Lack of toxicity of hydroethanolic extract from Mitragyna inermis (Willd.) O. Kuntze by gavage in the rat.

In traditional medicine in Mali, extracts derived from Mitragyna inermis (Willd.) O. Kuntze (Family: Rubiaceae) are commonly used to treat malaria. The antimalarial activity and the lack of genotoxicity in vitro and in vivo have been demonstrated in previous studies. Acute and chronic evaluation of the toxicity of the hydroethanolic extract of Mitragyna inermis leaves was performed in this study, according to the recommendations (cahier de l'Agence no. 3) of the French Drug Office. Two dosages (300 mg/kg and 3 g/kg) were given in one single administration by gavage to male and female rats. No animal died and no behavioral signs of acute toxicity were observed. Chronic toxicity studies over 28 days showed no changes in body weight and no macroscopic abnormality in the 14 organs examined after the animals were sacrificed. With the 3 g/kg/d drug dosage (100-fold higher than those proposed in man), only slight histological abnormalities were observed. Statistically significant differences, compared to control animals, in the weight of some organs and the values of some haematological or biochemical parameters were observed. However, these values always remained in the range given by the breeder for naive animals of the same strain. These investigations thus seemed to indicate the safety of repeated oral administration (up to 3 g/kg/d) of the hydroethanolic extract of Mitragyna inermis leaves, which can therefore be continuously used with safety by the African population in traditional treatment of malaria.

Population pharmacokinetics of cisplatin after 120-h infusion: application to routine adaptive control with feedback.

OBJECTIVE: A Bayesian population pharmacokinetics study of data from routine therapeutic drug monitoring cisplatin during a 5-day infusion of cisplatin. METHODS: A total of 95 kinetics data sets (58 patients) were available to perform this study. Individual pharmacokinetic parameters, estimated from 20 courses of treatment in 18 patients, were used to calculate the population parameters (cl: 0.175 +/- 0.034 L/h; t(1/2): 327 +/- 91 h). The accuracy of Bayesian forecasting was tested by comparing in 40 other patients the clearance values calculated either from a complete kinetics profile (eight sampling times) or from three early samples and the new population parameters. Finally, drug monitoring efficacy was assessed by comparing the target Cmax values with the Cmax obtained after dose adjustment based upon early Bayesian estimation of the individual pharmacokinetic parameters. RESULTS: : No significant difference was found between Bayesian and experimental clearances. Besides, dose-individualization proved to successfully adjust Cmax values around their respective target. CONCLUSION: The new reference pharmacokinetic population parameters lead to accurate estimation of individual pharmacokinetic parameters from a limited number of samples, thus allowing efficient therapeutic drug monitoring during 5-day infusion regimens of cisplatin.

[An experimental study on the systemic distribution of calibrated talc after intra-pleural injection]. / Etude expérimentale de la distribution systémique de talc calibré après injection intrapleurale.

INTRODUCTION: Among the agents used to produce pleural symphysis talc is the most effective and least expensive. However, its use is controversial on account of the description of respiratory complications associated with subsequent systemic spread of the talc particles. This hypothesis rests on clinical and experimental observations of talc particles in the viscera. However, all talc preparations are not identical and this extra-pleural spread could be dependent on particle size. This experimental study was undertaken to determine whether there was systemic spread of a calibrated talc preparation used routinely in clinical practice following intra-pleural administration in rats. METHODS: 48 rats received 20 mg (11 rats) and 40 mg (33 rats) of calibrated talc suspended in 1 ml of physiological saline by intra-pleural injection. The animals were randomised for sacrifice at 24 hours (22 rats) and 72 hours (22 rats) after the injection. The lungs, parietal pleura, diaphragm, liver, spleen, pericardium, brain and blood were examined by light microscopy and polarised light to search for bi-refringent particles. RESULTS: No deaths occurred during the procedure. At the time of sacrifice no pleural symphysis was seen. In 5 animals some talc particles were seen in the extra-thoracic organs: in the liver in 3 in the spleen in 1 and one particle in the brain of one animal examined by electron microscopy. No talc particles were found in the blood. CONCLUSIONS: Intra-pleural injection of calibrated talc, (Steritalc-Novatech-Plan de Grasse-France) has a weak systemic spread in > small animals. These results may be related to the diameter of the talc particles used (mean 33.6 microns; median 31.3 microns). The hypothesis that systemic spread is influenced by the diameter of the talc particles needs to be supported by experimental studies using talc particles of smaller diameter in order to compare the systemic distribution of the different preparations.

Bayesian population model of methotrexate to guide dosage adjustments for folate rescue in patients with breast cancer.

BACKGROUND: Methotrexate (MTX) infusions may induce severe side-effects, and alkaline hydration along with folinic acid rescue is a common way to reduce such toxic risks. The purpose of this study was to develop an adaptive rescue strategy based upon the early detection of patients with impaired MTX elimination. METHODS AND RESULTS: In this study, we propose a simple population-based Bayesian approach for predicting MTX plasma concentration from a limited number of samples, so as to adapt both duration and dosage of the rescue agent to be used next. Ten kinetic profiles obtained after 10 courses of MTX (1.5 g/m2) in seven patients with inflammatory breast cancer were used to establish the population pharmacokinetic parameters (Cl, 8.16 L/h; t1/2, 12.7 h). This population was next involved in the Bayesian estimation of MTX individual pharmacokinetic parameters from only two blood samples (T24 and T36 h), thus allowing one to forecast the elimination of this drug by predicting MTX levels at 48 h. According to the MTX concentrations predicted during the elimination phase, folinic acid rescue was then prolonged in patients likely to be overexposed. CONCLUSION: The Bayesian estimation presented in this study was an easy and convenient method to efficiently detect patients with impaired MTX elimination in routine clinical practice. This information enabled the introduction of strategies for minimizing the risk of severe drug toxicity.

Pharmacokinetics of intrapleural cisplatin for the treatment of malignant pleural effusions.

We determined the toxicity and pharmacokinetics of high-dose intrapleural cisplatin (CDDP) as a treatment of malignant pleural effusions (MPE). Fourteen patients with MPE were enrolled in this study. After complete drainage of the fluid, a catheter was inserted into the pleural cavity during a thoracoscopy. CDDP (300 mg) was administered via the catheter in a 6-h infusion. Peak levels, the areas under the concentration curve (AUC), and drug half-lives were measured in pleural fluid and plasma samples collected at 0 (baseline), 6, and 24 h as well as 4, 14, and 21 days after intrapleural administration. The dosage of CDDP ranged from 153 to 203 mg/m2. The time interval between infusion was prolonged until a maximum of 109 days. Only 7/40 infusions were associated with adverse effects in 4 patients (18%). Residual concentrations in pleural fluid (0.66+/-0.07 microgram /ml) were three-fold higher than in plasma (0.13+/-0.07 microgram/ml). In pleural fluid, maximal concentration (Cmax) varied from 19 to 900 microgram/ml and in plasma from 0.34 to 3.65 microgram/ml. AUC in plasma during the three courses was 112+/-49 microgram/ml/d. The T1/2 was 31+/-33 days higher than that previously reported after intravenous administration (8-15 days). Although intrapleural CDDP has the potential advantage of treating the underlying malignancy in addition to controlling the malignant effusion with a good tolerance, it cannot be recommended for the standard control of malignant pleural effusion. Indeed we observed a great variability of intrapleural CDDP concentration depending on the extent of pleural invasion and plasma diffusion. Further studies are needed to determine the value of high-dose intrapleural CDDP for the treatment of MPE.

Bayesian calculation of methotrexate clearance after low dose intramuscular administration in patients with rheumatoid arthritis.

OBJECTIVE: To determine a pharmacokinetic procedure (Bayesian method) for estimation of methotrexate (MTX) clearance, using only 2 blood samples, in outpatients with rheumatoid arthritis treated with low dose intramuscular (i.m.) MTX. METHODS: Population pharmacokinetic parameters were obtained by the weighted least squares (WLSQ) method in plasma samples from 14 patients with rheumatoid arthritis (RA). In each patient, 11 samples were measured by fluorescence polarization immunoassay, at Time 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, and 24 h after i.m. administration. These measures were validated by pharmacokinetic studies in 20 other patients with RA. Individual total body clearance of MTX was calculated using only 2 plasma samples (at 0.5 and 2 h after i.m. injection) by the Bayesian method using the population pharmacokinetic parameters. The clearance measures obtained by the Bayesian method were compared with those obtained by the WLSQ method. RESULTS: The pharmacokinetic variables (clearance, half-life, area under the curve) of 14 patients were determined, as well as the covariance and the mean values necessary to apply the Bayesian method. No significant difference was found between clearance values obtained by the Bayesian method compared to the WLSQ method, confirming the validity of the Bayesian values. CONCLUSION: The present population pharmacokinetic parameters allowed the determination of individual clearance of MTX with only 2 plasma samples (0.5 and 2 h after administration) in patients treated with low dose im MTX. Individual clearance is used to modulate MTX administration in patients presenting adverse reactions in spite of good clinical response. Individual determination of MTX pharmacokinetics in patients at risk for adverse MTX reactions could be useful for adjustment of the drug regimen.

Lack of correlation between pharmacokinetics and efficacy of low dose methotrexate in patients with rheumatoid arthritis.

OBJECTIVE: To determine if the variability in the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA) is correlated with its pharmacokinetics. METHODS: MTX pharmacokinetics was evaluated in 46 patients with RA starting a weekly intramuscular low dose MTX treatment. The patients were divided into 32 responders and 14 nonresponders to MTX according to the clinical response in the 6 months after the pharmacokinetic study. MTX plasma (at T0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h) and urine concentrations were measured with the TDx Abbott fluorescence polarization immunoassay. RESULTS: The MTX dosage, age, sex, RA duration, hepatic and renal functions of responders and nonresponders were not different. No difference was found either in peak concentration, residual 24th hour concentration, area under the curve, total body clearance, renal clearance, and terminal T1/2 life of MTX in responders and nonresponders. Surprisingly, patients with adverse reactions had higher total body and renal MTX clearances than those without side effects during the study. CONCLUSION: These data suggest that plasma MTX measurements are not helpful in defining an optimal treatment regimen.

Pharmacokinetics of a single oral dose of clobazam in patients with liver disease.

The pharmacokinetic effect of a single oral in dose of 20 mg clobazam was studied in 15 patients with liver disease and in 6 healthy volunteers. Plasma concentrations of clobazam and its main metabolite, norclobazam, were measured by gas liquid chromatography. Clobazam was rapidly absorbed. Peak plasma concentrations were 350 +/- 63 ng/ml at 1.7 +/- 0.8 hr in healthy volunteers, 239 +/- 70 ng/ml at 3 +/- 1.9 hr in patients with viral hepatitis and 240 +/- 113 ng/ml at 2.5 +/- 1.5 hr in patients with cirrhosis. Total distribution volume was 173 +/- 88 l and 168 +/- 71 l in patients with viral hepatitis and cirrhosis respectively, and 81 +/- 20 l in volunteers. Corresponding half-life values were 47 +/- 18 hr and 51 +/- 21 hr in patients and 22 +/- 6.3 hr in volunteers. The difference between patients was not significant, whereas the difference between patients and volunteers was significant.

Pharmacokinetics of folinic acid and 5-methyltetrahydrofolic metabolite after repeated oral administration of calcium folinate following methotrexate treatment.

The pharmacokinetic profiles of folinic acid (FA) and its active metabolite, 5-methyltetrahydrofolic acid, were studied after oral administration of decreasing doses of calcium folinate during 37 courses of high and intermediate dose methotrexate treatment in 25 lymphoma patients. FA was administered at a dose of 6 x 50 mg in 15 courses, 6 x 25 mg in seven courses, 6 x 15 mg in 10 courses and 6 x 7.5 mg in 5 courses. FA, 5-methyltetrahydrofolic acid, methotrexate and 70H-methotrexate were assayed simultaneously by high performance liquid chromatography. When FA was administered at doses between 50 and 15 mg, maximum concentrations of both the drug and its metabolite were always obtained after 1 to 2 h and remained stable. The same was true for the equilibrium concentration of the two products at doses over 15 mg. These findings suggest saturation of absorption and metabolism of folinic acid at doses over 15 mg.

Is there an interaction between low doses of corticosteroids and methotrexate in patients with rheumatoid arthritis? A pharmacokinetic study in 33 patients.

A study of methotrexate (MTX) pharmacokinetics with and without prednisolone was performed in 33 patients with rheumatoid arthritis. Ten mg im MTX were given on Day 0; patients were divided into 3 groups of 11 persons: Group 1: no corticosteroid; Group 2: prednisolone 15 mg/day per os from D -3 on; Group 3: patients continuing longterm prednisolone treatment (15 mg/day). Groups 1 and 2 were randomized. MTX plasma concentrations were measured at T 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12 and 24 h using fluorescence polarization immunoassay (TDx Abbott). There was no difference between MTX pharmacokinetics of Groups 1 and 2. Area under the curve (AUC), Cmax and residual concentration at 24th h were higher, while total body and renal MTX clearances were lower in Group 3 vs Groups 1 and 2. Only the differences in AUC and total clearance were significant (p < 0.01 and p < 0.05). Tmax and terminal half-life did not differ. Our data suggest a possible influence of prednisolone on MTX pharmacokinetics in longstanding steroid treated patients. The pharmacological processes that might be involved are discussed.

Influence of food on the tyramine pressor effect during chronic moclobemide treatment of healthy volunteers.

An open study was carried out to examine the effect of moclobemide, a new antidepressant reversible inhibitor of MAO-A, on the pressor response induced by oral tyramine added to meals of different lipid and protein composition, and to correlate the blood pressure increase in the tyramine test with that obtained during an exercise test. Eight healthy volunteers of both sexes participated in the study. A tyramine sensitivity and an exercise test were performed beforehand. Subjects were included if, under fasting condition, their systolic blood pressure (SBP) increased by more than 30 mmHg after administration of 400 or 600 mg tyramine. Exercise tests were performed to determine the grade of effort that corresponded to a rise in SBP of 30 mmHg. Subjects received moclobemide 600 mg/d. Starting on Day 7, each subject consumed a standardized meal (52 g lipids, 43 g proteins, 86 g carbohydrates) just before taking moclobemide. Tyramine was added to these meals in daily increasing doses of 50, 100, 150...mg until an increase in SBP > or = 30 mmHg was obtained. On moclobemide treatment, an average dose of 250 mg tyramine (range 150-400 mg) increased SBP by 36.6 mmHg. The time to reach peak SBP was longer (175 min) than in the fasting condition before the trial (40.6 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age and antiepileptic drugs on plasma levels and kinetics of clobazam and N-desmethylclobazam.

The authors monitored the plasma levels of clobazam (CLO) and its principal metabolite, N-desmethylclobazam (NCLO) during chronic treatment of more than 400 epileptic patients receiving different co-medications, such as phenytoin (PH), carbamazepine (CBZ), sodium valproate (VPA) and phenobarbital (PB). This study investigated the influence of age and antiepileptic drugs on plasma levels of CLO and NCLO. Plasma concentrations measured 3 hr after morning administration of CLO varied from 30 to 700 [formula; see text] for CLO, and from 160 to 7000 [formula; see text] for NCLO. Plasma levels of CLO were higher in patients aged 20-30 years. NCLO concentrations increased with age up to 20 years. Coadministered antiepileptic compounds significantly decreased maximal plasma levels of CLO. Moreover, PH and CBZ a significantly increased the plasma levels of NCLO. Results on the influence of CBZ on CLO kinetics were confirmed in a group of ten patients receiving PB and VPA and later PB, VPA and CBZ as CLO associated drugs. The influence of VPA on the pharmacokinetics parameters of CLO was also evaluated in a patient in the latter group.

[Determination of the optimal dose of bromazepam in the elderly]. / Recherche d'une posologie optimale du bromazépam chez le sujet âgé.

The aim of our study was to determine in patients over 70 years, the optimal dose of Bromazepam. Seven patients were administered a unique dose of Bromazepam (3 mg), then repeated doses (1.5 mg) every 12 hours for 9 days. Cmax was 42.5 +/- 12 ng/ml in Tmax ranged from 2 to 12 hours after the first dose-concentrations of Bromazepam at steady-state were between 79 and 157 ng/ml. Half life was 30.5 +/- 14.7 hrs for the unique and the repeated doses. Sleeping was noted for concentrations over 40 ng/ml. The dose of 1.5 mg bid is recommended in old patients.