Influence of gender on the pharmacokinetics, safety, and tolerability of cerivastatin in healthy adults.

The pharmacokinetics, safety, and tolerability of cerivastatin, a synthetic HMG-CoA reductase inhibitor were studied in 49 healthy volunteers. In this double-blind, parallel group, multiple-dose study, volunteers were randomized as age-matched, male-female pairs and stratified into younger (18-65 years, premenopausal females) or older (65-85 years, postmenopausal females) groups. Thirty-two (16 female, 16 male) subjects received 0.2 mg cerivastatin daily for 7 days; 17 received placebo. Between all males and females, no differences in cerivastatin pharmacokinetics were observed. The AUCnorm in older females was 21% higher than in older males, while the AUCnorm in younger females was 26% lower than in younger males. The Cmax in older females was 30% higher than in age-matched males or younger males and females. All other pharmacokinetic parameters, including half-life, tmax, accumulation ratios, and steady state plasma levels were similar in all treatment groups. The most common adverse events, including headache (4), dyspepsia (4), and rash (4), were equally distributed between groups. Treatment-emergent elevations (< 2 x ULN) in creatine kinase occurred in one subject. Transaminase elevations occurred in nine subjects, most were less than 3 x ULN, and were equally distributed between groups. In conclusion, cerivastatin was well tolerated. The minor differences in the pharmacokinetics of cerivastatin 0.2 mg between genders does not require modification of dosage.

A dose-response study of the efficacy and safety of ipratropium bromide nasal spray in the treatment of the common cold.

Rhinorrhea is an annoying symptom of the common cold for which effective therapy is not currently available. Ipratropium bromide (IB) is an anticholinergic drug that has been shown to decrease glandular secretion when applied topically to the nasal mucosa. The purpose of this study was to compare the efficacy and safety of three doses of IB nasal spray versus either vehicle or no treatment in relieving rhinorrhea in patients with naturally acquired colds. Rhinorrhea severity was measured objectively by determining nasal discharge weights and subjectively by means of visual analog scale scores. Compared with either vehicle or no treatment, IB nasal spray produced a significant decrease in the severity of rhinorrhea. A dose of 84 micrograms (two sprays of a 0.06% solution in buffered saline solution) in each nostril was more efficacious than a 42 microgram per nostril dose and only marginally less efficacious than a 168 micrograms per nostril dose. The 84 micrograms per nostril dose also was associated with fewer adverse events than was the higher dose. None of the adverse events related to intranasal IB therapy was of a serious nature. The use of IB nasal spray appears to be a rational and safe approach to relieving rhinorrhea associated with the common cold.

Gastrointestinal absorption of pravastatin in healthy subjects.

The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greatest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.

A comparison of inhaled ipratropium, oral theophylline plus inhaled beta-agonist, and the combination of all three in patients with COPD.

To evaluate the role of inhaled ipratropium bromide alone vs oral theophylline plus inhaled beta-agonist or the combination of all three in patients with stable COPD, the following double-blind, placebo-controlled study was conducted. Forty-eight patients with stable COPD (mean age, 61.8 years, with mean baseline FEV1 < 1.0 L) were randomized on four separate days to receive the following drug regimens: (1) theophylline tablets (dose previously determined to result in blood level of 12 to 18 mg/L), followed by inhaled albuterol (2 puffs via metered-dose inhaler [MDI]), followed by inhaled placebo (2 puffs via MDI); (2) oral placebo followed by ipratropium (2 puffs via MDI; 36 micrograms), followed by inhaled placebo; (3) oral theophylline, followed by albuterol, followed by ipratropium; or (4) oral placebo followed by two inhaled placebos. On study days, spirometry and heart rate were measured at time 0, 30 min, 60 min, and hourly for 6 h. The FEV1 peak change (liters) and area under the curve (liter x hours) for the treatment groups were compared. Ipratropium was more effective than placebo (p = 0.001 and p = 0.0078, respectively). The combination of albuterol and theophylline was superior to ipratropium alone (p = 0.001 and p = 0.0001, respectively), and all three drugs together were superior to the combination of albuterol and theophylline (p = 0.0373 and p = 0.0289), respectively; one-sided test of hypotheses). Peak heart rates were significantly higher for treatment groups compared with placebo groups (p = 0.0001). However, theophylline and albuterol and the combination of all three drugs resulted in greater peak heart rates than did ipratropium alone (p = 0.001). These data suggest that for patients with stable COPD, combination therapy with ipratropium (two puffs), theophylline, and albuterol (two puffs) is superior to ipratropium alone or the combination of theophylline and albuterol.

A double-blind, placebo-controlled study of the safety and efficacy of ipratropium bromide nasal spray versus placebo in patients with the common cold.

Ipratropium bromide (IB) has been found to reduce secretions in the upper respiratory tract; this is accomplished through competitive inhibition of acetylcholine at muscarinic receptors that control rhinorrhea production. This study compared the safety and efficacy of IB with placebo in the symptomatic relief of rhinorrhea in patients with the common cold. Human subjects with symptoms of a common cold, primarily rhinorrhea, were enrolled and treated with either IB (84 micrograms/nostril) or placebo; each was administered as two sprays per nostril, four times a day, for 4 days. Primary efficacy analyses were in-clinic measurements of nasal discharge weights over a 3-hour period after administration on days 1 and 2 and assessment of rhinorrhea symptoms by use of a subjective patient-completed visual analog rating scale. IB significantly reduced rhinorrhea an average of 18% over placebo for days 1 and 2 (p = 0.01). Visual analog scale scores showed an average improvement in rhinorrhea of 22% over placebo (p = 0.001). When patients with relatively minor rhinorrhea (baseline weight of nasal discharge < or = 1.0 gm) were excluded, IB produced an average reduction in nasal discharge of 23% over placebo for days 1 and 2 (p = 0.003).

Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects.

The relative bioavailability and pharmacokinetics of ofloxacin tablets and a reference oral solution of ofloxacin were compared in 32 normal male subjects using a randomized two-way crossover design. After an overnight fast, subjects were randomized to receive a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) and blood samples were obtained prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose. After a 5-day wash-out period, subjects were administered the same dose but of the other formulation, and blood samples were collected in an identical manner. Plasma concentrations of ofloxacin were determined by high-pressure liquid chromatography. The results showed that ofloxacin tablets were more slowly absorbed when compared to the solution and mean peak plasma concentrations were obtained in about 1.5 hours for the tablet preparation. Maximum plasma concentrations were higher after administration of the solution (Cmax = 2.24 micrograms/ml, 200 mg; Cmax = 3.25 micrograms/ml, 300 mg) compared to the tablet (Cmax = 1.74 micrograms/ml, 200 mg; 2.61 micrograms/ml, 300 mg). The bioavailability of ofloxacin tablets was greater than 98% compared to the solution. The other pharmacokinetic parameters were similar between the two dosage formulations. Ofloxacin tablets revealed an apparent volume of distribution of 1.5 l/kg, an elimination half-life of 5.6 hours, and a total clearance of 251 ml/min. In addition, a linear increase in plasma concentrations was observed when the dose of ofloxacin was increased. In summary, ofloxacin tablets was found to be reliably bioavailable and bioequivalent to the reference solution.

Multicenter evaluation of the hemodynamic effects of bisoprolol in patients with mild to moderate hypertension.

Twenty-six patients with mild-to-moderate essential hypertension participated in a 6-week outpatient, multicenter, randomized, double-blind, placebo-controlled two-way crossover study to assess the hemodynamic effects of bisoprolol (20 mg QD) at steady state. Hemodynamic assessments included sitting blood pressure, heart rate, and left-ventricular ejection fraction by radionuclide ventriculography after 7 days of bisoprolol or placebo at trough (24 h post-dose) and peak (3 h post-dose) values. The group adjusted mean ejection fraction was not significantly different in patients receiving bisoprolol compared with the placebo group at either peak or trough measurements; in fact, means in patients taking bisoprolol were slightly higher than in the placebo group. No symptomatic hypotension was documented. Blood pressure, measured 24 hours after dosing, was significantly lower in those receiving bisoprolol when compared with the placebo group, by 7.7 mm Hg and 9 mm Hg for diastolic and systolic blood pressure, respectively. Similarly, mean values of heart rate were 10 beats/min lower in the bisoprolol patients than in the placebo group. Only headache and insomnia occurred as adverse events. Bisoprolol (20 mg QD) effectively lowered blood pressure over a 24-hour period without significantly reducing ejection fraction or causing adverse clinical or biochemical events.

Arbaprostil [15(R)-15-methyl prostaglandin E2] in a single nighttime dose of either 50 or 100 micrograms in acute duodenal ulcer.

To determine the efficacy of single nighttime doses of arbaprostil [15(R)-15-methyl prostaglandin E2], 50 or 100 micrograms for 4 wk, a double-blind randomized placebo-controlled multiclinic trial was undertaken. Success was defined as complete healing of the ulcer documented by endoscopy. Fifty-one of 64 patients enrolled were considered evaluable. Ulcer healing was documented in 64.3%, 85.7%, and 31.2% of the 100-micrograms arbaprostil, 50-micrograms arbaprostil, and placebo treatment groups (p value vs. placebo = 0.003 and 0.002, respectively). No difference in side effects or changes in laboratory parameters were found between the treatment groups except that diarrhea, usually mild, was found more often in the 100-micrograms arbaprostil group (60.0%) than in the 50-micrograms arbaprostil (31.8%) or placebo groups (23.5%) (p value 100 micrograms arbaprostil vs. placebo = 0.02). A single nighttime administration of arbaprostil seems to be a safe and efficacious agent for the treatment of acute duodenal ulcer.

The effects of age and race on nitrendipine pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of a single 20-mg dose of nitrendipine (NTP) were studied in four groups of subjects (n = 9 per group). Group 1 were young white normotensive males, Group 2 were elderly white hypertensive males, Group 3 were black hypertensive males aged 40-55 years, and Group 4 were white hypertensive males aged 40-55 years. All other medications were withdrawn prior to NTP dosing. NTP was given in the morning 1 h after breakfast. Plasma samples for NTP assay were collected at predetermined times up to 48 h after dosing. Blood pressure was monitored before dosing, and at 0.5, 1, 3, 5, 12, and 24 h postdose. Pharmacokinetic parameters were found to be dependent on age. The area under the curve for Groups 1, 2, 3, and 4 was 50.5 +/- 19.4, 186 +/- 120, 107 +/- 49, and 88 +/- 43 ng h/ml, respectively (p less than 0.05). Corresponding values of elimination half-life were 9.9 +/- 1.3, 20 +/- 6.5, 13.3 +/- 6.1, and 15.9 +/- 8.0 h (p less than 0.05). Both diastolic and systolic blood pressures were significantly reduced from the baseline value in Groups 2, 3, and 4, with diastolic pressure remaining significantly lower than baseline at 24 h postdose. Based on the increased plasma levels and slower elimination of NTP in the elderly, as well as the measured blood pressure lowering, once daily dosing of NTP may be appropriate in some patients.

Effects of carvedilol on blood pressure in patients with mild to moderate hypertension. A dose response study.

Carvedilol 12.5, 25 and 50 mg was administered once daily for 4 weeks to patients with mild to moderate hypertension. The purpose of the study was to investigate the antihypertensive action of carvedilol when administered once daily and to investigate the pharmacokinetics of carvedilol in patients with mild to moderate hypertension. Measurable decreases in blood pressure (BP) occurred within 1 hour after the first dose. Peak decreases in supine diastolic blood pressure (DBP) were 9.0 +/- 6.8, 15.5 +/- 6.7, 14.7 +/- 10.6 and 22.5 +/- 7.6mm Hg (+/- SD) for the placebo, 12.5, 25 and 50mg carvedilol groups, respectively, and occurred between 3 and 7 hours after the dose. Administration of carvedilol once daily for 4 weeks kept supine DBP below baseline levels for 24 hours. Trough supine DBP after 4 weeks of treatment were 0.6 +/- 6.5, 7.3 +/- 7.9, 8.8 +/- 7.4 and 12.1 +/- 3.8mm Hg (+/- SD) below baseline. Serum levels of carvedilol were proportional to the dose. Peak serum levels were 39 +/- 27, 75 +/- 38 and 161 +/- 131 mu/L for carvedilol 12.5, 25 and 50mg. The kinetics of carvedilol did not change with repeated administration. Carvedilol was well tolerated; 2 patients experienced dizziness associated with postural hypotension after administration of the 50mg dose. Carvedilol 12.5, 25 and 50mg effectively reduced BP for 24 hours when administered once daily.

Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam.

Sixty volunteers with insomnia participated in a randomized, double-blind, controlled clinical trial. After an initial six nights of placebo, 30 subjects (the abrupt-withdrawal group) received 0.5 mg of triazolam nightly for 7 to 10 nights, after which they received placebo. The other 30 subjects (the tapered-dosage group) received the same initial placebo treatment, then triazolam at 0.5 mg for seven nights, at 0.25 mg for two nights, and at 0.125 mg for two nights, and then placebo. As compared with the initial placebo period, the triazolam period significantly reduced the interval before the onset of sleep (sleep latency), and it prolonged sleep duration, reduced the number of awakenings, and improved the self-rated soundness of sleep in all cohorts. In the abrupt-withdrawal group, plasma levels of triazolam were undetectable the morning after the first night of placebo substitution, and subjects reported prolongation of sleep latency (57 minutes longer than base line), reduction in sleep duration (1.4 hours less than base line), and increased awakenings (1.2 per night above base line). The symptoms of rebound sleep disorder lasted one or possibly two nights, and there was a reversion toward base line on subsequent placebo nights. In the tapered-dosage group, however, plasma triazolam levels fell gradually to zero, and rebound symptoms were decreased or eliminated. Thus, rebound sleep disorder following abrupt discontinuation of triazolam can be attenuated by a regimen of tapering.

Effect of food on nifedipine pharmacokinetics.

The effect of food on the bioavailability of nifedipine (Procardia), 10 mg capsules, was studied. Each of 15 male volunteers received a single oral 10 mg dose with 120 ml water under three conditions: fasting, after a low-fat (high-carbohydrate) meal, and after a high-fat meal. An open, three-way Latin-square design was employed with a 4-day washout period between administrations. Serial blood samples were collected just before the dose (0 hour) and from 0 to 8 hours after administration. Nifedipine assays were performed by GLC/electron capture detection. Diet did not appreciably alter the AUC from 0 to 8 hours, the AUC from 0 to infinity, or the elimination half-life. The time to peak (tmax) and peak concentrations (Cmax) were significantly altered by food. The mean Cmax values for fasting, low-fat, and high-fat meals were 78.9, 42.2, and 58.7 ng/ml, respectively. The mean tmax values for these three conditions were 0.97, 1.89, and 1.07 hours, respectively. The results indicate that food, in particular a low-fat (high-carbohydrate) meal, slows the rate but does not alter the extent of nifedipine absorption. Insofar as certain side effects (e.g., flushing and headache) may be related to the high peak plasma levels associated with rapid absorption, administration with meals might serve to reduce the incidence of such effects. Clinical trials would be necessary to confirm this possibility. For the majority of patients on routine maintenance therapeutic regimens, nifedipine capsules may be administered without regard to food intake.

Interaction of diazepam with famotidine and cimetidine, two H2-receptor antagonists.

Famotidine is currently under investigation as an H2-receptor antagonist. Eleven healthy male volunteers received a single 10 mg intravenous dose of diazepam on three occasions: once during coadministration of famotidine 40 mg bid, once during coadministration of cimetidine 300 mg qid, and once without other drug treatment (control). Multiple blood samples were drawn during the seven days after each diazepam dose. Diazepam and desmethyldiazepam plasma concentrations were measured by electron capture gas chromatography. There were no significant differences among the three treatment conditions in diazepam central compartment volume or total volume of distribution. During the cimetidine as compared with the control treatment, diazepam elimination half-life was significantly increased (72 vs 55 hr, P less than .05), total area under the curve (AUC) increased (11.8 vs 9.8 hr-micrograms/mL, P less than .05), and total clearance reduced (0.20 vs 0.28 mL/min/kg, P less than .05). Seven-day AUC for desmethyldiazepam also increased (4.6 vs 3.8 hr-micrograms/mL, P less than .05). However, there were no significant differences between famotidine and control treatment conditions in diazepam elimination half-life (53 vs 55 hr), total AUC (9.5 vs 9.8 hr-micrograms/mL), or total clearance (0.28 vs 0.28 mL/min/kg) or in seven-day AUC for desmethyldiazepam (3.9 vs 3.8 hr-micrograms/mL). Thus, therapeutic doses of cimetidine significantly impair the clearance of diazepam and desmethyldiazepam. Therapeutic doses of famotidine do not impair diazepam and desmethyldiazepam kinetics, suggesting that there is no significant kinetic interaction when diazepam and famotidine are administered concurrently in clinical practice.

Pharmacokinetics of dezocine, a new analgesic: effect of dose and route of administration.

The pharmacokinetics of intravenous (IV) dezocine, and bioavailability of intramuscular (IM) and subcutaneous (SQ) dezocine, were evaluated in healthy male volunteers. Elimination half-life following 5, 10, and 20 mg IV doses averaged 2.6-2.8 h, and was independent of dose. Clearance decreased slightly, although significantly, with dose. After Deltoid IM injection, dezocine was rapidly absorbed (peak level: 0.6 h after dose), with bioavailability 97%. Thus dezocine has extensive distribution, high clearance and short half-life over a range of IV doses. It is rapidly and completely absorbed following IM or SQ administration.

Lidocaine plasma concentrations following administration of intraoral lidocaine solution.

Seventeen healthy male volunteers received 15 mL of 2% solution (300 mg) of lidocaine hydrochloride every three hours for eight consecutive doses. Modes of administration were as follows: (A) each dose washed throughout the oral cavity, then spit out without swallowing; (B) each dose washed, then swallowed; and (C) each dose swallowed directly. Plasma levels of lidocaine and its two metabolites (monoethylglycinexylidide [MEGX] and glycinexylidide [GX]) were measured during and after the period of dosage. In trial A, levels of all three compounds were very low, in no case exceeding 0.3 microgram/mL. During trial C, the mean peak levels of lidocaine and MEGX, respectively, were 0.5 and 0.6 microgram/mL after the first dose, and 0.8 and 1.3 microgram/mL after the eighth dose. Both compounds were essentially undetectable by 12 hours after the last dose. Levels in trial B were very similar to those in trial C. Thus, recommended topical oral cavity use of 2% lidocaine leads to negligible systemic levels of lidocaine and metabolites. Even when doses are swallowed, systemic levels do not approach a toxic range.

Absolute bioavailability and effect of food and antacid on diazepam absorption from a slow-release preparation.

A series of healthy volunteers received a single 7.5-mg intravenous dose of diazepam on one occasion and a single 15-mg oral dose of slow-release diazepam (DZ-SR) on another occasion. Diazepam concentrations were measured by gas chromatography in multiple plasma samples drawn during seven days after each dose. Absorption of diazepam from DZ-SR was slow, with mean +/- S.E. peak concentrations attained at 3.8 +/- 0.5 hours after dosage. Absolute bioavailability of DZ-SR averaged 0.98 +/- 0.06. In two other studies, diazepam absorption from DZ-SR was evaluated when coadministered with a standard breakfast or with an antacid preparation (Maalox). Neither food nor antacid altered the rate of diazepam absorption and did not impair the completeness of absorption. Higher peak total plasma diazepam concentrations occurred in the postprandial as opposed to the fasting state, but this was an artifact of reduced protein binding (increased free fraction) due to fasting. Thus, diazepam absorption from DZ-SR is slow and essentially complete.

Bioavailability of two manufacturers' sustained-release quinidine gluconate tablets at steady state.

Steady-state bioavailability of sustained-release quinidine gluconate tablets manufactured by two companies was compared in a crossover study. The tablets were Quinaglute Dura-Tabs, manufactured by Berlex Laboratories, Inc., and generic quinidine gluconate tablets, manufactured by Bolar Pharmaceutical Company. Sixteen healthy male volunteers were given multiple doses of the two products in randomized sequence. Blood samples were obtained immediately before administration of the seventh dose (hour 72) and at 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after administration. Plasma samples were assayed for quinidine content by high-performance liquid chromatography. The tablets manufactured by Berlex provided statistically significantly higher plasma levels during the second half of the dosing interval (six to 12 hours postdose). A 29% difference in plasma levels was observed between the products at the end of the dosing interval. The Bolar quinidine gluconate tablets had a statistically significant lower area under the curve (AUC). The greatest difference in AUC occurred during the last six hours of the dosing period. The six- to 12-hour AUC for the Bolar tablets was 24% less than that for Berlex tablets. The generic tablets also achieved peak plasma level 31% sooner than did Quinaglute Dura-Tabs. The pharmacokinetic characteristics of the two products at steady state indicate that the Bolar quinidine gluconate tablet exhibited a more rapid onset of peak plasma levels and a more rapid decline to minimum plasma levels. In summary, the data from this multiple-dose study, performed using commercially available material, indicate that differences exist in pharmacokinetic performance of the products. However, the exact correlation between pharmacokinetic data and clinical effectiveness has not been established.

Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation.

The rate and extent of accumulation of clobazam and its major metabolite, desmethylclobazam, during multiple dosage with clobazam were evaluated in 4 similarly sized groups of young male, young female, elderly male, and elderly female volunteers. Subjects received single 10mg doses of clobazam daily for 22 consecutive days. Plasma levels were measured during and after the period of dosage. Compared with the young male subjects, elderly males had slower rates of clobazam accumulation and washout, higher steady-state plasma levels, and lower steady-state clearance. Accumulation of desmethylclobazam also was slower and more extensive in the elderly male group. Among females, however, age-related kinetic differences did not approach significance. Among all subjects, pharmacokinetic variables for clobazam determined in a previous single-dose study were highly consistent with the multiple-dose pharmacokinetic profile. Single-dose vs post-multiple dosage half-life, single-dose vs steady-state clearance, observed vs predicted accumulation ratios, and observed vs predicted steady-state plasma concentrations were all highly correlated, with regression line slopes close to unity. Thus, reduced single-dose clearance of clobazam in elderly men leads to slower and more extensive accumulation during multiple dosage. The single-dose pharmacokinetic profile of clobazam is highly predictive of drug behaviour during repeated dosage, suggesting that clobazam kinetics are dose- and concentration-independent within the range studied, and that self-induction or inhibition of clearance is not evident during 3 weeks of dosage.