Safety, efficacy and population pharmacokinetics of fixed-dose combination of artesunate-mefloquine in the treatment of acute uncomplicated Plasmodium falciparum malaria in India.

BACKGROUND & OBJECTIVES: India has switched over to artemisinin-based combination therapy (ACT) for the treatment of acute uncomplicated Plasmodium falciparum malaria and the ACT used in the national programme is artesunate + sulphadoxine-pyrimethamine. Since the efficacy of ACT is dependent also on the partner drug, there is a need to evaluate and deploy multiple ACTs. METHODS: This multicentre, single-arm, open-label clinical trial was carried out to assess the efficacy, safety and population pharmacokinetics of a fixed dose combination (FDC) artesunate mefloquine (ASMQ) in P. falciparum infected, Indian adults at Panjim, Goa, and Mangalore, Karnataka between December 2007 and November 2008. RESULTS: A total of 77 patients (males 74) were screened and enrolled: 42 at Goa and 35 at Mangalore with a median age of 25 yr (range 18-55 yr). One patient failed in treatment on D53, a PCR proven new infection, seven developed recurrent vivax parasitaemia and 11 did not have a parasitological endpoint. By per protocol analysis, the D63 cure rate was 58/59 (98.3; 95% C.I. 90.9-99.9%), and 58/58, with PCR correction. ASMQ was well-tolerated and no serious adverse events were reported. INTERPRETATION & CONCLUSION: The study showed that the ASMQ FDC was efficacious and well-tolerated for the treatment of acute, uncomplicated P. falciparum malaria in highly endemic, chloroquine resistant areas of Goa and Mangalore. It is a viable option for India.

Effect of artesunate and mefloquine in combination on the Fridericia corrected QT intervals in Plasmodium falciparum infected adults from Thailand.

OBJECTIVE: To ascertain whether mefloquine (MQ) produces electrocardiogram (ECG) changes that could be a risk for Torsades de Pointe (TdP), a potentially malignant, ventricular tachyarrhythmia. METHODS: We measured the Fridericia corrected QT (QTcF) intervals on 12 lead ECGs on days (D) 0, 3, 7 in Plasmodium falciparum infected adults, treated with oral artesunate (AS) and MQ as a new fixed dose (n = 25) combination or loose tablets (n = 25) over 3 days. Target total doses were 12 mg/kg of AS and 24-25 mg/kg of MQ. MQ concentrations ([MQ]) were measured by HPLC. RESULTS: All ECG intervals were similar between drug arms and were combined for analysis. Mean QTcF values were 389 (D0), 407 (D3) and 399 (D7) ms (Ps < 0.003 vs. D0); corresponding heart rates and [MQ]s were 83, 67 and 73 beats/minute (Ps ≤ 0.0003 vs. D0) and 0, 3095 and 1721 ng/ml. One male patient (loose arm) had a D3 QTcF 504 ms (D0 406 ms, D7 433 ms). In the modelling of QTcF and JTcF from D0 to D7, significant effects were observed individually for [MQ], temperature and heart rate (HR). The MQ AUC(0-∞) was not a significant factor. Using a manual descending, model building approach to select variables, the HR was the only significant variable (P = 0.001) over time in the model that best explained the changes in the QTcF and JTcF intervals. CONCLUSIONS: In this small group of patients, slowing heart rates due to malaria resolution best explained the observed increases in the QTcF intervals.

New fixed-dose artesunate-mefloquine formulation against multidrug-resistant Plasmodium falciparum in adults: a comparative phase IIb safety and pharmacokinetic study with standard-dose nonfixed artesunate plus mefloquine.

A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P < or = 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P < or = 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.

Fluoronaphthyridines and -quinolones as antibacterial agents. 5. Synthesis and antimicrobial activity of chiral 1-tert-butyl-6-fluoro-7-substituted-naphthyridones.

A series of novel 7-substituted-1-tert-butyl-6-fluoronaphthyridone-3- carboxylic acids has been prepared. These derivatives are characterized by chiral aminopyrrolidine substituents at the 7 position. In this paper we report the full details of the asymmetric synthesis of this series of compounds. Structure-activity relationship studies indicate that the absolute stereochemistry at the asymmetric centers of the pyrrolidine ring is critical for maintaining good activity. Compounds 60 and 61 (3-amino-4-methylpyrrolidine enantiomers) were selected for preclinical evaluation.

Fluoronaphthyridines and -quinolones as antibacterial agents. 3. Synthesis and structure-activity relationships of new 1-(1,1-dimethyl-2-fluoroethyl), 1-[1-methyl-1-(fluoromethyl)-2-fluoroethyl], and 1-[1,1-(difluoromethyl)-2-fluoroethyl] substituted derivatives.

A series of novel N-1-(mono-,-(di- and -(trifluoro-tert-butyl)quinolones and -naphthyridines has been prepared. Structure-activity relationship (SAR) studies indicated that the in vitro antibacterial potency was the following order: 1-(1,1-dimethyl-2-fluoroethyl) greater than 1-[1-methyl-1-(fluoromethyl)-2-fluoroethyl] greater than 1-[1,1-(difluoromethyl)-2-fluoroethyl] substituents. In the quinolone series the monofluoro-tert-butyl derivatives were found to possess better in vitro antibacterial activity than the nonfluorinated-tert-butyl equivalents. In vivo PD50 values of the 1-fluoro-tert-butyl-substituted derivatives reflect pharmacokinetic behavior and incomplete oral absorption.

Fluoronaphthyridines and quinolones as antibacterial agents. 2. Synthesis and structure-activity relationships of new 1-tert-butyl 7-substituted derivatives.

A number of 7-substituted-1-tert-butyl-6-fluoroquinolone-3-carboxylic acids and 7-substituted-1-tert-butyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids have been prepared and tested for antibacterial activities. Among those the 7-aminopyrrolidinyl 20b and the 7-diazabicyclo naphthyridine 18b are the most potent compounds in vitro and in vivo. Physicochemical data and acute toxicity are also discussed. Compound 18b, BMY 40062, exhibits the most favorable overall properties, considering in vitro and in vivo microbiological activity, its low toxicity, and pharmacokinetic profile, and was selected for clinical evaluation.

Determination of sub-nanogram amounts of dihydroergotamine in plasma and urine using liquid chromatography and fluorimetric detection with off-line and on-line solid-phase drug enrichment.

A highly sensitive and selective high-performance liquid chromatographic method, involving sample pre-treatment, column switching and fluorimetric detection, is described for the determination of dihydroergotamine in plasma and urine samples. The pre-chromatographic sample treatment consists of extraction by means of an Extrelut column for plasma samples, and pre-separation with enrichment steps on a Sep-Pak column for urine samples. The samples are then injected onto a pre-separation column (Aquapore), and the fraction containing dihydroergotamine are automatically diverted onto an analytical column (ODS reversed phase). An acetonitrile-ammonium carbamate gradient is used as the mobile phase. High recovery of dihydroergotamine from both plasma (87%) and urine (100%) and a detection limit as low as 100 pg/ml were achieved, with a linear response up to 5 ng/ml. The assay demonstrated a high degree of selectivity with regard to the extensive metabolism of dihydroergotamine especially to the main metabolite 8'-hydroxydihydroergotamine. The assay was successfully applied for more than one year to the determination of plasma and urine concentrations of dihydroergotamine after parenteral administration.

Effect of the binding of isradipine and darodipine to different plasma proteins on their transfer through the rat blood-brain barrier. Drug binding to lipoproteins does not limit the transfer of drug.

Brain extraction of two calcium channel antagonists, isradipine (PN 200-110) and darodipine (PY 108-068) was investigated using the carotid injection technique in rats. An inhibitor effect of binding to plasma proteins on the brain extraction was also investigated. Equilibrium dialysis at 37 degrees C showed that both drugs were highly bound to human serum proteins, including albumin, alpha-1 acid glycoprotein and lipoproteins. The free dialyzable drug fraction was inversely related to the protein concentration. The brain extraction of the drugs in the presence of either albumin or alpha-1 acid glycoprotein was inversely related to the protein concentrations in the presence of either albumin or alpha-1 acid glycoprotein, but it was higher than expected from the in vitro measurement of the dialyzable fraction. Despite a significant degree of binding to lipoproteins, no significant reduction in the brain extraction of the drugs was observed, regardless of the class or the concentration of lipoproteins. These data indicate that the amount of circulating darodipine or isradipine available for entry in a peripheral tissue such as brain exceeds the dialyzable fraction of drug. However, the in vivo exchangeable drug fraction still parallels the dialyzable fraction, except if the drug is lipoprotein bound.

Binding of (+)-PN 200-110 to rat pituitaries and to normal and adenomatous human pituitaries.

Endocrine cells possess voltage-sensitive Ca2+ channels involved in the modulation of hormonal secretion. Using the dihydropyridine, (+)-PN 200-110, we have investigated the binding characteristics of this ligand to pituitary membrane Ca2+ channels from normal rat, normal and adenomatous human pituitaries. [3H]PN 200-110 binds specifically to rat pituitary membranes to one class of sites (Kd = 0.41 +/- 0.10 mM; Bmax = 39 +/- 1.3 fmol/mg protein). At 37 degrees C, equilibrium is reached in 45 min and half-life of the binding is 13 min. No significant changes were observed for either the Kd or Bmax values between normal rat and human pituitaries or between the different types of adenomas (GH- and PRL-secreting and non-secreting). As the secretory activity of the pituitary adenomas, involving Ca2+ mobilization, varies from one adenoma to another, our results could indicate that, if there is a modified regulation of Ca2+ entry in the adenomas, it may not be related to a varying number of calcium channels, at least the channels labeled by the dihydropyridine (+)-PN 200-110.

Species differences in metabolism of ketotifen in rat, rabbit and man: demonstration of similar pathways in vivo and in cultured hepatocytes.

In vitro drug metabolism by cultured rat, rabbit and human adult hepatocytes has been studied, using ketotifen (ZADITEN) as a model substrate because it is biotransformed in vivo by various metabolic pathways in man and animals. The major in vivo pathways were demonstrated in vitro, namely oxidation in rat hepatocytes, oxidation, glucuronidation and sulfation in rabbit hepatocytes, reduction and glucuronidation in human hepatocytes. Human hepatocytes were the most stable in culture, displaying ketotifen biotransformation for at least one week. These results clearly demonstrated that cultured hepatocytes retain their in vivo specific drug metabolizing activities, including inter-species polymorphism, for a few days. Therefore, pure hepatocyte cultures represent a useful system suitable for drug metabolism studies.

[Pharmacokinetics and metabolism of cyclosporin; drug interactions]. / Pharmacocinétique et métabolisme de la cyclosporine; interactions médicamenteuses.

The pharmacokinetic properties of cyclosporine and mainly its absorption and hepatic elimination can vary in each patient in relation to the subject's individual characteristics (inter-subject variability), as well as in an individual patient during his treatment because of clinical episodes or drug interactions (intra-subject variabilities). Therefore, it appears compulsory to follow regularly cyclosporine blood levels or even to characterise each subject following a dose-test during the initiation of treatment, in order to adapt an individual posology aiming to minimise as far as possible the risk of nephrotoxicity.

[Reference values of chemical constituents and plasma enzymes in minipigs]. / Valeurs de référence des constituants chimiques et des enzymes plasmatiques chez le miniporc.

Nine male minipigs Pitman Moore have been studied from weaning (To) and during 6 months and the following constituents have been measured: albumin, amylase, bilirubin, calcium, CK, cholesterol, creatinine, copper, iron, GGT, glucose, LDH, magnesium, PAL, phospholipids, potassium, proteins, sodium, ALT, ASP, triglycerides, urea, zinc. These animals were fed a standardized diet. At 6 months of age their weight increased progressively to 12 kg. Several factors of variation have been studied; time of blood sampling age of animals. We obtained the following results: values of bilirubin, CK and TGO were always lower at 8 a.m. than 12 a.m. and 6 p.m. The effects of age were variable. They are no variation in the values of only 4 parameters (calcium, sodium, potassium and triglycerides), while the others constituents were increased or decreased. Reference values for 21 blood parameters in Pitman Moore minipigs are described.

Impaired regulation of beta 2-adrenergic receptor density in mononuclear cells during chronic renal failure.

Previous investigations have suggested that beta-adrenoceptor-mediated responses were decreased in uremia. To evaluate this phenomenon further, beta 2-receptor density in mononuclear cells, plasma catecholamines and plasma parathyroid hormone were studied in two groups of normotensive patients: group U, twenty-five chronic uremic patients with end-stage renal failure; group C, twenty-eight control subjects. Each group was divided into three age and sex-matched subgroups. Beta 2-receptor density was determined using (-)125 iodocyanopindolol. Despite a significant increase in plasma epinephrine in the group of uremic patients, there was a significant increase in beta 2-adrenoceptor density. On the other hand the uremic state did not influence (-)125 iodocyanopindolol binding affinity and plasma norepinephrine. Parathyroid hormone, as expected, was significantly elevated in all the uremic subgroups. It can be concluded that the uremic state is associated with an unexpected upregulation of beta 2-receptor density in mononuclear cells. The role of an endogenous beta-blocking substance is suggested.

Pharmacokinetics of guanfacine in patients with impaired renal function and in some elderly patients.

The effects of renal impairment and age on the pharmacokinetics of guanfacine were evaluated. In normal subjects, guanfacine was found to be rapidly and completely absorbed, with an absolute bioavailability close to 100% and therefore no evidence of a noticeable first-pass effect. Its kinetics were best described by a 2-compartment model, with an elimination half-life of the beta phase of 17 hours. The major route of excretion was in the urine, with urinary excretion of 80% of a given dose within 4 days. Linearity of dose and thus predictability of blood levels were observed for single doses and at steady state. Although cumulative urinary excretion and renal clearance of unchanged guanfacine were reduced in patients with renal insufficiency, total clearances, serum levels, elimination rates constants and elimination half-lives differed very slightly, or at most by a factor of 1.5 to 2 between patients with normal and severely impaired renal function. Age-related decreases in urinary excretion and renal clearance of guanfacine were observed in 6 elderly patients and were accompanied by an increased proportion of metabolites to parent drug, confirming the significant nonrenal clearance of the drug. Based on pharmacokinetic studies in these target groups and on the dual renal and nonrenal clearance of guanfacine, the drug may, most probably, be administered to elderly patients and patients with renal insufficiency without dosage adjustment.

Plasma protein binding and erythrocyte partitioning of nicardipine in vitro.

Using isotope techniques, equilibrium dialysis, and incubation experiments, we characterized the binding of nicardipine to isolated plasma proteins, human serum, blood cells, and platelets. Nicardipine was mainly bound to lipoproteins, orosomucoïd, albumin, and erythrocytes in human blood. Nicardipine, pindolol, and imipramine were found to share the same site on orosomucoïd. The determinants of nicardipine binding to lipoproteins were triglycerides, phospholipids, and cholesterol ester. Nicardipine partitioned into erythrocytes, showing a constant ratio of distribution between the intra- and extracellular compartments. Nicardipine partitioned less to erythrocytes when increasing amounts of binding plasma proteins were present in the extracellular compartment. In human blood, 12 to 18% of total nicardipine was present in erythrocytes. The overall binding of nicardipine in serum varied from 98 to 99.5% and correlated with serum orosomucoïd and serum lipid concentrations.

Hydergine pharmacokinetics in the elderly.

The pharmacokinetics of Hydergine was studied following intramuscular administration in a group of 6 subjects aged 76-86 and following oral administration in 6 subjects aged 66-86. Comparison with a control group of healthy volunteers (average age of 25) showed: --a marked reduction (- 50%) in renal clearance (p less than 0.001), related to the decrease in creatinine clearance in this population; --a lowering (- 30%) in metabolic clearance (p less than 0.02) in elderly subjects probably related to the decrease in hepatic blood flow observed with age; --a marked increase in bioavailability (X 2.5) following oral administration in elderly subjects, due either to increased absorption, or to a decreased hepatic first-pass effect. These results underline the value of studying the kinetics of geriatric drugs in the target population.

Nicardipine: pharmacokinetics and effects on carotid and brachial blood flows in normal volunteers.

The effects of nicardipine, 20 mg, three times daily, nicardipine slow release, 30 mg, twice daily and a placebo on brachial and carotid arteries diameters and flows have been investigated by the pulsed Doppler technique during a single blind and cross-over study performed in six healthy volunteers. Simultaneously, nicardipine plasma levels and relative bioavailability were determined. Nicardipine significantly increased brachial and carotid arteries diameters (by 16 and 10% respectively) and flows (by 60 and 35% respectively). These effects peaked after 4 h and lasted no longer than 6 h. Forearm vascular resistance was significantly decreased. Hence nicardipine dilated both large and small arteries. Nicardipine slow release elicited the same effects on brachial and carotid arteries diameters and flows as nicardipine. These effects peaked at 6 h and lasted up to 10 h. Although the profiles of the pharmacodynamic effects and of the kinetics of nicardipine were almost parallel in each individual after administration of both nicardipine formulations, there was no correlation between the nicardipine plasma relative bioavailability and its effects on brachial and carotid arteries blood flows when considering all subjects together.

[Pharmacokinetics: a contribution in clinical geriatric pharmacology?]. / La pharmacocinétique: un apport en pharmacologie clinique gériatrique?

Clinical pharmacology in elderly patients and its therapeutic implications come up against the difficulty to consider independently the factor age from the other factors, influencing the kinetics in this population. The knowledge of pharmacokinetics give essential informations for the development of new pharmaceutical forms, adjustment of dosage regimen and recommendations for drug intake in order to minimize the variations in bioavailability and to improve compliance. In regard of results, obtained in such studies, individualized treatment in function of age could possibly be considered. These different aspects are illustrated by recent studies on dihydroergotoxine, a geriatric drug for which improvements in therapy, based on new kinetic informations and the development of new galenical forms, can be expected. Though pharmacokinetics is a useful tool in clinical pharmacology in elderly patients, more informations of the influence of age on the physiology and biochemistry are needed to better explain the difference of response of this population to drug treatment.

Metabolism of ketotifen by human liver microsomes. In vitro characterization of a tertiary amine glucuronidation.

Biotransformation of ketotifen was investigated in vitro using human liver microsomes. Three of the four metabolic pathways observed in vivo in man were exhibited under the conditions of incubation, namely demethylation, N-oxidation, and N-glucuronidation, the absent route being the ketoreduction, which probably has a cytosolic localization. The kinetic parameters of the N-glucuronidation (KM for ketotifen and UDPGA and Vmax) were determined with native and detergent-treated microsomes. Treatment by Triton X-100 increased by about 3-fold the conjugation reaction. No sex difference was observed and N-glucuronidation did not seem to be inhibited either by bilirubin or by 4-nitrophenol. Thus, human liver microsomes are a useful and suitable in vitro model for studying metabolic routes, specific for man, as in the case of ketotifen. Obviously, the results obtained can only reflect partially the multiplicity of in vivo events and interpretation has to be complemented by investigations with other models.