Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.

It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-γ agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-γ agonists.

Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery.

BACKGROUND: Atrial arrhythmias occur commonly after cardiac surgery and are a cause of significant morbidity and increased hospital costs, yet there is no well-studied treatment strategy to deal with them expeditiously. The purpose of this study was to determine the efficacy and safety of ibutilide fumarate, an approved drug for the rapid conversion of atrial fibrillation and flutter, in patients after cardiac surgery. METHODS AND RESULTS: Patients with atrial fibrillation or flutter occurring 1 to 7 days after surgery and lasting 1 hour to 3 days were randomized to receive two 10-minute blinded infusions of placebo or 0.25, 0.5, or 1.0 mg of ibutilide fumarate. Treatment was considered successful if sinus rhythm was restored for any period of time by hour 1.5. A total of 302 patients were randomized, 201 with fibrillation and 101 with flutter. Treatment with ibutilide resulted in significantly higher conversion rates than placebo, and efficacy was dose related (placebo 15%; ibutilide 0.25 mg 40%, 0.5 mg 47%, and 1.0 mg 57%). Conversion rates at all doses were higher for atrial flutter than for atrial fibrillation. Mean time to conversion decreased as the dose was increased. Polymorphic ventricular tachycardia was the most serious adverse effect and occurred in 1.8% of the ibutilide-treated patients compared with 1.2% of patients who received placebo. CONCLUSIONS: Ibutilide is a useful and safe treatment alternative for the atrial arrhythmias that occur after cardiac surgery.

Suppression of inducible ventricular tachycardia by ibutilide in patients with coronary artery disease. Ibutilide Investigators.

BACKGROUND: Recent studies suggest that class III antiarrhythmic agents may have enhanced efficacy in the treatment of ventricular tachycardia. This study describes the first clinical assessment of the new class III agent ibutilide to suppress inducible monomorphic ventricular tachycardia (VT) in human beings. METHODS AND RESULTS: Fifty-five patients with coronary artery disease and inducible sustained monomorphic VT at baseline received either low (0.005 mg/kg + 0.001 mg/kg, load and maintenance infusion, respectively), middle (0.01 mg/kg + 0.002 mg/kg), or high dose (0.02 mg/kg + 0.004 mg/kg) infusions of ibutilide followed by repeat programmed ventricular stimulation. The mean age of the study group was 65.5 +/- 9.5 years and mean left ventricular ejection fraction was 36% +/- 11%. Of 48 evaluable patients, 21 (44%) were rendered noninducible after ibutilide, with no difference in efficacy among the three dosing groups (p = 0.83). Ventricular effective refractory periods, QTc interval, and ventricular monophasic action potential duration were prolonged over baseline at all tested cycle lengths. The QTc and action potential prolongation were dose related. Serious drug-related adverse reactions included sustained polymorphic VT in two patients (3.6%), spontaneous monomorphic VT in one patient (1.8%), heart block in one patient (1.8%), and hypotension in one patient (1.8%). CONCLUSIONS: Ibutilide prolongs ventricular repolarization in human beings and demonstrates efficacy in suppressing inducible monomorphic VT. Significant cardiovascular side effects occurred in 12.7% of patients.

Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or fibrillation.

OBJECTIVES: This multicenter study compared the efficacy and safety of ibutilide versus procainamide for conversion of recent-onset atrial flutter or fibrillation. BACKGROUND: Ibutilide fumarate is an intravenous (IV) class III antiarrhythmic agent that has been shown to be significantly more effective than placebo in the pharmacologic conversion of atrial flutter and fibrillation to sinus rhythm. Procainamide is commonly used for conversion of recent-onset atrial fibrillation to normal sinus rhythm. METHODS: One hundred twenty-seven patients (age range 22 to 92 years) with atrial flutter or fibrillation of 3 h to 90 days' (mean 21 days) duration were randomized to receive either two 10-min IV infusions of 1 mg of ibutilide fumarate, separated by a 10-min infusion of 5% dextrose in sterile water, or three successive 10-min IV infusions of 400 mg of procainamide hydrochloride. RESULTS: Of the 127 patients, 120 were evaluated for efficacy: 35 (58.3%) of 60 in the ibutilide group compared with 11 (18.3%) of 60 in the procainamide group had successful termination within 1.5 h of treatment (p < 0.0001). Seven patients were found to have violated the protocol and were not included in the final evaluation. In the patients with atrial flutter, ibutilide had a significantly higher success rate than procainamide (76% [13 of 17] vs. 14% [3 of 22], p=0.001). Similarly, in the atrial fibrillation group, ibutilide had a significantly higher success rate than procainamide (51% [22 of 43] vs. 21% [8 of 38], p=0.005). One patient who received ibutilide, which was found to be a protocol violation, had sustained polymorphic ventricular tachycardia requiring direct current cardioversion. Seven patients who received procainamide became hypotensive. CONCLUSIONS: This study establishes the superior efficacy of ibutilide over procainamide when administered to patients to convert either atrial fibrillation or atrial flutter to sinus rhythm. Hypotension was the major adverse effect seen with procainamide. A low incidence of serious proarrhythmia was seen with the administration of ibutilide occurring at the end of infusion.

Acute hemodynamic effects of intravenous ibutilide in patients with or without reduced left ventricular function.

Many antiarrhythmic agents have adverse hemodynamic effects which limit their use in patients with impaired ventricular function or during tachyarrhythmias. Ibutilide is an intravenous, selective class III antiarrhythmic agent that is effective for conversion of atrial fibrillation or flutter. This multicenter, randomized, placebo-controlled, dose-ranging study evaluated the effects of intravenous ibutilide on hemodynamic parameters during invasive monitoring in 47 patients with or without reduced left ventricular ejection fraction (LVEF) > 35% or < or = 35%. Patients received either placebo or ibutilide as a 10-minute loading and a 30-minute maintenance infusion using 1 of the following dosing regimens: placebo then placebo (n = 12); 0.01 then 0.002 mg/kg (n = 12); 0.02 then 0.004 mg/kg (n = 12); or 0.03 then 0.006 mg/kg (n = 11). Ibutilide significantly increased QT and QTc intervals in a dose-related manner with mean increases ranging from 51 to 99 ms, but did not alter the PR interval or QRS duration. During ibutilide infusion, a few small but statistically significant changes from baseline in several hemodynamic variables were present. However, the changes in cardiac output, pulmonary artery or capillary wedge pressures, blood pressure, or heart rate in patients receiving ibutilide were not significantly different from the changes in patients receiving placebo. Thus, ibutilide did not cause clinically important adverse hemodynamic effects, even in patients with depressed ventricular function. One patient developed 2 episodes of nonsustained torsades de pointes during ibutilide. These results demonstrate that with careful monitoring for proarrhythmia, ibutilide can be used safely from a hemodynamic standpoint in the acute treatment of arrhythmias, even in patients with reduced ventricular function.

The cost-effectiveness of ibutilide versus electrical cardioversion in the conversion of atrial fibrillation and flutter to normal rhythm.

Atrial fibrillation and atrial flutter are cardiac rhythm disorders that are often symptomatic and may interfere with the heart's function, limiting its effectiveness. These arrhythmias are responsible for a large number of hospitalizations at a significant cost to the healthcare system. Electrical cardioversion (EC) is the most common nonpharmacologic intervention used to convert atrial fibrillation and atrial flutter to normal rhythm. Electrical cardioversion is highly successful in converting patients to normal rhythm; however, it is more traumatic and resource intensive than pharmacologic treatment. Recently, a new rapid-acting drug, ibutilide, was approved for the conversion of atrial fibrillation and atrial flutter. Ibutilide is administered through intravenous infusion and does not require anesthetization of the patient, as is required for EC. A decision-tree model was developed to estimate the cost-effectiveness of ibutilide therapy compared with EC therapy. Clinical outcomes were based on a phase III trial of ibutilide, and resource use was based on the literature and physician clinical judgment. A stepped conversion regimen of first-line ibutilide followed by EC for patients who fail to convert is less expensive and has a higher conversion rate than first-line EC. Sensitivity analysis shows that our results are robust to changes in cost and effectiveness estimates.

Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators.

BACKGROUND: Currently available antiarrhythmic drugs have limited efficacy for acute termination of atrial fibrillation and flutter, especially if the arrhythmia is not of recent onset. The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter. METHODS AND RESULTS: Two hundred sixty-six patients with sustained atrial fibrillation (n = 133) or flutter (n = 133), with an arrhythmia duration of 3 hours to 45 days, were randomized to receive up to two 10-minute infusions, separated by 10 minutes, of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. The conversion rate was 47% after ibutilide and 2% after placebo (P < .0001). The two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%). Efficacy was higher in atrial flutter than fibrillation (63% versus 31%, P < .0001). In atrial fibrillation but not flutter, conversion rates were higher in patients with a shorter arrhythmia duration or a normal left atrial size. Arrhythmia termination occurred a mean of 27 minutes after start of the infusion. Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion. The arrhythmia required cardioversion in 3 patients (1.7%) and was nonsustained in 12 patients (6.7%). CONCLUSIONS: Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter and under monitored conditions is an alternative to current cardioversion options.

Efficacy of ibutilide for termination of atrial fibrillation and flutter.

The clinical utility of ibutilide fumarate (Corvert) for the acute conversion of atrial tachyarrhythmias to normal sinus rhythm has been demonstrated in several randomized, placebo-controlled clinical trials. The efficacy of intravenous ibutilide for rapid conversion of atrial flutter is in the range of 50-70%, whereas its efficacy for conversion of atrial fibrillation is 30-50%. Approximately 80% of atrial tachyarrhythmias that terminate do so within 30 minutes from the initiation of the intravenous infusion. Ibutilide is more effective than either intravenous procainamide or intravenous sotalol for conversion of atrial fibrillation and atrial flutter to sinus rhythm. Age, presence of structural heart disease, gender and concomitant medication do not appear to influence the efficacy of ibutilide; however, shorter duration of atrial fibrillation is a strong predictor of successful termination. Plasma concentration of ibutilide and QTc interval prolongation are not directly correlated with the success rate for conversion of atrial tachyarrhythmias. Ibutilide's greater efficacy compared with other antiarrhythmic drugs may be related to its ability to cause greater prolongation of atrial monophasic action potential duration relative to atrial cycle length. Termination of atrial flutter with ibutilide was preceded by increased atrial cycle length variability. Ibutilide rapidly and effectively converts atrial fibrillation and atrial flutter to sinus rhythm when administered as a 1-mg total dose followed by a second 1-mg dose. It should be used in conjunction with continuous electrocardiographic monitoring for at least 4 hours after the termination of the infusion, or until the QTc interval returns to baseline. Hypokalemia and hypomagnesemia should be corrected before the start of the infusion. An external cardiac defibrillator, intravenous magnesium, and an external transcutaneous cardiac pacemaker should be readily available for immediate use in the event that palymorphic ventricular tachyarrhythmias occur. Ibutilide is a new intravenous agent that safely and rapidly converts atrial fibrillation and atrial flutter to sinus rhythm.

Safety and risk/benefit analysis of ibutilide for acute conversion of atrial fibrillation/flutter.

Safety data were reviewed from several controlled clinical trials of ibutilide, a new class III antiarrhythmic drug recently approved for the acute interruption of atrial fibrillation and flutter. Noncardiovascular adverse effects of ibutilide were similar in frequency to those with placebo. Cardiovascular adverse effects occurred in 24.9% of 586 ibutilide-treated patients as compared with 22.2% of 108 sotalol-treated patients, and 7.1% of 127 patients who received placebo. Polymorphous ventricular tachycardia, diagnosed as torsades de pointes, was more common with ibutilide than with placebo or sotalol treatment. It occurred in 4.3% of patients, including 1.7% whose torsades de pointes was sustained and required cardioversion. In the ibutilide group, 4.9% of patients had nonsustained monomorphic ventricular tachycardia compared with 3.7% of patients who received sotalol and 0.8% of patients who received placebo. All of the sustained arrhythmias except 1 occurred within 1 hour of the end of ibutilide infusion, and all were successfully terminated without sequelae. In a multiple logistic regression analysis, bradycardia, low body weight, and history of congestive heart failure were predictive of the occurrence of torsades de pointes. Hypotension, conduction block, bradycardia, and all other cardiovascular adverse effects all occurred at similar rates in the ibutilide- and placebo-treated groups. For patients who failed to convert while receiving ibutilide, there was no decrease in the efficiency of cardioversion, nor was there an increase in the mean energy requirements for subsequent electrical cardioversion. Analysis of a 3-month follow-up study showed that patients receiving ibutilide had similar outcomes compared with patients receiving placebo. One placebo-treated patient died. Other than torsades de pointes, ibutilide has a very good safety profile. Under the proper clinical conditions, this complication of ibutilide therapy can be rapidly diagnosed and effectively treated.

Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: a dose-response study.

OBJECTIVES: Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter. BACKGROUND: Ibutilide fumarate is an investigational class III antiarrhythmic agent that prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current. It can be administered intravenously and has a rapid onset of electrophysiologic effects. METHODS: The efficacy and safety of ibutilide were studied in 200 patients with atrial flutter > 3 h in duration or atrial fibrillation 3 h to 90 days in duration. Patients were randomized to receive a single intravenous dose of placebo or an infusion of ibutilide fumarate at 0.005, 0.010, 0.015 or 0.025 mg/kg body weight over 10 min. Conversion was defined as termination of the atrial arrhythmia during or within 60 min after infusion. Forty-one patients received placebo and 159 received ibutilide (0.005 mg/kg [n = 41], 0.010 mg/kg [n = 40], 0.015 mg/kg [n = 38] or 0.025 mg/kg [n = 40]). RESULTS: The arrhythmia terminated in 34% of drug-treated patients. The rates of successful arrhythmia termination were 3% for placebo and 12%, 33%, 45% and 46%, respectively, for 0.005-, 0.010-, 0.015- and 0.025-mg/kg ibutilide. The placebo and 0.005-mg/kg ibutilide groups had lower success rates than all other dose groups (p < 0.05). The mean time to termination of the arrhythmia was 19 min (range 3 to 70) from the start of infusion. Successful arrhythmia termination was not affected by enlarged left atrial diameter, decreased ejection fraction, presence of valvular heart disease or the use of concomitant medications (beta-adrenergic blocking agents, calcium channel blocking agents or digoxin). Arrhythmia termination was not predicted by the magnitude of corrected QT interval prolongation but was associated with a shorter duration of atrial arrhythmia. The most frequent adverse events in ibutilide-treated patients were sustained and nonsustained polymorphic ventricular tachycardia (3.6%). All patients with sustained polymorphic ventricular tachycardia were successfully treated with direct current cardioversion and had no recurrence. The occurrence of proarrhythmia did not correlate with ibutilide plasma concentration. CONCLUSIONS: These data demonstrate that ibutilide is able to rapidly terminate atrial fibrillation and atrial flutter.

Pilot study of the pharmacokinetics of methylprednisolone after single and multiple intravenous doses of methylprednisolone sodium succinate and methylprednisolone suleptanate to healthy volunteers.

The pharmacokinetics of methylprednisolone were evaluated in 29 healthy volunteers after multiple intravenous doses of methylprednisolone sodium succinate or the novel prodrug, methylprednisolone suleptanate. Subjects were assigned randomly to one of four treatment groups (40, 100, 250, or 500 mg) and then randomly assigned to receive either the sodium succinate or suleptanate prodrugs. Doses were administered every 6 hours for 48 hours. Plasma and urine were assayed for methylprednisolone and unchanged prodrug using HPLC methods. Methylprednisolone pharmacokinetics exhibited both a dose and time dependency, which was similar for administration of both prodrugs. After first-dose administration, mean clearance increased from 19.5 L/hr for 40-mg doses to 27.7 L/hr after 500-mg doses of the sodium succinate ester, and from 20.1 to 31.7 L/hr after the suleptanate ester. After multiple dosing, mean clearance values increased from 31.1 to 44.7 L/hr for sodium succinate dosing, and from 31.5 to 46.0 L/hr for suleptanate dosing. Apparent systemic clearance values determined after multiple dosing were 1.5- to 1.8-fold greater than corresponding first-dose values. No dependence on time was apparent for any prodrug pharmacokinetic parameter. These data suggest that the dose dependency of methylprednisolone pharmacokinetics is related to dose-dependent prodrug hydrolysis, whereas the time dependence possibly reflects auto-induction of methylprednisolone metabolism. Based on comparison of methylprednisolone pharmacokinetic parameters derived for each prodrug, methylprednisolone suleptanate resulted in a faster and slightly more efficient conversion to methylprednisolone than methylprednisolone sodium succinate.

Influence of tretinoin on the percutaneous absorption of minoxidil from an aqueous topical solution.

Nineteen healthy male volunteers completed a three-way, randomized, crossover study to determine the effect of the synthetic retinoid, tretinoin, on percutaneous absorption of minoxidil. Subjects received, for 20 days, twice-daily administrations of 1 ml of an aqueous 2% topical minoxidil solution either alone, with once-daily applications of a 0.05% tretinoin cream, or with once-daily applications of a vehicle control cream. When minoxidil was coadministered with tretinoin cream, minoxidil absorption was increased nearly threefold, compared with a 1.3-fold increase in absorption observed with coadministration of vehicle control cream. Transepidermal water loss measurements, which are sensitive to changes in stratum corneum function, were also significantly increased with tretinoin. No treatment-related changes in stratum corneum thickness were observed on the basis of skin biopsy analysis. The findings indicate that percutaneous minoxidil absorption is enhanced by tretinoin as a result of increased stratum corneum permeability.

New methods to detect the effect of alteration in gastric pH and intestinal transit by metoclopramide and propantheline using a continuous gastric pH probe and hydrogen breath analysis.

UNLABELLED: The effects of oral doses of metoclopramide (M, 10 mg) and propantheline (P, 30 mg) on alteration in gastric pH and emptying were determined using a continuous pH probe (Digitrapper, Synectics) and hydrogen breath analysis (HBA, QuinTron) in eight male subjects. The four phases consisted of HBA, HBA and pH probe, and HBA and pH probe and either P or M. Baseline pH measurements were recorded for 60 min prior to dosing with 10 g of lactulose in three of the periods. Dosing with P or M was given 30 min before administration of lactulose. HBA and continuous gastric pH were measured for 120 min. M produced earlier and higher peak hydrogen concentration than control (p less than 0.0001). P decreased peak hydrogen and increased gastric pH from approximately 2.0 to 4.0 (p less than 0.0001). CONCLUSIONS: 1) HBA can be used to detect alterations of intestinal motility; 2) The gastric pH probe produces a small increase in intestinal motility; and 3) The combination of the gastric pH probe and HBA could be a useful technique to simultaneously evaluate gastric pH and gastrointestinal motility.

Pharmacokinetics of furegrelate after oral administration to normal humans.

Furegrelate sodium is a thromboxane synthetase inhibitor with potential for the treatment of various diseases including hypertension, thrombosis, and renal disorders. The absorption and disposition of the parent drug in normal male volunteers have been studied after single- and multiple-dose oral administration. The results from the single-dose study indicate that furegrelate is rapidly absorbed, with a Tmax of 1.0-1.7 hr, has an apparent terminal disposition rate constant of 0.12-0.17 hr-1, and is eliminated primarily by the kidney, with 62-78% of the dose excreted as parent drug. After multiple-dose oral administration for 4.5 days using a b.i.d. dosing regimen, no apparent change in the absorption, disposition, and elimination kinetics is detected and only a slight potential for drug accumulation is observed.

Relationships between thromboxane production, platelet aggregability, and serum concentrations of ibuprofen or flurbiprofen.

Arachidonate-induced ex vivo platelet aggregations were performed before and after subjects received various doses of either ibuprofen or flurbiprofen. Both ibuprofen and flurbiprofen reduced the initial rate of thromboxane B2 (TxB2) production, but about 10% of control TxB2 production was refractory to either drug. Aggregation was observed after TxB2 concentrations exceeded a threshold of about 40 ng/ml. Once the threshold was achieved, aggregation and TxB2 production occurred independently of either drug. Ibuprofen and flurbiprofen concentrations of about 3 and 0.2 micrograms/ml, respectively, inhibited aggregation during the 5-minute testing period. A pharmacodynamic model was developed that predicts TxB2 production, aggregation lag times, and percent aggregation as a function of the time course of drug concentrations in serum.

Plasma levels of the prodrug, arbaprostil, [(15R)-15-methylprostaglandin E2], and its active, antiulcer (15S) epimer in humans after single dose oral administration.

Arbaprostil [(15R)-15-methylprostaglandin E2] is an antiulcer prodrug being evaluated for the treatment of gastric and duodenal ulcers in humans. It epimerizes in acidic gastric fluid to produce the biologically active form, (15S)-15-methyl-PGE2, which acts directly on the gastric mucosa and possesses both gastric acid antisecretory and cytoprotective properties. Because of its local mode of action, plasma levels of the two epimers may have greater relevance to drug safety than to therapeutic efficacy. In the present study, plasma concentrations of both 15-methyl-PGE2 epimers resulting from a gastric acid antisecretory dose of arbaprostil oral solution (50 micrograms) were measured in eight male volunteers having sufficient gastric acidity for prodrug activation (pH less than 3). Arbaprostil was determined with a newly developed RIA having a sensitivity of 10 pg X mL-1. The accuracy of the RIA was confirmed by parallel analysis of plasma samples by HPLC. (15S)-15-Methyl-PGE2 was also determined by HPLC. Arbaprostil was both rapidly absorbed and eliminated (tmax of 15-30 min and plasma t1/2 of 20 min), but there was large intersubject variability in its observed maximum plasma concentration (38 to 348 pg X mL-1). The concentration of (15S)-15-methyl-PGE2 did not exceed 25 pg X mL-1 In six subjects and 50 pg X mL-1 in the remaining two subjects. The significance of these results is discussed.

Tolerance and pharmacology of ciprostene, a stable epoprostenol (prostacyclin) analogue in humans.

Safety, tolerance, and pharmacology of 9-beta-methylcarbacyclin calcium (ciprostene calcium) was investigated in healthy male volunteers. This stable prostacyclin analogue was infused intravenously into groups of 12, 11, and three volunteers for three, six, and eight hours, respectively, in doses up to 480 ng/kg/min. Based on the tolerance data obtained, a single-blind, placebo-controlled study was conducted. Seven subjects were infused for 8 hr/d for three days with ciprostene at a maximum dose of 160 ng/kg/min and seven subjects received placebo. One subject from each group did not complete the infusion schedule, and they were not included in the final analysis. During infusion of ciprostene, consistent changes in blood pressure and heart rate did not occur. Most frequent adverse drug reactions consisted of headache, restlessness, nausea, perspiration, flushing, and jaw pain. As compared with placebo, ADP-induced platelet aggregation was inhibited during the infusion period (P = .048). Significant (P = .04) elevations of platelet cyclic AMP were observed in subjects during infusion of ciprostene. Pre- versus postinfusion routine laboratory evaluations, fibrinogen concentration, antiplasmin activity, and plasminogen and template bleeding times remained unchanged. Placebo- and drug-treated subjects had a daily postinfusion shortening of euglobulin clot lysis time (ECLT). The preinfusion minus postinfusion ECLT for ciprostene subjects on days 2 and 3 (133 and 118 min, respectively) compared with placebo (239 and 217 min) suggest a trend to increased fibrinolytic activity. Based on the outcome of this trial, it is estimated that ciprostene is about 15 times less potent than prostacyclin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration.

Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.