The E isomer of 2-ene-valproic acid (delta 2(E)-VPA) is the major active metabolite of the antiepileptic drug valproate (VPA) in various species, including humans. Experimental studies on delta 2(E)-VPA and VPA indicate that delta 2(E)-VPA may be a useful antiepileptic drug itself. delta 2(E)-VPA has the same wide spectrum of anticonvulsant activity as VPA with a somewhat higher anticonvulsant potency in rodent and dog models of different seizure types. As VPA, delta 2(E)-VPA increases presynaptic gamma-aminobutyric acid (GABA) levels in the brain, presumably by an effect on GABA synthesis and/or GABA degradation. delta 2(E)-VPA is a much more potent inhibitor of the human brain GABA-degrading enzyme than VPA. In high doses delta 2(E)-VPA is more sedative in rodents than is VPA; LD50 values are about the same. In mouse and rat models for teratogenicity, delta 2(E)-VPA does not induce teratogenic effects, whereas VPA is teratogenic in these models. Pilot rat studies on liver toxicity of VPA and VPA metabolites suggest that delta 2(E)-VPA is not hepatotoxic. In view of the rare but serious hepatotoxicity and teratogenicity of VPA in humans, delta 2(E)-VPA obviously merits interest as a valuable alternative drug in antiepileptic therapy.
New developments in the treatment of bacterial infections are discussed. The most important developments include oral broad-spectrum cephalosporin derivatives and extended-spectrum injectable cephalosporins with improved activity against Gram-positive bacteria. Meropenem is a new carbapenem agent with markedly improved activity against Gram-negative bacteria. Many fluoroquinolones are in various phases of development. The most interesting new compound is sparfloxacin. Azithromycin is a new macrolide which, because of its very long half-life, attains very high levels in most tissues. Potential uses of the newer agents are discussed.
Interferon alpha is the only available therapy for patients with chronic hepatitis B. With interferon alpha 3-15 MU thrice weekly or 5 MU daily during 3-6 months one-third of the patients achieve seroconversion of HBeAg and HBV-DNA together with normalization of aminotransferases and slight improvement of histology. Loss of HBsAg is reported in a minority of responders during treatment, but increases during follow-up. Patients with baseline alanine aminotransferase of at least twice the upper limit of normal and low HBV-DNA concentration achieve the best response rates. HIV-positive patients with low CD4 counts and Asians are poor responders. As side-effects influenza-like symptoms are experienced by almost all patients. Mild leukopenia, thrombocytopenia and decreased hairgrowth are frequently reported. Severe depression, depersonalization and psychosis are reported in a small number of patients but tend to be poorly recognized in some studies. The decision whether dose reduction is indicated seems strongly related to the opinion of the investigator. Although long-term effects on the occurrence of cirrhosis and the development of hepatocellular carcinoma are not available yet, the achieved results are promising.
Future advances in the pharmacotherapy of lung disease will occur mainly in the treatment of asthma, and will include the development of new long-actingβ2-agonists, long-acting parasympatholytics, phosphodiesterase inhibitors, corticosteroids with fewer systemic side-effects, and other antiinflammatory drugs. Free radicals play an important role in most lung diseases, including asthma, emphysema, fibrosis, and adult respiratory distress syndrome. The search for free radical scavengers is now in progress. Replacement therapy with α1-antitrypsin and surfactant is now possible. Progress in this area stems principally from a better understanding of the pathogenesis of lung disease.
Some new concepts in the delivery of hormones are described. Transmucosal or transdermal penetration of hormones can be facilitated, often by the use of absorption enhancers. Studies of nasal insulin delivery are described. Recently developed iontophoretic delivery devices can be useful for pulsatile transdermal administration of peptide hormones. A self-regulating delivery system releasing insulin in response to glucose levels is described. A vaginal ring relasing ethinylestradiol and 3-ketodesogestrel is a new concept in long-acting contraception. A nasal estradiol formulation, containing the absorption enhancer dimethyl-β-cyclodextrin, is an interesting alternative to oral and transdermal delivery of female sex hormones.
A number of lines of evidence indicate that metabolites of valproate rather than the parent drug, mediate the microvesicular steatosis which characterizes valproate-associated liver injury. In this article, two mechanisms are discussed whereby valproate may cause hepatic steatosis through interference with the process of fatty acidβ-oxidation. In the first, valproate itself enters the mitochondrion where it competes for the enzymes and/or co-factors involved in theβ-oxidation of endogeneous substrates, while in the second, valproate is metabolized via the hepatotoxic terminal olefin, Δ4-valproate, to a variety of chemically reactive intermediates which inhibit key enzymes in theβ-oxidation cycle.
The identification of new anticonvulsant drugs depends on the use of different animal models of epilepsy. The models should be mechanism-independent, able to screen a large number of compounds, at limited cost and technical expertise. Primary screening models include genetic or reflex models of epilepsy and electrically and chemically induced seizures. Once active compounds have been identified, more advanced mechanistic and seizure-specific models are needed to refine the choice of a lead compound. These can be either in vivo or in vitro models. Models known to interact with specific receptors or the production of the putative neurotransmitters of neural excitability or inhibition are valuable in assessing possible mechanisms of action. In vitro models have evolved as important tools in correlating changes in electrical phenomena and therapeutic spectrum. The use of the hippocampal slice and the cultured neuron permits classification of anticonvulsant activity based on cellular actions of the drug. Interactions by the experimental drugs with specific subcellular fractions of the central nervous system augment information on possible mechanisms of action. The final choice of compounds for development requires synthesizing and comparing all of the pharmacodynamic information with the pharmacokinetic and toxicologic data. In the final analysis, no single animal model of epilepsy known today can assure the development of better drugs for all treatment of the epilepsies.
The quality of protective gloves was studied. Protective gloves are part of the personal safety equipment for staff handling cytotoxic drugs. A study using raster electron microscopic photography, measurement of thickness by micrometer screw and permeability of carmustine by high pressure liquid chromatographic assay was carried out. The results show differences between different types of gloves.
In this report we describe the conditions of collection, storage and handling of urine samples, collected after oral dosing with indometacin in man, in order to maintain the integrity of the labile glucuronide formed. We found that the body clearance occurs predominantly by renal metabolism, due to glucuronidation in the human kidney. These glucuronides may be converted to isomeric glucuronides and/or the parent compound indometacin during the residence time in the bladder.
A simple reversed-phase high pressure liquid chromatographic method was developed for the determination of cefuroxime in the serum of patients undergoing coronary artery bypass grafting. The serum was cleaned up with a 3.3% solution of perchloric acid in water. Cefalexine was used as an internal standard. Detection was made by a UV multi-wavelength detector. The optimum wavelength for cefuroxime is 275 nm. The absolute recovery of this method was 90.9%; the limit of quantification was 0.7 mg/l. This analytical method was used in a study to investigate the cefuroxime serum concentration--time curves in 26 patients undergoing coronary artery bypass grafting. It was found that one single dose is sufficient to obtain effective serum concentrations.
The pharmacokinetics of amoxycillin (500 mg) given by intravenous injection and as two oral formulations on three consecutive days were investigated in eight frail elderly in-patients. Marked interindividual variation was found in all kinetic parameters after intravenous injection. The area under the curve (AUC) ranged from 32 to 155 mg.l-1.h and the distribution volume ranged from 13 to 37.1. The mean plasma clearance was 109 ml/min (range 53 to 255 ml/min). Elimination half-life ranged from 1.6 to 3.0 h (mean 2.4 h). The absolute bioavailability after oral administration was highly variable and ranged from 24 to 86% (mean 55%). The bioavailability of the two formulations was not significantly different. The performance of a pharmacokinetic study in these patients was very difficult, regarding their inability to tolerate an intravenous infusion, incontinence, disruption of everyday routine and problems with drinking the required volume of water.
The approach in treatment in medical oncology and particularly in the management of solid tumours has to integrate — at least — two targets: the enhancement of therapeutic efficacy, and the respect of global budget assigned to health. Different teams are implicated in such an approach and especially physicians and pharmacists. We decided to conduct a comparative study of three techniques of administering drugs as a continous infusion. We analysed time and materials required for the preparation in the centralized preparation unit, and for dispensing and nursing in the health units. The use of programmable pumps (CADD-1) leads to overall saving costs of 27 to 40% compared to administration by means of an infusion bag or a motor-drive syringe.
Calmodulin is the most important intracellular receptor protein for the second messenger calcium. The calcium-calmodulin complex regulates a number of physiological processes. An increasing number of pharmaceutical products is reported to interfere with the calcium-calmodulin complex. Despite the fact that the precise mechanisms of action of these so-called calmodulin antagonists await further clarification, reports accumulate in the literature indicating a broadening spectrum of putative therapeutic applications of calmodulin antagonists. Some of these applications, such as in cell proliferation, hypertension, congestive heart failure, arrhythmia and gastro-intestinal disorders, are discussed in the present review.
This article provides a short overview of enzymes involved in activation, transport and oxidation (β andω) of valproate and other fatty acids.
In 1987, the manager of the Saint-Joseph Hospital (Paris, France) requested a reorganization of cytotoxic drug preparation. Protection for staff who handle hazardous drugs was the main concern. The conclusions drawn from a first analysis emphasize the advantages of a centralized reconstitution unit against a decentralized system. Subsequently, a workload study and an economic study (investment, maintenance, supplies, staff costs, comparative balance sheet and a 5-year simulation) were carried out, but to choose between a laminar airflow in aseptic room and an isolator in a conventional room. The selected isolator is the first of the conception: the central half-suit uses as a server, and four sleeves located on one side allow two technicians to work in a sterile and closed area without sterile garments.
