An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction.

BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Helicobacter pylori does not migrate from the antrum to the corpus in response to omeprazole.

BACKGROUND: Omeprazole is known to have an effect on Helicobacter pylori in vivo. One opinion is that H. pylori "migrates" from the antrum to the corpus in response to omeprazole therapy. METHODS: To determine whether H. pylori migrates in response to omeprazole, we assessed the presence of H. pylori in the antrum and corpus in duodenal ulcer patients receiving omeprazole for 4 wk. Culture and histological examination of antral biopsies (Genta stain) were performed before patients received omeprazole, at the end of therapy, and 4-6 wk later. The end points were presence or absence of H. pylori and the number of H. pylori colonies per biopsy. RESULTS: Seventy-two patients had H. pylori in both the antrum and corpus at entry and 4-6 wk after ending therapy. Three general patterns were prevalent at the end of omeprazole therapy: antrum- and corpus-positive (54%), antrum-negative and corpus-positive (24%), both antrum- and corpus-negative (21%), and one patient had antrum-positive with corpus-negative (1%). Evaluation of the number of colonies per biopsy in those who remained H. pylori-positive in both the antrum and corpus throughout showed that the number of H. pylori decreased in both the antrum and corpus during therapy (507 +/- 60 vs. 225 +/- 51, p < 0.01 and 415 +/- 58 vs. 290 +/- 46 0.1) for antrum and corpus, respectively, and tended to return to pre-therapy levels 4-6 wk later. The number of H. pylori in the corpus also decreased in the antrum-negative and corpus-positive group during therapy with omeprazole (433 +/- 87 vs. 185 +/- 61, p < 0.05). In most of the patients studied, the number of H. pylori in the corpus was less posttreatment than it was pretreatment. The decrease in H. pylori load was also reflected in the development of false-negative urea breath tests. CONCLUSIONS: Omeprazole is detrimental to H. pylori in both the antrum and the corpus; migration from the antrum to the corpus in response to omeprazole is a myth.

Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state.

This study was conducted to determine (i) the effect of omeprazole on steady-state concentrations of clarithromycin and 14-(R)-hydroxyclarithromycin in plasma and gastric mucosa, (ii) the effect of clarithromycin on steady-state concentrations of omeprazole in plasma, and (iii) the effect of clarithromycin on the suppression of gastric acid secretion by omeprazole. Twenty healthy, Helicobacter pylori-negative male subjects completed this three-period, double-blind, randomized crossover study. In period 1, all subjects received 40 mg of omeprazole each morning for 6 days. Twenty-four-hour gastric pH monitoring took place on days -1 and 6. Pharmacokinetic sampling took place on day 6. In periods 2 and 3, subjects were randomly assigned to receive either 40 mg of omeprazole or omeprazole placebo daily for 6 days plus clarithromycin (500 mg) every 8 h for 5 days with a single 500-mg dose on day 6. Gastric tissue and mucus samples were obtained via endoscopy on day 5. Gastric pH monitoring and pharmacokinetic sampling took place on day 6. Two-week washout intervals separated the three study periods. Clarithromycin increased mean omeprazole area under the concentration-time curve from 0 to 24 h from 3.3 +/- 2.0 to 6.3 +/- 4.5 micrograms.h/ml (P < 0.05) and harmonic mean half-life from 1.2 to 1.6 h (P < 0.05) but did not significantly alter the effect of omeprazole on gastric pH. Mean clarithromycin area under the concentration-time curve from 0 to 8 h increased from 22.9 +/- 5.5 (placebo) to 26.4 +/- 5.7 micrograms.h/ml (omeprazole) (P < 0.05) when clarithromycin was administered with omeprazole. Analysis of variance revealed that mean concentrations of clarithromycin in tissue and mucus were statistically significantly higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo (P <0.001). Mean maximum observed concentrations of clarithromycin in the gastric fundus increased from 20.8 +/- 7.6 (placebo) to 24.3 +/- 6.4 micrograms/g (omeprazole), and those in the gastric mucous from 4.2 +/- 7.7 placebo to 39.3 +/- 32.8 micrograms/g (omeprazole). Similar increases were observed for the 14-(R)-hydroxyclarithromycin. These results show that omeprazole increases concentrations of clarithromycin in gastric tissue and mucus and may provide a mechanism for synergy between clarithromycin ad omeprazole that explains the excellent eradication of H. pylori seen in clinical trials.