A double-blind, placebo-controlled study to assess tolerability, pharmacokinetics and preliminary pharmacodynamics of single escalating doses of Z13752A, a novel dual inhibitor of the metalloproteases ACE and NEP, in healthy volunteers

AIMS: The objective of this study was to evaluate the tolerability of a novel dual ACE-NEP inhibitor, Z13752A, after the oral administration of rising single doses in healthy volunteers. This study was also a preliminarily investigation of Z13752A pharmacodynamics (PD) and pharmacokinetics (PK). METHODS: In this randomized, placebo-controlled, sequential study, two alternating panels of eight healthy male volunteers each (six subjects receiving the active treatment + two subjects receiving placebo) were treated with increasing oral doses of Z13752A: 10, 50, 200, and 600 mg were given to panel I and 20, 100, 400 and 800 mg were given to panel II. The study was double-blind relative to placebo or active treatment, and was open with respect to the dose levels. The same volunteer received placebo only once. RESULTS: Single oral doses of Z13752A, as high as 800 mg, were well tolerated. Only six mild-to-moderate adverse events mainly headache, were reported and appeared to be of little clinical relevance. After administration of 200, 400, 600 and 800 mg of Z13752A, a nonsignificant fall in diastolic blood pressure was detected, in both the standing and supine position. After single oral doses of Z13752A, ACE inhibition appeared to be significant at all the doses tested, linearly correlated with the dose and was almost complete at doses > or = 100-200 mg. NEP inhibition was indicated by elevation of ANP and cGMP plasma concentrations in almost all subjects. In the 200-800 mg dose range, Z13752A produced a 50-100% increase of plasma cGMP levels and a 50-80% elevation in urinary cGMP concentrations. Detectable plasma levels of Z13752A were found in all the treated subjects. Z13752A was well and rapidly absorbed, with peak concentrations reached approximately 2.5 h after administration. The mean apparent elimination half-life from plasma was approximately 12 h. The pharmacokinetics of Z13752A after single oral doses were characterized by low intersubject variability and appeared to be dose-independent. CONCLUSIONS: Z13752A showed a good single dose tolerability profile at doses up to 800 mg. The pharmacokinetic data indicate that Z13752A administered orally is rapidly absorbed and available to the systemic circulation in humans. The relatively slow clearance indicates that a once-a-day dose regimen could be considered for Z13752A.     

Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers

OBJECTIVE: A novel sulfonamide derivative, S-3304, was discovered as a potent matrix metalloproteinase (MMP) inhibitor. It is a more specific inhibitor to MMP-2 and MMP-9 (in vitro) than to MMP-1, and may therefore lack the musculoskeletal side effects seen with non-specific inhibitors. The aim of the present study was to investigate the safety, tolerability and pharmacokinetics of S-3304 when administered as single and multiple oral doses to healthy male volunteers. MATERIALS AND METHODS: 48 male volunteers received single oral doses ranging from 10 - 800 mg S-3304 or placebo under fasting conditions. At the 200 mg dose level, effects of high-fat diets were studied in a crossover design. In the multiple dose design, 24 male subjects were administered 200 mg, 400 mg or 800 mg S-3304 or placebo b.i.d. after meals for 10 - 17 days. Studies were conducted in a randomized double-blind fashion. Safety assessment was conducted based on blood chemistry, hematology, urinalysis, electrocardiogram and physical examination. Pharmacokinetic parameters were determined for S-3304 and its metabolites. All subjects were enrolled in the studies after obtaining informed consent. RESULTS: Adverse events reported after single dose administration of S-3304 or placebo were all of mild severity. Adverse events reported in the multiple dose treatment with S-3304 or placebo were mostly of mild severity, except for two episodes of moderate headache and two episodes of moderate myalgia. Most commonly reported adverse events in the multiple treatments with S-3304 were headache and somnolence. No clinically significant changes were observed in the clinical laboratory tests, except for reversible elevation of alanine aminotransferase of one subject at 800 mg S-3304 b.i.d. In the single dose administration, Cmax and mean AUC0-infinity linearly increased up to 63,167 ng/ml and 311,960 ng x h/ml at the 800 mg dose level, respectively; tmax and t1/2 ranged from 2 - 3 hours and from 9.5 - 15.5 hours, respectively. High-fat diets reduced Cmax from 21,565 ng/ml to 14,095 ng/ml but did not alter AUC0-infinity. Hydroxylated metabolites were detected in plasma in concentrations less than 1% of S-3304. Less than 1% S-3304 was excreted in urine. The AUC of one dosing interval and Cmax did not change after multiple doses but t1/2 increased from 9.5 - 10.0 hours to 12.5 - 13.5 hours. The 6beta-hydroxycortisol/ cortisol ratio was not changed after multiple doses suggesting no effect on CYP3A4 activity. CONCLUSION: S-3304 demonstrated a good safety profile and good systemic exposure when administered orally up to 800 mg b.i.d. during 10 - 17 days. At the highest dose level of 800 mg b.i.d., it was free of rheumatoid arthritis-like symptoms.     

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.     

The dose dependency of the alpha-adrenoceptor antagonist and beta-adrenoceptor partial agonist activity of dilevalol and labetalol in man.

1. The alpha-adrenoceptor antagonist, beta 1-adrenoceptor antagonist and beta 2-partial agonist activity of dilevalol, a beta-adrenoceptor antagonist with vasodilating properties and labetalol were investigated in two studies. 2. In the first study, six healthy male subjects received serially increasing concentrations phenylephrine after single oral doses of dilevalol 200 mg, labetalol 400 mg and placebo at weekly intervals in a randomised double-blind manner. An exercise step test was performed at the end of the infusions. 3. The doses of phenylephrine required to increase systolic and diastolic blood pressures by 20 mmHg (PS20 and PD20 respectively) were increased by labetalol 400 mg (P < 0.05) but unchanged by dilevalol 200 mg. The dose ratios for PS20 (means +/- s.d.) were: dilevalol 200 mg 1.1 +/- 0.1, labetalol 400 mg 2.2 +/- 0.1. There was no difference in the percentage reduction in exercise tachycardia between dilevalol and labetalol. 4. In the second study, 10 healthy male subjects received infusions with serially increasing concentrations of phenylephrine and angiotensin II before and after single oral doses of dilevalol 200, 400 and 800 mg, labetalol 200 mg and placebo at weekly intervals in a double-blind randomised manner. Finger tremor was measured (piezoelectric accelerometer) with each infusion. An exercise step test was performed at the end of the infusions. 5. The PS20 and PD20 of phenylephrine were increased by labetalol 200 mg and unchanged by dilevalol. The dose ratios for PS20 were: dilevalol 200 mg 1.1 +/- 0.2. dilevalol 400 mg 1.1 +/- 0.4, dilevalol 800 mg 1.4 +/- 0.4 and labetalol 200 mg 2.5 +/- 0.7. The dose ratios for PD20 were: dilevalol 200 mg 1.1 +/- 0.4, dilevalol 400 mg 0.9 +/- 0.3. dilevalol 800 mg 1.3 +/- 0.4 and labetalol 200 mg 2.3 +/- 0.9. 6. The PS20 and PD20 of angiotensin II were unchanged by any of the drugs. 7. Exercise heart rate was reduced by dilevalol 200 mg (130 +/- 13 beats min-1), 400 mg (123 +/- 12 beats min-1), 800 mg (125 +/- 9 beats min) and labetalol 200 mg (143 +/- 12 beats min-1) vs placebo (161 +/- 17 beats min-1). 8. Finger tremor was significantly increased by dilevalol 800 mg (13.17 +/- 10.51 vs 6.62 +/- 4.51 centivolts for placebo: P < 0.01). Neither phenylephrine nor angiotensin II had an effect on finger tremor. 9. In conclusion, dilevalol 200, 400 and 800 mg demonstrated beta 1-adrenoceptor antagonist activity with no evidence of alpha 1-adrenoceptor antagonist activity. Labetalol 200 and 400 mg showed both beta 1- and alpha 1-antagonist activity. Dilevalol 800 mg demonstrated significant partial beta 2-adrenoceptor agonist activity by increasing finger tremor.     

Observations on the clinical pharmacology and plasma concentrations of diacetolol, the major human metabolite of acebutolol.

1 The pharmacological effects and plasma levels of diacetolol, the major human metabolite of acebutolol, were measured in a double-blind, balanced study in which five healthy men received single oral doses of diacetolol 100, 200, 400 and 800 mg, or placebo, at weekly intervals. 2 Resting and exercise heart rate (HR), forced expiratory volume in 1 second (FEV1), resting and exercise peak expiratory flow rate (PEFR), and plasma concentrations of diacetolol were determined at 0, 2, 4, 6, 8 and 24 h after each treatment. 3 Diacetolol caused a slight dose-related reduction in resting HR and a substantial dose-related reduction in exercise HR. AT the same time it was found that diacetolol had no significant effects on FEV1 and resting and exercise PEFR. 4 Mean highest observed plasma concentrations (ng/ml) of diacetolol were 177 at a mean of 4.4 h after the 100 mg dose, 243 at 4.0 h after the 200 mg dose, 807 at 5.2 h after the 400 mg dose, and 1,306 at 4.4 h after the 800 mg dose. 5 Using the mean data, there was a strong correlation (r = 0.90) between % reduction in exercise HR and the logarithm of the plasma concentration of diacetolol. 6 Diacetolol exhibits marked cardiac beta-adrenoceptor blocking activity in man which is still evident 24 h after the administration of the higher doses of the drug. No adverse effects on pulmonary function could be detected.     

Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects

In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 μg, aclidinium 800 μg, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate-corrected QT interval (QTcI). Secondary measures included Bazett-corrected QT interval (QTcB), Fridericia-corrected (QTcF) intervals, 12-lead electrocardiogram (ECG) readings, and 24-hour 12-lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time-matched baseline on day 3 was -1.0 milliseconds at 2 hours for aclidinium 200 μg, -1.8 milliseconds at 5 minutes for 800 μg, +11.0 milliseconds at 4 hours for moxifloxacin, and -1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 μg and were detected only up to 1 hour after the 800-μg dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 μg, has a favorable cardiovascular safety profile with no effect on QT interval.     

The assessment in man of the beta-adrenoceptor blocking activity and cardioselectivity of H-I 42 BS, a long acting beta-adrenoceptor blocking drug.

The pharmacokinetic and pharmacodynamic effects of the beta-adrenoceptor antagonist H-I 42 BS were examined in healthy subjects. In an open dose ranging study, H-I 42 BS 50, 100, 200 and 400 mg were given as single oral doses to four subjects. H-I 42 BS 400 mg caused maximum reduction in exercise heart rate (20.4 +/- 1.0%--mean +/- s.d.) at 4 h and still reduced exercise heart rate at 96 h (18.4 +/- 7.2%). Seven subjects received in double-blind, randomised order, single oral doses of H-I 42 BS 50, 100 and 200 mg, atenolol 50 and 100 mg and placebo. H-I 42 BS 400 mg was given in a single blind manner as the last dose of the study. Both H-I 42 BS and atenolol reduced supine and standing heart rate and systolic blood pressure (P less than 0.05) although atenolol had the more marked effect. The maximum percent reduction of exercise heart rate after H-I 42 BS 50 mg was 10.9 +/- 7.1%, after 100 mg was 18.7 +/- 5.8%, after 200 mg was 20.6 +/- 6.4% and after 400 mg was 21.9 +/- 8.2%. H-I 42 BS 400 mg still caused 11.0 +/- 3.5% reduction at 168 h. Atenolol 50 mg caused maximum percent reduction of exercise heart rate of 26.0 +/- 6.0% but did not reduce exercise heart rate after 24 h. The mean peak plasma concentrations for all doses of H-I 42 BS occurred at 5.1 +/- 1.5 h. The plasma elimination half-life was 47.6 +/- 8.1 h. There was a linear correlation between the dose and AUC0-infinity (r = 0.97). The cardioselectivity of H-I 42 BS and atenolol was compared. Six subjects received in double-blind random order H-I 42 BS 100 and 400 mg, atenolol 50 mg and placebo. After each dose, graded infusions of isoprenaline were given until the heart rate increased by 50 beats min-1. Dose-response curves for heart rate, diastolic blood pressure, forearm blood flow and finger tremor were constructed. There was no difference in the dose-response curves for forearm blood flow or finger tremor after H-I 42 BS 400 mg or atenolol 50 mg. Atenolol 50 mg caused more attenuation (P less than 0.01) of the diastolic blood pressure response. These results indicate that H-I 42 BS is a cardioselective beta-adrenoceptor antagonist with a long duration of action in man.     

Antihypertensive effect of diacetolol in essential hypertension.

1 Diacetolol is the N-acetylated metabolite of acebutolol and possesses beta-adrenergic receptor blocking properties. 2 Its antihypertensive action was assessed in accordance with a double-blind randomised cross-over scheme in 17 patients with moderate essential hypertension previously well controlled with acebutolol. 3 Significant reductions in lying mean arterial blood pressure were observed with daily doses of 200 mg (- 9%), 400 mg (- 10%) and 800 mg (- 14%), and were associated with significant decreases in heart rate and plasma renin activity. 4 The diacetolol mean plasma level measured 8 to 10 h after drug ingestion was proportional to the dose (207 +/- 27, 394 +/- 63 and 823 +/- 135 ng/ml for respectively 200, 400 and 800 mg/day).     

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor,omapatrilat in healthy subjects

AIMS: To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects. METHODS: The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days. RESULTS: In the multiple-dose study, peak plasma concentrations (Cmax = 10-895 ng ml(-1); tmax = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, Cmax (1-1009 ng ml(-1)) and AUC(0,t) (0.4-1891 ng ml(-1) h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 +/- 4.1 (+/- SD) ng 24 h(-1) in the placebo group to 60.0 +/- 18.2 ng 24 h(-1) in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies. CONCLUSIONS: Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.     

Steady-state pharmacokinetics and pharmacodynamics of CHF3381, a novel antineuropathic pain agent, in healthy subjects

AIMS: To evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles of CHF3381, a dual NMDA and MAO-A inhibitor, after multiple oral doses in healthy subjects. METHODS: Forty-eight young males received CHF3381 at doses of 100 mg twice daily, 200 mg twice daily, 400 mg twice daily or placebo for 2 weeks according to a double-blind, randomized, parallel group design. Plasma and urine concentrations of the parent drug and of two major metabolites (CHF3567 and 2-aminoindane) were measured over time. MAO-A activity in plasma was estimated by measuring plasma concentrations of 3,4-dihydroxyphenylglycol. Sustained attention, memory and sedation were assessed throughout the study with standard psychometric tests. RESULTS: Most of the adverse events were mild in intensity, with dose regimens of 100 mg twice daily and 200 mg twice daily being indistinguishable from placebo. After 400 mg twice daily, the most frequent adverse events were mild dizziness, asthenia and insomnia. At steady-state, 400 mg twice daily slightly increased supine heart rate (+ 9 +/- 2 beats min(-1)) and diastolic blood pressure (+6 +/- 2 mmHg) compared with placebo. There were no dose-dependent or consistent effects of CHF3381 on attention, motor co-ordination or memory, but 400 mg twice daily significantly decreased alertness compared with placebo. Plasma concentrations of CHF3381 peaked at around 3 h and were dose-proportional. The elimination half-life of CHF3381 was estimated to be 4-6 h. At steady-state, significant CHF3381 plasma concentrations were detected at predose with a modest accumulation (1.3-1.5 times), showing that the drug given twice daily is active over the entire 24 h period. Plasma concentrations of CHF3567 and of 2-aminoindane were also proportional to the dose of CHF3381. CHF3381 dose-dependently inhibited MAO-A activity with peak effects at steady-state of 27 +/- 4%, 46 +/- 2% and 65 +/- 5% after 100 mg twice daily, 200 mg twice daily and 400 mg twice daily, respectively. There were no significant effects of CHF3381 on attention (rapid visual information processing), motor co-ordination (body sway) or memory (learning memory task) at any of the doses. At steady-state, there was a significant decrease in alertness (Bond & Lader visual analogue scale) in the 400 mg twice daily group compared with placebo. CONCLUSIONS: A twice daily regimen of CHF3381 appears to be adequate from a pharmacokinetic and pharmacodynamic perspective. Plasma concentrations reached with 400 mg twice daily exceeded those observed in animals receiving pharmacologically active doses in chronic pain models.     

Etintidine-propranolol interaction study in humans

Etintidine HCl is a potent H2-blocker. The effect of clinical doses of etintidine on the disposition of a single oral dose of propranolol was investigated in 12 normal subjects. This was a double-blind, two-way crossover study. Each subject received etintidine (400 mg) or placebo twice a day with meals for 4 days on two occasions (separated by 4 days). On each occasion, the subjects were fasted overnight on Day 3 and were given an oral dose of Inderal (40 mg propranolol hydrochloride) 30 min following the administration of the morning dose of etintidine or placebo on Day 4. Blood samples were collected prior to and up to 24 hr following the administration of propranolol. The plasma samples were analyzed for propranolol and 4-hydroxypropranolol by HPLC. Comparison of the pharmacokinetic parameters of propranolol between etintidine and the placebo groups indicates that etintidine significantly increased the AUC0-infinity values (573.5 vs. 146.4 ng.hr/ml, p = 0.0001) and prolonged the elimination half-life (4.61 vs. 2.33 hr) of propranolol. Statistical evaluation of the pharmacokinetic parameters of 4-hydroxypropranolol indicates that etintidine also increased the AUC0-24 values (43.8 vs. 16.4 ng.hr/ml, p = 0.0028) and prolonged the elimination half-life (4.87 vs. 1.97 hr) of 4-hydroxypropranolol. The data suggest that etintidine, like cimetidine, impaired the elimination of propranolol. Etintidine also protracted the elimination of 4-hydroxypropranolol, an active metabolite of propranolol.     

Single dose safety, tolerance, and pharmacokinetics of HP 029 in healthy young men: a potential Alzheimer agent

1,2,3,4-tetrahydro-9-aminoacridin-1-ol maleate (HP 029) is a new cholinergic compound that has been shown to enhance memory in animals and therefore may be potentially effective in humans for the treatment of Alzheimer's disease (AD). The initial safety, tolerance, and pharmacokinetics of HP 029 after single oral doses were assessed in a randomized, double-blind, placebo controlled study in 70 healthy young men (eight dose groups). The test doses ranged from 5 to 200 mg. There were 9 subjects per dose group, 6 on HP 029 and 3 on placebo. The 5 and 100 mg dose groups had only 8 subjects. Plasma and urine samples were analyzed for nonconjugated HP 029 using an HPLC assay with a detection limit of 1 ng/ml. HP 029 was rapidly absorbed after oral dosing with mean peak plasma levels occurring between 0.75 and 1.2 hours. The mean peak levels ranged from 12.7 and 234.7 ng/ml after the 10 and 200 mg doses, respectively. There were dose related increases in peak plasma levels, AUCs, and the amounts of drug excreted in the urine. The mean plasma half-life was about 2.0 hours and was not affected by dose. About 6 to 11% of the dose was eliminated in the urine. HP 029 was renally cleared at a high rate and independent of dose. There were no clinically important or drug-related changes in any of the physical examinations, audiograms, or ophthalmologic examinations. There were only minor within-subject fluctuations in vital signs, ECGs, and laboratory values, none of which were clinically meaningful or drug related after any of the doses of HP 029.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.     

Inhaled corticosteroids in asthma: a dose-proportionality study with triamcinolone acetonide aerosol.

The systemic exposure to triamcinolone acetonide (TAA) after inhalation of aerosolized drug has not been examined previously. This study evaluates the plasma concentrations, pharmacokinetics and dose proportionality of TAA after single oral inhalations at doses of 400, 800, and 1600 mcg. Nine moderately asthmatic male patients received each of the doses in a randomized crossover manner using a 1-week washout period between dosing. Serial blood samples were collected for 10 hours postdosing for the determination of plasma TAA concentrations by using a specific radioimmunoassay. The pharmacokinetic profiles that were obtained showed slow and limited absorption over the first 4 hours after dosing followed by rapid elimination with a half-life of approximately 2 hours (range: 1.8-2.3 hr). Comparison of pharmacokinetic parameters from each dose group showed excellent proportionality and consistent absorption for all patients. Mean Cmax values ranged from 0.51 ng/mL after the 400 mcg dose to 1.01 ng/mL and 1.97 ng/mL after the 800 and 1600 mcg doses, respectively. Mean AUC0-10 values for these same doses were 2.6 ng x hr/mL, 5.3 ng x hr/mL and 10.5 ng x hr/mL, respectively. The results suggest that systemic exposure to TAA is minimal after oral inhalation, occurs in a dose proportional fashion, and produces circulating plasma concentrations which are unlikely to have significant adverse systemic effects.     

Plasma nitrazepam concentrations after an acute intake and their correlation to sedation and serum growth hormone levels.

Concentrations of nitrazepam in plasma were determined by gas chromatography in healthy volunteers after an acute peroral administration of nitrazepam (5 and 10 mg). Placebo tablets were also used, and an assessement of subjective drug effects was made during each medication. In addition serum growth hormone levels were determined. The peak plasma nitrazepam concentration was achieved at 120 minutes (46.9 +/- 3.2 ng/ml, mean +/- S.E.M.) after 5 mg of nitrazepam and at 180 minutes (82.8 +/- 10.5 ng/ml) after the dose of 10 mg. The half-life of nitrazepam in plasma ranged from 16.5 to 48.3 (mean 28.8) hours. A significant positive correlation was seen between the subjective sedative effects and the magnitude of the peak nitrazepam concentrations in plasma. This drug effect was highly significant when the plasma levels of nitrazepam were rising. The subjective sedative effects were more prominent after 10 mg than after 5 mg dose of nitrazepam. The plasma nitrazepam concentration was not significantly correlated with the subjective sedative effect the next morning, 12 hours after the drug intake. Serum growth hormone levels rose significantly during the study both after 5 mg and 10 mg nitrazepam doses (peak levels 16.3 +/- 4.0 and 12.7 +/- 3.1 ng/ml) and were significantly higher than after placebo administration (3.7 +/- 0.7 ng/ml).     

A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain.

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser-induced pain was studied in a double-blind, placebo controlled, three way cross-over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S- and R-enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1-4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2-4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01-0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S- and R-ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.     

Chlormezanone plasma and blood levels in patients after single and repeated oral doses and after suicidal drug overdose

Chlormezanone plasma concentrations were determined in 5 volunteers (group 1) after a single oral dose of 200 mg of chlormezanone with high performance liquid chromatography. A plasma elimination half-life of 23 +/- 2.3 h was calculated. The mean peak chlormezanone plasma level was 1.86 +/- 0.2 micrograms/ml, 1 h after ingestion. Additionally, chlormezanone plasma levels were determined after repeated oral doses of chlormezanone recommended for treatment of muscular spasms due to degenerative skeletal disease. After 5 days of repeated daily doses of 3 x 200 mg (group 2; 12 patients) or 3 x 400 mg (group 3; 10 patients) of chlormezanone, mean predose chlormezanone plasma levels were 12.0 +/- 2.0 micrograms/ml (group 2) and 22.7 +/- 4.0 micrograms/ml (group 3), respectively. Comparable plasma concentrations were determined after 10 days of repeated doses of 3 x 200 mg or 3 x 400 mg of chlormezanone in 3 patients from each of these 2 groups. In 7 patients of group 3, chlormezanone had to be discontinued on the 5th day due to increasing muscular weakness, ataxia and exercise-inducible tachycardia. After a loading dose of 800 mg and repeated doses of 3 x 200 mg chlormezanone to 5 patients (group 4), plasma levels of 6.5 +/- 2.1 micrograms/ml, 8.9 +/- 2.2 micrograms/ml, 12.7 +/- 2.0 micrograms/ml, and 10.4 +/- 2.4 micrograms/ml were determined after 2, 8, 16, and 36 h, respectively. Trace amounts of a degradation product of the acid-labile chlormezanone could be detected in plasma besides the unchanged drug after administration of repeated oral doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.