Pharmacodynamics of MK-0963, a new 5 alpha-reductase inhibitor: effects on serum androgen concentrations.

The hormonal effects after a 10-day administration of a 4-azasteroid inhibitor of 5 alpha-reductase, MK-0963 (previously L-654,066), were evaluated in 35 healthy male volunteers in an increasing-dose, five-panel design. Marked suppression of serum dihydrotestosterone was observed after the once-daily administration at each active dose level (placebo, 0.1, 0.5, 1.0, 10, and 25 mg). Maximum dihydrotestosterone suppression occurred at doses greater than or equal to 10 mg. The mean percentage (+/- SE) decreases in dihydrotestosterone at 24 hours after the last dose in the groups treated with the 10 and 25 mg doses were 78% +/- 4.9% and 80% +/- 2.9%, respectively. The 25 mg dose maintained a dihydrotestosterone suppression of at least 70% for more than 6 days after the last dose. No consistent changes in serum testosterone were noted. This study shows that administration of multiple doses of MK-0963 results in a substantial suppression of serum dihydrotestosterone with no consistent influence on serum testosterone concentrations.

Pharmacodynamics and dose-response relationship of famotidine: a double-blind randomized placebo-controlled trial.

The dose-response relationship of oral famotidine at doses up to 10 mg was evaluated in 10 healthy male subjects to assess the extent and duration of inhibition of meal-stimulated intragastric acid secretion. Each subject received single oral administrations of famotidine 0.5, 2.5, 5.0, and 10.0 mg and placebo in a double-blind, randomized, cross-over fashion. Intragastric pH was measured every 4 seconds for 24 hours and expressed as the mean pH for each 10-minute interval. Standard high-protein meals were provided 1 hour before each dose of study drug and at 3 and 9 hours postdose. The mean intragastric pH was significantly higher after famotidine doses 2.5, 5.0, and 10.0 mg than after placebo at times 2.5 to 3.0, 1.8 to 3.2, and 1.7 to 4.2 hours postdose, respectively. There were no significant differences in mean pH seen between famotidine 0.5 mg versus placebo. The range of the pH means between 1.7 and 3.2 hours postdose was placebo (1.0 to 1.3), famotidine 0.5 mg (1.1 to 1.4), 2.5 mg (1.4 to 1.7), 5.0 mg (1.7 to 2.1), and 10.0 mg (2.0 to 2.3). There was a statistically significant linear dose-response relationship between famotidine dose and intragastric pH between 1.7 and 3.8 hours and from 6.3 to 8.7 hours after ingestion.

Symptoms of preterm labor and self-diagnostic confusion.

The purpose of this study was to learn how women experiencing preterm labor come to know a health deviation exists, and what they do when faced with such a problem. Grounded theory methodology was used as the research approach. Extensive interviews were conducted with 28 women about their care-seeking experiences with preterm labor. Ambiguous symptoms, absence of a meaningful label to attach to symptoms, and the context of pregnancy with its expected discomforts come together to create a situation of diagnostic confusion. Appropriate action to take in response to the diagnostic confusion is not self-evident. Deliberate and protracted efforts to make sense of and deal with symptoms of preterm labor are attempted. Making sense consists of three subprocesses: comparing, gathering data, and seeking information. Strategies used to deal with the symptoms include self-treating, ignoring, positive thinking, and waiting. Recourse to a professional is used as the strategy of last resort when symptoms can no longer be contained.

Timentin in the treatment of symptomatic complicated urinary tract infections in adult patients.

The safety and effectiveness of Timentin were evaluated in 34 adult patients with symptomatic complicated urinary tract infections, principally due to multiply-drug-resistant bacteria. Although a wide variety of organisms, particularly gram-negative bacilli, were found, Escherichia coli was the most frequent, accounting for 14 of 45 (31 percent) pathogens isolated. Ten (22 percent) isolates were Pseudomonas aeruginosa; 11 (24 percent) were Proteus or Morganella species; three (7 percent) were Citrobacter; one (2 percent) was Klebsiella pneumoniae; two (4 percent) were Staphylococcus aureus; and two (4 percent) were enterococci. Ninety-three percent of all pathogens isolated produced a beta-lactamase. Eight (24 percent) infections were polymicrobial; seven (21 percent) were associated with bacteremia. Clinical improvement occurred in 30 of 34 (86 percent) patients. All bacteremias were cured. Although bacteriologic cure occurred in only 32 percent of patients, control of sepsis and temporary eradication of bacteria (bacteriologic improvement) occurred in 96 percent. Not surprisingly, the rates of relapses and reinfections were high. It was concluded that Timentin is a useful agent in the management of complicated urinary tract infection and offers clinicians an alternative to more toxic antibiotics, such as aminoglycosides.

Primaxin in the treatment of acute bacterial pneumonia in adults.

Imipenem (N-Formimidoyl thienamycin) (MK-0787) is a new beta-lactam carbapenem antibiotic. When it is combined with the renal dipeptidase inhibitor cilastatin (MK-0791) the combination is known as primaxin. In this study 28 adult patients (24 males and 4 females) with acute bacterial pneumonia were treated with primaxin. Twenty-one patients were evaluable and 20 (95%) were clinically cured of their pneumonia. Bacteriological cures were demonstrated in 84% of the cases. One patient with a susceptible Pseudomonas aeruginosa failed. Major complications or toxic reactions included antibiotic associated diarrhoea in one patient; hypotension in one patient; increased grand mal seizures in one patient and elevated liver function studies in one patient. Results of this study suggest that primaxin will be useful in the treatment of a variety of serious Gram-positive and Gram-negative pneumonias. The true incidence of possible toxic reactions with this drug is not known at this time and awaits further experience.

Cefmenoxime pharmacokinetics in patients with renal insufficiency.

The pharmacokinetics of cefmenoxime were determined after a 30-min intravenous infusion of 15 mg/kg of total body weight to 33 adult subjects with normal renal function (CLCR, greater than 80 ml/min per 1.73 m2, group I), mild renal insufficiency (CLCR, 40 to 79 ml/min per 1.73 m2, group II), moderate renal insufficiency (CLCR, 10 to 39 ml/min per 1.73 m2, group III), or severe renal impairment, (CLCR, less than 10 ml/min per 1.73 m2, group IV) or to patients between hemodialysis (CLCR, less than 10 ml/min per 1.73 m2, group V). Concentrations of cefmenoxime in serum and urine were determined by high-pressure liquid chromatography, and serum concentrations were fit to a two-compartment model. There was no significant relationship between creatinine clearance and either peak serum concentrations or volume of distribution at steady state. Patients in group I excreted 81% of the dose into the urine within 24 h; recovery decreased with worsening renal function. The mean terminal half-lives in groups I to V were 1.06, 1.50, 3.55, 4.60, and 11.4 h, respectively. There were good linear relationships between creatinine clearance, and the elimination rate and total body clearance of cefmenoxime. Dosage recommendations for subjects with renal insufficiency are proposed.