Plasma concentrations and bioavailability of propranolol by oral, rectal, and intravenous administration in man

Eight normal male volunteers received 80 mg doses of propranolol by the oral and rectal routes and 2.2 mg by intravenous administration in a crossover fashion. Plasma concentrations of propranolol were measured by a gas chromatographic method using an electron capture detector. Individual subject concentration-time data were analysed and results indicated that the data fit a two compartment model with first order absorption. An approximately two-fold higher plasma propranolol concentration was observed after rectal administration as compared with oral dosing. Statistical analysis of the difference in the total AUCs indicates a significantly higher bioavailability of propranolol administered by the rectal route. The reduced bioavailability after oral administration indicates a substantial first pass effect but that it is possible to bypass the liver, at least partially, by giving the drug rectally to man.     

Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia.

BACKGROUND: There is an increasing recognition that the pathophysiology of mental disorders could be the result of deregulation of synaptic plasticity with alterations of neurotrophins. The valine (Val)66-to-methionine (Met) variant, located in the pro brain-derived neurotrophic factor (BDNF) sequence, has been extensively studied through linkage and association approaches in several psychiatric disorders. METHODS: We performed a meta-analysis restricted to individual case-control studies in different categories of mental disorders and BDNF Val66Met polymorphism. We included data from 39 case-control studies encompassing psychiatric phenotypes: eating disorders, substance-related disorders, mood disorders, and schizophrenia, among others. RESULTS: The association of Val66Met was confined to three diagnoses: substance-related disorders, eating disorders, and schizophrenia. The Val/Met and the Met/Met genotypes increase the risk for eating disorders up to 33%, while these same genotypes confer a 21% protective effect in substance-related disorders. The homozygous carriers Met/Met showed a 19% increased risk of schizophrenia with respect to the heterozygous state. CONCLUSIONS: The study confirms the association of Val66Met to substance-related disorders, eating disorders, and schizophrenia. It remains to be determined if other variants in tight linkage disequilibrium with Val66Met could configure an extended functional haplotype that would explain observed discrepancies in risk estimations across studies.     

Cerebrospinal fluid purine metabolites after complex febrile convulsions

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and uric acid were determined in cerebrospinal fluid (CSF) of 15 children after complex febrile seizures (CFS) and in 27 after simple febrile seizures (SFS), and compared with those in a control group of 63 children. There was no statistically significant difference between the groups for any of these metabolites, suggesting that CFS and SFS neither significantly disturb the metabolism of nucleotides, nucleosides or bases nor significantly deplete neuron adenosine triphosphate levels.     

Induced luteolysis in the primate: rapid loss of luteinizing hormone receptors

The molecular mechanisms involved in luteolysis are still unclear in the primate. This study aimed to investigate the effect of induced luteolysis on the ovarian luteinizing hormone (LH) receptor and the steroidogenic enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the marmoset monkey. Luteolysis was induced in the mid-luteal phase either directly by systemic prostaglandin F2alpha (PGF2alpha), or indirectly by LH withdrawal using systemic gonadotrophin releasing hormone antagonist (GnRHant) treatment. The LH receptor was studied by isotopic mRNA in-situ hybridization and in-situ ligand binding and 3beta-HSD expression was studied using isotopic mRNA in-situ hybridization and immunohistochemistry. Induced luteolysis was associated with a reduction in the expression of LH receptor (P < 0.0001) and 3beta-HSD mRNA, closely followed by a reduction in the LH receptor (P < 0.05) and 3beta-HSD protein concentrations within 24 h. There were no differences in the findings whether luteolysis was induced with PGF2alpha or GnRHant. This study shows that disparate mechanisms to induce luteolysis in the primate result in an identical rapid loss of the LH receptor and 3beta-HSD. In conclusion, induced luteolysis leads to rapid loss of the steroidogenic pathway in luteal cells.      

The measurement of transforming growth factor type beta (TGF beta) levels produced by peripheral blood mononuclear cells requires the efficient elimination of contaminating platelets.

In recent years there has been an increasing interest in measuring the levels of TGF beta produced by peripheral blood mononuclear cells (PBMC), since its abnormal regulation seems to be involved in several pathological states. Platelet-contamination, a common feature in PBMC populations isolated by the standard Ficoll-Paque method, would theoretically disturb the measurement of the levels of TGF beta produced by mononuclear cells, since platelets represent an important source of this cytokine. In this study, supernatants of PBMC cultures from healthy subjects, either platelet-contaminated or uncontaminated, were assayed for TGF beta activity in three different bioassays. We report that the presence of platelets led in most cases to an important overestimation of the TGF beta levels produced by MNC in the Swiss-3T3 bioassay and in a PBMC proliferation assay. In contrast, in the Mv1Lu bioassay these levels were significantly underestimated, an effect which we attribute to the presence of other platelet-derived growth factors. These results suggest that the elimination of platelets from PBMC cultures is essential if TGF beta production by mononuclear cells is to be studied.     

New microsatellite multiplex PCR for Candida albicans strain typing reveals microevolutionary changes

Five new microsatellite loci were described and characterized for use as molecular markers for the identification and genetic differentiation of Candida albicans strains. Following the typing of 72 unrelated clinical isolates, the analysis revealed that they were all polymorphic, presenting from 5 to 30 alleles and 8 to 46 different genotypes. The discriminatory power obtained by combining the information generated by three microsatellites used in a multiplex PCR amplification strategy was 0.99, the highest ever reported. The multiplex PCR was later used to test a total of 114 C. albicans strains, including multiple isolates from the same patient collected from different body locations and along episodes of vulvovaginal infections. Three different scenarios for strain relatedness were identified: (i) different isolates that were revealed to be the same strain, (ii) isolates that were the same strain but that apparently underwent a process of microevolution, and (iii) isolates that corresponded to different strains. Analysis of the microevolutionary changes between isolates from recurrent infections indicated that the genotype alterations observed could be the result of events that lead to the loss of heterozygosity (LOH). In one case of recurrent infection, LOH was observed at the CAI locus, and this could have been related to exposure to fluconazole, since such strains were exposed to this antifungal during treatment. The analysis of microsatellites by a multiplex PCR strategy was found to be a highly efficient tool for the rapid and accurate differentiation of C. albicans strains and adequate for the identification of fine microevolutionary events that could be related to strain microevolution in response to environmental stress conditions.