Safety,pharmacokinetics, and pharmacodynamics of CHF 3381, a novel N-methyl-D-aspartate antagonist,after single oral doses in healthy subjects

A double-blind, randomized, placebo-controlled study was performed to assess the safety, tolerability, and pharmacokinetics of single oral doses of CHF 3381 in 56 young healthy male volunteers. The central nervous system effects of CHF 3381 were also evaluated, as well as the effect of food on the rate and extent of CHF 3381 absorption. Seven doses of CHF 3381 (25, 50, 100, 200, 300, 450, and 600 mg) were evaluated in an escalating order. At each dose level, 6 subjects were given CHF 3381, and 2 subjects were given placebo. Safety and tolerability evaluation included adverse events, physical examination, vital functions, electrocardiogram, laboratory tests, and 24-hour Holter (100-mg and 450-mg dose panels). Plasma and urinary concentrations of CHF 3381 and its two main metabolites (CHF 3567 and 2-aminoindane) were measured with a validated high-performance liquid chromatography method. Central nervous system effects were evaluated with the simple reaction time (SRT); learning memory task (LMT); Bond & Lader Visual Analog Scale for alertness, contentedness, and calmness; Addiction Research Center Inventory (ARCI); and electroencephalogram. There were no serious adverse events; the most frequent adverse events were dizziness, abnormal thinking, and asthenia. The number of adverse events with moderate intensity increased sharply with the dose, with no or few events up to 450 mg and 17 events with 600 mg. Therefore, 600 mg was defined as the maximum tolerated dose. There were no significant treatment effects on cardiovascular function and electrocardiogram parameters at any CHF 3381 dose or on oral temperature or laboratory tests. There were no clinically significant changes in laboratory variables. CHF 3381 was absorbed rapidly (tmax = 0.5-2 h) and cleared from plasma with a half-life of 3 to 4 hours. Plasma levels of CHF 3381 and its two major metabolites were found to be proportional to the dose. 2-Aminoindane formed slowly and reached much lower concentrations compared to the parent compound and the other metabolite (CHF 3567). Within 48 hours after dosing, 2% to 6% of the administered dose was found in the urine as unchanged drug, about 50% to 55% as the acid derivative (CHF 3567), and 2% to 3% as 2-aminoindane. Ingestion of food did not affect the extent of absorption of the drug, while the rate of absorption was considerably reduced (tmax = 4 h). No significant effects of CHF 3381 were observed on attention (SRT) or memory (LMT). Visual analog scales revealed a decreasing effect of CHF 3381 on alertness at 1 hour that reached statistical significance at 300 and 600 mg. EEG spectral analysis revealed minor decreasing effects of the 200-mg dose on total electric power measured at 2 hours. A stimulant effect was detected by the ARCI scale 24 hours after the 300-mg dose and might be related to the slow formation of the 2-aminoindane metabolite. In conclusion, this study has shown that the maximum tolerated dose of CHF 3381 after single oral administration in young healthy male volunteers is 600 mg. CHF 3381 displays linear pharmacokinetics in the dose range of 25 to 600 mg. The compound is rapidly absorbed and cleared from plasma with a half-life of 3 to 4 hours. The ingestion of food seems to not affect the extent of absorption of the drug. Minor effects on the central nervous system were detected at doses equal to or greater than 300 mg.     

Effects of single and multiple doses of a new reversible MAO-A inhibitor,befloxatone, on psychomotor performance and memory in healthy subjects

The effects on memory, psychomotor performance and mood of two dosage regimens of befloxatone, a new reversible and selective MAO-A inhibitor were assessed in a randomized, double-blind, cross-over, placebo-controlled study involving 12 healthy young male volunteers. Befloxatone and a placebo were orally administered as single (5 and 10 mg) and repeated doses (10 mg once daily and 5 mg twice daily) at one week wash-out intervals. Objective tests evaluated both memory (working memory, immediate and delayed free recall of a word list, dual coding and faces recognition) and vigilance continuous performance task (CPT), and digit symbol substitution (DSST). Subjective mood and sleep were assessed using visual analogue scales and the Leeds Sleep Evaluation Questionnaire. Statistical analysis was conducted using an ANOVA with pairwise comparisons using the Student Newman Keuls procedure. Both dosage regimens of befloxatone (10 mg once daily or 5 mg twice daily) were free of any detrimental effect on vigilance (CPT) and information processing (DSST) and did not significantly disrupt short- and long-term memory (working memory, free recall of words, dual coding and faces recognition). In addition, no subjective sedation or sleep disturbances were recorded. In conclusion, this study gives no evidence to suggest that befloxatone, at a daily dose which shows potent MAO-A inhibition, has any sedative or amnestic properties likely to interfere with the activities of everyday-life in young subjects and therefore may be safely administered in depressed outpatients.     

Preclinical evaluation of CHF3381 as a novel antiepileptic agent

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4-5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED50 Approximately/=10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED50 approximately/=100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [(3)H]-TCP from binding to NMDA receptor channels (Ki, 8.8 microM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD50 approximately/= 300 mg/kg p.o., congruent with 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.     

Indantadol, a novel NMDA antagonist and nonselective MAO inhibitor for the potential treatment of neuropathic pain

Indantadol is an oral and nonselective monoamine oxidase inhibitor and NMDA antagonist that is being developed by Vernalis plc, under license from Chiesi Farmaceutici SpA, for the potential treatment of neuropathic pain. In preclinical studies, indantadol exhibited neuroprotective effects after kainite-induced seizures, and displayed anticonvulsant and antihyperalgesic activity. Indantadol also caused a dose-dependent decrease in exploratory motility. In a human heat-capsaicin-induced pain model, indantadol at a dose of 500 mg effectively reduced the area of secondary hyperalgesia to 67%. Indantadol undergoes extensive liver metabolism, withthe formation of two major metabolites - CHF-3567 and 2-aminoindane. The drug is excreted in urine partially as the parent compound, but mostly as CHF-3567. The tolerability profile of indantadol at single doses up to 600 mg and twice-daily doses up to 400 mg in clinical trials was significantly more favorable than for other NMDA antagonists. Most side effects have been observed to be mild, and include dizziness and asthenia. Indantadol is currently in phase II clinical trials in patients with diabetic peripheral neuropathic pain. Given the results available to date, indantadol may have a role in the treatment of neuropathic pain if the favorable pharmacokinetic profile and efficacy of the drug are maintained in more extensive clinical trials.     

Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.

The pharmacokinetic profile and biochemical efficacy of idrapril calcium, a novel angiotensin converting enzyme (ACE) inhibitor, were evaluated in healthy volunteers after multiple dosing for 5 days at the doses of 100, 200 and 400 mg twice daily. The study was conducted as a double-blind, cross-over comparison of idrapril calcium against placebo. Plasma concentrations of idrapril were determined by an indirect enzymatic method. Urinary concentrations were measured by reverse phase high performance liquid chromatography (h.p.l.c.). Plasma samples were also analysed for ACE activity. The pharmacokinetics of idrapril calcium did not change significantly between day 1 and day 5. The values of Cmax and AUC were dose-related over the range of doses tested; tmax was 3-4 h and apparent elimination half-life was 1.4-1.6 h. Plasma ACE activity was maximally inhibited (94-96%) at all dose levels and remained more than 80% depressed from 2 to at least 6 h after idrapril calcium. Although the maximum effect was not dose-related, the duration of inhibition showed some dose-dependency, ACE activity returning to 56, 45 and 29% of the basal value 12 h after the 100, 200 and 400 mg doses, respectively. There were no clinically significant adverse events experienced by the volunteers. No dose-related effects on blood pressure or heart rate were observed. There were no changes in clinical pathology tests, urine analyses or electrocardiograms after dosing with idrapril calcium. Idrapril calcium, the prototype of a new class of ACE inhibitors, appears to be well-tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atovaquone suspension in HIV-infected volunteers: pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study

STUDY OBJECTIVE: To evaluate the pharmacokinetics and safety of atovaquone suspension in volunteers infected with the human immunodeficiency virus ((HIV). DESIGN: Open-label, nonrandomized study. SETTING: Two clinical research centers. PATIENTS: Twenty-two HIV-infected volunteers with a median CD4 cell count of 37 cells/mm3. INTERVENTIONS: Patients received atovaquone suspension fasting or fed for 2-week periods with crossover at dosages of 500 mg/day, and randomization to fasting or fed at dosages of 750 and 1000 mg/day. A subset of patients also received 750 mg twice/day with food, and a subset of those who received 1000 mg/day fasting also received 1000 mg with food. During a long-term dosing phase, a subset of subjects were evaluated for an interaction between atovaquone and trimethoprim-sulfamethoxazole (TMP-SMX). MEASUREMENTS AND MAIN RESULTS: Average steady-state atovaquone concentrations at 500 mg were 6.7 +/- 3.2 microg/ml fasted and 11.3 +/- 5.0 microg/ml with food; at 750 mg, 9.9 +/- 7.1 microg/ml fasted and 12.5 +/- 5.9 microg/ml with food; at 1000 mg, 9.7 +/- 4.3 microg/ml fasted and 13.6 +/- 5.0 microg/ml with food; and at 1500 mg, 21.1 +/- 5.0 microg/ml with food. Thus, plasma concentrations were not proportional to dose. Concomitant food ingestion resulted in a 1.3- to 1.7-fold increase in values. Average steady-state concentrations were less than 10 microg/ml in 21% and more than 15 microg/ml in 36% of patients at 1000 mg/day with food; at 750 mg twice/day, all five patients had levels above 15 microg/ml. Atovaquone suspension was well tolerated; diarrhea, nausea, fatigue, and rash were the most common adverse events. Concomitant administration of TMP-SMX did not change atovaquone concentrations and resulted in small decreases in concentrations of TMP (16%) and SMX (10%). CONCLUSION: Plasma concentrations are significantly higher when atovaquone suspension is administered with food compared with fasting. Total doses of 1500 mg/day are likely to achieve concentrations effective for prophylaxis of Pneumocystis carinii pneumonia.     

A randomized controlled assessment of the effects of different dosing regimens of budesonide on the HPA-axis in healthy subjects

AIMS: To investigate the effect on the hypothalamo-pituitary-adrenal (HPA) axis of treatment with budesonide, 400 microg once daily, morning or evening, or 200 microg twice daily, and 800 microg twice daily via Turbuhaler in a randomized, placebo-controlled, double-blind, double-dummy crossover study. METHODS: Healthy men received budesonide, 400 microg in the morning (08.00-09.00 h) or evening (20.00-21.00 h), budesonide, 200 microg twice daily, 800 microg twice daily, and placebo twice daily, for 1 week each. Plasma and urine samples were obtained over 24 h on day 7 for cortisol determination. Twenty-five subjects completed all treatments, and 27 were included in the analysis. RESULTS: The 24 h plasma cortisol concentrations vs placebo (95% CI) were 98% (89, 108) for 400 microg in the morning, 92% (83, 100) for 400 microg in the evening, 95% (86, 104) for 200 microg twice daily, and 76% (70, 84) for 800 microg twice daily. CONCLUSIONS: Budesonide at a dose of 400 microg day-1 via Turbuhaler had no statistically significant effect on 24 h cortisol production, irrespective of whether treatment is given once or twice daily, whereas a dose of 800 microg twice daily resulted in a statistically significant suppression vs placebo. Neither could a significant difference be found between morning and evening dosing.     

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.     

The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine or high dose ranitidine.

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/- s.d. values of AUC were 105 +/- 40 micrograms l-1 for placebo treatment, 111 +/- 45 micrograms l-1 h for ranitidine and 211 +/- 64 micrograms l-1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/- 14, 39 +/- 27 and 76 +/- 40 micrograms l-1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.     

Single- and multiple-dose pharmacokinetics of pirfenidone, an antifibrotic agent, in healthy Chinese volunteers

A randomized, dose-escalating study evaluated the pharmacokinetics of single and multiple oral doses of pirfenidone, a promising antifibrotic agent, in 48 healthy Chinese volunteers. The effects of sex and food on the pharmacokinetics of pirfenidone were also evaluated. Pharmacokinetics was determined from serial blood samples obtained up to 12 hours after administration of single 200-, 400-, or 600-mg doses of pirfenidone and after multiple doses of 400 mg administrated 3 times daily (tid). Plasma levels of pirfenidone and areas under the curve were found to be proportional to dose. Pirfenidone was rapidly absorbed (t(max) = 0.33-1 hours) and cleared (t((1/2)) = 2-2.5 hours). Pharmacokinetic parameters after multiple doses were similar to those after single doses. Food had a significant effect (P < .01) on the extent of absorption (AUC(0-infinity) = 37.4 +/- 15.4 mg x h/L [fed] vs 46.6 +/- 16.8 mg x h/L [fasted]), rate of absorption was considerably (P < .001) prolonged (t(max) = 1.5 +/- 0.4 hours [fed] vs 0.7 +/- 0.2 hours [fasted]), and peak concentrations were significantly (P < .001) decreased (C(max) = 9.2 +/- 2.9 mg/L [fed] vs 13.0 +/- 1.8 mg/L [fasted]). No significant sex differences were noted for pharmacokinetic variables. Pirfenidone was well tolerated. These results support a tid regimen of pirfenidone for the management of idiopathic pulmonary fibrosis. Concomitant intake of food will reduce the rate and extent (about 20%) of absorption, which is associated with better tolerability of pirfenidone.     

Monotherapy with conventional and controlled-release carbamazepine: a double-blind, double-dummy comparison in epileptic patients.

1. Twenty-one epileptic patients completed a double-blind, double-dummy, random order, crossover comparison of conventional carbamazepine (CBZ, Tegretol, Ciba-Geigy) with a new controlled-release formulation (CBZ-CR, Tegretol Retard). All participants were stabilised on maximally tolerated doses of CBZ as monotherapy (one twice daily, twelve three times daily, eight four times daily). Each preparation was taken with a matched placebo of the other for 4 weeks. 2. Peak serum CBZ concentrations (mean +/- s.e. mean) were lower (CBZ 11.4 +/- 0.4 mg l-1; CBZ-CR 10.4 +/- 0.5 mg l-1; P less than 0.01) and times to peak longer (CBZ 3.6 +/- 0.5 h, CBZ-CR 5.2 +/- 0.7 h, P less than 0.01) during CBZ-CR treatment. Mean CBZ concentrations, however, were also slightly reduced with the new formulation (CBZ 9.9 +/- 0.3 mg l-1; CBZ-CR 9.1 +/- 0.5 mg l-1, P less than 0.05) and this was associated with greater seizure frequency (CBZ 2.8 +/- 1.2, CBZ-CR 3.8 +/- 0.9; P less than 0.05) during the CBZ-CR treatment phase. 3. Diurnal fluctuations (CBZ 41 +/- 3%, CBZ-CR 28 +/- 2%, P less than 0.01) and variations (CBZ 53 +/- 5%, CBZ-CR 33 +/- 3%; P less than 0.01) in serum CBZ concentration were substantially less with CBZ-CR and were similar to those calculated during a 6 or 8 hourly dosage interval with conventional CBZ (fluctuation 33 +/- 3%, variation 42 +/- 5%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nizatidine on paracetamol and its metabolites in human plasma

The effect of the histamine H2-receptor antagonist, nizatidine, on plasma concentrations of paracetamol has been investigated with respectto hepatic metabolism. Paracetamol (1000 mg) together with 300 or 150 mg nizatidine or placebo was orally administered to five healthy male volunteers. Venous blood samples were taken before and after administration. Plasma paracetamol and paracetamol conjugates (glucuronide and sulfate) were measured by high-performance liquid chromatography. The pharmacokinetic parameters were calculated from the plasma paracetamol concentration-time curves of each volunteer. The plasma nizatidine concentration was highest (2420.0+/-192.4 and 996.0+/-54.6 ng mL(-1)) in the sample taken 1 h after administration of 300 mg nizatidine (high dose) and 150mg nizatidine (low dose), respectively. Plasma paracetamol concentrations with nizatidine (high and low doses) were increased significantly at 45-120 min and 45-60 min, respectively, compared with placebo. The total area under the plasma paracetamol concentration-time curve from 0 to 180 min (2361.5+/-146.4 and 2085.75+/-73.5 microg min mL(-1)) significantly increased after coadministration of nizatidine (high and low doses), respectively (P < 0.01 vs placebo). Paracetamol glucuronide concentrations with nizatidine (high and low doses) were decreased significantly at 30-45 min and 30 min, respectively, compared with placebo. However, plasma paracetamol sulfate concentrations with nizatidine (high and low doses) were not significantly altered. The coadministration of nizatidine (150 and 300 mg) dose-dependently reduces plasma paracetamol glucuronide concentrations and increases plasma paracetamol concentrations. The effects of nizatidine could result from the inhibition of glucuronyltransferase. Thus, care is necessary when paracetamol and nizatidine are coadministered.     

CHF3381, a novel antinociceptive agent, attenuates capsaicin-induced pain in rats

Here, we have examined the effect of the novel antinociceptive agent CHF3381 on the development of nocifensive behaviour as well as secondary mechanical allodynia and hyperalgesia induced by intraplantar injection of capsaicin in rats. Vehicle, CHF3381 or gabapentin were orally administered 1 h before capsaicin injection. The duration of nocifensive behaviour was measured during the first 5 min after capsaicin injection. Secondary mechanical allodynia and hyperalgesia were measured at 5 and 15 min after capsaicin injection, respectively. CHF3381 produced a significant suppression of nocifensive behaviour and completely blocked the development of mechanical allodynia and hyperalgesia at 100 and 200 mg/kg. Gabapentin weakly inhibited the development of nocifensive behaviour and mechanical allodynia. On the contrary, gabapentin (100 mg/kg) completely prevented the development of mechanical hyperalgesia. In conclusion, CHF3381 had full efficacy for all the capsaicin-induced pain parameters tested, suggesting that CHF3381 may have a therapeutic utility in the management of pain states involving central sensitisation.     

Tolerance and pharmacokinetics of oral fendiline

Two studies with healthy volunteers were carried out to correlate safety with pharmacokinetics of the calcium antagonistic drug N-(3,3-diphenylpropyl)-(1-phenylethyl)-amine (fendiline, Sensit) after single and multiple oral doses. In the first study single doses of 200, 400, 600, 800, 1000, and 1200 mg of fendiline hydrochloride were administered to 6 subjects per dose level. 3 additional subjects per dose level received placebo. No significant objective or subjective effects were noted in the dose range studied. The pharmacokinetic analysis revealed that doses higher than 800 mg were absorbed incompletely. In the second study initially 400 mg twice daily was given to 9 subjects. 3 additional subjects received placebo. Due to subjective intolerability (trembling, dizziness) after 5 days, the dose was reduced stepwise to 2 X 200 mg and was then continued for another 19 days. The pharmacokinetic evaluation revealed manifold interindividual differences in plasma levels for maximal concentrations (9-170 ng/ml) as well as for minimal concentrations (4-96 ng/ml). The absorption profile in both studies has linear and nonlinear components. Maximal plasma levels were reached after about 4 h. Terminal elimination half-lives were about 20 h.     

Observation on the efficacy and pharmacokinetics of betaxolol (SL 75212), a cardioselective beta-adrenoceptor blocking drug.

1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10, 20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times. The maximum effect (34.4 +/- 2.2%) occurred after 40 mg. 3 There was a small decline in effect from the peak to 24 h when 40 mg produced a 23.3 +/- 2.7% reduction and a further decline to 48 h when there was a 14.6 +/- 1.8% reduction. 4 Plasma levels of betaxolol were measured in these studies. The peak plasma concentration occurred between 3 and 8 h with different doses. The plasma elimination half-lives after 10, 20 and 40 mg were 11.4 +/- 2.5, 15.9 +/- 4.9 and 15.1 +/- 3.1 h. 5 The effects of 40 mg betaxolol, 200 mg atenolol, 160 mg propranolol, 160 mg oxprenolol, 400 mg sotalol and placebo on an exercise tachycardia were compared in five subjects who received all treatments in random order. 6 There was no significant difference in the maximum reduction produced in an exercise tachycardia by the different drugs. 7 The effect of all drugs decreased with time. The effect of oxprenolol had worn off at 24 h but at 48 h only atenolol and betaxolol produced significant reductions in the exercise tachycardia. 8 Plasma concentrations of the different drugs were measured and plasma elimination half-lives determined. The half-life for betaxolol was 24.5 h which was longer than that for any of the other drugs. 9 These observations show that betaxolol is a potent beta-adrenoceptor antagonist with a long duration of effect on an exercise tachycardia and a long plasma elimination half-life.     

Orexin receptor antagonism: an ascending multiple-dose study with almorexant

The objectives of this study were to investigate the multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual orexin receptor antagonist almorexant. Healthy subjects received daily doses of almorexant (100, 200, 400 or 1000 mg) or placebo in the morning for four days followed by two days with evening administration (Days 5-6). Each dose level was investigated in a new group of 10 subjects (eight active, two placebo, 1:1 sex). Dose-dependent increases in frequency and intensity were observed for somnolence and other adverse events. Pharmacokinetics at steady state showed rapid absorption, low concentrations eight hours post-dose, and minimal accumulation. Following evening, administration absorption was delayed and C(max) decreased. Almorexant at 400 and 1000 mg administered in the morning reduced vigilance, alertness, visuomotor coordination, and motor coordination assessed in a psychometric test battery. Polysomnography recordings following evening administration showed a trend towards shorter latency to sleep stages 3 and 4, and shorter latency to, and longer time in, rapid-eye-movement sleep at higher doses when compared to placebo. Whether these findings in healthy subjects translate into relevant sleep-enabling effects in insomnia patients needs to be investigated in future studies.     

Converting enzyme inhibition in coronary artery disease: a randomized, placebo-controlled trial with benazepril.

The antiischemic efficacy of the converting enzyme inhibitor (CEI) benazepril was investigated in a randomized, placebo-controlled double-blind study with intraindividual crossover in 11 normotensive patients with angiographically proven coronary artery disease. Bicycle ergometry and 24-h ambulatory ECG were performed before and after 2-week treatment with placebo and benazepril, respectively. Plasma concentrations of atrial natriuretic peptide (ANP) and plasma renin activity (PRA) were measured before each exercise test. Maximal exercise-induced ST-segment depression was not significantly influenced by benazepril therapy (placebo 2.09 +/- 1.22 mm, benazepril 1.91 +/- 1.00 mm). Systolic blood pressure/heart rate (SBP/HR) product at maximum workload remained almost constant with 253 +/- 43 with placebo and 253 +/- 39 with benazepril treatment. The number of anginal attacks and ischemic episodes detected by ambulatory ECG were not significantly reduced. PRA increased significantly from 2.18 +/- 3.76 to 9.62 +/- 8.49 ng/ml/h after benazepril (p less than 0.005), whereas plasma concentrations of ANP remained unchanged (28.04 +/- 12.39 vs. 26.73 +/- 11.09 pg/ml). Therefore, measurement of ST-segment depression with exercise in 11 normotensive patients with coronary artery disease produced no evidence of an antiischemic action for the CEI benazepril 10 mg twice daily (b.i.d.) for 2 weeks, but an improvement was observed in six patients.     

Steady-state disposition of diflunisal: once- versus twice-daily administration

To evaluate the steady-state bioequivalence of the nonsteroidal antiinflammatory analgesic agent, diflunisal, administered once versus twice daily, 13 healthy volunteers received diflunisal as follows: 1000 mg at 8:00 AM and 500 mg at 8:00 AM and 8:00 PM, each for 14 days in a randomized crossover study. The mean (+/- SD) steady-state peak plasma concentrations were significantly greater after once-daily dosing (186 +/- 25 micrograms/ml vs 150 +/- 37 micrograms/ml; p less than 0.01). The time to peak concentration was also longer after the single-dose regimen (2.5 +/- 0.8 vs 1.9 +/- 0.9 hr; p less than 0.05). The regimens were similar with respect to the mean 24-hour area under the plasma concentration-time curve at steady state (2839 +/- 612 vs 2782 +/- 778 micrograms.hr.ml-1), steady-state plasma concentrations (118 +/- 25 vs 116 +/- 32 micrograms/ml), trough plasma concentration (85 +/- 27 vs 92 +/- 28 micrograms/ml) as well as 24-hour urinary excretion (776 +/- 79 vs 771 +/- 89 mg) of diflunisal. Based on urinary recoveries, the bioequivalence ratio (once vs twice daily) was 1.01 +/- 0.08. These results indicate that diflunisal administered once daily might offer comparable therapeutic effects but be more convenient than a twice-daily regimen.     

Pharmacokinetic and Pharmacodynamic Interaction between Allopurinol and Probenecid in Healthy Subjects

BACKGROUND AND OBJECTIVE: Combination therapy with allopurinol and probenecid is used to treat tophaceous gout in patients who do not respond sufficiently to allopurinol alone. However, the potential interaction between these drugs has not been systematically investigated. The objective of this study was to investigate the pharmacokinetics and hypouricaemic effect of oxypurinol (the active metabolite of allopurinol) and probenecid when administered alone and in combination in healthy subjects. METHODS: An open-label, randomized, three-way crossover clinical trial was conducted in 12 healthy adults. Subjects were randomized to receive treatment for 7 days with allopurinol (150 mg twice daily), probenecid (500 mg twice daily) or combination therapy with both drugs, with a 7-day washout period between treatments. Venous blood samples were collected predose (at 0 hours) and 1, 2, 3, 4, 6, 8, 10 and 12 hours after dosage for determination of oxypurinol and/or probenecid concentrations. Plasma and urinary urate concentrations were determined on each study day and at the end of each washout period. Pharmacokinetic and pharmacodynamic parameters were analysed using two-way ANOVA. RESULTS: Coadministration of allopurinol and probenecid significantly reduced average steady-state plasma oxypurinol concentrations (mean+/-SD: allopurinol alone 9.7+/-2.1 mg/L vs combination 5.1+/-1.0 mg/L, p<0.001). Probenecid concentrations were unaffected. Plasma urate concentrations decreased (p<0.01) during allopurinol therapy (0.16+/-0.05 mmol/L), probenecid therapy (0.13+/-0.02 mmol/L) and combination therapy (0.09+/-0.02 mmol/L) compared with baseline (0.30+/-0.05 mmol/L). CONCLUSION: Coadministration of allopurinol and probenecid to healthy subjects had a greater hypouricaemic effect than either allopurinol or probenecid alone, despite a reduction in plasma oxypurinol concentrations when the drugs were taken concomitantly.