R. Hulhoven

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 ≥ 70 mh/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%).

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.

Clinical trials with daunorubicin-DNA and adriamycin-DNA in acute lymphoblastic leukemia of childhood, acute nonlymphoblastic leukemia, and bronchogenic carcinoma.

SummaryTreatment with daunorubicin-DNA (DNR-DNA) or adriamycin-DNA (ADM-DNA) has been evaluated in acute lymphoblastic leukemia of childhood (ALL), acute nonlymphoblastic leukemia (ANLL) and bronchogenic carcinoma (BC). The Five-year survival rate in 69 children with ALL was 73.7% when ADM-DNA was introduced in the treatment and 38% with DNR-DNA (P=0.03).A randomization between free DNR and DNR-DNA for remission induction in 26 patients with ANLL has shown that the drugs were of equivalent effectiveness. The one-year survival rate was 66% for the DNR group and 64% for the DNR-DNA group.In 59 patients with BC, a randomized trial between ADM-DNA and cyclophosphamide-vinblastine (CTX-VLB) did not show an advantage infavor of one of these treatments. In anaplastic BC (51 patients), there was no difference in survival rate or remission rate between patients treated with ADM or ADM-DNA.No cardiotoxicity was noted among the patients treated with the complexed drugs. ADM-DNA and DNR-DNA are as effective as the free drugs. Cardiotoxicity appears to be reduced.

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

SummaryAdinazolam 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 adinazolams 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 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 H1 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 31/2 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 allotted 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.

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 (α-phase), 19.8 min (β-phase) and 8.9 h (γ-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.

Beta-Blocking Agents and Plasma Lipids: An Update

Several earlier studies have shown that hypertension is an atherogenic factor of greater clinical significance when it is associated with high plasma lipid levels causing cardiovascular disease (1,2).

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%.

Chimiotherapie des stades avances de la maladie de Hodgkin stades III b et IV

SummaryIn a series of 38 patients treated for advanced Hodgkin’s disease with the MOPP combination chemotherapy of DeVita, Serpick and Carbone, the complete remission rate was 84%. In this series 1/4 of the patients had been previously treated with other methods. Most of them, with a relapse of their disease, had a larger extension of their disease in comparison with the initial stage.In the evaluation of complete remission, the persistence of a splenomegaly (3 patients) is not necessarily a sign of incomplete remission; the histological study of the three spleens demonstrated no involvement of Hodgkin’s disease.The treatment is generally well tolerated. For the whole group, no more than an average decrease of 10 to 15% of the theoretical dose, mainly of the alkylating agents, was applied. The decrease was more important in patients who didn’t respond to the treatment; this allows us to suppose that haematological intolerance is a factor in bad prognosis.With a view to determining the best therapy for mai...