Uptake and utilization of directly acting antiviral medications for hepatitis C infection in U.S. veterans.

New drugs therapies have revolutionized the treatment of hepatitis C virus (HCV) infection. The objectives of this study were to evaluate uptake and utilization of boceprevir and telaprevir in the Department of Veterans Affairs (VA). We evaluated whether therapies conformed to response-guided protocols, whether they replaced standard interferon plus ribavirin treatment, and whether IL-28B was used to guide treatment. We performed an administrative data-based analysis of all patients receiving pharmacologic treatment for HCV in VA from October 2009 to July 2013. There were 12 737 new HCV prescriptions in VA during this time, with 5564 boceprevir or telaprevir prescriptions (44%) and 7173 prescriptions (56%) written for standard interferon plus ribavirin treatment. Prescriptions for the new treatments heavily favoured boceprevir vs telaprevir (83% vs 17%). Sixty-two percent (62%) of boceprevir-treated patients completed their minimum-specified protocol, while 69.2% of telaprevir-treated patients completed their minimum-specified protocol. From October 2010 to July 2012, 4090 patients had an IL-28B test; less than 16% of these tests guided subsequent HCV prescriptions. Uptake of boceprevir and telaprevir was rapid; the number of patients initiating treatment approximately doubled in the period after their introduction. While new prescriptions favor boceprevir or telaprevir over standard interferon plus ribavirin therapy, there appears to still be a strong role of interferon plus ribavirin in treating HCV patients. This work can inform our understanding of how other new effective HCV therapies will be used, their diffusion, and the timing of their diffusion in actual clinical practice.

Chemical submission: results of 4-year French inquiry.

Psychoactive substances may be administered without the knowledge of a victim in order to induce incapacitation and thus facilitate criminal actions. The characteristics of the victims and the drugs used in such suspected chemical submissions (CS) were analyzed in 309 cases collected from October 2003 to December 2007 through a national survey. Out of 309 cases, 158 met all criteria of CS. The victims were mostly female (n = 89, 56%). The type of aggression was mostly sexual assault (in 79 cases 50%). Benzodiazepines and related drugs were detected in 129 victims (82%) and were mostly clonazepam, zolpidem, and bromazepam whereas flunitrazepam and gamma hydroxybutyrate, well known for their use in CS, were identified in 11 (7%) and five (3%) of the 158 victims. CS is not an anecdotal phenomenon in France. Information for health professionals and workers in forensic structures as well as education of the general population associated with preventive measures such as drug dosage form changes should contribute to improved care management of victims and decreased risk.

Platelet PMCA- and SERCA-type Ca2+ -ATPase expression in diabetes: a novel signature of abnormal megakaryocytopoiesis.

BACKGROUND: Previous studies have shown platelet Ca(2+) abnormalities in diabetes mellitus and some reports suggest abnormal platelet production. Platelet Ca(2+) homeostasis is controlled by a multi-Ca(2+)-ATPase system that includes two plasma membrane Ca(2+)-ATPase (PMCA) and seven sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) isoforms. In addition, we recently found that the expression of PMCA4b and SERCA3 isoforms may serve as new markers of abnormal megakaryocytopoiesis [Nurden P et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Blood 2006; 108: 2587-95]. AIM: To analyze the expression of major platelet Ca(2+)-ATPases in 27 patients with type 1 or type 2 diabetes (T1D or T2D) compared with normal donors. METHODS: Investigation of protein and mRNA expressions of PMCA1b and PMCA4b, and SERCA2b, SERCA3a and SERCA3b, using specific Western blotting and reverse transcriptase-polymerase chain reaction, respectively. RESULTS: Remarkably, all patients with T1D were found to present a higher expression of PMCA4b protein (212% +/- 28%; n = 10) and PMCA4b mRNA (155% +/- 16%; n = 17), coupled with a higher expression of SERCA3b mRNA (165% +/- 9%) in some cases. Patients with T2D (n = 10) were also studied for protein expression and were found to present similar major upregulation of the expression of PMCA4b protein (180% +/- 28%; n = 10). Lastly, five of 10 patients with T1D were studied for PMCA4b expression after insulin treatment, with four of five recovering normal expression (96% +/- 15%; n = 5). CONCLUSIONS: Compared with the expression of PMCA4b upon platelet maturation, platelets from diabetic patients exhibit similarities with immature megakaryocytes. Thus, this study reinforces the idea that abnormal megakaryocytopoiesis can provide additional insights into diabetes and could represent a novel therapeutic target for antithrombotic drugs.

Psychological stress and cortisol secretion in anhedonic alcoholic men.

We investigated plasma cortisol in a psychological stress paradigm in seven weaned anhedonic alcoholics in comparison with seven age-matched healthy controls. Alcoholics had significantly higher mean plasma cortisol at baseline and no increase following a psychological stress paradigm. Anhedonic alcoholics judged the experimental situation less agreeable than controls. Anhedonic alcoholics may have blunted cortisol response to psychological stress.

Memory one month after acute carbon monoxide intoxication: a prospective study.

BACKGROUND: Serious delayed neuropsychological sequelae may complicate carbon monoxide intoxication. The existence of minor manifestations, especially memory disturbances, is not well documented. AIMS: To study several memory functions after carbon monoxide intoxication. METHODS: In a prospective study, 32 poisoned patients without risk factors for cognitive disturbances were compared to 32 paired control subjects one month after acute carbon monoxide intoxication (blood carbon monoxide concentration at least 1.0 mmol/l), who had been treated with standard conventional therapy. Psychometric tests included Buschke's verbal memory testing, verbal digit span, Corsi's visuospatial span, reaction times, Stroop's colours decoding test, and verbal fluency test. RESULTS: (1) Memory functions in poisoned subjects were not worse than in the control group and were even better in some areas: learning, word recall, and quality of learning by Buschke's verbal memory testing. Attention was also better in the patients, in whom visual reaction time was shorter than in controls. (2) Results of several memory functions-quality of learning and immediate visual memory-were positively correlated with the initial carbon monoxide level. CONCLUSIONS: In a highly selected subset of patients devoid of risk factors for memory impairment, memory, objectively evaluated by psychometric testing, was not worse one month after carbon monoxide intoxication in patients undergoing standard treatment than in paired control subjects.

Cognitive functions in workers exposed to toluene: evaluation at least 48 hours after removal from exposure.

OBJECTIVES: Long-term exposure to toluene may result in subtle impairment of cognitive functions. However, it is not clear whether this impairment is due to the presence of the solvent in the body or if it persists after its elimination from blood. The aim of this study is to compare cognitive functions between toluene-exposed workers (at least 48 h after removal from exposure) and non-exposed workers. METHODS: Seventy-two workers exposed for at least 5 years to toluene (9 to 467 ppm) completed a questionnaire and psychometric tests. The results were compared with those of 61 non-exposed workers. An alveolar air sample was taken just before the tests to ensure the absence of toluene. RESULTS: Results of the vocabulary test were slightly better in exposed (correct words: 21 +/- 0.6) than in non-exposed workers (19 +/- 0.8) (P < 0.05). No differences were found for simple reaction time, digit symbol, digit span, continuous tracking test, color word and switching attention test. CONCLUSIONS: The results of this study do not support the notion of the persistence of cognitive effects of toluene after elimination of the solvent from blood.

[Non-accidental criminal poisonings]. / Empoisonnements criminels non médicamenteux.

Among the different types of chemical aggressions, murder is very rare. Most cases are less straight forward: "jokes", ill-wills, impulsive acts.... Pesticides, metals, household products and illicit drugs are most often in cause, in addition to self-defence sprays. Intoxication may be suspected by the victim, in which case paranoia should be eliminated. In other cases, unusual circumstances or symptoms are suspected by the physician. The toxicological analysis must be guided by the clinical context.

Anhedonia and relapse in alcoholism.

The aim of this study was to determine the role of anhedonia among other psychopathological dimensions in the relapse of alcoholics 6 months after withdrawal. Psychometric assessments included: the Social and Physical Anhedonia Scales, the Sensation Seeking Scale, the Pleasure-Displeasure Scale (including Fawcett-Clark's Pleasure Scale), the Depressive Mood Scale, the Thymasthenic Syndrome Rating Scale and the Comprehensive Psychopathological Rating Scale. Forty-four alcoholics participated in the study. The baseline values recorded during the second week of treatment showed that the more anhedonic the alcoholics were, the less they sought sensations. Type 2 alcoholics (Cloninger's classification) scored higher on the Thrill and Adventure Seeking Subscale. Relapsed alcoholics had higher baseline values on the Thrill and Adventure Seeking Subscale. This was in agreement with the step-wise discriminant analysis which showed that this subscale was the main variable that differentiated abstinent alcoholics from those who relapsed. Our results indicate that anhedonia does not predict relapse.

Impact of long-term ethanol consumption on CYP1A2 activity.

Ethanol is a well-known inducer of CYP2E1; whether or not it is an inducer of other cytochromes has not been investigated systematically. The aim of our study was to evaluate the impact of ethanol consumption on the activity of CYP1A2, which has been shown to be influenced by drugs (inhibited or induced). We evaluated CYP1A2 activity by the ratio of the molar urinary concentrations of the three end products of paraxanthine demethylation of caffeine to the molar concentration of a paraxanthine 8-hydroxylation product. This urinary metabolite ratio has previously been shown to correlate with caffeine clearance. The caffeine metabolites were measured in urine collected during the 3 hours after oral administration of 200 mg caffeine. The caffeine test was performed in 12 smokers (> 25 cigarettes/day) and 12 nonsmokers, all of whom were alcoholic inpatients (daily intake > 100 mg absolute ethanol), within the first 3 days of their hospital stay and after 14 days of abstinence from ethanol. In alcoholic patients who were smokers the molar urinary concentration ratio was 3.14 +/- 0.97 before withdrawal and 4.01 +/- 0.92 after 14 days of abstinence from ethanol. In contrast, in alcoholic patients who were nonsmokers it was 2.62 +/- 0.95 and 2.18 +/- 0.96 before and after withdrawal, respectively. In volunteers who were smokers the molar urinary concentration ratio was 5.02 +/- 1.51, whereas in volunteers who were nonsmokers it was 3.22 +/- 1.46. Our results confirm the well-known induction of CYP1A2 activity by tobacco smoking and show that this induction is masked by long-term ethanol consumption.

A comparative study between carbohydrate-deficient transferrin and gamma-glutamyltransferase for the diagnosis of excessive drinking in a liver unit.

AIM: To compare the efficacy of carbohydrate-deficient transferrin and gamma-glutamyltransferase for the diagnosis of excessive alcohol intake in patients admitted in a liver unit. METHODS: The 346 patients were divided into three groups of alcoholics: 57 patients (31 men, 26 women) with a normal liver, 77 patients (51 men, 26 women) with non-cirrhotic alcoholic liver disease, and 61 patients (43 men, 18 women) with alcoholic cirrhosis; and three groups of non-alcoholics: 35 abstainers (21 men, 14 women), and 58 healthy blood donors (26 men, 32 women), and 58 patients (32 men, 26 women) who had a non-alcoholic liver disease. Carbohydrate-deficient transferrin and gamma-glutamyltransferase were measured at admission using commercially available kits. RESULTS: Carbohydrate-deficient transferrin was more sensitive than gamma-glutamyltransferase in patients without alcoholic liver disease, in both men (85 vs 54%) and women (64 vs 36%). Carbohydrate-deficient transferrin sensitivity decreased slightly but not significantly according to the severity of the liver disease in men and women. The sensitivity of gamma-glutamyltransferase which was low in men and women without alcoholic liver disease, improved in groups with moderate or severe alcoholic liver disease: not less than 80% in men and up to 100% in women. The specificity of carbohydrate-deficient transferrin in patients with non-alcoholic liver disease was consistently higher than that of gamma-glutamyltransferase (80% vs 60%). CONCLUSIONS: In liver units, carbohydrate-deficient transferrin can help to identify excessive drinkers without liver disease with a higher efficacy than that of gamma-glutamyltransferase; carbohydrate-deficient transferrin can also be used to distinguish between alcoholics with moderate liver disease and patients with non-alcoholic liver diseases.

Alcohol consumption and visual contrast sensitivity.

Visual contrast sensitivity (VCS) was measured in 30 alcoholic patients and 52 controls. The results showed a significant reduction in VCS for all the spatial frequencies. The mean reduction for all spatial frequencies was 2.49 dB below the level of the control group. Optimal sensitivity corresponded to a lower spatial frequency in patients than controls, i.e. 1 cycle/degree (c/d) versus 2 c/d. Curves for VCS were normal for five patients. Abnormalities in VCS were suggestive of optic nerve dysfunction for 15 patients (50%), which were probable in seven cases (23%) and possible in eight others (27%). For 10 subjects, the abnormalities were indicative of ametropia. Daily alcohol intake and daily tobacco consumption were not significantly different in the patients who displayed VCS abnormalities, reflecting alcohol-tobacco amblyopia, from those who did not. The presence of higher gamma-glutamyl transpeptidase and mean corpuscular volume levels in patients who had VCS abnormalities indicative of alcohol-tobacco amblyopia suggests that alcohol consumption is involved in the development of these abnormalities.

Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics.

Chlorzoxazone is mainly metabolized to 6-hydroxychloroxazone (6-OHchlorzoxazone) by the ethanol-inducible cytochrome P450 2E1 (CYP2E1). To evaluate the impact of ethanol consumption on the enzyme induction, the pharmacokinetics of chlorozoxazone and 6-OHchlorzoxazone were studied in alcoholic and control subjects. Fifteen alcoholic male inpatients (all smokers, daily intake 333 +/- 191 g of absolute ethanol) and 20 healthy male volunteers (10 smokers and 10 non-smokers, weekly intake < 100 g of absolute ethanol) participated in this study. Following a 12 hr fasting period, each subject was orally administered 500 mg of chlorzoxazone. Venous blood and urine samples were collected over a 10 hr period. Areas under the curve of plasma concentration versus time (AUC) of chlorzoxazone and 6-OHchlorzoxazone was calculated. The total plasma clearance of chlorzoxazone was measured as the dose/AUC ratio. The mean total plasma clearance was not different between smoker and non-smoker controls but it was enhanced by 73% in alcoholic patients. These results indicate a negligible and non-significant effect of cigarette smoking in controls but an increased metabolism of chlorzoxazone in alcoholic patients (P < 0.05). This increase was corroborated by the 2-fold enhancement of the 6-OHchlorzoxazone/chlorzoxazone AUC ratio, compared to controls. A good correlation was found between this AUC ratio and the 6-OHchlorzoxazone/chlorzoxazone concentration ratio at t = 2 hr in patients and in controls (r = 0.88 and 0.85, respectively, P < 0.01). The concentration ratio increased by 150% in alcoholic patients and decreased by 65% in the seven alcoholics tested after 7 days of alcohol abstinence. It is therefore concluded that the 6-OHchlorzoxazone/chlorzoxazone concentration ratio at t = 2 hr could constitute a simple and non-traumatic marker of CYP2E1 induction.

Effects of occupational lead exposure on motor and somatosensory evoked potentials.

In order to objectivate the effects of inorganic lead compounds on the nervous system, 17 men occupationally exposed have been recorded for Motor Electric Potentials (MEPs) of the abductor policis brevis muscles with transcranial, cervical root and peripheral electrical stimulations, for Somatosensory Evoked Potentials (SEPs) of median and tibial posterior nerves, and for Electromyography (EMG). Considering each subject, 16 out of the 17 lead exposed ones exhibited electrophysiological abnormalities, occurring at both peripheral and central levels for the somatosensory as well as for the motor systems. As compared to a normal control group, the lead exposed one showed decreased sensory and motor peripheral conduction velocities, increased motor central conduction time, and delayed cortical P22 SEPs component that could be interpreted as a sensory-motor cortical dysfunction. The respective contributions of MEPs and SEPs are compared to clinical, biological and EMG examinations in the evaluation of the neurotoxic effects of inorganic lead compounds.

[Acute alcoholic intoxication and accidents]. / Alcoolisation aiguë et accidents.

Many studies have shown the role of alcohol intake, even in low quantities, as a risk factor in accidents, mainly road accidents, but also in accidents occurring in the home and at the workplace. For a blood alcohol level of 0.5 g per litre, the risk of accident is already two-fold. Accidents occur more often to persons who drink occasionally than to those who are alcohol-dependent. For a subject of average body weight, it is accepted that one glass of an alcohol-containing drink can raise the blood alcohol level by approximately 0.2 g per litre. One to two hours is required to eliminate this quantity of alcohol.

Evoked potentials in workers occupationally exposed to organic solvents.

Somatosensory, Brainstem Auditory and Pattern Reversal Evoked Potentials (SEPs, BAEPs, PREPs) are recorded in workers occupationally exposed to mixtures of organic solvents, in order to specify the levels of the nervous system affected by a long term exposure to solvents, and to analyze the effects of age and gender. The most significant differences are found for SEPs; they objectivate peripheral impairments magnifying the differential effects of age observed in the control subjects, and show the higher sensitivity of women. The central impairment is pointed out by the latency delay of P22 component mainly, whose age-related increase is amplified by solvent exposure.