Pharmacokinetics of isosorbide dinitrate and its mononitrate metabolites after intravenous infusion

Plasma concentrations of isosorbide dinitrate (ISDN) and its two active metabolites 2-isosorbide mononitrate (2-ISMN) and 5-isosorbide mononitrate (5-ISMN) have been measured during and for 6 hr after intravenous infusion at a rate of 2.5 mg/hr during 1.75 hr in six cardiac patients, by a capillary gas chromatographic method. Data were analyzed by simultaneous modeling of the observed kinetics of the three compounds. Two or three phases were detected on the postinfusion ISDN concentration-time curves. ISDN concentrations declined with a mean terminal half-life of 2.81 hr +/- 0.7 SD. The mean systemic clearance of ISDN (2.9 L/min +/- 0.7 SD) and its mean total volume of distribution (259 L +/- 48 SD) were relatively high. Plasma 5-ISMN concentrations were 5- to 6-fold greater than those of 2-ISMN during the whole observation period. Maximum levels of 2-ISMN (6.7 ng/ml +/- 0.9 SD) and of 5-ISMN (27 ng/ml +/- 6 SD) occurred within a few minutes after the end of infusion. The mean half-lives of 2-ISMN (1.59 hr +/- 0.19 SD) and of 5-ISMN (3.78 hr +/- 0.79 SD) estimated by the model were smaller than those calculated by a model-independent method (2.95 hr +/- 0.41 SD and 5.98 hr +/- 2.22, respectively), but were in good agreement with those reported in the literature following separate administration of both metabolites to man. This study shows how such modeling can distinguish between metabolite formation and elimination processes and allow the determination of metabolite half-lives after administration of the precursor drug.     

Challenges in accessing multidisciplinary pain treatment facilities in Canada

PURPOSE: The objective of this survey was to examine the services offered by multidisciplinary pain treatment facilities (MPTFs) across Canada and to compare access to care at these MPTFs. METHODS: A MPTF was defined as a clinic that advertised specialized multidisciplinary services for the diagnosis and management of patients with chronic pain, having a minimum of three different health care disciplines (including at least one medical speciality) available and integrated within the facility. The search method included approaching all hospital and rehabilitation centre administrators in Canada, the Insurance Bureau of Canada, the Workplace Safety and Insurance Board or similar body in each province. Designated investigators were responsible for confirming and supplementing MPTFs from the preliminary list for each province. Administrative leads at each eligible MPTF were asked to complete a detailed questionnaire regarding their MPTF infrastructure, clinical, research, teaching and administrative activities. RESULTS: Completed survey forms were received from 102 MPTFs (response rate 85%) with 80% concentrated in major cities, and none in Prince Edward Island and the Territories. The MPTFs offer a wide variety of treatments including non-pharmacological modalities such as interventional, physical and psychological therapy. The median wait time for a first appointment in public MPTFs is six months, which is approximately 12 times longer than non-public MPTFs. Eighteen pain fellowship programs exist in Canadian MPTFs and 64% engage in some form of research activities CONCLUSION: Canadian MPTFs are unable to meet clinical demands of patients suffering from chronic pain, both in terms of regional accessibility and reasonable wait time for patients' first appointment.     

Prevalence of autoimmune thyroid disorders in a Spanish multiple sclerosis cohort

The aim of the study was to determine the prevalence of thyroid autoimmune disorders in a cohort of untreated multiple sclerosis (MS) patients and compare it with a stratified sample of an adult population. We prospectively studied 93 untreated MS patients. The control group included 401 healthy subjects selected by stratified sampling in a non-iodine-deficient area. Antithyroid antibodies (ATA) (antibodies against peroxidase and thyroglobulin) were considered positive at titres ≥149 IU/ml. Antibodies were positive in 11 MS patients (11.8%; 95% CI 5.3–18.4%). This prevalence was five times higher ( P  = 0.0001) when compared with that in the control population. We found six cases with subclinical hypothyroidism (6.45%; 95% CI 11.4–1.5) in contrast to 2.24% in the control group. Comparing MS with positive and negative ATA, there was a non-significant, slightly higher frequency of low Expanded Disability Status Scale (EDSS) score in the ATA-positive group (81% vs. 73.2%). One year after start of interferon (IFN) treatment, only one patient developed subclinical thyroid dysfunction. MS patients have a higher prevalence of ATA compared with the general population. An initial ATA and thyroid-stimulating hormone (TSH) determination is recommended in all MS patients. A periodic assessment of thyroid function during IFN treatment only seems to be justified in those cases where positive ATA or dysfunction is present before treatment.     

Effects of neonatal bilateral eye enucleation on postnatal development of the monoamines in posterior thalamus of the rat

Summary Levels of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (serotonin, 5-HT) and their metabolites, and the activities of tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH) and monoamine oxidase A and B (MAO-A and MAO-B) have been determined in the rat posterior thalamus after enucleation during postnatal development. DA and 5-HT turnover rate have been measured as 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) accumulation rates after central decarboxylase inhibition by 3-hydroxybenzylhydrazine (NSD-1015). The major changes were an increase in noradrenergic and serotoninergic metabolism in enucleated animals compared with control animals. A decrease of the MAO-A to MAO-B ratio during postnatal development was found.Abbreviations DA dopamine - DOPAC 3,4-dihydroxyphenylacetic acid - HVA homovanillic acid - DOPA 3,4-dihydroxyphenylalanine - NA noradrenaline - MHPG 3-methoxy-4-hydroxyphenylgly-col - NMN normetanephrine - TRP tryptophan - 5-HTP 5-hydroxytryptophan - 5-HT serotonin - 5-HIAA 5-hydroxy-3-indolacetic acid - TH tyrosine hydroxylase - TPH tryptophan hydroxylase - MAO-A monoamine oxidase-A - MAO-B monoamine oxidase-B Recipients of fellowships from I.I.E. del FISS Reincorporación de doctores y tecnólogos del M.E.C., and Perfeccionamiento de doctores y tecnólogos del MEC, Spain