The effect of sertraline on the pharmacokinetics of desipramine and imipramine.

OBJECTIVE: To examine the pharmacokinetic interaction between the selective serotonin reuptake inhibitor sertraline and the tricyclic antidepressants desipramine or imipramine in 12 healthy male subjects. METHODS: Participants received a 50 mg single dose of either desipramine or imipramine under three conditions: alone, after a single 150 mg dose of sertraline, and after the eighth daily 150 mg dose of sertraline. Plasma samples were analyzed for desipramine or imipramine concentration by HPLC with electrochemical detection, and pharmacokinetics were determined with use of noncompartmental analysis of individual data. RESULTS: Multiple-dose, but not single-dose, treatment with sertraline significantly reduced apparent plasma clearance (CL/F) and prolonged the half-life of desipramine relative to baseline. These changes resulted in higher plasma desipramine concentrations, as indicated by a significant increase in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] (22% and 54%, respectively). Both single- and multiple-dose treatment with sertraline significantly reduced the CL/F of imipramine. This effect was stronger after multiple predoses of sertraline, when imipramine Cmax and AUC(0-infinity) were increased by 39% and 68%, respectively. These treatment effects were consistent between individuals. CONCLUSIONS: This pharmacokinetic interaction is likely the result of an inhibition of CYP2D6 tricyclic metabolism by sertraline. When a tricyclic antidepressant, such as desipramine or imipramine, is coadministered with sertraline, lower dosages of the tricyclic agents may be necessary to prevent elevated tricyclic levels.

Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine.

OBJECTIVE: To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates. BACKGROUND: Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions. METHODS: Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments. RESULTS: Mean value +/- SD plasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetine (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event. CONCLUSION: Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.

Combined effects of fenmetozole and ethanol.

Eight male subjects took none or 200 mg fenmetozole 1 hr before drinking a beverage containing none or 50 ml/70 kg ethanol. Tests designed to measure mental and motor performance were administered 2 hr after fenmetozole ingestion. Fenmetozole alone impaired standing steadiness but improved mental performance in one test. Fenmetozole did not antagonize the decrement in performance induced by this amount of ethanol. In combination, the subjective symptoms caused by fenmetozole were additive with those of ethanol.

Effects of renal dysfunction on the pharmacokinetics of loracarbef.

Loracarbef, the first carbacephem antibiotic to undergo clinical development, is excreted primarily unchanged in the urine (> 90%). Data analyzed from subjects with various degrees of renal dysfunction who were given single oral doses of loracarbef indicated a linear relationship between creatinine clearance (CLCR) and plasma clearance [CLP (L/hr) = 0.106.CLCR (ml/min/1.73 m2)]. The mean area under the plasma concentration-time curve in normal subjects and in patients with severe renal insufficiency (no dialysis/receiving dialysis) was 32 micrograms.hr/ml and 1085 micrograms.hr/ml/103 micrograms.hr/ml, respectively. Therefore, for individuals with moderate renal insufficiency (CLCR, 10 to 49 ml/min/1.73 m2), the dose should be halved or the dosing interval doubled; patients with severe renal insufficiency who are not receiving dialysis should be treated with the normal dose given once every 3 to 5 days. Loracarbef is readily cleared from plasma by hemodialysis; dosing should be repeated after a hemodialysis treatment.

Pharmacokinetics and safety of duloxetine, a dual-serotonin and norepinephrine reuptake inhibitor.

The pharmacokinetics and safety of duloxetine were evaluated in a single-blind, placebo-controlled, escalating multiple-dose study in 12 healthy male subjects. In the treatment group (n = 8), duloxetine was administered orally at a starting dose of 20 mg twice daily (bid) and escalated at weekly intervals to 30 mg bid, then to 40 mg bid. The observed plasma concentration-time data at all three dose levels were adequately described by a one-compartment model with a first-order absorption rate constant. The mean oral clearance, apparent volume of distribution, and half-life values were 114 L/h (range: 44 to 218 L/h), 1943 L (range: 803 to 3531 L), and 12.5 h (range: 9.2 to 19.1 h), respectively. Somnolence, nausea, and dry mouth were observed following the initial dose, but they resolved with continuing drug administration. Duloxetine was not associated with clinically significant changes in blood pressure (BP) or heart rate (HR) measured in the standing position. However, in recumbent position, small increases in systolic (< or = 9 mmHg) and diastolic (< or = 5 mmHg) BP and small decreases in HR (< or = 6 beats/min) were observed. Abrupt discontinuation of duloxetine was associated with a small increase in mean HR (< or = 12 beats/min). In 3 subjects, abrupt discontinuation was also associated with transient sleep disturbance. No clinically important changes in electrocardiograms, cardiac intervals, clinical laboratory tests, and neurological functions were observed. These results indicate that duloxetine exhibits linear pharmacokinetics with respect to dose and duration of treatment and that a multiple oral dose regimen starting at 20 mg bid and gradually escalating up to 40 mg bid was generally well tolerated.

Local and systemic phentolamine antagonism of norepinephrine-induced hand vein constriction.

The dorsal hand vein distention technique has been used to study the effects of alpha-adrenergic receptor antagonists on alpha-agonist-induced venoconstriction. Using this technique, we investigated the dose-effect relationships between different intravenous routes of phentolamine (an alpha-antagonist) administration on norepinephrine (an alpha-agonist)-induced hand vein constriction. Hand vein studies were done on healthy men; each man was studied on up to four occasions. On one occasion for each man, graded doses of phentolamine were infused into a hand vein preconstricted (submaximally) with norepinephrine. The dose of phentolamine producing a half maximal response (ED50) for reversal of venoconstriction, and the maximal reversal were calculated. On the other three occasions (randomly allocated) for each man, graded doses of norepinephrine were infused into a hand vein before and during intravenous infusions of (1) control (vehicle solutions); (2) systemic (other arm vein) phentolamine; and (3) local (hand vein) phentolamine. Systemic and local phentolamine dose ratios (ED50 of norepinephrine during phentolamine, divided by ED50 of norepinephrine before phentolamine; divided by the control dose ratio) were calculated. These studies show that phentolamine (administered directly into a preconstricted hand vein) can completely reverse norepinephrine-induced venoconstriction. Phentolamine, administered by either local or systemic intravenous infusion, induces a significant rightward shift (approximately 10-fold) in responsiveness to norepinephrine-induced venoconstriction. To achieve comparable degrees of alpha-antagonism, however, systemic phentolamine must be administered intravenously at a dose approximately 3,000-fold higher than that of local phentolamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of zatosetron on ipecac-induced emesis in dogs and healthy men.

Serotonin receptor (5-HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5-HT3 receptor antagonists also have antiemetic activity in ipecac-induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5-HT3 receptor antagonist, on ipecac-induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion in healthy men. In separate randomized, placebo-controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac-induced emesis in both groups. In dogs, zatosetron inhibited ipecac-induced emesis in a dose-dependent manner with a 100-micrograms/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5-HIAA/creatinine ratio (mg/g) or 5-HIAA excretion rate (microgram/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac-induced emesis in healthy men, as has been shown previously with other 5-HT3 receptor antagonists in chemotherapy-induced emesis in cancer patients. We did not observe the increase of urinary 5-HIAA in our study with ipecac-induced emesis, however, as has been described previously in cisplatin-induced emesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Olanzapine: interaction study with imipramine.

Olanzapine is an "atypical" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two-way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor-speed tasks (finger tapping and visual-arm random reach) compared with baseline or imipramine treatment. Peak 6-hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were < 19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6.

Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men.

STUDY OBJECTIVE: To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. DESIGN: Two-way, randomized, crossover study. SETTING: Clinical research laboratory. SUBJECTS: Nineteen healthy males (16 smokers, 3 nonsmokers). INTERVENTIONS: Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. MEASUREMENTS AND MAIN RESULTS: Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4'-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. CONCLUSION: As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.

Conversion of cefamandole nafate to cefamandole sodium.

The rate of hydrolysis of the formyl moiety of cefamandole nafate was determined as a function of pH, temperature, and concentration of added sodium carbonate or tromethamine. The reaction rate was sensitive to hydroxide ion in the pH 5.5-8.0 range with half-life values of hours to minutes. Hydrolysis was rapid upon the addition of sodium carbonate or tromethamine. Chirality in the 7-D-mandelamido side chain was unaffected by hydrolysis.

Recent graduates' and current dental students' evaluation of their prosthodontic curriculum.

This survey of recent graduates and third- and fourth-year dental students at Indiana University School of Dentistry determined whether the prosthodontic curriculum adequately prepared students for the prosthodontic portion of dental practice and whether there was material that should be added to or omitted from the prosthodontic curriculum. The survey evaluated 106 topics in the prosthodontic curriculum and areas related to prosthodontics. On the basis of their importance to the respondents, 59.4% of the topics were considered adequately emphasized, 2.9% of the topics were overemphasized and should be reduced in emphasis or eliminated, and 37.7% of the topics were underemphasized, which indicated the need to increase time devoted to these topics. Most of the underemphasized topics dealt with new materials, alternate techniques, private practice and its management, and the prosthodontic needs of special types of patients.

Effect of tibenelast (a phosphodiesterase inhibitor) and theophylline on isoproterenol-stimulated heart rate, cyclic AMP and norepinephrine levels.

The effect of the phosphodiesterase inhibitors (tibenelast, theophylline) and placebo on isoproterenol-induced changes in heart rate, cAMP and norepinephrine levels in normal male volunteers was studied. Heart rates in response to isoproterenol dosing were fitted by linear regression, and horizontal shifts in the regression lines were examined between the three treatments. The shift of the regression line after placebo compared to the preplacebo line was to the right by 2.6 +/- 2.2 ng ISO/kg/min, theophylline pretreatment shifted this line to the left by 2.4 +/- 1.8 ng/kg/min (p < 0.05) and tibenelast by 3.7 +/- 1.9 ng/kg/min (p < 0.02). Both tibenelast and theophylline increased the heart rate response to isoproterenol infusion, whereas norepinephrine and cAMP levels were not different in any treatment.

Pharmacokinetics of dirithromycin.

Dirithromycin is a new member of the macrolide class of antibiotics and has been developed for oral administration. Dirithromycin is a 14-membered lactone ring macrolide and is the C9-oxazine derivative of erythromycylamine. The human pharmacokinetics and clinical pharmacology of dirithromycin have been studied. Dirithromycin has unique pharmacokinetics which distinguish it from erythromycin. In man, following an oral 500 mg dose of dirithromycin, a mean peak plasma concentration (Cmax) of 0.48 mg/L (range 0.1-1.97) was observed at 4 h. The mean area under the plasma concentration versus time curve (AUC0-24h) measured 3.37 mg.h/L (range 0.39-17.16). No plasma accumulation was observed with multiple-dose administration. Dirithromycin may be taken without regard to meals, although food and H2-receptor antagonists may increase the systemic bioavailability in some patients. Based upon drug interaction studies performed with antipyrine and theophylline, dirithromycin has shown less potential to interact with other drugs metabolized by the cytochrome P450 system that does erythromycin. Plasma concentrations and AUCs were low due to rapid movement of the drug from the vascular space to the extravascular compartment, as reflected by tissue concentrations, which exceeded plasma concentrations 4 h after dosing. Dirithromycin achieves relatively high tissue concentrations (approximately 0.8-5.0 mg/kg) 4-24 h after dosing. The extensive tissue penetration is reflected in a large mean apparent volume of distribution of 800 L (range 504-1041). Dirithromycin is rapidly converted by non-enzymatic hydrolysis during absorption to erythromycylamine, which is microbiologically active. In a 14C-radiolabelled study, 60-90% of the administered dose was hydrolysed to erythromycylamine within 35 min of infusion. After 1.5 h, conversion to erythromycylamine in serum was virtually complete. Plasma protein binding was determined to be 15-30% by ultracentrifugation. Dirithromycin is characterized by a plasma elimination half-life of 44 h (range 16-65 h) that permits once-daily administration. Total body clearance was 226-1040 mL/min in the 14C-radiolabelled study. The primary route of elimination of dirithromycin/erythromycylamine was faecal/hepatic. Following intravenous administration, approximately 17-25% of the radioactivity appeared in the urine and 62-81% appeared in the stool, indicating predominantly hepatic excretion. With oral administration 1.2-2.9% of the radioactivity appeared in the urine and 81-97% in the stool. The major part of urinary excretion occurs within the first 48 h post-administration; however, urinary excretion of radioactivity lasted longer than 240 h. The absolute bioavailability calculated from dose-corrected urinary excretion data was 10% (6-14%).

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies.

PURPOSE: While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. METHODS: We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. RESULTS: Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.

Why rate of absorption inferences in single dose bioequivalence studies are often inappropriate.

PURPOSE: Peak drug concentration (Cmax) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). Cmax serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of Cmax, not the time to Cmax (Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to Cmax (Tmax) instead of Cmax. METHODS: We have previously redirected attention to Tmax as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts Tmax easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for Tmax treatment differences. Three separate BE studies are then analyzed by both methods. RESULTS: By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended" analysis of BE studies. First, Cmax, a continuous variable peak-height or extent measure has usurped Tmax's function and performs erratically as a substitute measure for the rate of absorption. Second, Tmax, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, Cmax), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired alpha level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.

Computerization of a bioassay: quantitation of slow reacting substance of anaphylaxis (SRS-A).

The bioassay for SRS-A using isolated guinea-pig ileum bathed in atropine and pyrilamine has been computerized resulting in a more accurate collection and calculation of data. Areas under the polygraph tracings are calculated by a computer interfaced with the recording polygraph. After comparison of ileal responses obtained with known amounts of SRS-A standard, the computer determined the relative amounts of SRS-A in unknown samples. The program provided for a correction to adjust for changes in tissue responsiveness. Using this bioassay, we showed that ovalbumin-induced release of SRS-A from sensitized guinea-pig lung was parallel to the release of histamine measured fluorometrically. Ethanol inhibited release of these mediators of anaphylaxis in a similar fashion. Conversely, isoproterenol reduced ovalbumin-induced release of SRS-A to a greater extent than the release of histamine. The versatility of this technique should enable other bioassays to be improved in addition to greatly facilitating the determination of various pharmacologic analyses.

Safety and effectiveness of probucol as a cholesterol lowering agent.

Monitored clinical studies conducted in 1133 patients, involving 3928 patient years of experience with probucol, have shown that it is an effective cholesterol lowering agent and is well tolerated during long term administration (some patients treated for as long as nine years). The incidence of morbidity and mortality in patients treated with probucol is in the expected range. Although a possibly protective action is suggestive against certain endpoints, the lack of long term parallel placebo groups does not allow for a statistical contrast of the results. Therefore, it is preferable to limit conclusions to observing that no excess of cardiac deaths, sudden deaths or cardiac morbidity occurred in probucol treated men with or without ischemic heart disease compared with men not receiving probucol.

Pharmacokinetics of cefaclor AF: effects of age, antacids and H2-receptor antagonists.

The pharmacokinetics and bioavailability of cefaclor advanced formulation (cefaclor AF) were investigated in two studies, one comparing healthy elderly and younger volunteers and the other assessing the effects of an antacid and H2-receptor antagonist on cefaclor AF bioavailability. The pharmacokinetics of a 750 mg dose of cefaclor AF were studied in 30 subjects ranging in age from 65 to 84 years and 10 control subjects 21-45 years of age. Compared with controls, elderly subjects exhibited higher plasma concentrations of cefaclor which were attributed to lower plasma clearance. There was a strong association between age and renal function, and the plasma clearance of cefaclor was highly dependent upon renal function. Thus, elderly patients with impaired renal function had a reduced ability to eliminate cefaclor. Due to a short elimination half-life and wide therapeutic index, dosage adjustments are not necessary in patients exhibiting moderate renal dysfunction. The 15 healthy men in the second trial were crossed over to receive five treatments, including cefaclor AF (500 mg) alone, cefaclor AF with or preceded by cimetidine, cefaclor AF followed by Maalox TC and cefaclor immediate release (500 mg) alone. Cefaclor AF and immediate release cefaclor had similar bioavailability, but plasma concentrations were maintained for a longer period of time when cefaclor AF was administered. Cimetidine did not alter the bioavailability of cefaclor AF but Maalox TC, coadministered with cefaclor AF, reduced the extent of absorption. This suggests that cefaclor AF bioavailability is influenced by the antacid Maalox TC but not by H2-receptor antagonist cimetidine.

Prolongation of the QT interval induced by probucol: demonstration of a method for determining QT interval change induced by a drug.

Sudden death has occurred in monkeys fed large doses of probucol, a cholesterol-lowering drug, given in combination with an atherogenic diet. These monkeys develop prolonged QT intervals and high serum levels of probucol. We investigated the effect of probucol on QT interval and the incidence of ventricular ectopy during a double-blind placebo-controlled study in 16 patients with less than 600 premature ventricular complexes (PVCs) per day and a corrected QT interval of less than 0.44 second. Seven patients received probucol and nine patients received placebo. Three 24-hour continuous ECG recordings were obtained prior to entry into the study and three additional recordings were obtained after 6 months of drug or placebo therapy. A 15-second ECG tracing was sampled from the continuous ECG recording every 30 minutes and, for the group, 15,000 QT intervals were measured permitting construction of QT versus R-R regression lines for each patient before and during therapy. Comparison of the regression lines revealed that the measured QT interval prolonged 20 +/- 18 msec during the awake state and 24 +/- 20 msec during sleep (mean + standard deviation) at matched heart rates in the seven patients receiving probucol (p less than 0.01). Using Bazett's formula to correct for rate, corrected QT interval prolonged 22 +/- 23 msec in the awake state and 20 +/- 18 msec in the asleep state (p less than 0.01). In probucol treated patients QT interval prolongation was directly related to increasing probucol plasma levels (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of ex vivo neutrophil activation by oral LY293111, a novel leukotriene B4 receptor antagonist.

1. The effects of orally administered LY293111 on ex vivo neutrophil Mac-1 upregulation were determined in a total of 24 healthy male subjects within three study periods. 2. In the first period, eight volunteers received 60 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1 week follow-up. The average ex vivo Mac-1 response of the LY293111 group was 56% of the predose control (95% confidence interval (CI) 44.3 to 67.9%; P < 0.01). The inhibitory effect was maximum at the end of dosing and had disappeared by day 14. 3. In the second period, eight subjects received 120 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1 week follow-up. The average response of the LY293111 group was 70% of the pre-dose control (95% CI 59.7 to 81.0%; P < 0.01). The inhibitory effect was maximum the day following the initial dose and continued throughout the dosing period. 4. In the third period, eight subjects received 200 mg LY293111 or placebo twice daily in 15 total doses over 8 days followed by a 1 week follow-up. Mac-1 upregulation was 64% of pre-dose levels (95% CI 53.8 to 75.1%; P < 0.01) over the course of the study period. The inhibition had disappeared 2 days following the final dose. Alternate neutrophil stimulation by fMLP was not inhibited. 5. No statistically significant inhibition was observed for placebo-treated subjects. 6. No statistically significant differences were apparent between the active dose regimens. 7. The results indicate that orally administered LY293111 is pharmacologically active in humans. Results from this study may be useful in determining dose selection for efficacy trials.