David A. Krupa

Efficacy and safety of rofecoxib in patients with chronic low back pain: results from two 4-week, randomized, placebo-controlled, parallel-group, double-blind trials.

Study Design. Two replicate, 4-week, randomized, double-blind, placebo-controlled, trials of rofecoxib 25 and 50 mg versus placebo for chronic low back pain. Objectives. To determine the efficacy and safety of two doses of rofecoxib compared to placebo in the treatment of chronic low back pain. Summary of Background Data. Although nonsteroidal anti-inflammatory drugs are commonly prescribed for chronic low back pain, their efficacy is unproven and toxicity can be serious. These studies evaluated the efficacy and tolerability of rofecoxib, a selective COX-2 inhibitor, in the treatment of chronic low back pain. Methods. Patients with chronic low back pain were randomized 1:1:1 to rofecoxib 25 mg, 50 mg, or placebo once daily. Primary endpoint: Low Back Pain Intensity. Secondary endpoints: Pain Bothersomeness, Global Assessments of Response to Therapy, Global Assessment of Disease Status, Roland-Morris Disability Questionnaire, SF-12 Health Survey, Use of Rescue Acetaminophen, and Discontinuations Due to Lack of Efficacy. Results. Combining both studies, 690 patients were randomized to placebo (N = 228), rofecoxib 25 mg (N = 233), or rofecoxib 50 mg (N = 229). Mean (± SD) age was 53.4 (± 12.9) years, pain duration 12.1 (± 11.8) years, 62.3% female. Both rofecoxib groups improved significantly. Mean differences from placebo in pain intensity were −13.50 mm, −13.81 mm (25, 50 mg doses) respectively (P < 0.001). Both regimens were superior to placebo in eight of nine secondary endpoints. Fifty mg provided no advantage over 25 mg. Both rofecoxib regimens were well tolerated, although 25 mg had a slightly better safety profile. Conclusions. Rofecoxib significantly reduced chronic low back pain in adults and was well tolerated.

A Comparison of Adverse Renovascular Experiences Among Osteoarthritis Patients Treated with Rofecoxib and Comparator Non-selective Non-steroidal Anti-inflammatory Agents

Summary Background: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs -specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients. Objective: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators. Methods: Renovascular adverse experiences (AEs) in over 5000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50mg tid, nabumetone 1500mg qd). Results: The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5mg/day, rofecoxib 25mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group). Conclusions: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.

Oral Administration of the Growth Hormone Secretagogue MK-677 Increases Markers of Bone Turnover in Healthy and Functionally Impaired Elderly Adults†

Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin‐like growth factor I (IGF‐I). We determined the effect of chronic administration of the GH secretagogue, MK‐677, on serum IGF‐I and markers of bone turnover in 187 elderly adults (65 years or older) enrolled in three randomized, double‐blind, placebo‐controlled clinical studies lasting 2–9 weeks. Urine was collected for determination of N‐telopeptide cross‐links (NTXs), a marker of bone resorption, and blood was collected for determination of serum osteocalcin and bone‐specific alkaline phosphatase (BSAP), as bone formation markers, and serum IGF‐I levels pre‐ and post‐treatment. Dose response data were initially obtained in healthy elderly subjects who received oral doses of 10 mg or 25 mg of MK‐677 or placebo for 2 weeks (n = 10–12/group). Treatment with 10 mg and 25 mg of MK‐677 for 2 weeks increased mean urine NTXs 10% and 17%, respectively (p < 0.05 vs. placebo). Additionally, 50 healthy elderly subjects received either placebo (n = 20) for 4 weeks or 25 mg of MK‐677 (n = 30) daily for 2 weeks followed by 50 mg daily for 2 weeks. MK‐677 increased mean serum osteocalcin by 8% (p < 0.05 vs. placebo). In both studies, MK‐677 increased serum IGF‐I levels significantly (55–94%). Subsequently, the biological effects of MK‐677 were studied in 105 elderly subjects who met objective criteria for functional impairment. Subjects were randomized to receive oral doses of placebo for 9 weeks or either 5, 10, or 25 mg of MK‐677 daily for an initial 2 weeks followed by 25 mg of MK‐677 daily for the next 7 weeks(n = 63 on MK‐677 and n = 28 on placebo completed 9 weeks of therapy). Treatment with MK‐677 (all MK‐677 groups combined) for 9 weeks increased mean serum osteocalcin by 29.4% and BSAP by 10.4% (p < 0.001 vs. placebo) and mean urinary NTX excretion by 22.6% (p < 0.05 vs. placebo). The change from baseline serum osteocalcin correlated with the change from baseline serum IGF‐I in the MK‐677 group (r = 0.37; p < 0.01). In conclusion, once daily dosing with MK‐677, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.

Treatment with the Oral Growth Hormone Secretagogue MK-677 Increases Markers of Bone Formation and Bone Resorption in Obese Young Males†

The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK‐677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double‐blind, parallel, placebo‐controlled study. Twenty‐four healthy obese males, 19–49 years of age, with body mass index > 30 kg/m2 were treated with MK‐677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK‐677 increased markers of bone formation; a 23% increase in the carboxy‐terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK‐677 treatment (p < 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p < 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK‐677; serum levels of the carboxy‐terminal cross‐linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p < 0.05 vs. placebo) and 46% (p < 0.05 vs placebo), respectively. MK‐677 increased serum insulin‐like growth factor binding protein‐5 (IGFBP‐5) by 43–44% after 2–8 weeks of treatment (p < 0.01 vs. placebo). Serum IGFBP‐4 was increased by 25% after 2 weeks of treatment (p < 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin‐6 was not significantly changed by active treatment. In conclusion, short‐term treatment of healthy obese male volunteers with the GH secretagogue MK‐677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF‐I and IGFBP‐5 and a transient increase in serum IGFBP‐4 were found. Future long‐term studies are needed to investigate if prolonged treatment with MK‐677 increases bone mass.

Use of gastroprotective agents and discontinuations due to dyspepsia with the selective cyclooxygenase-2 inhibitor etoricoxib compared with non-selective NSAIDs*

SUMMARY Background: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are non-selective cyclooxygenase-1 (COX-1) and COX-2 inhibitors and are associated with upper gastrointestinal (GI) dyspeptic symptoms often resulting in GI co-medication usage or treatment discontinuation. Objective: To compare the rates of new use of gastroprotective agents and discontinuations due to dyspepsia with the COX-2 selective inhibitor etoricoxib compared with non-selective NSAIDs. Research design and methods: This pre-specified combined analysis used data from nine randomized, double-blind, controlled, clinical trials with etoricoxib in patients with osteoarthritis, rheumatoid arthritis, chronic low back pain, or ankylosing spondylitis. The cumulative incidences of (1) new use (new prescription or increased dose) of gastroprotective agents (GPA) and (2) discontinuation due to dyspeptic symptoms were compared among patients treated with etoricoxib (60 mg, 90 mg, or 120 mg daily) vs. non-selective NSAIDs (diclofenac 50 mg. t.i.d. or naproxen 500 mg. b.i.d.). Results: The overall rates/100 patient-years for new use of GPAs were 9.1 and 13.0 for etoricoxib and NSAIDs, respectively (RR = 0.75; 95% confidence interval [CI] 0.64, 0.89; p < 0.001). A benefit with etoricoxib was seen in the first 6 months when most new GPA usage occurred; after 6 months new use of GPAs was similar between etoricoxib and NSAIDs. The rates/100 patient-years of treatment discontinuation due to dyspeptic symptoms with etoricoxib and NSAIDs were 1.5 and 2.7, respectively (RR = 0.60; 95% CI 0.41, 0.87; p = 0.007). Analyses of placebo-controlled treatment periods showed significantly more new GPA use and more discontinuations due to dyspeptic symptoms with NSAIDs vs. placebo, but not with etoricoxib vs. placebo. Conclusion: In this combined analysis of clinical trials of patients with OA, RA, chronic low back pain, or AS, new use of gastroprotective agents was significantly lower with etoricoxib than with the comparator non-selective NSAIDs during the initial 6 months of treatment and similar thereafter. There were significantly fewer discontinuations for dyspeptic symptoms with etoricoxib than with NSAIDs over the entire follow-up period.

Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone–insulin‐like growth factor I axis in growth hormone–deficient children

Ibutamoren mesylate (MK‐0677), an orally active nonpeptide growth hormone (GH) secretagogue, stimulates GH release through a pituitary and hypothalamic receptor that is different from the GH–releasing hormone receptor. We evaluated the safety and tolerability and the GH–insulin‐like growth factor (IGF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children (15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 ± 0.8 years (mean ± SD), bone age of 7.4 ± 0.7 years, growth velocity <10th percentile for age, height <10th percentile for age, and a maximum GH response of ≤10 μg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1–7 or 8–14) and matching placebo for the alternate 7 days (groups I and II, respectively) or 0.8 mg/kg per day for 7 days (days 8–14, group III). On day 15 all patients received an 0.8‐mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose before advancement to the high dose. Hormonal profiles were evaluated on day −1 (baseline) and day 15, and the results were expressed as the change from baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 μg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 μg · h/L (range, 1.3 to 35.6) for the GH area under the concentration‐time curve from time zero to 8 hours (AUC0–8) (P < .001), 12 μg/L (range, −4 to 116) for serum IGF‐I (P = .01), and 0.4 μg/L (range, −0.9 to 1.5) for serum IGF‐binding protein 3 (IGFBP‐3) (P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24‐hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short‐term administration of ibutamoren mesylate can increase GH, IGF‐I, and IGFBP‐3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.

Topical anti-androgenicity of a new 4-azasteroid in the hamster

The topical anti-androgenic activity of L-651,580 (methyl 3-oxo-4-methyl-4-aza-5 alpha-androst-1-ene-17 beta-carboxylate) was established in a series of for experiments using castrated male hamsters. During each 21-day experiment, the animals received a daily subcutaneous injection of 40 micrograms testosterone propionate or 20 micrograms dihydrotestosterone propionate. Test compound in 25 microliters of gel was applied daily to the left flank organ. Compounds assayed included L-651,580, WIN 17,665 (17 alpha-propyltestosterone), and SH-434 (17 beta-hydroxy-1 alpha-methyl-17 alpha-propyl-5 alpha-androstan-3-one). Endpoints were flank organ area, sebaceous gland area, and prostate weight. Very similar results were obtained with L-651,580 and WIN 17,665. Daily doses of 0.25 mg or more of either compound usually produced a significant reduction in the areas of treated flank organs and sebaceous glands underlying treated flank organs. Neither compound caused significant changes in the area of the contralateral flank organs and sebaceous glands, which indicated they possess little or no systemic activity at topically effective treatment levels. In direct comparisons, SH-434 was less anti-androgenic than L-651,580 or WIN 17,665, although in one experiment, 0.5 mg/d of SH-434 significantly reduced the area of treated flank organs and sebaceous glands. Neither WIN 17,665 nor SH-434 caused a change in prostate weight; however, in one of four tests, a significant decrease was induced by the 0.5 mg/d level of L-651,580. The results of these experiments show that the topical anti-androgenicity of L-651,580 compares very favorably with that of WIN 17,665 and SH-434. They also indicate that the topical administration of effective dosage levels of L-651,580 causes few, if any, systemic effects.