Pharmacokinetics of phenprobamate after oral administration to healthy subjects

Phenprobamate (CAS 673-31-4) is a centrally acting skeletal-muscle relaxant agent. There are only two studies in the literature about the pharmacokinetics of phenoprobamate in man. The inconsistency between the results of these studies can be attributed partly to the different analytical methodologies used. A sensitive, specific and reproducible HPLC-assay, which may increase the reliability of the pharmacokinetic studies of phenprobamate in plasma, has been developed recently. The objective of this investigation was to assess the single-dose kinetics of phenprobamate in human and to determine the pharmacokinetic parameters of clinical and regulatory concern. The plasma pharmacokinetics of phenprobamate have been investigated following single oral administration at a dose of 800 mg in eleven healthy volunteers.     

Ex vivo generation of functional dendritic cells from mobilized CD34+ hematopoietic stem cells

Gene engineering to enhance tumour immunogenicity and elicit curative responses against established tumours and tumour recurrences has become an attractive prospect. Gene engineering enables new genes to be selectively inserted into the genome of a tumour cell, or the construction of new fusion plasmids coding tumour antigens and immunomodulatory molecules. The rationale behind current research is to enhance the immune recognition of tumour antigens through their association with the molecules on which immune recognition depends. The immunotherapy data obtained in many experimental tumour systems provide a realistic assessment of the potential and limits of this technological approach. Experimental vaccination of rodents has been shown to induce a significant immune memory, even against poorly immunogenic tumours, that can prevent tumour growth and cure initial metastases, but is poorly effective against established tumours. Its use in tumour prevention is a fresh dawning perspective.     

Causes of ear trauma in Kenyan patients

Ear trauma is one of the most important epidemiological factors in causation of deafness. The causation of otologic trauma in eighty three patients is analysed. The triad of pain, hearing loss and tinnitus comprised the most frequent presenting complaints. Physical assault was the most common causation in 49.4% of the cases, road traffic accidents in 19.3% and self-inflicted injury in 15.6%. Law enforcement agencies constituted the most prominent factor in assault cases. Iatrogenic trauma was confined to 13.3% who were all below ten years of age. Road traffic accidents and violence from law enforcers were significant contributors to severe otologic damage as defined by dead ears and cerebrospinal otorrhoea.     

Has risk associated with smoking increased? Results from the Copenhagen Center for Prospective Population Studies

BACKGROUND: Two recent much cited publications have raised the concern that risk associated with cigarette smoking has so far been underestimated. In this study we wish to determine whether excess all-cause mortality associated with smoking has increased during the last 20-30 years in a study population representative of the general Danish population and whether any such changes relate to changes in smoking behaviour. METHODS: Pooled data from three prospective population studies conducted in Copenhagen with detailed information on smoking habits. A total of 31,194 subjects, 17,669 males and 13,525 females, initially examined between 1964 and 1992 with examinations repeated at intervals from 1-10 years, were followed until 1995 for all-cause mortality. Relative mortality risk in smokers versus never-smokers was calculated within periods of five calendar years and compared throughout the study period. RESULTS: Male smokers' exposure did not change during the study period whereas female smokers' exposure to tobacco increased in terms of age at smoking onset, quantity smoked and depth of inhalation. During follow-up 5744 males and 2900 females died. In males, death rate ratios (comparing continuous smokers with never-smokers) did not change in the study period. In females, ratios increased from 1964-1978 to 1979-1994 by a factor of 1.3 (95% confidence interval 1.0-1.8). CONCLUSIONS: In agreement with the observed changes in smoking habits, excess mortality in male smokers did not increase whereas excess mortality in female smokers increased slightly.     

In vitro maintenance of Schistosoma japonicum and surgical transfer from donor to na?ve recipient pigs

The insulin receptor (IR) is a membrane-bound glycoprotein composed of alpha and beta subunits derived from a common precursor. This processing is observed for both subtypes A and B of the IR and its physiological importance is poorly understood. In order to investigate the functional consequences of the absence of IR precursor cleavage, using site-directed mutagenesis of the hIRB cDNA, we have produced two mutants replacing the sequence Arg-Lys-Arg-Arg by either His-Lys-His-Arg or Arg-Lys-Arg-Ser. These two mutants, stably expressed in CHO, were structurally and functionally characterized in comparison to the wild-type human IR. These mutations result in the production of uncleaved receptors which are expressed normally at the cell surface. These receptors bind insulin with a normal affinity and activate the tyrosine-kinase resulting in normal phosphorylation of the receptors. These uncleaved receptors can mediate both the metabolic and mitogenic effects of insulin. These results provide evidence for a fully functional uncleaved insulin receptor of the B subtype (exon 11 + ) in contrast to the uncleaved A subtype (exon 11 -) described in the literature, which shows a reduced affinity for insulin and cannot therefore correctly transduce the insulin signal.     

PDLLA microspheres containing steroids: spray-drying, o/w and w/o/w emulsifications as preparation methods

Sea urchins of the genus Arbacia (order Stirodonta) have discontinuous allopatric distributions ranging over thousands of kilometers. Mitochondrial DNA (mtDNA) sequences were used to reconstruct phylogenetic relationships of four Arbacia species and their geographic populations. There is little evidence of genetic structuring of populations within species, except in two cases at range extremes. The mtDNA sequence differentiation between species suggests that divergence occurred about 4-9 MYA. Gene sequences encoding the sperm protein bindin and its intron were obtained and compared with the mtDNA phylogeny. Sea urchins among the well-studied echinoid order Camarodonta, with degrees of mtDNA divergence similar to those of Arbacia species, are known to have remarkable variation in bindin. However, in Arbacia, little variation in deduced amino acid sequences of bindin was found, indicating that purifying selection acts on the protein. In contrast, bindin intron sequences showed much differentiation, including numerous insertion/deletions. Fertilization experiments performed between a divergent pair of Arbacia species from the Atlantic and Pacific Oceans revealed no evidence of blocks to gamete recognition. In Arbacia, fertilization specificities may have evolved relatively slowly as a result of extensive gene flow within species, greater functional constraint on the bindin polypeptide, or reduced selective pressure for species recognition in singly occurring species.     

Associations between skeletal muscle properties, physical fitness, physical activity and coronary heart disease risk factors in men

High physical fitness and physical activity are associated with favourable lipid levels, especially a high level of high density lipoprotein cholesterol (HDL-C). A person's skeletal muscle properties, metabolism and percentage of different muscle fibres (ST-%), which may modify coronary heart disease (CHD) risk factors, such as serum insulin, obesity and serum sex hormones may also influence his fitness level and leisure-time physical activity. We studied the associations of physical fitness, physical activity and ST-% with serum lipids and lipoproteins in 72 healthy men. Their parameters were compared with those of 20 men with defined CHD. Significant interrelationships between ST-%, fitness and leisure-time physical activity index (LTPAI) were observed. Multiple regression analysis showed that ST-%, fitness and leisure-time physical activity explained about 32% of the variation in HDL-C in the healthy men. In healthy men ST-% correlated positively with fitness (r(s) = 0.62, P < 0.001) and with LTPAI (r(s) = 0.62, P < 0.001). Fitness level also correlated significantly with LTPAI (r(s) = 0.81, P < 0.001). Serum insulin showed negative associations with ST-% (r(s) = -0.63, P < 0.001) and fitness (r(s) = -0.54, P < 0.001) and LTPAI (r(s) = -0.62, P < 0.001). Free fraction of testosterone correlated negatively with serum HDL-C level (r(s) = -0.34, P < 0.01), with fitness (r(s) = -0.41, P < 0.001) and with LTPAI (r(s) = -0.54, P < 0.001). In sedentary men with the lowest fitness and physical activity the mean of ST-% (45%) was similar to that in CHD patients (44%). However, ST-% in men in the highest tertile of physical activity and fitness (68%) was significantly higher than in CHD patients and in men in the lowest tertile of physical activity and fitness. Skeletal muscle enzyme activity in lipid metabolism was significantly lower in both CHD patients and in sedentary and low-fit men than that in fitter and physically active men. The present data imply that skeletal muscle properties are important determinants of risk profiles, such as physical activity, fitness and serum lipid and lipoprotein patterns. Although fitness is a graded, independent predictor of mortality from CHD, a relatively high fitness level is not enough. This was clearly observed in the clustering analysis, in which the healthy men, according to their ST-%, fitness, leisure-time physical activity and serum sex hormone binding globulin (SHBG), fell into three natural groups: (i) Inactive men with lowest ST-% (mean 42%), lowest fitness (10.7 METs) and lowest HDL-C (1.36 mm/l); (ii) Fit men with high ST-% (66%), high fitness (14.5 METs) and moderately high HDL-C (1.54 mol/l); (iii) Active men with high ST-% (66%), highest fitness (14.9 METs) and highest serum HDL (1.83 mmol/l). The results support the idea that both fitness and physical activity give further protection against CHD by modifying risk factors. Our findings also suggest that skeletal muscle properties should be considered in the studies which assess CHD risk factors and their modifications especially in the field of health-related fitness.