Lack of hemodynamic interaction between CGRP-receptor antagonist telcagepant (MK-0974) and sumatriptan: results from a randomized study in patients with migraine.

OBJECTIVE: The objective of this article is to assess the effects of sumatriptan monotherapy, telcagepant monotherapy, and their combination on blood pressure (BP) in migraine patients during a headache-free period. METHODS: A double-blind, placebo-controlled, four-period, single-dose, randomized crossover study in 24 migraine patients was conducted. In each period, patients received a single oral dose of sumatriptan 100 mg alone, telcagepant 600 mg alone, sumatriptan 100 mg coadministered with telcagepant 600 mg, or placebo. Semi-recumbent BP was measured pre-dose and at seven post-dose time points over a period of six hours. Individual time-weighted averages in mean arterial pressure (MAP) were evaluated using a linear mixed-effects model. The pharmacokinetics of sumatriptan alone and in the presence of telcagepant were also evaluated using limited sampling times. RESULTS: The mean difference in time-weighted (0-2.5 h) MAP (90% confidence interval) was 1.2 mmHg (-0.2, 2.7) between telcagepant and placebo, 4.0 mmHg (2.5, 5.5) between sumatriptan and placebo, and 1.5 mmHg (0.0, 3.0) between telcagepant with sumatriptan vs sumatriptan alone. When coadministered with telcagepant, the AUC0-6h and C(max) of sumatriptan were increased by 23% and 24%, respectively. The small MAP increases observed after coadministration could possibly be associated with the slight elevations in sumatriptan levels. CONCLUSION: Telcagepant does not elevate mean MAP, and coadministration of telcagepant with sumatriptan results in elevations in MAP similar to those observed following administration of sumatriptan alone in migraineurs during the interictal period. When coadministered, telcagepant slightly increases the plasma levels of sumatriptan, but without an apparent clinically meaningful effect.

Calcitonin gene-related peptide8-37 antagonizes capsaicin-induced vasodilation in the skin: evaluation of a human in vivo pharmacodynamic model.

The purpose of this study was to identify the mediators involved in capsaicin-induced vasodilation in the human skin and to evaluate a pharmacodynamic model for the early clinical evaluation of calcitonin gene-related peptide (CGRP) receptor antagonists. Dermal blood flow (DBF) response of the forearm skin to topically applied capsaicin was measured using laser Doppler perfusion imaging in 22 subjects. The effect of intra-arterially administered CGRP(8-37) (1200 ng . min(-1) . dl(-1) forearm), indomethacin (5 mug . min(-1) . dl(-1) forearm), and N(G)-monomethyl-l-arginine (l-NMMA; 0.2 mg . min(-1) dl(-1) forearm), and orally administered aprepitant (375 mg) on capsaicin-induced dermal vasodilation was assessed. Furthermore, the diurnal variation of the DBF response to capsaicin was studied. CGRP(8-37) inhibited the capsaicin-induced DBF increase: 217(145, 290)% in infused versus 370 (254, 486)% in the noninfused arm [mean (95% CI); p = 0.004]. In contrast, indomethacin, l-NMMA, aprepitant, and the time of assessment did not affect the DBF response to capsaicin. Thus, capsaicin-induced vasodilation in the human forearm skin is largely mediated by CGRP, but not by vasodilating prostaglandins, nitric oxide, or substance P. The response to capsaicin does not display a circadian rhythm. A pharmacodynamic model is proposed to evaluate CGRP receptor antagonists in humans in vivo.

Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1.

Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of niacin-induced vasodilation.

The nasal mucosal late allergic reaction to grass pollen involves type 2 inflammation (IL-5 and IL-13), the inflammasome (IL-1ß), and complement.

Non-invasive mucosal sampling (nasosorption and nasal curettage) was used following nasal allergen challenge with grass pollen in subjects with allergic rhinitis, in order to define the molecular basis of the late allergic reaction (LAR). It was found that the nasal LAR to grass pollen involves parallel changes in pathways of type 2 inflammation (IL-4, IL-5 and IL-13), inflammasome-related (IL-1ß), and complement and circadian-associated genes. A grass pollen nasal spray was given to subjects with hay fever followed by serial sampling, in which cytokines and chemokines were measured in absorbed nasal mucosal lining fluid, and global gene expression (transcriptomics) assessed in nasal mucosal curettage samples. Twelve of 19 subjects responded with elevations in interleukin (IL)-5, IL-13, IL-1ß and MIP-1ß/CCL4 protein levels in the late phase. In addition, in these individuals whole-genome expression profiling showed upregulation of type 2 inflammation involving eosinophils and IL-4, IL-5 and IL-13; neutrophil recruitment with IL-1α and IL-1ß; the alternative pathway of complement (factor P and C5aR); and prominent effects on circadian-associated transcription regulators. Baseline IL-33 mRNA strongly correlated with these late-phase responses, whereas a single oral dose of prednisone dose-dependently reversed most nasal allergen challenge-induced cytokine and transcript responses. This study shows that the LAR to grass pollen involves a range of inflammatory pathways and suggests potential new biomarkers and therapeutic targets. Furthermore, the marked variation in mucosal inflammatory events between different patients suggests that in the future precision mucosal sampling may enable rational specific therapy.

Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test.

BACKGROUND: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. OBJECTIVES: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. METHODS: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. RESULTS: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts. CONCLUSION: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma.

Effect of MK-386, a novel inhibitor of type 1 5 alpha-reductase, alone and in combination with finasteride, on serum dihydrotestosterone concentrations in men.

Two isozymes (types 1 and 2) of 5 alpha-reductase (5 alpha R; EC 1.3.99.5), with differential tissue distribution, have been identified in humans. These enzymes catalyze the reduction of testosterone (T) to dihydrotestosterone (DHT). The contributions of each of these isozymes to serum and tissue concentrations of DHT remain to be fully defined. Finasteride, a selective inhibitor of type 2 5 alpha R, lowers circulating DHT levels by approximately 70% in men after treatment with 5 mg daily. MK-386 (4,7 beta-dimethyl-4-aza-5 alpha-cholestan-3-one) is a new selective inhibitor of type 1 5 alpha R. A single rising dose, alternating panel, trial in 16 healthy males (age range, 21-25 yr) studied the effect of 0.1-100 mg MK-386. DHT was maximally reduced by 20-30% relative to placebo at MK-386 doses of 10 mg or more, orally, by 24 h posttreatment (P < 0.01 vs. placebo). No consistent effect on T concentrations was evident. In a second trial, finasteride (5 mg) was given for 19 days to 10 healthy young men (age range, 24-47 yr); a 25-mg dose of MK-386 was added for 2 days of combination therapy after at least 10 days of finasteride treatment. Withdrawal of MK-386 was followed by 5-6 days of finasteride follow-up treatment. Finasteride alone reduced DHT, on the average, by 68.7% (SE = 3.4%). Addition of MK-386 suppressed DHT by 89.5% (SE = 1.4%) relative to baseline (P < 0.01 vs. effect of finasteride alone). Small increases in serum T were observed with finasteride alone and in combination with MK-386 (approximately 10% and 19%, respectively). These data are consistent with selective 5 alpha R type 1 inhibition in man by MK-386 and the prediction that types 1 and 2 5 alpha R account for all, or nearly all, of circulating DHT. Further clinical trials are needed to assess the therapeutic utility of type 1 5 alpha R inhibition as well as that of combined inhibition of types 1 and 2 5 alpha R.

In-vitro metabolism of celecoxib, a cyclooxygenase-2 inhibitor, by allelic variant forms of human liver microsomal cytochrome P450 2C9: correlation with CYP2C9 genotype and in-vivo pharmacokinetics.

In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.

Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the airways of patients with asthma.

Montelukast, a new specific oral cysteinyl LT3-receptor antagonist was evaluated for its activity in attenuating inhaled leukotriene D4 (LTD4) bronchoconstriction in patients with asthma. In two double-blind, placebo-controlled, randomized crossover studies, patients with mild asthma (forced expiratory volume in 1 second [FEV1] > or = 70%) were studied. In trial A, LTD4 challenge began 4 hours (peak plasma concentration) after a single dose of placebo or 5, 20, 100, and 250 mg montelukast. In trial B, and LTD4 challenge was started 20 hours after administration of placebo, 40 mg montelukast, or 200 mg montelukast. During each challenge, twofold increasing concentrations of LTD4 were inhaled until specific airways conductance (sGaw) decreased by at least 50% (PC50) or the highest concentration of LTD4 was inhaled. In trial A with all doses and in trial B with the 200 mg dose, bronchoconstriction was attenuated (50% fall in sGaw was not observed) up to the highest dose of LTD4 administered. In trial B, during the 40 mg period, only two of six patients exhibited a 50% fall in sGaw; PC50 ratios (montelukast 40 mg/placebo) were 18 and 45 in these two patients. These results indicate that montelukast is a highly potent and long-lasting antagonist of LTD4-induced bronchoconstriction in patients with asthma.

Pharmacokinetics and pharmacodynamics of multiple oral doses of MK-0591, a 5-lipoxygenase-activating protein inhibitor.

The pharmacodynamics, kinetics, and tolerability of a new orally active 5-lipoxygenase inhibitor were evaluated in healthy male volunteers. MK-0591, 50, 125, and 250 mg every morning and 250 mg every 12 hours, was administered for 10 days. Leukotriene B4 biosynthesis ex vivo in ionophore (A23187)-stimulated whole blood and leukotriene E4 levels in urine were determined. Leukotriene B4 production was inhibited up to 90% of baseline for 12 hours after administration at the highest dose. The degree of leukotriene B4 inhibition ex vivo in whole blood significantly correlated with plasma MK-0591 concentrations (0 to 1500 ng/ml; r = 0.73). Urinary leukotriene E4 was inhibited by > 80% at 24 hours after administration for all dose levels. Pharmacokinetics of MK-0591 were linear, with a half-life of approximately 6 hours. Very little accumulation was seen after multiple dosing. MK-0591 had no effect on testosterone levels, and good tolerability was shown at all dose levels of MK-0591 administered for up to 10 days.

Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men.

MK-383 (L-tyrosine, N-(n-butylsulfonyl)-O-[4-butyl(4-piperidinyl)], monohydrochloride monohydrate) is a potent and specific platelet fibrinogen receptor antagonist that may be useful in preventing processes that lead to occlusive thrombus formation in the lumen of the blood vessel. Two placebo-controlled phase I trials were completed in 56 healthy volunteers to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-383 administered as 1- and 4-hour infusions in the presence and absence of aspirin. When administered to healthy male subjects by constant infusions up to 0.4 microgram/kg/min over 1 hour or up to 0.2 microgram/min over 4 hours, it provided a well-tolerated reversible means of inhibiting platelet function. At infusion rates of 0.25 and 0.15 microgram/kg/min for 1 and 4 hours, respectively, MK-383 extended baseline bleeding time by 2.0- to 2.5-fold and inhibited adenosine diphosphate (ADP)-induced platelet aggregation by at least 80%. The pharmacokinetics of MK-383 include a mean plasma clearance of 329 ml/min, steady-state volume of distribution of 76 L, and half-life of 1.6 hours. The percentage of dose excreted in the urine was 37%. Correlations between MK-383 plasma concentration (C) and inhibition of platelet aggregation were examined by fitting with a sigmoid maximum-effect model. The plasma concentration yielding 50% inhibition (C50) for MK-383 in healthy volunteers is approximately 13 ng/ml, with a Hill coefficient > 5. Based on a naive pooled analysis, an exponential empirical model best describes the MK-383 C-extension of template bleeding time (BTE) relationship. The model indicates that the MK-383 plasma concentration necessary to double BTE is approximately 30 ng/ml (i.e., 2.5-fold greater than the C50 for ADP-induced inhibition of platelet aggregation). The pharmacokinetics of MK-383 was unaffected by pretreatment with 325 mg aspirin 1 day before and 1 hour before infusion. Conversely, aspirin pretreatment reduced C50 and increased bleeding time extension, suggesting that aspirin may have an additive effect with respect to inhibition of platelet function. Based on the putative role of the fibrinogen receptor in thrombotic processes and an acceptable human pharmacokinetic-pharmacodynamic profile, MK-383 should be evaluated in patients with unstable angina.

Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase. The induction of COX-2 after inflammatory stimuli has led to the hypothesis that COX-2 inhibition primarily accounts for the therapeutic properties of NSAIDs. METHODS: Chinese hamster ovary (CHO) cell lines that express each COX isoform were used to characterize the in vitro selectivity of rofecoxib. Single oral doses of rofecoxib and indomethacin were then assessed in subjects with use of ex vivo COX-isoform specific assays (serum thromboxane B2 [TXB2] and lipopolysaccharide [LPS]-stimulated whole blood prostaglandin E2 and assays of COX-1 and COX-2 activity, respectively). A double-blind, parallel-group study compared the analgesic efficacy of rofecoxib to placebo and ibuprofen in 102 patients with dental pain. RESULTS: Rofecoxib showed a >800-fold COX-2 selectivity with use of CHO cells that express human COX-1 and COX-2. In subjects, dose- and concentration-dependent inhibition of LPS-stimulated prostaglandin E2 was observed with both rofecoxib (IC50 [the concentration estimated to produce 50% inhibition], 0.77 micromol/L) and indomethacin (IC50, 0.33 micromol/L). Whereas indomethacin inhibited TXB2, (IC50, 0.14 micromol/L), no inhibition was observed with rofecoxib even at doses of up to 1000 mg. In the dental pain study, total pain relief (TOTPAR) over the 6 hours after dosing was similar between 50 mg and 500 mg rofecoxib and 400 mg ibuprofen (P > .20). All active treatments showed greater improvement than placebo (P < .001) CONCLUSIONS: Rofecoxib inhibited COX-2 without evidence of COX-1 inhibition, even at oral doses of up to 1000 mg. Nonetheless, rofecoxib showed analgesic activity indistinguishable from that observed with ibuprofen, a nonisoform-selective COX inhibitor. These results support the hypothesis that the analgesic effects of NSAIDs primarily derive from inhibition of COX-2.

Effects of enteric-coated, low-dose aspirin on parameters of platelet function.

BACKGROUND: Aspirin is widely used as an anti-thrombotic drug; however, it has been suggested that enteric-coated formulations of aspirin may be less bioavailable and less effective as anti-thrombotic agents. AIM: To assess the effect of a formulation of enteric-coated, low-dose (81 mg) aspirin on serum generated thromboxane B2 and platelet aggregation in healthy subjects. METHODS: Twenty-four subjects participated in a double-blind, randomized, placebo-controlled, parallel-group, multiple-dose study. Twelve subjects in each of two groups received a daily oral dose of enteric-coated aspirin (81 mg) or matching placebo for 7 days. Serum thromboxane B2 and platelet aggregation (using 1 mm arachidonic acid and 1 microg/mL collagen as agonists) were measured 1-3 days prior to day 1, on day 1 (prior to therapy) and 4 h after the last dose on day 7. RESULTS: After seven daily doses of enteric-coated aspirin, the mean percentage inhibition from baseline of ex vivo generated serum thromboxane B2 was 97.4%, compared with a 7.8% increase after placebo treatment. The mean percentage inhibition of arachidonic acid- and collagen-induced platelet aggregation was 97.9% and 70.9%, respectively, following enteric-coated aspirin, compared with - 1.0% and 2.7%, respectively, after placebo. CONCLUSIONS: The anti-platelet effects of multiple, daily, low-dose aspirin (as assessed by inhibition of serum thromboxane B2 and platelet aggregation) are not adversely affected by enteric coating.

Effect of multiple doses of montelukast, a CysLT1 receptor antagonist, on digoxin pharmacokinetics in healthy volunteers.

The effect of multiple oral doses of montelukast, a cysLT1 receptor antagonist, on the pharmacokinetics of oral digoxin was studied in healthy male volunteers in a randomized double-blind two-period crossover study. Subjects received 10 mg of montelukast or placebo daily for 11 days. On day 7, they received a single 0.5 mg oral dose of digoxin elixir. The pharmacokinetic parameters of digoxin (AUC0-->24' AUC0-->infinity' Cmax' tmax' t1/2) and cumulative urinary excretion over 120 hours were not affected by the multiple doses of montelukast. The 90% confidence interval for each of these parameters fell within prespecified clinically acceptable bounds. Side effects were mild and transient. This suggests that concurrent administration of montelukast and digoxin was well tolerated. Concurrent treatment with montelukast has no effect on the pharmacokinetics of digoxin.

Effect of montelukast on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Montelukast, a cysteinyl leukotriene receptor antagonist, is being developed for the treatment of asthma and related diseases. This study was designed to evaluate whether montelukast at clinically used dosage levels would interfere with the anticoagulant effect of warfarin. In a two-period, double-blind, randomized crossover study, 12 healthy male subjects received a single oral dose of 30 mg warfarin on the 7th day of a 12-day treatment with montelukast, 10 mg daily by mouth, or a placebo. Montelukast had no significant effect on the area under the plasma concentration-time curves and peak plasma concentrations of either R- or S-warfarin. However, slight but statistically significant decreases in time to peak concentration of both warfarin enantiomers and in elimination half-life of the less potent R-warfarin were observed in the presence of montelukast. These changes were not considered as clinically relevant. Montelukast had no significant effect on the anticoagulant effect of warfarin, as assessed by the international normalized ratio (INR) for prothrombin time (AUC0-144 and INR maximum). The results of this study suggest that a clinically important interaction between these drugs is unlikely to occur in patients requiring concomitant administration of both drugs.

Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers.

Steady-state inhibitory activity of rofecoxib (Vioxx) on COX-2 versus COX-1 was compared with that of commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in 76 healthy volunteers randomized to placebo, rofecoxib 12.5 mg qd, rofecoxib 25 mg qd, diclofenac 50 mg tid, ibuprofen 800 mg tid, sodium naproxen 550 mg bid, or meloxicam 15 mg qd. All of these doses include the high end of the approved clinical dose range. Ex vivo whole-blood assays were used to determine the effect on COX-2 and COX-1 activity, respectively. Urinary prostanoids were also measured. Mean inhibition of COX-2 (measured as the weighted average inhibition [WAI] of lipopolysaccharide [LPS]-induced PGE2 generation over 8 hours on day 6 vs. baseline) was -2.4%, 66.7%, 69.2%, 77.5%, 93.9%, 71.4%, and 71.5% for placebo, rofecoxib 12.5 mg, rofecoxib 25 mg, meloxicam, diclofenac, ibuprofen, and naproxen, respectively. Corresponding values for mean inhibition of COX-1 (measured as TXB2 generation in clotting whole blood) were -5.15%, 7.98%, 6.65%, 53.3%, 49.5%, 88.7%, and 94.9%. Rofecoxib had no significant effect on urinary excretion of 11-dehydro TXB2, a COX-1-derived product. These data support the contention that rofecoxib is the only drug of the regimens tested that uniquely inhibits COX-2 without affecting COX-1.

Hormonal effects, tolerability, and preliminary kinetics in men of MK-906, a 5 alpha-reductase inhibitor.

The hormonal effects following the acute (single dose) administration of a 4-azasteroid inhibitor of 5 alpha-reductase (MK-906) were evaluated in 10 healthy male volunteers. Marked suppression of serum dihydrotestosterone (DHT) was observed after the administration of single doses as low as 12.5 mg. The mean percent decrease in DHT at 24 hours in the group treated with a single 25-mg dose was 56% +/- 10% compared with the baseline. The suppression of plasma DHT levels continued for up to 72 hours. This study demonstrates that administration of single oral doses (12.5 to 400 mg) of MK-906 results in a significant decrease in the conversion of testosterone to DHT.

Effect of benazepril, a converting enzyme inhibitor, on plasma levels and activity of acenocoumarol and warfarin.

The effect of benazepril (CGS 14824), 20 mg/day orally, on the steady-state pharmaco-dynamics and plasma levels of the anticoagulants, warfarin and acenocoumarol, was studied in healthy volunteers. The anticoagulant activity of acenocoumarol was not affected by benazepril; there was an apparent slight but statistically significant reduction of the anticoagulant effect of warfarin. The magnitude of the inhibitory effect was considered not to be clinically important. There was no effect of benazepril on plasma steady-state levels of either anticoagulants.

Human pharmacokinetics and tolerability of L-697,639, a non-nucleoside HIV-1 reverse transcriptase inhibitor.

L-697,639, a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in vitro, was administered to healthy male volunteers to investigate the pharmacokinetics and tolerability of single and multiple oral doses. Single doses ranging from 25 to 500 mg, and multiple doses of up to 100 mg every 12 h for ten days, produced no clinically important adverse events. Dose proportionality with respect to AUC was seen over the range of 25-100 mg administered as a single dose. Single doses of 200 mg and 500 mg resulted in an increase in AUC and Cmax that was less than proportional to the increase in dose. The mean Cmax after single doses of 25 and 500 mg were 0.9 and 5.8 microM respectively. Mean Tmax values ranged from 1.7-3 h. Mean AUCs (0-48 h) were from 6.05 to 50.3 microM h after doses from 25 to 500 mg respectively. After the 500-mg dose less than 0.7% appeared unchanged in the urine over 48 hours. During multiple doses, steady-state was reached on day 3 and slight accumulation occurred (approximately 1.5-fold). L-697,639 was well tolerated for up to ten days at doses that resulted in mean steady-state trough concentrations that exceed their in-vitro susceptibilities.

Pharmacokinetic and pharmacodynamic interaction between the lipoxygenase inhibitor MK-0591 and the cyclooxygenase inhibitor ibuprofen in man.

Twelve healthy male subjects participated in a double-blind, placebo-controlled, randomized, three-period, crossover study to investigate the safety, tolerability, biochemical activity and pharmacokinetics of ibuprofen, a cyclooxygenase inhibitor and MK-0591, a 5-lipoxygenase inhibitor, given as single entities and in combination. Each subject received for three consecutive 8-day periods, separated by 1 week washout, each of the following treatments: ibuprofen 600 mg three times a day with 125 mg MK-0591 twice a day, ibuprofen 600 mg three times a day with placebo for MK-0591 and MK-0591 125 mg twice a day with placebo for ibuprofen. Cyclooxygenase inhibition was measured by platelet thromboxane (TxB2) generation test, and 5-lipoxygenase inhibition was measured by urinary leukotriene E4 excretion and ex vivo LTB4 generation in calcium-ionophore-stimulated blood. TxB2 suppression on day 8 by ibuprofen was not affected by concomitant treatment with MK-0591. MK-0591 alone had no effect on TxB2 generation. Leukotriene biosynthesis was inhibited by more than 90% by MK-0591 alone and by combined treatment, while ibuprofen alone had no effect. Coadministration appears to affect the pharmacokinetics of MK-0591 (decrease of area under the plasma concentration-vs-time curve [AUC] and maximum plasma concentrations [Cmax]) and of ibuprofen (increase of AUC and half-lives of elimination (t1/2) of the (S)-enantiomer, increase of t1/2 the (R)-enantiomer). Combined treatment had no effect on creatinine clearance nor on the number and intensity of the reported adverse experiences.

Lack of interaction between famotidine and warfarin.

In eight healthy male volunteers taking daily subtherapeutic doses of warfarin (mean daily dose = 4.0 mg), the addition of famotidine 40 mg once-a-day for seven days did not alter the prothrombin time profile, thrombotest coagulation time or total warfarin steady-state plasma concentration. Plasma peak concentration, time to peak concentration and area under curve for famotidine were not affected by the co-administration of warfarin. However the plasma half-life of famotidine was slightly, but statistically significantly longer (p less than 0.05) during maintenance treatment with warfarin (mean +/- s.e.m.: 2.58 +/- 0.14 h versus 2.96 +/- 0.16 h respectively).