Family-based association study of the 5-HT transporter gene and schizophrenia

The gene coding for the 5-HT transporter (5-HTT) is considered as a candidate gene for schizophrenia, because this transporter plays a key role in serotonin neurotransmission. Previous genetic studies focusing on this gene yielded conflicting results, presumably because of stratification biases linked to the case-control association study approach, and the potential genetic and phenotypic heterogeneity of schizophrenia. We investigated the 5-HTTLPR and 17-bp VNTR (variable number of tandem repeats) polymorphisms of this gene in 103 trios using the transmission disequilibrium test. No preferential transmission of either allele of the 17-bp VNTR was observed, but an excess of transmission of the L allele of the 5-HTTLPR polymorphism was detected (p = 0.03). As the haplotype analyses did not improve the strength of the association, our data provide convergent evidence for a significant role of the 5-HTTLPR promoter polymorphism of the 5-HTT gene in the vulnerability to schizophrenia.     

Preserved pharmacological activity of hepatocytes-treated extracts of valerian and St. John's wort

The two herbal extracts valerian (Valeriana officinalis L.) and St. John's wort (Hypericum perforatum L.) were studied for their metabolic changes upon incubation with freshly prepared rat hepatocytes and subsequently analysed phytochemically as well as pharmacologically in vitro. Quantitative HPLC analysis of valerian extracts revealed considerable metabolic activities with regard to sesquiterpenes and iridoids. The amount of acetoxyvalerenic acid decreased 9-fold, while that of hydroxyvalerenic acid correspondingly increased 9-fold due to O-deacetylation. The valepotriates didrovaltrate, isovaltrate and valtrate decreased 2-, 18- and 16-fold, respectively. However, the binding affinities of the incubated extracts to the benzodiazepine and picrotoxin binding site of the GABA (A) receptor were quite similar to those of the non-incubated extracts. Neither valerenic acids nor valepotriates exhibited any significant effect on the two binding sites when tested as single compounds. Therefore, either other constituents represent the active ones or multiple compounds are necessary for the observed inhibitory and allosteric effects at the GABA (A) receptor. Extracts of St. John's wort were less potently metabolised than valerian. The amount of pseudohypericin and the main flavonoids (hyperoside, rutin, isoquercitrin, quercitrin, quercetin and I3,II8-biapigenin) slightly decreased during the 4-h incubation period. Both the antagonist effect at the corticotropin-releasing factor (CRF) type 1 receptor and the binding inhibition at the 5-HT transporter were attenuated during the metabolic treatment. The reduced antagonist effect correlates with the decreasing amount of pseudohypericin known to be a CRF (1) receptor antagonist. In conclusion, the incubation of plant extracts with freshly prepared rat hepatocytes represents a useful approach to study the pharmacological action of metabolised plant extracts. The consistent pharmacological activity of both valerian and St. John's wort is concordant with the known clinical efficacy of pharmacological activities.     

The mineralogical and petrographical work of the pharmacists in the Museum

Three famous pharmacists were working in the Muséum national d'histoire naturelle in Paris, in the field of earth sciences: Louis Nicolas Vauquelin (1763-1829), André Laugier (1770-1832) and Alfred Lacroix (1863-1948). Vauquelin, professor of Chemical arts, established the chemical composition of numerous minerals, which led him to the discovery of new chemical elements. He also took a hand in demonstrating the extra-terrestrial origin of meteorites. Laugier, professor of General chemistry, was an admitted expert in the analytical field of these rocks. Lacroix, who held during more than forty years the chair of Mineralogy in the Museum, carried out major scientific work. This field working naturalist who was also famous vulcanologist placed his studies of the mineral species into a petrographical context. He described numerous new minerals, took an interest in their origin and classification of the volcanic rocks, as well as in contact metamorphism. In other respects, he increased the collections in the Museum (minerals, rocks, meteorites). The works of Vauquelin, Laugier and Lacroix contributed to advance those begun by some scientists of the Jardin du Roi, as Buffon or the Rouelle brothers before the French Revolution.     

AVP V1b selective antagonist SSR149415 blocks aggressive behaviors in hamsters

Arginine vasopressin (AVP) has been implicated in a variety of physiological and behavioral responses to stress. Synthesis of receptor-selective AVP agonist and antagonist compounds allows differential analysis of the specific roles of particular receptor subtypes with respect to these responses. Here, effects of the recently synthesized AVP V1b selective antagonist, SSR149415, were examined for offensive aggression in male Syrian hamsters, using a resident-intruder paradigm. Oral administration of vehicle or 1, 10, or 30 mg/kg of SSR149415 to resident hamsters was followed by evaluation of a range of aggression-related measures of residents confronted by intruders. The 10 and 30 mg/kg doses significantly reduced the duration of offensive sideways and chase behaviors, and the 30 mg/kg dose also reduced chase frequency. The 10 and 30 mg/kg dose also significantly reduced frequency and duration of olfactory investigation and duration of flank marking. These findings suggest a link between activity of the V1b receptor and the modulation of offensive aggression. These findings agree with previous research on V1b receptor effects in suggesting that antagonism of this receptor may be useful in modulating a range of emotional responses to highly stressful or threatening conditions.     

The utility of the population approach applied to bioequivalence in patients: comparison of 2 formulations of cyclosporine

Mixed-effect modeling was used to compare the population pharmacokinetics of 2 formulations of cyclosporine in patients. An open-label, multicenter, conversion study in stable, 6-month post-renal allograft recipients was conducted to compare the safety and pharmacokinetics of oral Pliva Cyclosporine Soft Gelatin Capsules (USP Modified) with Neoral (cyclosporine soft gelatin capsules, USP Modified) in stable post-renal transplant patients. Blood samples were collected predose and for 12 hours postdose on days 1, 14, 15, 28, and 29. Whole-blood samples were analyzed for cyclosporine using high-performance liquid chromatography and mass spectroscopy. Estimates of pharmacokinetic parameters were generated using noncompartmental and population compartmental pharmacokinetic analysis. Moreover, the effects of demographic factors on the pharmacokinetics of cyclosporine were evaluated using the nonlinear mixed-effects modeling program NONMEM. The rate and extent of bioavailability of cyclosporine did not differ between Pliva Cyclosporine Soft Gelatin Capsules and Neoral. In the final model, gender and actual body weight significantly affected the central and peripheral volumes of distribution. In addition, the pharmacokinetics of cyclosporine was defined robustly in this patient population using population pharmacokinetic approaches. Results indicate that the Pliva Cyclosporine Soft Gelatin Capsules and Neoral are bioequivalent when administered to renal transplant patients. Pliva Cyclosporine Soft Gelatin Capsules can then be substituted for Neoral in stabilized patients without anticipating dose adjustments.     

A phase I and pharmacokinetic study of VNP40101M,a new alkylating agent,in patients with advanced or metastatic cancer

Summary Purpose: VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion. Study design: The starting dose was 3 mg/m² every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m². Beyond 100 mg/m², dose increments were 25%. Initially, 1–2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related grade 2 adverse event, all dose levels required assessment of 3–6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose. Results: Twenty-six patients in 13 dose levels ranging from 3–305 mg/m² were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m², six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes. Conclusions: The MTD and recommended dose for phase II trials is 305 mg/m² every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.Supported by Vion Pharmaceuticals, Inc.     

Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years

BACKGROUND: An increasing incidence of oral carcinoma among young adults has been reported in the U.S. and Europe. Although the association between human papillomavirus infection and tonsillar carcinoma is now well established, to the authors' knowledge little is known about incidence trends in tonsillar carcinoma among younger adults. The objective of the current study was to explore the trends in both oral cavity and pharyngeal squamous cell carcinoma (SCC) in younger U.S. populations, in particular tongue and tonsillar SCC. METHODS: Using the 1973-2001 Surveillance, Epidemiology and End Results (SEER) database, we computed age, race, and site-specific trends of oral and pharyngeal (excluding nasopharynx) carcinoma incidence rates. The percent change (PC) and annual percent change (APC) were computed to explore trends in incidence rates over time. RESULTS: There were 2262 SCC of the oral cavity and 1251 SCC of the pharynx reported to the SEER program from 1973 to 2001 in adults aged 20-44 years. There was a statistically significant increase in the incidence of oral tongue SCC (APC = +2.1; P < 0.001), base of tongue SCC (APC = +1.7; P = 0.04), and palatine tonsil SCC (APC = +3.9; P < 0.001) among younger white individuals, whereas the incidence of SCC in all other oral and pharyngeal sites decreased or remained constant. CONCLUSIONS: The increase in tonsil SCC incidence from 1973 to 2001 paralleled the increase in tongue SCC, whereas SCC in all other oral and pharyngeal sites remained constant or decreased. This may suggest similar etiologic factors for SCC affecting the palatine tonsils and tongue in younger populations.     

Principles and practices of neurodevelopmental assessment in children: lessons learned from the Centers for Children's Environmental Health and Disease Prevention Research

Principles and practices of pediatric neurotoxicology are reviewed here with the purpose of guiding the design and execution of the planned National Children's Study. The developing human central nervous system is the target organ most vulnerable to environmental chemicals. An investigation of the effects of environmental exposures on child development is a complex endeavor that requires consideration of numerous critical factors pertinent to a study's concept, design, and execution. These include the timing of neurodevelopmental assessment, matters of biologic plausibility, site, child and population factors, data quality assurance and control, the selection of appropriate domains and measures of neurobehavior, and data safety and monitoring. Here we summarize instruments for the assessment of the neonate, infant, and child that are being employed in the Centers for Children's Environmental Health and Disease Prevention Research, sponsored by the National Institute of Environmental Health Sciences and the U.S. Environmental Protection Agency, discuss neural and neurobiologic measures of development, and consider the promises of gene-environment studies. The vulnerability of the human central nervous system to environmental chemicals has been well established, but the contribution these exposures may make to problems such as attention deficit disorder, conduct problems, pervasive developmental disorder, or autism spectrum disorder remain uncertain. Large-scale studies such as the National Children's Study may provide some important clues. The human neurodevelopmental phenotype will be most clearly represented in models that include environmental chemical exposures, the social milieu, and complex human genetic characteristics that we are just beginning to understand.     

The increasing burden of pelvic fractures in older people, New South Wales, Australia

Despite their significant health burden, epidemiological information regarding pelvic fractures is scarce. In this study, we examine trends in admission for pelvic fractures to acute hospitals in New South Wales, Australia, between July 1988 and June 2000, using routinely collected hospital separations statistics. Over this period, the number of admissions for pelvic fractures among those aged 50 years and over increased by 58.4% in men and 110.8% in women. Age-specific rates of admissions per 100,000 population for pelvic fracture also rose significantly, particularly for those aged at least 75 years. The number and proportion of transport related pelvic fractures fell significantly for both men (chi(2)=23.82, d.f.=1, p<0.001) and women (chi(2)=49.26, d.f.=1, p<0.001) while those resulting from falls increased significantly over the 12-year-period. Falls are increasingly becoming the single most important cause of pelvic injuries in older people, suggesting that preventive measures aimed at reducing the risk of falls need to be pursued. Factors contributing to the rise of fall-related pelvic fractures need to be investigated to inform strategies aimed at reversing the observed increase in the number and age-specific rates of pelvic fractures in older people.     

Thiopental produces immobility primarily by supraspinal actions in rats

The spinal cord mediates most of the immobilizing action of inhaled anesthetics. In the present study we investigated whether spinal or supraspinal sites mediate the immobilizing action of thiopental in rats. Thiopental was administered IV, intrathecally (IT), intracerebroventricularly (ICV), or simultaneously IT and ICV. Only the IV infusion produced anesthesia, defined as immobility in response to application of a tail clamp (i.e., the equivalent of minimum alveolar concentration, MAC). Consequently, the MAC-sparing effect (for isoflurane) of thiopental was used to assess the immobilizing contribution of IT and ICV infusions of thiopental. Thiopental concentrations were determined in whole brain, spinal cord, and a slice of cerebral cortex distant from the infusion sites. These concentrations were correlated with the MAC-sparing effect of the thiopental infusions in a multiple regression model. To assess the rate at which thiopental penetrates the cord, rat spinal cords were equilibrated in a bath of thiopental ex vivo and the concentration of thiopental in the cord was measured as a function of equilibration time. This was repeated in vivo with IT infusions of thiopental spanning the time of the behavioral studies. We found that IT or ICV infusion of thiopental 25 microg/min decreased isoflurane MAC <25%. The associated thiopental concentrations in the spinal cord after IT infusion, and in the whole brain after ICV infusion of 25 microg/min thiopental, exceeded by 500% and 680%, respectively, the concentrations found in the spinal cord and in the whole brain after IV infusion of thiopental in a dose that produced anesthesia in the absence of isoflurane. The percentage decrease in the MAC of isoflurane correlated primarily with the concentration of thiopental found in cerebral tissue not in contact with the cerebral ventricles. The spinal cord infusion produced an approximately 20% decrease in MAC. Ex vivo IT thiopental readily diffused into the spinal cord, with a time constant of approximately 1 h. We conclude that, unlike inhaled anesthetics, the immobilizing action of thiopental is largely supraspinal. Centers in the brain other than those near the third and fourth ventricles produce the greatest effect.