Effect of brivaracetam on cardiac repolarisation--a thorough QT study.

OBJECTIVES: To assess the effect on cardiac repolarisation of the investigational synaptic vesicle protein 2A (SV2A) ligand brivaracetam. RESEARCH DESIGN AND METHODS: Subjects received double-blind, multiple bid doses of placebo (n = 53), brivaracetam 75 mg (n = 39) or brivaracetam 400 mg (n = 40), or open-label single-dose moxifloxacin 400 mg (positive control, n = 52). Continuous 12-lead ECG recordings were performed at baseline and after last dosing, using a Mortara Holter device. Plasma samples were obtained before and up to 12 h after last dosing for drug determination. Triplicate ECGs were extracted before each sample, and read centrally in a blinded manner. QT was corrected using a centre- and gender-specific correction (QTc(SS) ). MAIN OUTCOME MEASURES: The primary endpoint was the largest time-matched mean difference of QTc(SS) change from baseline between drug and placebo (maximum DeltaDeltaQTc(SS)). The same approach was adopted using the Fridericia's correction (QTc(F)). The relationships between DeltaQTc(SS) and plasma concentration of brivaracetam and moxifloxacin were fitted to a straight line using linear least-squares regression. RESULTS: Mean maximum DeltaDeltaQTc(SS) for brivaracetam 75 and 400 mg bid, and moxifloxacin 400 mg was 0.2 ms, -1.1 ms and 12.4 ms, respectively. The one-sided 95% upper limit for 75 mg and 400 mg brivaracetam was 4.3 ms and 3.0 ms, respectively; the one-sided 95% lower limit for moxifloxacin was 8.6 ms. After brivaracetam no QTc(SS) intervals > 480 ms or changes from baseline of > 60 ms were observed. DeltaQTc(SS) did not increase with plasma concentration of brivaracetam, whereas there was a statistically significant rise with increasing moxifloxacin concentrations. CONCLUSIONS: The study was found to be valid in terms of assay sensitivity and the results demonstrated the absence of effects of brivaracetam on cardiac repolarisation. These results suggest that no intensive cardiac monitoring is required during the subsequent stages of brivaracetam development.

Levocetirizine in 1-2 year old children: pharmacokinetic and pharmacodynamic profile.

BACKGROUND: Levocetirizine is an antihistamine with high affinity and selectivity for H1-receptors, which exhibits an excellent benefit/risk ratio in the treatment of allergic rhinitis and urticaria. This is the first study performed with this drug in very young children. OBJECTIVE: The aim of this study was to confirm the intended regimen of levocetirizine (0.125 mg/kg twice a day) for further studies in children aged 12-24 months. MATERIAL AND METHODS: The pharmacokinetic/pharmacodynamic profile of levocetirizine was studied in 15 toddlers suffering from recurrent cough and other allergy-related symptoms, aged 20.7 +/- 3.7 months, and treated twice a day with 0.125 mg/kg for 90 days. A histamine-induced wheal and flare test (W&F) was performed prior to treatment. Blood was sampled at 1, 2, 4, 6, 9 and 12 hours after the first dose. Twelve hours after the evening dose on Days 3-6, and on day 90, a histamine-induced wheal and flare test was repeated and a blood sample was taken for trough value assessment. RESULTS: A peak plasma level of 286 +/- 68 ng/ml was observed after one hour. The elimination half-life was 4.1 +/- 0.7 hours, the apparent body clearance 1.05 +/- 0.10 ml/min/kg, and the apparent volume of distribution 0.37 +/- 0.06 l/kg. Morning trough values at Days 3-6, and at Day 90 were respectively 78 +/- 30 ng/ml and 110 +/- 86 ng/ml. The median inhibition of the wheal was 100% at Days 3-6, and Day 90. That of the flare was 99.6% at Days 3-6, and 98.9% at Day 90. The overall safety profile of this three-month open study was good. CONCLUSION: This first study with levocetirizine in children aged 12-24 months shows the adequate pharmacokinetic/pharmacodynamic profile and the good safety profile of 0.125 mg/kg levocetirizine given twice a day, which can be proposed for further studies in this age group.

Pharmacokinetics and pharmacodynamics of cetirizine in infants and toddlers.

The pharmacokinetics of the second generation H1-receptor antagonist cetirizine were studied in 15 infants and toddlers (mean +/- SD age, 12.3 +/- 5.4 months) who were treated with a single 0.25 mg/kg dose of cetirizine solution. The infants and toddlers were hospitalized for recurrent respiratory infections or other hypersensitivity-related diseases. Blood samples were collected at 1/2, 1, 11/2, 2, 4, 6, 8, 12, and 24 hours, and a 24-hour urine sample was obtained. A peak plasma level of 390 +/- 135 ng/ml was observed after 2.0 +/- 1.3 hours. The elimination half-life was 3.1 +/- 1.8 hours, the apparent oral body clearance was 2.13 +/- 1.15 ml/min/kg, and the apparent volume of distribution was 0.44 +/- 0.19 L/kg. The excretion of unchanged cetirizine in six complete urinary collections was 62.7% +/- 13.2% of the administered dose. An additional pharmacodynamic study (inhibition of the histamine-induced wheal and flare) was performed in 10 of these infants and toddlers, after the intake of 0.25 mg/kg cetirizine twice a day for at least 4 days. A 90% +/- 12% inhibition of the wheal and a 87% +/- 17% inhibition of the flare were still observed 12 hours after the last intake. The duration of the H1-inhibition by cetirizine at the cutaneous level is thus longer in infants and toddlers than could be inferred from its pharmacokinetics; the level of inhibition at 12 hours was the same as in older age groups.

Effect of 1-28 alpha-h atrial natriuretic peptide on acute renal failure in cadaveric renal transplantation.

The efficacy and safety of (1-28) alpha-human ANP in preventing acute tubular necrosis (ATN) in cadaveric renal transplantation was tested by comparing ANP infusion with a maximal hydration (MH) regimen which we previously reported as effective in lowering the incidence of ATN (1, 2). Since the production of endogenous ANP increases with volume overloading (3), we hypothesized that increased endogenous ANP production may contribute to the beneficial effects of MH in renal transplant recipients. We thus conducted an open randomized study comparing the effect on early renal allograft function of MH (control group) versus moderate hydration plus ANP infusion (ANP group). Forty patients were blindly paired in two groups of 20 according to the duration of cold ischemia time (mean +/- 2 h). The demographic characteristics of donors and recipients were similar. Using a Swan-Ganz catheter, hemodynamic parameters were monitored for 4 h after transplantation. The group receiving ANP and moderate hydration was perfused to a mean pulmonary arterial pressure (PAP) of < or = 20 mmHg. The PAP in patients receiving MH was driven to > or = 25 mmHg. In the ANP group, a bolus of 100 micrograms of ANP was infused into the graft's renal artery at the time of unclamping, followed by 24 h of continuous intravenous infusion at 0.03 microgram/kg/min. Thereafter, the patients received ANP at a rate of 0.01 microgram/kg/min until the serum creatinine reached < 2 mg/dl. As a consequence of the hydration regimen, the PAP at unclamping was lower in the ANP group than in the control group; 20 +/- 3 and 26 +/- 4 mmHg, respectively (p < 0.05). The ANP plasma levels were significantly higher during the first 3 d in the ANP group (p < 0.001). The median recovery rate of renal function was similar in both groups. No patients in the ANP group experienced ATN while 4 patients (20%) in the control group did (p = 0.125). The need for hemodialysis was markedly reduced in the ANP group compared to the control group (1 ANP-treated patient required dialysis once whereas 5 patients from the control group underwent dialysis a total of 26 times; p = 0.068). ANP administration was well-tolerated and no hypotensive episodes were reported. This preliminary study suggests that ANP infusion is at least as effective as maximal hydration in preventing ATN and represents an efficient alternative for transplantation centers which do not use maximal hydration as a standard regimen in managing kidney allograft recipients.

Lack of Clinically Relevant Interaction of Cetirizine on Theophylline Disposition in Healthy Subjects: A Placebo-Controlled Study.

The possible interaction of a steady-state cetirizine treatment, a nonsedating H(1) antihistamine, on the disposition of a single I.V. infusion of theophylline was studied in six healthy male volunteers. As a corollary, it was checked whether this single theophylline administration modified the steady-state condition of cetirizine. A three-period, two-treatment, crossover design was used, each period being separated by a washout of 1 week. Each period consisted of the oral administration of 10 mg cetirizine or of a matching placebo every 12 h for 3½ days, the last intake being followed, 1 hour later, by a single 1-h I.V. infusion of 240 mg theophylline or of placebo. The sequence of treatments (A = cetirizine + theophylline placebo, B = cetirizine placebo + theophylline, C = cetirizine + theophylline) was alloted by a double Latin-square randomization. The repeated administration of cetirizine induced a 3% decrease of the urinary elimination of unchanged theophylline; the total body clearance of theophylline was marginally (+5%) and not significantly modified. Theophylline slightly lengthened the elimination half-life of cetirizine (from 8.3 to 9.9 h), without modification of its apparent total body clearance; the half-life of cetirizine remaining in the normal range. These subtle modifications are not clinically relevant and it may, thus, be considered that cetirizine exerts no pertinent interaction on theophylline disposition.

Single-dose pharmacokinetics of cetirizine in patients with chronic liver disease.

The pharmacokinetics of the H1-receptor antagonist cetirizine were studied from 0 to 72 hours after a single dose of 20 mg in 5 patients with chronic hepatocellular liver disease (group A), in 5 patients with chronic cholestatic liver disease (group B), and in 16 healthy volunteers. The renal function of patients and volunteers was normal (creatinine clearance > or = 70 mL/min). Cetirizine pharmacokinetics were similar in the two groups of patients. The elimination t1/2 was prolonged in patients (mean +/- standard deviation; group A: 14.32 +/- 2.30 hours; group B: 13.86 +/- 3.14 hours) in comparison with the values observed in volunteers (9.42 +/- 2.4 hours). A reduced apparent oral body clearance also was observed in patients (group A: .48 +/- .23 mL/min/kg; group B: .41 +/- .09 mL/min/kg) in comparison with volunteers (.74 +/- .19 mL/min/kg). No differences were observed in the mean cumulative urinary excretion between patients (group A: 69 +/- 15%; group B: 69 +/- 13%) and volunteers (70.7 +/- 7.8%).

Effect of cimetidine on the pharmacodynamics, pharmacokinetics and biotransformation of a single oral dose of alpidem.

Alpidem is a new imidazopyridine derivative acting as an anxiolytic which may be prescribed with H2 receptor antagonists in patients with peptic ulcer. An open trial design (cimetidine, 1 g daily for 22 days) was carried out in eight healthy subjects. Alpidem, 50 mg was administered orally at 09:00 prior to any treatment and on days 2 and 18 of the cimetidine treatment period. Antipyrine clearance was also determined before and on day 21. Under these experimental conditions, the inhibitory effect of cimetidine on the cyt. P-450 monooxygenase system has been demonstrated (reduced clearance of antipyrine and its three main urinary metabolites) but the plasma pharmacokinetics of alpidem and its three main plasma metabolites did not appear to be modified. Alpidem induced no sedative effect but there was an insignificant trend to impair slightly the psychometric tests 1 h post-drug by the combination with cimetidine. Pharmacokinetic and pharmacodynamic evaluations did not show significant interactions with cimetidine following alpidem 50 mg administration.

Influence of repeated administration of cimetidine on the pharmacokinetics and pharmacodynamics of adinazolam in healthy subjects.

Adinazolam is a new triazolobenzodiazepine bearing an alkyl-amino side chain. A cross-over double-blind placebo controlled study was carried out in 12 healthy volunteers, in order to check the possible interaction between cimetidine and adinazolam after repeated co-administration. Cimetidine or placebo were given during 17 days. Beginning on Day 8 of each treatment, adinazolam was given in the increasing doses following sequence of doses for 3 days: 10 mg b.i.d., 20 mg b.i.d. and 20 mg t.i.d. A pharmacokinetic and pharmacodynamic study was performed on the third day at each dose. A wash-out of three weeks was included between the two treatments. Cimetidine increased significantly the AUC values of both adinazolam and N-desmethyladinazolam, reduced the oral clearance of adinazolam, and prolonged adinazolam's half-life. The digit symbol substitution test was significantly affected at each dose level while the manual dexterity was marginally impaired by adinazolam plus cimetidine. Saftee-up interview and Clyde mood scale indicated an increased sedation under adinazolam plus cimetidine in four subjects.

Lack of interaction between zolpidem and H2 antagonists, cimetidine and ranitidine.

Zolpidem is a new imidazopyridine derivative acting as a hypnotic which may be prescribed with H2 receptor antagonists in patients with peptic ulcer. A cross-over study (cimetidine, 1 g daily for 19 days; ranitidine, 300 mg daily for 19 days; wash-out period: 20 days) was carried out in six healthy volunteers. Zolpidem, 20 mg was administered orally at 09h00 prior to any treatment and on days 2 and 17 of each treatment period. Antipyrine clearance was also determined before and on day 18 of each treatment period. Under these experimental conditions, the inhibitory effect of cimetidine on the Cyt P-450 mono-oxygenase system has been demonstrated (reduced clearance of antipyrine, p less than 0.01) but the pharmacokinetics of zolpidem did not appear to be modified. Zolpidem induced hypnotic effects for the first 3 h which tend to be prolonged by the combination with cimetidine. Psychometric and pharmacokinetic evaluations did not show significant interactions with either anti-H2 receptor agent following zolpidem administration.

Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic.

The combined use of a hypnotic and a neuroleptic is a rather frequent situation, encountered especially in the psychiatric sphere. We therefore tested zolpidem and chlorpromazine in six healthy subjects by using a double-blind latin square design. All of them received single doses of 20 mg zolpidem (ZOL), 50 mg chlorpromazine (CPZ) and the combination of ZOL + CPZ. The medication was given as a single dose in the morning and each treatment being separated by a 1-week interval. Zolpidem produced moderate to severe sedation varying according to the subjects. Psychometric performances (manual dexterity, Stroop test), alertness and psychomotricity (visual analogue scales) were reduced up to 3 h after drug intake. Chlorpromazine alone did not have much effect. Combined administration of ZOL and CPZ was rather more effective than ZOL alone. The pharmacokinetics of ZOL or CPZ remained unchanged except for the elimination half-life of CPZ, which increased significantly when administered along with ZOL. No other pharmacodynamic or pharmacokinetic interaction between ZOL and CPZ was evident. The fact that the ZOL and CPZ combination accentuated the pharmacodynamical effects can be explained to result from the summation of each of their own pharmacological effect.

Pharmacokinetic consequences of long term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects.

The influence of administration of cimetidine (1 g daily for 2 weeks) on the pharmacokinetics of alprazolam (0.5 mg t.i.d. for 1 week) and triazolam (0.5 mg nightly for 1 week) was investigated in two groups of 8 healthy subjects. The plasma AUC of these triazolobenzodiazepines were significantly increased. Moreover, for triazolam, the C max was increased and the plasma elimination half-life was prolonged; oral clearance of the two triazolobenzodiazepines was markedly reduced. It is suggested that the combined treatment cimetidine-alprazolam requires a reduced daily dosage (one third) of alprazolam or increased dosage intervals (b.i.d. instead of t.i.d.). For triazolam, used as a hypnotic drug, such dosage reduction appears unsuitable if administered on a once-nightly basis.

Phase I-II study of aclarubicin for treatment of acute myeloid leukemia.

Aclarubicin (ACM) was administered as induction treatment to 40 patients with acute myeloid leukemia (AML) who were either refractory to initial induction chemotherapy or in relapse. Thirty-eight patients with AML, 2-80 years of age (mean +/- SE, 35.0 +/- 3.2), were evaluated during this study. Seventeen of these patients were given ACM after an unsuccessful attempt had been made to attain a complete remission (CR) with various regimens that included doxorubicin or daunorubicin; this group was considered resistant to these drugs. ACM was administered by rapid iv injection. Thirteen patients received a single course of ACM at a daily dose of 10-30 mg/m2 until a maximum total dose of 300 mg/m2 was reached or until unacceptable toxicity appeared. Of these patients, two (15%) attained a CR. The other 25 patients were given 10-day courses of ACM at a daily dose of 15 mg/m2 with 10-day intervals between courses; courses were repeated until the blast cells were cleared from peripheral blood and bone marrow or until progressive disease became evident. With this regimen, 11 patients (44%) attained a CR. The overall CR rate for the 38 patients was 34%. Total doses necessary to achieve a CR ranged from 150 to 600 mg/m2. A CR was attained by six patients who were previously resistant to a regimen containing moderate doses of doxorubicin. The incidence and severity of the toxic effects were related to the dose of ACM administered per course of therapy. The incidence of mucositis, diarrhea, vomiting, and infection in patients who received doses greater than 150 mg/m2/course was significantly higher than that observed in patients who received a dose of 150 mg/m2/course. In the latter patients, toxicity was within acceptable limits. Alopecia was not observed. Three patients had transient T-wave inversion, and reversible atrial flutter developed in one patient. Our results indicate that ACM is a major new drug for the treatment of AML.

Plasma kinetics of mitoxantrone in leukemic patients.

The plasma kinetics of mitoxantrone (MX), a new cytostatic anthracenedione, were investigated with HPLC in five leukemic patients suffering from acute myeloid leukemia, at the dose of 24 mg m-2 infused over 30 min at constant rate. The decay of the plasma concentrations was best fitted to a three compartment model with average elimination half-lives of respectively 4.1 min (alpha-phase), 19.8 min (beta-phase) and 8.9 h (gamma-phase), a mean distribution volume of 317 l m-2 and an average total body clearance of 0.37 l min-1 m-2. The cumulative urinary recovery of unchanged MX was 7.5% of the administered dose in 4 days, with the highest elimination during the first day. No MX urinary metabolites or conjugates have been detected.

Phase I-II study of aclacinomycin for a treatment of acute myeloid leukemia.

Aclacinomycin A (ACM) was administered for induction treatment to 40 previously treated acute myeloid leukemia (AML) patients. 38 patients aged 2 to 80 years (mean +/- SE, 35.0 +/- 3.2 years) with overt AML were evaluated; of these, seventeen patients were given ACM after an unsuccessful attempt to obtain a complete remission (CR) with various regimens comprising adriamycin (ADM) or daunorubicin (DNR) and were considered resistant to these drugs. Thirteen patients received ACM at a daily dose of 10 to 30 mg/m2 IV bolus until the maximum total dose of 300 mg/m2 per course was reached or until unacceptable toxicity appeared; of these patients, 2 (15%) attained a CR. Twenty-five patients were given 10-day courses of ACM at the daily dose of 15 mg/m2 IV bolus with 10-day intervals between courses; with this regimen 11 patients (44%) attained a CR. The overall CR rate was 34%. Total doses necessary to attain a CR ranged from 150 to 600 mg/m2. CR was attained by 6 patients (35%) of the 17 who were previously resistant to ADM or DNR. The incidence and severity of the toxic effects such as mucositis, diarrhea, vomiting and infection were related to the dose of ACM administered during each course of therapy. However, in patients who received 150 mg/m2 per course the toxicity was within acceptable limits. Alopecia was not observed. Transient T-wave inversion was observed in 3 patients and atrial flutter developed in one patient. Therefore, we conclude that ACM is a new major drug in the treatment of AML.

Acute cardiovascular and renal changes induced by mitoxantrone in rabbits. A pharmacokinetic approach.

The acute effects of a single i.v. bolus injection of mitoxantrone (MX), a cytostatic drug, on mean arterial pressure (MAP), left ventricular pressure (LVP), dp/dtmax and ECG, were investigated at different doses (1,2,3,5 and 10 mg/kg) in conscious rabbits. Low values of MAP, LVP and dp/dtmax and increased heart rate were observed at 2 h after injection at all dose levels exceeding 1 mg/kg. Plasma kinetics and urinary elimination of MX were determined by high-pressure liquid chromatography (HPLC) and appraised at two dose levels (1.5 mg/kg and 3 mg/kg). MX plasma decay curve at both doses could be fitted to a curve with three exponential components, with an average elimination (3rd component) half-life of about 3.5 h (1.5 mg/kg) and about 5 h (3 mg/kg), respectively. Renal failure was observed in 3 mg/kg-dosed rabbits (elevation of BUN and plasma creatinine, anuria), and resulted in a considerable delay in the MX plasma decay and in a depressed urinary elimination of MX. All but one rabbit died within 24 h. The 1.5 mg/kg-dosed rabbits survived till 24 h, without signs of renal failure, with a 24 h urinary MX recovery of 20%.