Intranasal ketorolac tromethamine (SPRIX(R)) containing 6% of lidocaine (ROX-828) for acute treatment of migraine: safety and efficacy data from a phase II clinical trial.

OBJECTIVE: Ketorolac is a non-triptan, non-opioid, mixed cyclooxygenase (COX)1/2-inhibitor for short-term management of moderate-to-severe acute pain. This trial evaluated an intranasal formulation of ketorolac tromethamine (SPRIX®) containing 6% lidocaine (ROX-828) for the acute treatment of migraine with and without aura as defined by the International Headache Society. METHODS: Patients were randomly assigned 1:1 to self-treat with intranasal ROX-828 (31.5 mg ketorolac tromethamine/200 µL, containing 6% of lidocaine) or placebo (with 6% lidocaine) within four hours of a new migraine attack rated ≥ moderate in pain intensity. Assessments included headache intensity and associated migraine symptoms (nausea, vomiting, phonophobia, photophobia) measured at baseline and at regular intervals through 48 hours post-dosing, and global impression of efficacy (seven-point scale) measured at two hours. RESULTS: Randomized patients who had a migraine attack (N = 140) were evaluable (ROX-828, N = 68; placebo, N = 72). Patients receiving ROX-828 showed a significant (p < 0.05) improvement in pain relief at all time points except 0.5 and 24 hours compared with those who received placebo. More patients achieved pain-free status with ROX-828 than with placebo at 1.5, 3, 4, 24 and 48 hours (p < 0.05); significance at the two-hour time point, which was the primary endpoint, was not met. Patients' global impression of efficacy showed statistically significantly better results for patients receiving ROX-828 than for those receiving placebo. Associated migraine symptoms were significantly improved (p < 0.05) with ROX-828 relative to placebo at several time points throughout the observation period. The most frequently reported adverse events in both groups were associated with nasal discomfort. CONCLUSION: Self-administered intranasal ROX-828 was well tolerated. While the primary endpoint was not met, the results provide preliminary evidence that ROX-828 improves migraine pain.

Course, patterns, and risk-factors for chemotherapy-induced emesis in cisplatin-pretreated patients: a study with ondansetron.

Vomiting and nausea are the most distressing side-effects of cancer chemotherapy. With standard antiemetic regimens (e.g. metoclopramide based combinations) sufficient antiemetic control is achieved in 50-70% of cisplatin treated patients. Ondansetron, a selective 5-HT3-receptor antagonist has shown efficacy in cisplatin-induced emesis. In the present study, we evaluated the safety and efficacy of ondansetron in cisplatin pretreated patients who had suffered from severe emesis in spite of antiemetic prophylaxis. Complete antiemetic control was reached in 43.5% on the day of treatment and in 27.2% of the patients regarding a worst day analysis. 25% of the patients suffered from severe cisplatin-induced emesis (greater than 5 emetic episodes per 24 h). We try to characterise risk-factors for cisplatin-induced emesis by performing a multivariate analysis. Sex, cisplatin dose, and combination therapy with cisplatin plus anthracyclines seem to be independent risk-factors for vomiting on day 1 and on worst day. Delayed emesis occurred less often when sufficient antiemetic protection from acute vomiting had been obtained. Female sex, cisplatin dose and recurrent disease seem to influence the probability for occurrence of delayed vomiting.

Double-blind randomised trial of the antiemetic efficacy and safety of ondansetron and metoclopramide in advanced breast cancer patients treated with epirubicin and cyclophosphamide.

Ondansetron was compared with metoclopramide for antiemetic efficacy in a randomised double-blind trial in 122 patients with advanced breast cancer. All patients were treated with epirubicin (greater than 50 mg/m2) and cyclophosphamide (greater than 500 mg/m2). 50 patients receiving ondansetron and 60 with metoclopramide were considered evaluable. Ondansetron was at least as effective as metoclopramide in the control of vomiting and nausea. The percentage of patients with complete plus major control was 72% (59-85%) vs. 61% (48-74%) on day 1 (P = 0.230) and 79% (67-91%) vs. 66% (53-78%) on days 2-3 after chemotherapy (P = 0.122). Over the 3-day study period, nausea was absent or mild in 60% of the patients treated with ondansetron, compared to 45% given metoclopramide (P = 0.064). No major drug-related side-effects were reported. 1 patient receiving ondansetron experienced gastrointestinal disturbance and headache. Episodes of diarrhoea, fever, hyperkinetic syndrome, fatigue, restlessness and migraine with vomiting were reported by 5 patients treated with metoclopramide. None of the changes in the biochemical or haematological parameters was attributed to the antiemetic treatments.

Tolerance and pharmacokinetics of oral fendiline.

Two studies with healthy volunteers were carried out to correlate safety with pharmacokinetics of the calcium antagonistic drug N-(3,3-diphenylpropyl)-(1-phenylethyl)-amine (fendiline, Sensit) after single and multiple oral doses. In the first study single doses of 200, 400, 600, 800, 1000, and 1200 mg of fendiline hydrochloride were administered to 6 subjects per dose level. 3 additional subjects per dose level received placebo. No significant objective or subjective effects were noted in the dose range studied. The pharmacokinetic analysis revealed that doses higher than 800 mg were absorbed incompletely. In the second study initially 400 mg twice daily was given to 9 subjects. 3 additional subjects received placebo. Due to subjective intolerability (trembling, dizziness) after 5 days, the dose was reduced stepwise to 2 X 200 mg and was then continued for another 19 days. The pharmacokinetic evaluation revealed manifold interindividual differences in plasma levels for maximal concentrations (9-170 ng/ml) as well as for minimal concentrations (4-96 ng/ml). The absorption profile in both studies has linear and nonlinear components. Maximal plasma levels were reached after about 4 h. Terminal elimination half-lives were about 20 h.

Evaluation of two new megestrol acetate tablet formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet (Megace). The tablets were administered to 24 male subjects in a three-way cross-over study, balanced for sequence, with a week between administrations. The 40 mg tablets were administered q.i.d. at 08.00, 12.00, 18.00 and 22.00 h, while the 160 mg tablets were administered once at 08.00 h. Plasma samples were collected at appropriate times out to 96 h after administration and were analysed for megestrol acetate with a validated high performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h), the absorption rate constant was the same for each of the tablets. Relative to the 40 mg q.i.d. dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97 per cent and 118 per cent, respectively.

Bioequivalence evaluation of new megestrol acetate formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet. The tablets were administered to 24 male subjects in a three-way crossover study, balanced for sequence, with 1 week between administrations. The 40 mg tablets were administered qid at 8 AM, 12 PM, 6 PM, and 10 PM, while the 160 mg tablets were administered once at 8 AM. Plasma samples were collected at appropriate times up to 96 hours after administration and were analyzed for megestrol acetate with a validated high-performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h) the rate of absorption was the same for each of the tablets. Relative to the 40 mg qid dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97% and 118%, respectively.

Pharmacokinetics and tolerability of suprofen. Experience with intramuscular application in healthy volunteers.

In the present randomized single-blind study local and systemic tolerability of alpha-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol) 200 mg/ml i.m. were compared with those of diclofenac 25 mg/ml and placebo. The three treatment groups consisted of 15 patients each and were homogeneous with respect to demographic parameters. The volunteers were assigned to these groups in random fashion and underwent treatment with 3 injections/day of either suprofen or diclofenac or placebo for 7 days. Mild local pain or systemic intolerance signs were equally rare in all three groups. The laboratory tests with the three preparations studied failed to indicate any negative influence on the hematopoietic organs or the adrenal activity. Abnormal changes in the ECG and the cardiovascular parameters during the treatment were not observed. Moderately or slightly elevated SGOT and SGPT values were seen during treatment with suprofen; however, these values returned to normal after the treatment. As compared with these elevations the values for subjects on diclofenac were higher and did not return to normal within 5 days following withdrawal of the drug. Moreover, the creatine phosphokinase activity, observed in both the suprofen and the diclofenac group, was so extremely high in subjects on diclofenac that this drug had to extremely high in subjects on diclofenac that this drug had to be withdrawn on day 4 of the study. On the basis of these results it can be stated that intramuscular injections of suprofen 200 mg/ml are locally and systemically well tolerated even on administration t.i.d. Measurement of the steady-state plasma level was not indicative of altered kinetic behaviour of suprofen. The plasma levels remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)

Local and systemic tolerability of suprofen. Experience with intravenous administration and infusion in healthy volunteers (1st comm.).

Local and systemic tolerability of alpha-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol 200 mg/ml intravenous injection and suprofen 200 mg/ml infusion were in the present single-blind crossover study assessed and compared with those of placebo i.v. 12 volunteers each were in random fashion assigned to one of the three treatment groups; for a period of 7 days the subjects received daily 2 intravenous injections or infusions of suprofen or placebo, respectively. Investigator and patients appreciation of local tolerability revealed that no pain or discomfort occurred in 98% of the subjects on suprofen and in 100% of those on placebo. The incidence of limited, moderate or mild, adverse reactions was in the suprofen group higher than in the placebo group. The laboratory tests for the treatment groups indicated no negative effects on either the hematopoietic organs or the liver function; no abnormal changes in ECG and cardiovascular parameters were observed during the treatment period. Tests of the renal parameters, i.e., creatinine clearance, creatinine, and urea (BUN), revealed negative shifts in the first two parameters, whereas BUN remained uninfluenced. On the basis of these results it can be stated that 200 mg/ml of suprofen, given either as intravenous injection or as infusion, were both locally and systemically well tolerated even on administration b.i.d. The more or less unfavorable shifts in the renal parameters, which occurred with placebo as well as with suprofen, require further investigation.

Local and systemic tolerability of suprofen. Experience with intravenous administration and infusion in healthy volunteers (2nd comm.).

12 healthy male volunteers who had given consent to the study each received in a randomized cross-over design 13 applications of 2-methyl-4-(2-thienylcarbonyl)-phenyl acetic acid (suprofen, Suprol) injection solution 200 mg/ml at 8 a.m. and at 2 p.m. as i.v. bolus injections or as infusions. It could be demonstrated, that suprofen given as multiple dose i.v. bolus injections or as multiple infusion doses was well tolerated. The peak plasma concentrations after i.v. bolus injections were in the range of 16.3 to 42.3 micrograms/ml (mean 26.5) and after 2 h between 1.3 and 9.8 micrograms/ml (mean 3.2). 1.5 h after the start of infusion (end of the infusion) the plasma concentrations were in the range of 4.0 and 11.2 micrograms/ml (mean 7.2) with a infusion rate of 4.6 mg/min for the first 30 min and then of 1.1 mg/min for about 57 additional min. At 2.5 h after the infusion applications the mean plasma level was 2.0 micrograms/ml. There was no indication of accumulation nor accelerated elimination during the 7-day period. There was no statistically significant difference between the plasma elimination after the last injection of the 7-day period and the plasma elimination after i.v. single injection as well as from the elimination after the last infusion of the 7-day period.

[The effect of cimetidine on the metabolism and effects of alcohol]. / Einfluss von Cimetidin auf den Abbau und die Wirkung des Alkohols.

This study was designed to show if therapeutic doses of cimetidine (Tagamet 400 Oblong-Filmtabletten; 400 mg b.i.d. and 400 mg t.i.d.) influence the elimination of alcohol. Following controlled alcohol doses to eight healthy volunteers without cimetidine and after three days cimetidine in the two dosage regimens, blood alcohol concentrations were determined and the degree of intoxication was recorded subjectively on a 100 mm scale. Statistical evaluation showed that the elimination and effects of the alcohol were similar on all three study days. One can conclude that, under these study conditions, cimetidine had no effect on the alcohol metabolism and blood concentration. Correlation between blood alcohol levels and degree of intoxication showed a significant linear relationship.

[Comparative studies on biologic availability and pharmacokinetics of bromazepam in tablets]. / Vergleichende Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik von Bromazepam aus Tabletten.

Ten male volunteers participated in a randomized crossover trial to compare the bioavailability of bromazepam (7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one) from two different preparations (Normoc, the test preparation, and a commercially available standard preparation). A single dose of 6 mg bromazepam was given. There was no difference in the USP XX rotating basket dissolution test between both preparations. The pharmacokinetic parameters elimination half-life, maximum plasma concentration and area under the curve were not significantly different. With the test preparation, however, smaller interindividual differences were seen. Only the time to peak plasma concentration showed a statistically significant difference. The test preparation yielded a flatter and smoother plasma bromazepam concentration curve compared with the standard preparation. This seems favourable in the case of subchronic dosing with regard to side effects, e.g. sedation.

Finger pulse plethysmographic effects of two oral sustained-release formulations of isosorbide dinitrate in normal man.

Two sustained release formulations of 40 mg isosorbide dinitrate, encapsulated pellets and a tablet, were compared double blind following oral administration of single doses in terms of response on finger pulse plethysmography in nine healthy male volunteers. Following both formulations there was a distinct effect on the depth of b-wave in the first derivative of the finger pulse up to 9 h after administration. This change of the parameter of nitrate action was significantly different from placebo for both formulations. The onset of action was more rapid and the peak response greater for the capsule than for the tablet. The overall effects in terms of area under the effect-time curves was also greater for the capsule than for the tablet, however, not statistically significant. Furthermore, the results show that the method of finger pulse plethysmography can be used to determine onset and duration of action nitrate compounds, after single dose administrations.