Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole Derivatives

Cellular chaperones that belong to the heat-shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2-amine structure show inhibition of HCV replication and binding to Hsp90, a series of twelve novel compounds based on this scaffold was designed and synthesized. The aim was improved Hsp90 affinity and anti-HCV activity. Through structural optimization, improved binding to Hsp90 and specific HCV inhibition in genotype 1b and 2a replicon models was achieved for three compounds belonging to the newly synthesized series. Furthermore, these compounds efficiently inhibited replication of full-length HCV genotype 2a in a reporter virus RNA assay with IC₅₀ values ranging from 0.03 to 0.6 μm .     

Substance use and social,health and safety-related factors among fatally injured drivers

Objective

The aim of this study was to examine different socio-demographic, health and safety-related factors, and psychoactive substance use among fatally injured drivers in road traffic accidents in Finland during 2006–2008.

Methods

An accident information register maintained by the Traffic Safety Committee of Insurance Companies (VALT) of the Finnish Motor Insurers’ Centre was used as basic data, and the basic data were complemented with further toxicological analytical information retrieved from autopsy reports from the Department of Forensic Medicine, Helsinki University. The data included all the drivers (n = 556) who were driving a motor vehicle and who died in a road traffic accident in Finland during 2006–2008.

Results

Of all the 556 fatally injured drivers 43% (n = 238) had psychoactive substance findings. 51% (n = 121) of substance positive drivers had a finding for alcohol only, the rest had a finding for one or more illicit/medicinal drugs impairing driving ability, and possibly also alcohol. Fatally injured drivers with alcohol findings were significantly younger (mean age 34 years) than sober drivers (mean age 44 years) or drivers with findings for drugs (mean age 45 years). Socio-demographic background did not differ substantially among drunken/drugged and sober drivers, although drivers with alcohol findings had a slightly lower education and socioeconomic position. Previous substance abuse problems were highly prevalent among drivers with substance findings and mental or both mental and physical health problems were more common among drivers with drug findings. The non-use of safety equipment and driving at a high speed were more common among fatally injured drivers with substance findings.

Conclusions

Substance abuse and mental health problems, as well as reckless driving behavior were more pronounced among fatally injured drivers with substance findings when compared to sober drivers. Thus, prevention and early intervention concerning substance abuse, mental health problems and DUI are essential. Improved traffic safety cannot be achieved by means of traffic policy only, but integration with other policies, such as health and social policy should be strengthened.     

Objectively measured tobacco exposure during pregnancy: neonatal effects and relation to maternal smoking

OBJECTIVES: To measure quantitatively and objectively the maternal and fetal tobacco exposure during pregnancy and its neonatal effects. DESIGN: Tobacco exposure was assessed from maternal serum samples, obtained during the first half of pregnancy and from umbilical serum samples obtained at delivery, by measuring the concentration of nicotine metabolite, cotinine. Data on the respective pregnancies and neonates were collected from the Finnish Medical Birth Registry. SETTING: Finland. SUBJECTS: One thousand two hundred and thirty-seven pregnancies and newborns, representing all pregnancies resulting in a liveborn infant during one week in one country. MAIN OUTCOME MEASURES: Gestational age, birthweight and crown-heel length of newborns. RESULTS: Cotinine (> 6 micrograms/l) was detected in either maternal or umbilical serum in 300 pregnancies, and these mothers and newborns were classified as exposed. Important differences occurred between measured exposure and reported smoking behaviour. Of the exposed mothers, 38% were nonsmokers and 3.4% of the nonexposed mothers were smokers. Tobacco exposure was associated with shorter gestational age, reduced birthweight and shorter crown-heel length of the newborns. After correction for parity, gender, and gestational age, the exposed newborns were on average 188 g (95% confidence interval (CI) 123-253 g) lighter and 10 mm (95% CI 7-13 mm) shorter than the nonexposed newborns. One micrograms/ml of cotinine in maternal serum resulted in a mean decrease of 1.29 g (95% CI 0.55-2.02 g) in birthweight and in a mean decrease of 0.059 mm (95% CI 0.035-0.083 mm) in birth length. Maternal cotinine concentrations better explained the neonatal findings than the reported smoking habits. CONCLUSIONS: There is a quantitative dose and effect relation between tobacco exposure and a decrease in the gestational age at birth and size of the neonate. The smoking habit reported by mothers themselves is not an accurate measure of fetal tobacco exposure.     

Random and systematic errors in case–control studies calculating the injury risk of driving under the influence of psychoactive substances

Between 2006 and 2010, six population based case–control studies were conducted as part of the European research-project DRUID (DRiving Under the Influence of Drugs, alcohol and medicines). The aim of these case–control studies was to calculate odds ratios indicating the relative risk of serious injury in car crashes. The calculated odds ratios in these studies showed large variations, despite the use of uniform guidelines for the study designs. The main objective of the present article is to provide insight into the presence of random and systematic errors in the six DRUID case–control studies. Relevant information was gathered from the DRUID-reports for eleven indicators for errors. The results showed that differences between the odds ratios in the DRUID case–control studies may indeed be (partially) explained by random and systematic errors. Selection bias and errors due to small sample sizes and cell counts were the most frequently observed errors in the six DRUID case–control studies. Therefore, it is recommended that epidemiological studies that assess the risk of psychoactive substances in traffic pay specific attention to avoid these potential sources of random and systematic errors. The list of indicators that was identified in this study is useful both as guidance for systematic reviews and meta-analyses and for future epidemiological studies in the field of driving under the influence to minimize sources of errors already at the start of the study.     

Taurine infused intrastriatally elevates, but intranigrally decreases striatal extracellular dopamine concentration in anaesthetised rats

In the present study we infused taurine (50, 150 or 450 mM, 2 microliters/min for 4h) into the dorsal striatum or into the substantia nigra via microdialysis probe and estimated the extracellular concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the dorsal striatum of anaesthetised rats. Intrastriatal infusion of taurine elevated striatal dopamine at all concentrations studied. At the 450 mM concentration taurine elevated the extracellular dopamine 10-fold, but only in the first 30 min sample after starting the taurine infusion. At 50 and 150 mM taurine elevated dopamine throughout the 4h infusion maximally up to 3-4-fold the control level. Extracellular DOPAC was increased by 150 and 450 mM taurine (up to about 150-160% of the control level), whereas at all three concentrations taurine decreased HVA to about 85% of the control; however, the decrease caused by 450 mM taurine was short-lasting. At all three concentrations taurine infused into the substantia nigra decreased the extracellular dopamine in the ipsilateral striatum to about 40-50% of the control, and increased extracellular DOPAC and HVA maximally to about 150% and 170% of the control, respectively. These results show that the effects of taurine on the concentrations of extracellular dopamine and its metabolites depend on its administration site on nigrostriatal dopaminergic neurons. It elevates the extracellular dopamine when given into the striatum, but when given into the cell body region of the nigrostriatal dopaminergic pathway it decreases the extracellular dopamine in the ipsilateral striatum.