Effects of hydroxypropyl-beta-cyclodextrin on the chemical stability and the aqueous solubility of thalidomide enantiomers

The aim of this work was to study the effect of hydroxypropyl-beta-cyclodextrin on the solubility and stability of thalidomide enantiomers in aqueous solutions for clinical oral administration to be used in HIV-infected children. For this reason racemic thalidomide was added to solutions containing different concentrations of hydroxypropyl-beta-cyclodextrin. True complexes were obtained by using hydroxypropyl-beta-cyclodextrin and the solubility of both thalidomide enantiomers was increased directly depending on the amount of hydroxylpropyl-beta-cyclodextrin in the medium although no enantioselective differences were observed at 37 degrees C. The chemical stability of thalidomide enantiomers is clearly improved by hydroxypropyl-beta-cyclodextrin. No enantioselective degradation of thalidomide was observed in sodium chloride solution (0.9%) samples stored at 6 degrees C for nine days when hydroxypropyl-beta-cyclodextrin was employed as excipient. Therefore a thalidomide solution suitable for oral administration can be prepared by adding hydroxypropyl-beta-cyclodextrin at 10% (w/v).     

Association of Moderate Consumption of Alcohol With Rates of Heavy Drinking and Abstinence in Spain

BACKGROUND: Moderate consumption of alcohol reduces general mortality among middle-aged and elderly persons through a reduction in cardiovascular risk. Furthermore, higher consumption of wine is associated with lower cardiovascular mortality in northern Spain. This information may be used to promote moderate consumption of alcoholic beverages in Spain. However, alcohol consumption is influenced by the drinking habits of the individual's social environment. Therefore, we examine the relation between average consumption of alcohol and the prevalence of heavy drinkers, who most often have adverse effects from alcohol, and the prevalence of abstainers, who do not benefit from alcohol, in Spain. METHODS: Spain's 17 administrative regions are the units of analysis. Alcohol consumption data were taken from the 1993 National Health Survey. Data were analyzed using weighted correlation coefficients and linear regression. RESULTS AND CONCLUSIONS: Mean alcohol consumption among moderate drinkers showed a positive correlation with the proportions of men (r = 0.63; p = 0.007) and women (r = 0.58; p = 0.015) whose alcohol intake was above the 90th percentile of consumption distribution. Similar results were yielded when median rather than mean consumption was used, and when heavy drinking was defined as the consumption of 210 g and 140 g of alcohol per week, in men and women, respectively. The association also was observed across all ages and all types of beverages. However, no statistically significant association was seen between mean and median alcohol consumption and the proportion of abstainers. SIGNIFICANCE: Moderate consumption of alcohol is associated with the prevalence of heavy drinkers in all regions of Spain. Therefore, promotion of moderate consumption of alcohol in Spain might be associated with a rise in the prevalence of heavy drinkers, those who most frequently suffer the harmful effects of alcohol.     

Expression of E-cadherin in 230 infiltrating ductal breast carcinoma

The immunohistochemical expression of E-cadherin (E-CD) was correlated to differentiation grade, tumor size, axillary lymph node metastasis, hormone receptor status and disease outcome in 230 infiltrating ductal breast carcinomas. E-CD expression was reduced in 116 tumors (50.4%). Reduced E-CD expression was more frequently found in high histological grade and progesterone receptor negative tumors. In contrast, preserved E-CD expression was more frequently observed in tumors with axillary lymph node metastasis, particularly in the group of patients with 1 to 3 positive lymph nodes. A weak association between reduced E-CD expression and shortened overall survival was found in univariate survival analysis, that was lost when the patients were adjusted for other pathological factors in multivariate analysis. These data indicate that E-CD may be considered a differentiation marker in ductal carcinomas of non special type. However, the relationship between E-CD expression and lymph node metastasis and disease outcome remains to be established.     

Training effects on intelligence of older persons

In the present study, we tried to answer two main questions: (1) do the elderly of low educational level improve their performance in ability tests when they are trained in inductive reasoning, spatial orientation, or everyday problem solving? (2) If such training were effective, what will the level of training transfer be? Ninety elderly participated in this study (36 women, 54 men; mean age = 67.87); 93.2% of them had less than 4 years of education. The study was based on an experimental-control group design with three main parts: pre-test, cognitive training (three training conditions - Inductive Reasoning, Spatial Orientation and Everyday Problem Solving vs. placebo control) and two post-tests with 3 months of interval. The results indicate that the elderly of low educational level improve their performance both in the domain and transfer test in two of the three training conditions: inductive reasoning and spatial orientation. Results are discussed in relation to other topics related to research studies.     

Treatment of idiopathic membranous nephropathy with the combination of steroids, tacrolimus and mycophenolate mofetil: results of a pilot study.

BACKGROUND: Membranous nephropathy is a common cause of nephrotic syndrome (NS) in adults. Its treatment is still under debate. METHODS: We report our experience in a pilot study using initially low doses of steroids and tacrolimus (Tac). After 3 months of treatment, mycophenolate mofetil (MMF) was added if the proteinuria was higher than 1 g/day. RESULTS: In accordance with this standard, 21 patients entered the study. A proteinuria level lower than 1 g/day was reached at month 3 of therapy with steroids and Tac in 11 patients. These patients continued this treatment for 12 months. MMF was added in nine cases after the third month and triple therapy was maintained for 12 more months. Two patients were withdrawn because of side effects. At the end of the treatment, remission of the NS was present in 15 out of all the patients (71.4%). Remission of the NS was complete in eight (53.3%) patients and partial in seven (46.7%) others. The remaining four patients did not respond. There were no significant changes in renal function. At a mean time of 23.1 months after treatment was discontinued, 11 (73.3%) patients had relapsed. CONCLUSIONS: In this trial, treatment with tacrolimus showed a good efficacy but a high relapse rate when it was discontinued.     

Physiological consequences of prolonged periods of flow limitation in patients with sleep apnea hypopnea syndrome

Flow limitation during sleep occurs when the rise in esophageal pressure is not accompanied by a flow increase which results in a non-rounded inspiratory flow shape. Short periods of flow limitation ending in an arousal or in a fall in SaO2 (hypopnea or upper airway resistance syndrome) are detrimental but the role of prolonged periods of flow limitation (PPFL) has not yet been clarified. This is important not only for diagnosis but also for nasal continuous positive airway pressure (CPAP) titration, especially for the automatic devices that need to be setup. The aim of this study was to analyze the effects of PPFL. We compared the behavior of the mean end-expiratory systemic blood pressure (SBP), end-tidal CO2, esophageal pressure and the pattern of breathing during a period of normal breathing at optimal (CPAP) and during PPFL at suboptimal CPAP in 14 patients with sleep apnea/hypopnea syndrome during a full polysomnography CPAP titration. The mean values of the parameters studied, at optimal and suboptimal CPAP were (1) SBP 92+/-13 vs. 91+/-15 mmHg (P: ns). At suboptimal CPAP, swings of blood pressure were associated with changes in pleural pressure; (2) SaO2 97.5+/-1.2 vs. 96.5+/-1.6 (P: 0.03), (3) end-tidal CO2 43.5+/-4 vs. 49.5+/-4 (P:0.001); (4) oesophageal pressure, 10.5+/-4 vs. 37.6+/-15 cmH2O (P:0.001) and (5) pattern of breathing: minute ventilation 6.6+/-1.4 vs. 6.1+/-1.2L/min (P: ns) and inspiratory time 1.24+/-0.3 vs. 1.66+/-0.4s (P:0.001). It can be concluded that PPFL induces significant physiological changes. Nevertheless, given the scant literature, clinical studies are warranted to elucidate the clinical role of these physiological changes.     

Tratamientos reparadores de la proteína CFTR en la fibrosis quística

Cystic fibrosis is a single gene, autosomal recessive disorder, in which more than 1,900 mutations grouped into 6 classes have been described. It is an example a disease that could be well placed to benefit from personalised medicine. There are currently 2 very different approaches that aim to correct the basic defect: gene therapy, aimed at correcting the genetic alteration, and therapy aimed at correcting the defect in the CFTR protein. The latter is beginning to show promising results, with several molecules under development. Ataluren (PTC124) is a molecule designed to make the ribosomes become less sensitive to the premature stop codons responsible for class i mutations. Lumacaftor (VX-809) is a CFTR corrector directed at class ii mutations, among which Phe508del is the most frequent, with encouraging results. Ivacaftor (VX-770) is a potentiator, the only one marketed to date, which has shown good efficacy for the class iii mutation Gly551Asp in children over the age of 6 and adults. These drugs, or a combination of them, are currently undergoing various clinical trials for other less common genetic mutations. In the last 5 years, CFTR has been designated as a therapeutic target. Ivacaftor is the first drug to treat the basic defect in cystic fibrosis, but only provides a response in a small number of patients. New drugs capable of restoring the CFTR protein damaged by the most common mutations are required.     

The association between mortality from ischaemic heart disease and mortality from leading chronic diseases.

AIMS: Coronary risk factors raise the risk of other chronic disorders. We therefore tested the hypothesis that the geographic distribution of ischaemic heart disease mortality is associated with that of other chronic diseases with which it shares risk factors. METHODS AND RESULTS: For the 50 provinces of Spain, we collected mortality data for the period 1980-1995 from the national vital statistics. We calculated age-adjusted mortality rates for the leading causes of death in quintiles of provincial distribution of ischaemic heart disease mortality, and correlation coefficients with respect to provincial ischaemic heart disease mortality. As expected, because they share risk factors with ischaemic heart disease, mortality from cerebrovascular disease, malignant tumours, lung cancer, respiratory diseases, chronic obstructive pulmonary disease, diseases of the digestive system, cirrhosis of the liver and all causes, increase with the rise from lower to higher quintiles of ischaemic heart disease mortality. Ischaemic heart disease mortality registered correlations over 0.5 (P<0.001) with mortality from many of the above diseases in the periods 1980-1984 and 1991-1995. Expectations were similarly borne out for disorders not sharing risk factors with ischaemic heart disease, in that mortality from prostate and breast cancer, injury and poisoning, traffic accidents and ill-defined causes in most cases did not show a provincial association with ischaemic heart disease mortality. In general, these results were observed for both sexes and across all age groups. CONCLUSION: Ischaemic heart disease mortality is associated with mortality from chronic diseases which share coronary risk factors, across provinces of Spain over the period 1980-1995. This suggests that the geographic variation in such chronic diseases is due to common factors, potentially susceptible to similar preventive interventions.