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Background : Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxy- genase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity. Aim : To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin. Methods Healthy subjects (n = 170; age range 18–54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score ≥ 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population. Results The percentage of subjects who developed a mucosal score ≥ 2 in the MK-0966 group (12%) was significantly lower (P

To assess the effects of prolonged administration of a novel analog of GH-releasing peptide (MK-677), nine healthy young men participated in a randomized, double blind, three-period cross-over comparison of orally administered placebo and 5- and 25-mg doses of MK-677. Each period involved bedtime administration of the drug for 7 consecutive days. At the end of each period, plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured at 0745 h, and 24-h profiles of plasma GH and cortisol were obtained at 15-min intervals together with the 24-h urinary excretion of free cortisol. Profiles of plasma free cortisol were calculated at hourly intervals. The amounts of GH secreted were similar in all three conditions, but GH pulse frequency was increased with both dosages of the drug, primarily because of an increase in the number of low amplitude pulses. Plasma IGF-I levels were increased in a dose-dependent manner, whereas IGFBP-3 levels were increased only with the highest dosage. There was a positive relationship between GH pulse frequency and IGF-I increase. Except for an advance in the nocturnal nadir and in the morning elevation, MK-677 had no effect on cortisol profiles. In particular, 24-h mean levels of plasma total and free cortisol and urinary excretion of free cortisol were similar under all conditions. The present data suggest that the use of MK-677 for the treatment of relative somatotropic deficiency, particularly in older adults compromised by such deficiency, deserves further investigation.

The susceptibility of diamondback moth, Plutella xylostella (L.), larvae to 2 avermectins, abamectin and MK-243 (4-epi-methylamino-4 deoxyavermectin B 1 hydrochloride), was assessed through toxicity evaluations of 17-19 geographically diverse populations. Both avermectins were very potent to 3rd-instar diamondback moth ; LC 50 s for abamectin and MK-243 ranged from 0.4 to 44.0 ng (AI)/ml and 0.2 to 8.0 ng (AI)/ml, respectively. Although most populations showed resistance to methomyl and permethrin, the populations were not resistant to abamectin or MK-243. Pairwise correlations indicated lack of cross or multiple resistance between the avermectins and methomyl and permethrin. This information will serve as an aid for resistance monitoring programs and permit comparative changes in susceptibility during commercial use. Such data are necessary to assist in decisions to recommend product use appropriately in the context of resistance management.

Patients treated with nonselective cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs]) often experience dyspepsia and upper gastrointestinal (GI) adverse effects, and frequently require GI comedications and diagnostic procedures.This study combined existing data to test the hypothesis that GI comedications and GI diagnostic procedures occur less frequently in osteoarthritis (OA) patients treated with rofecoxib compared with nonselective NSAIDs.Combined analysis of 8 randomized controlled clinical trials.Rheumatology and general practice clinics.Men and women aged 40 years and older with OA.Random assignment to placebo (n = 514), rofecoxib (n = 3357; 12.5, 25, or 50 mg daily combined; average 24.7 mg), or NSAIDs (n = 1564; ibuprofen 800 mg thrice daily, diclofenac 50 mg thrice daily, or nabumetone 1500 mg daily, combined).The cumulative incidence of patients using GI comedications (antacids, antispasmodics, antiflatulents, antiregurgitants, H2 antagonists, proton pump inhibitors, sucralfate, prostaglandins, other antiulcer therapy) and needing GI procedures (upper GI barium studies, upper or lower GI endoscopies) over 12 months.Compared with those treated with NSAIDs, patients treated with rofecoxib had a significantly lower incidence of GI comedication use (17.5% vs 27.0%, P.001) and GI procedures (3.3% vs 5.3%, P =.02) over 12 months. Similar results were seen in analyses of protocols with placebo; in these studies, rates of GI comedications and procedures were highest with NSAIDs, while those with rofecoxib and placebo were similar to each other.OA patients treated with rofecoxib for up to 12 months required significantly less GI comedication and significantly fewer GI procedures than those treated with NSAIDs.

Osteoarthritis (OA) clinical studies generally employ various endpoints to evaluate a spectrum of disease manifestations. Compared with individual endpoints, a composite measure might (1) provide a uniform outcome measure of OA efficacy with greater face validity, (2) address multiplicity, and (3) enhance precision. Combinations of endpoints were analyzed to investigate precision of composite measures of OA efficacy.We reanalyzed three 6 week, placebo controlled, double blind, parallel group studies (2 by the same protocol) of the cyclooxygenase-2 (COX-2) specific inhibitor rofecoxib. The average change from baseline at study weeks 2, 4, and 6 was assessed for 10 individual response variables, including patient and investigator global assessments, WOMAC 3.0V OA Index pain, stiffness and physical function subscales, graded study joint tenderness, and rescue analgesic use. Relationships among variables were evaluated using pairwise correlations and principal components analysis. The precision of variables to differentiate rofecoxib from placebo was evaluated using effect size (i.e., mean difference between rofecoxib versus placebo divided by pooled SD).Correlations among all pairs of response variables ranged from 0.5 to 0.9, except those with tenderness (0.4 to 0.6) and those with analgesic use (0.2 to 0.4). The first principal component explained about 70% of the total variability, with weights generally similar (0.17 for rescue analgesic use, 0.25 for tenderness, and 0.30 to 0.37 for the others). These results indicate that nearly all measures are closely related. Based on these results, various linear combinations of the 9 endpoints were formed and their precision to discriminate active treatment from placebo was compared to that of the individual endpoints. Effect sizes of the individual endpoints ranged from 0.6 to 1.1; those of the composites from 0.7 to 0.9. The results were very consistent between study protocols.In comparison to individual endpoints, composite analyses of OA clinical endpoints do not increase precision to discriminate active treatment from placebo.

Bodily pain and physical disability can negatively impact health-related quality of life (HRQL) in patients with osteoarthritis (OA).To assess the effects of treatment with a new agent, rofecoxib, on HRQL in patients with OA.Randomized, double-blind, 6-week clinical trial comparing treatment with rofecoxib, 5 to 50 mg, with placebo in 672 patients with OA of the hip or knee.Patient HRQL was assessed at baseline and at the end of treatment using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36).At 6 weeks, mean change from baseline in all SF-36 mental and physical health domain scores demonstrated significant improvement with rofecoxib use (P.05 for all doses for all SF-36 domains), with evidence of a dose-response relation. Improvements in mental and physical HRQL domains with rofecoxib treatment were significantly greater than those with placebo treatment (P.05 for each dose of rofecoxib vs placebo for all domains except general health) and highly correlated with improvements observed using disease-specific OA outcome measures such as the Western Ontario and McMaster Universities Osteoarthritis Index-visual Analog 3.0 OA index pain and physical function subscales. The effect of rofecoxib vs placebo treatment on mental health largely disappeared after adjustment for improvement in OA disease-specific measures.Rofecoxib treatment increased physical and mental HRQL domain scores on the SF-36. Improvements in mental health with rofecoxib use primarily resulted from effective treatment of OA (i.e., reduction in pain and improvement in physical function).

To determine the minimal perceptible clinical improvement (MPCI) in patients with osteoarthritis (OA) with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, and patient and investigator global assessment of disease status in randomized clinical trials for treatment of OA.Subjects with OA of the knee or hip were randomized to receive either rofecoxib 12.5 or 25 mg once daily, ibuprofen 800 mg 3 times daily, or placebo for 6 weeks. The WOMAC and global assessments were completed at baseline and Weeks 2, 4, and 6. A patient global assessment of response to therapy (0 to 4 scale) was used to "anchor" the WOMAC scores. MPCI was defined as the difference in mean change from baseline in WOMAC (100 mm normalized visual analog scale, VAS) between patients with 0 = "None" global response to therapy and patients with 1 = "Poor" global response to therapy.MPCI was determined to be 9.7, 9.3, and 10.0 mm for the WOMAC pain, physical function and stiffness subscales, respectively, and 11.1 mm for WOMAC question 1: Pain walking on a flat surface. The MPCI for the investigator was 0.4 with investigator assessment of disease status reported on a 0 to 4 Likert scale. Of note, the estimated MPCI for the WOMAC and investigator globals were similar irrespective of treatment, sex, age, or geographic region.In this analysis, mean changes of roughly 9 to 12 mm (100 mm normalized VAS) on WOMAC scales were perceptible changes to patients with hip and knee OA. A mean decrease of 0.4 in global disease status (0 to 4 Likert scale) as assessed by the investigator corresponded to the patients' MPCI. Understanding the minimal perceptible differences may permit a better assessment of the clinical relevance of therapeutic interventions in OA.

Compared with currently available NSAIDs (which inhibit COX-1 and COX-2 isoforms of cyclooxygenase), MK-0966 (a specific COX-2 inhibitor) is expected to cause less gastrointestinal toxicity.To compare the effect on the upper gastrointestinal mucosae of a high dose of MK-0966 with that of conventional doses of ibuprofen and aspirin.Healthy subjects (n = 170; age range 18-54 years) with endoscopically normal gastric and duodenal mucosa were randomized to either MK-0966 250 mg q.d. (n = 51), ibuprofen 800 mg t.d.s. (n = 51), aspirin 650 mg q.d.s. (n = 17), or placebo (n = 51) in this 7-day, double-blind, parallel-group study. The mucosae were evaluated by endoscopy using a predefined scale; scores could range from 0 to 4. The primary end-point was the percentage of subjects who developed a mucosal score/= 2 (i.e. the development of one or more erosions). To evaluate COX-1 activity, serum thromboxane B2 levels were determined in a subset of the population.The percentage of subjects who developed a mucosal score/= 2 in the MK-0966 group (12%) was significantly lower (P0.001) than that in the ibuprofen (71%) and aspirin (94%) groups, and was similar to that in the placebo group (8%). Only ibuprofen and aspirin significantly (P0.0001) reduced baseline thromboxane B2 levels. All treatments were generally well tolerated.In this acute short-term endoscopic study, MK-0966 250 mg q.d. (a dose at least 10 times higher than that demonstrated to reduce the signs and symptoms of osteoarthritis) produced significantly less gastrointestinal mucosal damage than either ibuprofen 800 mg t.d.s. or aspirin 650 mg q.d.s. and was comparable to placebo in this regard.

The effects of urinary symptoms on health-related quality of life (HRQL) are important in therapeutic decision making. Few have evaluated the treatment effects on HRQL in men with benign prostatic hyperplasia (BPH), even though increased urinary symptoms are associated with greater worry, bother, and interference with living activities. We report on patient assessments of such disease-specific measures as well as general HRQL measures from two placebo-controlled clinical trials of finasteride in the treatment of symptomatic BPH. Patients treated with finasteride appeared to have greater improvement than placebo-treated patients in disease-specific measures and in patient global assessment. The treated group appeared to have a greater mean increase in sexual domain scores. As expected, general measures (health rating, life satisfaction, ladder of life) changed little. Thus, treatment with finasteride appears to reduce bother, worry, and activity interference due to symptoms but in a small percentage of men may lead to slightly reduced sexual function.

A prodrug of methyldopa, the pivaloyloxyethyl (POE) ester, was administered orally to healthy human volunteers at doses equivalent to 500 and 1000 mg of methyldopa and was compared to oral and intravenous doses of methyldopa. The time courses of availability of methyldopa to the general circulation were compared and contrasted with the model-independent estimates of total systemic availability. The POE ester of methyldopa is completely hydrolyzed on the first pass; delivery of methyldopa to the general circulation was faster, more uniform, and more extensive compared to orally administered methyldopa. The systemic availability of methyldopa averaged 64% of the dose with a coefficient of variation (CV) of 15% for the prodrug treatments compared to 27% of the dose with a CV of 63% for methyldopa. First-pass metabolism of drug to the mono-O-sulfate conjugate of methyldopa was lower for the POE ester than for methyldopa.

In a pharmacokinetic drug interaction study, the purpose is to determine whether the coadministration of a drug A with a second drug B alters the absorption/distribution/metabolism/elimination profile of either drug. While the usual design for such studies is a three-period crossover, it cannot be analyzed as such, because the plasma-level data of drug B will be 0 when drug A is given alone, and vice versa. The easiest way to proceed is to do two sets of paired analyses, one on the absorption profile of A (A vs AB), and the other on the absorption profile of B (B vs AB). A complete separation of the total sources of variation and degrees of freedom is presented along with a numerical example.

Mevinolin reduces cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The safety and effectiveness of this agent was evaluated in a double-blind, placebo-controlled study in 59 healthy men (serum cholesterol 3.88--7.76 mmol/liter) in five centers. Subjects maintained their usual diet and activities. Doses of 6.25, 12.5, 25, or 50 mg twice daily for 4 wk produced mean reductions of total serum cholesterol fo 23--27% [vs. placebo (4%), P less than 0.01]. Mean low density lipoprotein cholesterol fell 35--45%, while high density lipoprotein and very low density lipoprotein cholesterol, and triglycerides were not significantly affected. Mean apolipoprotein B fell 27--34%. 50 mg was not significantly more effective than 6.25 mg. Mevinolin was generally well tolerated, and no serious clinical or laboratory abnormalities occurred. One subject (12.5 mg) was withdrawn because of abdominal pain and diarrhea. These results suggest that if long-term safety can be demonstrated, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase are likely to prove useful in the treatment of hypercholesterolemia.

In a pharmacokinetic drug interaction study, the purpose is to determine whether the coadministration of a drug A with a second drug B alters the absorption/distribution/metabolism/elimination profile of either drug. While the usual design for such studies is a three-period crossover, it cannot be analyzed as such, because the plasma-level data of drug B will be 0 when drug A is given alone, and vice versa. The easiest way to proceed is to do two sets of paired analyses, one on the absorption profile of A (A vs AB), and the other on the absorption profile of B (B vs AB). A complete separation of the total sources of variation and degrees of freedom is presented along with a numerical example.