The impacts of nitrous oxide gas on sleep quality during alcohol withdrawal.

BACKGROUND: Poor quality of sleep among alcoholics and persons undergoing alcohol withdrawal has been described as a possible cause of alcohol relapse. It has been suggested earlier that nitrous oxide gas has a significant effect on the signs of alcohol withdrawal syndrome (AWS) and thus might be expected to reduce sleep disturbance during withdrawal. The aim of the present study was to investigate sleep quality during alcohol withdrawal, to evaluate the correlation between sleep quality and the severity of AWS and alcohol craving, and to determine if nitrous oxide treatment does counteract withdrawal's effects on the quality of sleep. Voluntary patients (n = 105) admitted to the A-Clinic detoxification center with AWS were included in the study. The AWS patients were randomly assigned to one of the following 45-minute gas treatments: (1) nitrous oxide/oxygen; (2) normal air/O2; and (3) medical (normal) air. The study was single-blind by design. Sleep quality was assessed after these treatments during the inpatient period; sleep time, sleep efficiency and the fragmentation of sleep were recorded by wrist-worn actigraphs. Severity of AWS was evaluated by the Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar) and that of alcohol dependence and craving by the Obsessive Compulsive Drinking Scale [OCDS] and the Severity of Alcohol Dependence Data (SADD) questionnaire. RESULTS: The fragmentation index and the time awake while in bed were both much above the reference values for the Finnish population. These values reflect the restless and disturbed night sleep of the subjects. The only statistically significant effects between the treatment groups were found in the correlations of CIWA-Ar (severity of AWS) scores, OCDS-scores (alcohol craving) and coffee consumption, all of which were positively associated with movement time and negatively with total sleep time and sleep efficiency. The sleep quality of patients treated with nitrous oxide gas did not differ from the sleep quality of those treated with normal air. CONCLUSIONS: The severity of AWS and coffee consumption had the most significant negative impact on sleep quality. According to our results, nitrous oxide gas does not differ from placebo in its effect on sleep quality during alcohol withdrawal.

Challenges with advanced therapy medicinal products and how to meet them.

Advanced therapy medicinal products (ATMPs), which include gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products, are at the cutting edge of innovation and offer a major hope for various diseases for which there are limited or no therapeutic options. They have therefore been subject to considerable interest and debate. Following the European regulation on ATMPs, a consolidated regulatory framework for these innovative medicines has recently been established. Central to this framework is the Committee for Advanced Therapies (CAT) at the European Medicines Agency (EMA), comprising a multidisciplinary scientific expert committee, representing all EU member states and European Free Trade Association countries, as well as patient and medical associations. In this article, the CAT discusses some of the typical issues raised by developers of ATMPs, and highlights the opportunities for such companies and research groups to approach the EMA and the CAT as a regulatory advisor during development.

Hemostatic gene polymorphisms in severe acute pancreatitis.

OBJECTIVE: Systemic inflammatory reaction in acute pancreatitis (AP) is associated with activation of the coagulation system. The prothrombotic component of the coagulation system, which may promote microvascular thrombosis and vital organ injury, is strengthened by genetic factors such as polymorphism of plasminogen activator inhibitor type 1 (PAI-1) and factor V Leiden (FVL) mutation. This prompted us to study the occurrence of FVL and PAI-1 4G/5G polymorphisms in patients with AP. METHODS: This case control association study included 397 patients with AP and 310 controls. Severe AP was determined according to the Atlanta Classification. Genotyping was performed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry-assisted genotyping method. RESULTS: Factor V Leiden was identified in 5 (3.3%) of 152 cases of severe AP and in 8 (3.3%) of 245 cases of mild AP. The prothrombotic PAI-1 4G allele frequency was 0.49 for patients with severe AP and 0.57 for patients with mild AP (P < 0.05). Patients with septic infectious complications (n = 47) and patients with organ failure (n = 55) had genotype distribution not different from those with mild, uncomplicated disease (n = 245). CONCLUSIONS: The results do not support the hypothesis that prothrombotic polymorphisms such as FVL mutation and PAI-1 4G/5G are associated with AP severity.

Polymorphisms of the TNF, CD14, and HSPA1B genes in patients with acute alcohol-induced pancreatitis.

OBJECTIVES: Genotype assessment has been suggested to be a tool for predicting disease severity in acute pancreatitis (AP). To study this hypothesis, we performed genotype analysis of tumor necrosis factor (TNF) -308 A/G, CD14 -159C/T, and HSPA1B +1267 A/G polymorphisms. METHODS: This is a case-control association study of 397 patients with AP (214 of whom had an alcohol-induced AP) and 300 controls. The control group comprised 218 subjects with detailed data of alcohol consumption, 70 of whom were heavy drinkers (daily alcohol intake >40 g), and 92 blood donors. The severity of AP was determined according to the Atlanta classification. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry-assisted genotyping method. RESULTS: Major allele frequency in TNF gene was 0.87 for patients with AP and 0.86 for controls. For CD14, the gene major allele frequency was 0.60 for patients and 0.63 for controls. For HSPA1B, the major allele frequencies were 0.52 for patients and 0.49 for controls, respectively. The allele frequencies did not differ significantly between AP patients with organ failure and those with mild disease, patients with alcohol-induced AP, or those with biliary AP. The patients with septic infectious complications (n = 47) had genotype distribution no different from those with mild, uncomplicated disease (n = 245). CONCLUSIONS: The TNF, CD14, and HSPA1B polymorphisms studied seem not to play a role in determining the severity of AP or the risk of alcohol-induced AP and thus do not serve as a tool for predicting disease severity.

Disialotransferrin, determined by capillary electrophoresis, is an accurate biomarker for alcoholic cause of acute pancreatitis.

OBJECTIVES: Serum disialotransferrin is a specific marker of heavy alcohol consumption. We tested its accuracy and probability in detecting alcoholic cause of acute pancreatitis (AP). METHODS: Blood samples from 271 consecutive AP patients, admitted to the Helsinki University Central Hospital emergency unit, were analyzed. RESULTS: The median (range) disialotransferrin value was significantly higher (P = 0.001) in AP patients with alcoholic (n = 172) 1.6% (0.3%-14.4) than with biliary (n = 60) 0.7% (0.3%-1.3%) or other causes (n = 39) 0.8% (0.3%-4.1%). In receiver operating curve analysis, disialotransferrin, as a single analyte, was significantly (P = 0.001-0.0001) more accurate (area under the curve [AUC], 0.88; 95% confidence interval [CI], 0.84-0.92) in detecting alcoholic AP as compared with glutamyl transferase (AUC, 0.51; 95% CI, 0.45-0.57), aspartate aminotransferase (AUC, 0.57; 95% CI, 0.51-0.63), alanine aminotransferase (AUC, 0.63; 95% CI, 0.57-0.69), erythrocyte mean cell volume (AUC, 0.72; 95% CI, 0.67-0.78), amylase (AUC, 0.74; 95% CI, 0.67-0.78), C-reactive protein (AUC, 0.65; 95% CI, 0.59-0.71), and bilirubin (AUC, 0.55; 95% CI, 0.49-0.62). At a disialotransferrin cutoff of 1.2%, giving an 8% false-positive rate, the positive likelihood ratio was 8.47. Thus, a positive disialotransferrin test result, performed within 24 hours of admission, increased the probability of alcoholic AP from pretest 64% to posttest 94%. CONCLUSIONS: Disialotransferrin, determined by capillary electrophoresis, is accurate, simple, and a rapid single biomarker of the alcoholic cause of AP.

Long-term effects of and physiological responses to nitrous oxide gas treatment during alcohol withdrawal: a double-blind, placebo-controlled trial.

BACKGROUND: Nitrous oxide gas (N2O) has been proposed to be effective in the treatment of the alcohol withdrawal syndrome (AWS). This has not been proved, however, in studies performed according to good clinical practice guidelines. Moreover, previous studies have not measured end tidal N2O concentrations or physiologic responses during N2O treatment. We have recently reported that in a double-blind, randomized, controlled setting, N2O was not superior to placebo in relieving AWS symptoms. In this previous study, we did not find significant differences between the treatments either in the Clinical Institute Withdrawal Assessment of Alcohol scores or in the total use of benzodiazepines (diazepam and temazepam). The aim of the present study was to characterize other effects and side effects of the N2O treatment using several objective measures and to study the possible long-term efficacy of the treatment. METHODS: A total of 105 inpatients who had AWS and were admitted to the A-Clinic detoxification center were included in the study. The subjects were randomly assigned to one of the following three treatments: (1) N2O/oxygen (from 30 to 70% in oxygen), (2) air/oxygen (30%/70%), and (3) medical (normal) air. During the single 45-min treatment period, end-tidal N2O, carbon dioxide, and oxygen concentrations were measured. The physiologic responses were studied by measuring heart rate, blood pressure, pulse oximetric saturation, frontal muscle electromyographic activity, and plethysmographic pulse amplitude. Long-term effects were studied by measuring craving with the Obsessive-Compulsive Drinking Scale; severity of dependency with Severity of Alcohol Dependence Data; and liver enzymes with aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase 3 and 6 months after the treatment. RESULTS: Patients in the N2O group demonstrated significantly higher facial muscle electromyographic activity and higher pulse amplitude than the air-treated subjects. Self-reported side effects between the gas treatments, however, did not differ between the groups. Regarding long-term effects of the treatments, there were no differences between the groups. CONCLUSIONS: Contrary to previously published data, N2O treatment did not decrease craving or liver enzymes during the 6-month follow-up. At the concentration used, N2O treatment produced signs of arousal instead of strong sedation.