Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans.

BACKGROUND: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS: The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES: Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist.

In the accompanying paper we describe how MRK-409 unexpectedly produced sedation in man at relatively low levels of GABA(A) receptor occupancy (∼10%). Since it was not clear whether this sedation was mediated via the α2/α3 or α1 GABA(A) subtype(s), we characterized the properties of TPA023B, a high-affinity imidazotriazine which, like MRK-409, has partial agonist efficacy at the α2 and α3 subtype but is an antagonist at the α1 subtype, at which MRK-409 has weak partial agonism. TPA023B gave dose- and time-dependent occupancy of rat brain GABA(A) receptors as measured using an in vivo [(3)H]flumazenil binding assay, with 50% occupancy corresponding to a respective dose and plasma drug concentration of 0.09 mg/kg and 19 ng/mL, the latter of which was similar to that observed in mice (25 ng/mL) and comparable to values obtained in baboon and man using [(11)C]flumazenil PET (10 and 5.8 ng/mL, respectively). TPA023B was anxiolytic in rodent and primate (squirrel monkey) models of anxiety (elevated plus maze, fear-potentiated startle, conditioned suppression of drinking, conditioned emotional response) yet had no significant effects in rodent or primate assays of ataxia and/or myorelaxation (rotarod, chain-pulling, lever pressing), up to doses (10 mg/kg) corresponding to occupancy of greater than 99%. In man, TPA023B was well tolerated at a dose (1.5 mg) that produced occupancy of >50%, suggesting that the sedation previously seen with MRK-409 is due to the partial agonist efficacy of that compound at the α1 subtype, and highlighting the importance of antagonist efficacy at this particular GABA(A) receptor population for avoiding sedation in man.

Does the unfavorable pharmacokinetic and pharmacodynamic profile of the iNOS inhibitor GW273629 lead to inefficacy in acute migraine?

The objective of this study was to investigate the pharmacodynamics and pharmacokinetics of a single dose of GW273629, a selective iNOS inhibitor, given during and outside a migraine attack. GW273629 1500 mg was administered to 15 migraine patients both ictally and interictally. Nasal and exhaled nitric oxide (NO), plasma 3-nitrotyrosine, and nitrates were measured to assess systemic NO production. In addition, pharmacokinetics and treatment response were assessed. Data are mean (95% confidence interval [CI]). Plasma 3-nitrotyrosine was higher ictally: 11.96 (8.22, 15.71) ictally versus 2.74 (2.24, 3.24) ng/10 mg interictally (P < .0001). Exhaled and nasal NO showed a similar trend: 12.5 (6.5, 18.6) and 62.2 (41.5, 82.8) ppb ictally versus 9.9 (6.3, 13.4) ppb and 52.5 (38.5, 66.0) ppb interictally, respectively. Early absorption of GW273629 (AUC(0-2) [90% CI]) was reduced by 41 (22, 55)% during an attack. There was no improvement of headache or associated symptoms. Migraine headache is associated with reduced early absorption of GW273629 and excess NO production. In this open-label study, GW273629 was ineffective in the treatment of acute migraine.

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.

Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist.

Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.

Reproducibility of the capsaicin-induced dermal blood flow response as assessed by laser Doppler perfusion imaging.

AIMS: Part I: to establish the dose and appropriate application site of capsaicin on the human forearm in order to produce a robust and reproducible dermal blood flow (DBF) response. Part II: to evaluate the within-subject arm-to-arm and period-to-period reproducibility. METHODS: Both parts consisted of two study visits. In part I, placebo and 100, 300 and 1000 microg capsaicin were applied at four predefined sites on the volar surface of both forearms. Placebo and capsaicin doses were randomized and balanced by site between subjects. Changes in DBF were assessed by laser Doppler perfusion imaging up to 60 min after capsaicin application. In part II, only 1000 microg capsaicin was applied on the proximal forearm and changes in DBF assessed up to 30 min (t(30)). DBF response was expressed as percent change from baseline +/- SD and the corresponding AUC(0-30). Reproducibility assessment included calculation of the concordance correlation coefficient (CCC). RESULTS: Part I (n = 12 subjects): compared with placebo, 300 and 1000 microg capsaicin increased DBF (P < 0.05) at all time points except at 10 min. This increase was reproducible at the two most proximal sites from the 30-min time point onwards when compared between arms (CCC >or= 0.8, i.e. substantial to almost perfect reproducibility). In part II (n = 11), t(30) averaged 390 +/- 120% and arm-to-arm reproducibility was almost perfect (CCC = 0.91) for AUC(0-30). CONCLUSIONS: Capsaicin induces a reproducible within-subject arm-to-arm increase in DBF. We provide a non-invasive pharmacodynamic model in humans to test antagonists of mediators involved in capsaicin-induced dermal vasodilation, including calcitonin gene-related peptide antagonists.

The effect of MK-0524, a prostaglandin D(2) receptor antagonist, on prostaglandin D (2)-induced nasal airway obstruction in healthy volunteers.

INTRODUCTION: Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D(2) is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD(2) reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD(2) (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD(2) can be a useful tool for evaluating DP-receptor antagonists. OBJECTIVE: The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD(2) induced nasal congestion in healthy volunteers. METHODS: To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD(2) were performed to determine the PD(75), which is the intranasal dose of PGD(2) that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry. RESULTS: Following treatment with MK-0524, the PD(75) (mean+/-SD) was significantly shifted from 15.8 +/- 18.3 mug/nostril during the placebo period to more than 512 mug/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen. CONCLUSION: Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.

Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin.

OBJECTIVE: To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK1)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting. METHODS: This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10-12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1-3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day -1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily. RESULTS: The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC(0-24 h) and C(max). However, compared with placebo, trough S(-) warfarin concentrations decreased on days 5-8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011). CONCLUSION: These data are consistent with a significant induction of CYP2C9 metabolism of S(-) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7-10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.

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.

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.

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.

Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.

OBJECTIVE: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (Vioxx), characterized in vitro as a COX-2 inhibitor. METHODS: Four panels of healthy men (n = 8 per panel) were administered rofecoxib (n = 6) (25, 100, 250, 375 mg) or placebo (n = 2) once daily on day 1 and days 3-14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose. RESULTS: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9 h to 17.5 h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on day 14 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient. CONCLUSION: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

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.

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.

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.

Effect of clopidogrel on naproxen-induced gastrointestinal blood loss in healthy volunteers.

The effect of clopidogrel, a potent inhibitor of platelet aggregation, on naproxen-induced faecal blood loss was investigated in 30 healthy volunteers in a randomized, double-blind, placebo-controlled, two parallel treatment groups study. All subjects first received naproxen 250 mg b.i.d. during 7 days, after which they were randomly allocated to additionally receive either clopidogrel 75 mg once daily (n = 15) or matching placebo (n = 15) for 11 days. Faecal blood loss was measured by the 51Cr-labelled erythrocyte method during the last four days of each of the four study periods, i.e. baseline, treatment with naproxen alone, combined treatment and wash-out. Mean daily faecal blood loss was below 0.5 ml/day during the baseline period in both treatment groups and increased during treatment with naproxen alone to (mean +/- SD) 1.14 +/- 0.58 ml/day in the naproxen + placebo group and to 1.93 +/- 1.51 ml/day in the naproxen + clopidogrel group. Addition of clopidogrel to naproxen treatment was associated with an increase of the mean daily blood loss to 6.83 +/- 9.32 ml/day, which was statistically significantly higher than 1.75 +/- 1.40 ml/day observed during treatment with naproxen + placebo. During the wash-out period, mean daily blood loss decreased to 0.98 +/- 0.51 ml/day in the naproxen + placebo group and to 1.07 +/- 0.46 ml/day in the naproxen + clopidogrel group. Based on these results, it can be concluded that clopidogrel increases naproxen-induced gastrointestinal blood loss in healthy volunteers. Caution should therefore be called for when these drugs are coadministered.

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.