofecoxib disposition in human subjects, in contrast to previous findings in rats.