Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time. RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P <.01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P <.01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P <.05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869. CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

L-692,429, a nonpeptide growth hormone (GH) secretagogue, reverses glucocorticoid suppression of GH secretion.

The reversal of glucocorticoid-induced negative nitrogen balance by GH supports a possible therapeutic role for GH treatment in patients receiving these catabolic steroids. A GH secretagogue might be of similar utility. However, stimulated GH secretion is generally suppressed by glucocorticoids. To test whether L-692,429, a nonpeptide mimic of GH-releasing peptide-6, can overcome such suppression, a double blind, placebo-controlled, three-period, cross-over study was performed in nine healthy young men who received 0.2 mg/kg L-692,429, i.v., preceded by 4 days of prednisolone (20 mg, orally, three times daily) or placebo, and 0.75 mg/kg L-692,429 preceded by prednisolone only. The mean (SE) GH peak and area under the curve between 0-240 min after administration of 0.2 mg/kg L-692,429 in the absence of steroid were 53.8 (7.2) micrograms/L and 3481 (1005) micrograms/min.L, which were reduced to 25.1 (3.4) micrograms/L and 1342 (285) micrograms/min.L (P < or = 0.01) when treatment was preceded by 4 days of prednisolone. However, the suppressive influence of the steroid was attenuated by the high dose of L-692,429, which achieved a GH peak and area under the curve between 0-240 min of 42.6 (5.8) micrograms/L and 2298 (425) micrograms/min.L, respectively (P < 0.01 vs. 0.2 mg/kg L-692,429 plus prednisolone). L-692,429 stimulates GH secretion even in the setting of short term, high dose, concomitant glucocorticoid treatment, suggesting that such compounds might provide an alternative means of increasing circulating GH and reversing the catabolic effects of these steroids.

Neuroendocrine responses to a novel growth hormone secretagogue, L-692,429, in healthy older subjects.

L-692,429 (L), a novel nonpeptide mimic of GH-releasing peptide (GHRP), is a potent GH secretagogue in animals and young men. To assess the safety and efficacy of L in stimulating GH release in healthy older men and women, 16 subjects were admitted to a randomized, double blind, cross-over comparison of i.v. administered placebo, GH-releasing hormone [GHRH-(1-29)-NH2; 1 microgram/kg] and two doses of L (0.2 and 0.75 mg/kg). Blood samples were obtained at 5-min intervals for 60 min before and 240 min after each dose for measurement of GH; cortisol, PRL, and insulin-like growth factor-I (IGF-I) were measured less frequently. Peak and integrated GH concentrations increased significantly after L in a dose-dependent manner. Responses to L at either dose were significantly greater than the response to GHRH: peak GH responses in older men and women were (mean +/- SE; micrograms per L): after placebo, 1.2 +/- 0.2; L (0.2 mg/kg), 16.5 +/- 1.8; L (0.75 mg/kg), 32.2 +/- 3.9; and GHRH, 7.6 +/- 1.3 (P < 0.05, L vs. placebo or GHRH). Serum cortisol and PRL concentrations increased after both doses of L, but to values within the respective normal ranges. Serum IGF-I values did not change consistently in any group. The GH responses to GHRH and L (0.75 mg/kg) were highly correlated (r2 = 0.61; P < 0.0004). Deconvolution analysis demonstrated that the increase in serum GH concentrations stimulated by L and GHRH resulted from enhanced GH secretion rates, with no change in the half-life of GH disappearance. Amplitudes of GH secretory pulses were increased 11-, 18-, and 4-fold after L (0.2 mg/kg), L (0.75 mg/kg), and GHRH treatments, respectively. The number of GH secretory pulses was significantly increased by L (0.75 mg/kg; 4.6 +/- 0.4) and GHRH (4.4 +/- 0.3) compared to placebo (2.6 +/- 0.5), but the interval between pulses was shorter after L (0.75 mg/kg; 28.6 +/- 3.6 min) than after GHRH (50.7 +/- 7.7 min; P < 0.05). Adverse experiences were limited to brief episodes of flushing or a warm sensation about the upper body. L-692,429 is a potent GH secretagogue that is well tolerated in healthy older men and women. At the doses employed in this study, L elicited greater increases in GH secretion rates and serum GH concentrations than GHRH. L-692,429 may have therapeutic advantages over peptide GH secretagogues to restore endogenous GH secretion in GH deficiency states or the hyposomatotropism of aging.

Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6.

L-692,429, a substituted benzolactam, is a novel nonpeptide mimic of the GH secretagogue, GH-releasing peptide-6. The safety and GH secretory activity of L-692,429 (0.001-1.0 mg/kg, i.v.) were investigated in 24 healthy nonobese young (18-26 yr old) male volunteers who demonstrated a GH response of 7 micrograms/L or more after 1 microgram/kg, i.v. GH-releasing hormone [GH-releasing hormone-(1-29)NH2]. L-692,429 was administered as a 15-min iv infusion in an incremental dose, double blind, placebo-controlled, alternating panel fashion to 3 panels of 8 subjects each. Dose-dependent GH secretion was observed with a threshold dose of 0.05 mg/kg (4 of 6 subjects responded with peak GH > 7 micrograms/L), and 0.2 mg/kg produced a response in all 14 subjects tested (mean +/- SE peak GH, 41.0 +/- 6.3 micrograms/L). The maximum dose of 1.0 mg/kg L-692,429 resulted in a pronounced GH response (peak GH, 82.5 +/- 14.9 micrograms/L; n = 8). The GH peak was seen 30-45 min after initiation of the infusion. Small transient increases in cortical and PRL were observed (increases in cortical averaged 182.1 +/- 33.1 nmol/L and peak PRL was 21 +/- 2.6 micrograms/L after 1.0 mg/kg L-692,429, respectively), whereas no significant changes occurred in LH, FSH, TSH, insulin, or glucose concentrations. Plasma pharmacokinetic analysis revealed dose-related increases in plasma concentrations of L-692,429 and a half-life of 3.8 +/- 0.2 (+/- SE) h, a plasma clearance of 214 +/- 67 mL/min, and a steady state volume of distribution of 14.2 +/- 4.8 L. Facial flushing or a warm sensation were reported in 4 subjects, primarily at dose levels of 0.2 mg/kg L-692,429 or more, but no other clinical or laboratory adverse experiences appeared related to drug treatment. L-692,429, synthesized as a specific nonpeptide mimic of GH-releasing peptide-6, is thus a well tolerated, highly effective, and selective GH secretagogue in man.

MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism.

The reversal of diet-induced negative nitrogen balance by GH suggests a possible therapeutic role for GH treatment in catabolic patients. A double-blind, randomized, placebo-controlled, two-period cross-over study was designed to investigate whether MK-677, an orally active nonpeptide mimic of GH-releasing peptide, can reverse diet-induced protein catabolism. Eight healthy volunteers (ages 24-39 yr) were calorically restricted (18 kcal/kg.day) for two 14-day periods. During the last 7 days of each diet period, subjects received either oral MK-677 25 mg or placebo once daily. There was a 14- to 21-day washout interval between periods. During the first week of caloric restriction (i.e. diet alone), daily nitrogen losses were similar for both treatment groups (mean +/- SE; MK-677 group -2.67 +/- 0.40 g/day vs. placebo group -2.83 +/- 0.26 g/day). During the second week (diet and study drug), mean daily nitrogen balance was 0.31 +/- 0.21 g/day in the MK-677 treatment group compared with -1.48 +/- 0.21 g/day in the placebo group (P < 0.01). MK-677 improved nitrogen balance integrated over the 7 days of treatment; area under the curve day 8-14 nitrogen balance response was +2.69 +/- 5.0 (SE) for MK-677 and -8.97 +/- 5.26 g.day for placebo (P < 0.001). MK-677 produced a peak GH response of 55.9 +/- 31.7 micrograms/L after single dose (day 1 of treatment) and 22.6 +/- 9.3 micrograms/L after a week of dosing compared with placebo treatment peak GH values of approximately 9 (treatment day 1) and approximately 7 micrograms/L (treatment day 7). Following the initial 7-day caloric restriction, insulin-like growth factor-I (IGF-I) declined from 232 +/- 25 to 186 +/- 19 ng/mL in the MK-677 group and from 236 +/- 19 to 174 +/- 23 ng/mL in the placebo group. Mean IGF-I concentration increased significantly during MK-677 to 264 +/- 31 ng/mL (mean for the last 5 days of treatment) compared with 188 +/- 19 ng/mL with placebo (P < 0.01). No significant difference in IGF binding protein-2 was found between the MK-677 and placebo treatments. However, the mean in IGF binding protein-3 for the last 5 days of MK-677 treatment was also significantly increased to 3273 +/- 330 ng/mL (mean +/- SE) compared with placebo 2604 +/- 253 ng/mL (P < 0.01). Neither the serum cortisol nor the PRL response was significantly greater after 7 days of MK-677 dosing compared with 7 days of placebo. MK-677 (25 mg) was generally well tolerated and without clinically significant adverse experiences. In conclusion, MK-677 reverses diet-induced nitrogen wasting, suggesting that if these short-term anabolic effects are maintained in patients who are catabolic because of certain acute or chronic disease states, it may be useful in treating catabolic conditions.

Effect of obesity and feeding on the growth hormone (GH) response to the GH secretagogue L-692,429 in young men.

GH secretion and the response to GH secretagogues are significantly diminished in obese individuals. Previous studies have shown that L-692,429 (L), a nonpeptide mimetic of GH-releasing peptide, selectively stimulates GH release in normal young men and in the elderly, who also have diminished GH secretion. A paired, two-site study examined the effects of L on GH release in 12 healthy obese (part A; mean +/- SD: age, 26.1 +/- 3.3 yr; body mass index, 35.0 +/- 3.1 kg/m2) and 10 nonobese (part B; age, 22.2 +/- 2.3 yr; body mass index, < or = 27.0) young men. In part A, placebo, low dose L (0.2 mg/kg), or high dose L (0.75 mg/kg) was administered iv over 15 min on 3 separate occasions after an overnight fast. Samples for GH, PRL, and cortisol determinations were obtained every 15 min. GH release (mean +/- SE) was significantly increased by both doses of L compared to the effect of placebo: 12.6 +/- 1.8 micrograms/L (low dose), 18.5 +/- 2.7 micrograms/L (high dose), and 0.84 +/- 0.1 microgram/L (placebo), respectively (P < 0.05). In a subset of 6 obese men, in samples collected every 5 min, the GH response to both doses of L was significantly greater than that to 1 microgram/kg GHRH. To compare the response to low dose L in the obese and to determine the effects of feeding on this response, 0.2 mg/kg L was administered as described in part A to nonobese young men after an overnight fast (fasted) or a standardized breakfast (fed; part B). Low dose L was an effective GH secretagogue in nonobese young men; however, this effect was attenuated with feeding [43.6 +/- 7.9 (fasted) vs. 17.7 +/- 4.8 (fed) micrograms/L]. Of note, the response to low dose L in fasted obese individuals was similar to that in fed nonobese individuals. The administration of L was well tolerated in both groups. We conclude that L is an effective GH secretagogue in obese and nonobese young men and may have therapeutic benefits when administered to relative (obese or elderly) or absolute GH-deficient individuals.

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.

Topically administered norfloxacin compared with topically administered gentamicin for the treatment of external ocular bacterial infections. The Worldwide Norfloxacin Ophthalmic Study Group.

In this double-masked study, we randomly assigned 488 patients with clinical signs of acute bacterial conjunctivitis or blepharitis, or both, to treatment with either norfloxacin ophthalmic solution 0.3% (245) or gentamicin ophthalmic solution 0.3% (243) for one week. Of the patients with positive cultures, 71% (85 of 120) of the norfloxacin-treated patients and 65% (86 of 133) of the gentamicin-treated patients were clinically cured. An additional 25% (30 of 120) of norfloxacin-treated patients and 32% (43 of 133) of gentamicin-treated patients were clinically improved. On the basis of posttreatment cultures, 89% of all cultured bacteria were eradicated (146 of 179 organisms) or suppressed (14 of 179 organisms) after treatment with norfloxacin. The condition of five norfloxacin-treated patients did not clinically improve, compared with the condition of eight gentamicin-treated patients. Both antibiotics had similar efficacy against gram-positive and against gram-negative organisms. One norfloxacin-treated patient and two gentamicin-treated patients withdrew from the study because of local intolerance. Norfloxacin appears to be an effective and relatively safe agent for the treatment of bacterial infections of the eyelids or conjunctiva, or both. In this study, norfloxacin was clinically and microbiologically similar in activity to gentamicin.

The safety and efficacy of topical norfloxacin compared with placebo in the treatment of acute, bacterial conjunctivitis. The Norfloxacin-Placebo Ocular Study Group.

Two hundred and eighty-four patients with acute conjunctivitis were enrolled in a double-masked study comparing norfloxacin ophthalmic solution with placebo. The proportion of patients who were clinically improved after 5 days treatment was 88.1% in the norfloxacin group and 71.6% in the placebo group (p less than 0.01). The proportion of patients who had all organisms eradicated, including the coagulase-negative staphylococci, after two to three days treatment was 52.7% for norfloxacin and 23.9% for placebo (p less than 0.01) and 64.7% and 26.3% (p less than 0.01) respectively when the coagulase-negative staphylococci were not included. Adverse experiences occurred in 4.2% of the patients receiving norfloxacin compared to 7.1% of the placebo patients. None of the adverse experiences was serious.

The safety and efficacy of topical norfloxacin compared with chloramphenicol for the treatment of external ocular bacterial infections. The Norfloxacin-Chloramphenicol Ophthalmic Study Group.

Two hundred and forty-six patients with signs of acute bacterial conjunctivitis and/or blepharitis were randomised to receive either norfloxacin or chloramphenicol for one week in this double-masked parallel group study. Ninety-two per cent of the norfloxacin-treated patients and 93% of the chloramphenicol-treated patients were rated as either clinically improved or cured at the end of the treatment period. Based upon pre-treatment bacteriological cultures, 31.3% of the patients had significant bacterial infection of the lids and/or conjunctiva. All of these culture-positive patients were rated as either clinically improved or cured. Based upon post-treatment cultures, 72 of 82 strains of Gram-positive and Gram-negative bacteria were eradicated or suppressed following treatment with either norfloxacin or chloramphenicol. However six of 41 strains persisted for norfloxacin and four of 41 for chloramphenicol. Two norfloxacin-treated patients and three chloramphenicol-treated patients had adverse experiences, predominantly ocular discomfort, which required cessation of drug therapy. Norfloxacin appears to be an effective and relatively safe agent for the treatment of bacterial infections of the lids and/or conjunctiva. In this study, norfloxacin was clinically and microbiologically similar in activity to chloramphenicol.

Initial human experience with MK-462 (rizatriptan): a novel 5-HT1D agonist.

AIMS: We evaluated the pharmacokinetics and pharmacodynamics of oral MK-462 in comparison with oral sumatriptan in healthy male volunteers. METHODS: Sixteen healthy male volunteers were studied in a rising, single dose, alternating panel design with eight subjects per panel. Matching placebo was administered to two of eight study subjects at each dose level of MK-462 in a randomized, double-blind fashion. RESULTS: MK-462 was rapidly absorbed with a median tmax of 1.3 h (range 1-3 h) vs a tmax for sumatriptan of 2.5 h (range 1-4 h, P < 0.001). Administration of either MK-462 or sumatriptan produced maximal mean elevations of 5-10 mmHg in systolic and diastolic blood pressures without effect on heart rate; the changes occurred sooner following MK-462, consistent with more rapid absorption. Both MK-462 and sumatriptan provoked mild increases in serum growth hormone without any effect on serum prolactin concentrations. The most commonly reported symptom following MK-462 was drowsiness. CONCLUSIONS: These results indicate that the novel 5-HT1D agonist, MK-462, is rapidly absorbed following oral administration and warrants further investigation of its utility in the treatment of acute migraine.