Formulation of rate-modulating pellets for the release of ibuprofen: an extrusion-spheronization process

Purpose: To develop a stable and reproducible modified release pellet formulation containing ibuprofen.Methods: Using extrusion-spheronization technology to produce pellets.Results: The percentage yield, size distribution and overall pellet shape within the desired size range of 1000-1400 microm was found to be dependent on various process variables. These include extrusion and spheronization speed, spheronization time and composition of the granulation fluid. Formulation factors such as viscosity grade of hydroxypropylmethylcellulose and concentration of microcrystalline cellulose were shown to influence the drug release rate of the pellets. In vitro dissolution studies revealed that the pellets behaved in a pH-dependent manner. Pellets exposed to different drying techniques exhibited an increase in drug release rate in the order corresponding to oven-dried, vacuum-dried, fluid bed-dried and freeze-dried pellets. In conjunction with scanning electron microscopy, kinetic modelling and statistical treatment of dissolution data, it was confirmed that the predominant release rate-controlling mechanism was diffusion, as evidenced from the power law expressions incorporating Fickian and relaxational parameters (M(t) /M(infinity) = K(1)t(n); M(t) /M(infinity) = K(1)t(2n)). Matrix swelling and erosion were not significant factors in modulating the drug release rate.Conclusions: The pH-dependent property of the pellets may be strategically employed towards development of a site-specific drug delivery system for non-steroidal anti-inflammatory agents. In general, targeting the delivery of an agent with potential for gastric irritation to the proximal intestine/colon may effectively reduce its ulcerogenic effect and ultimately contribute towards improved patient compliance.     

Switch movements and the myosin crossbridge stroke

The myosin II motor from Dictyostelium discoideum has been engineered to contain single tryptophan residues at strategic locations to probe movements of switch 1 and switch 2. The tryptophan residue at W501 probes movement of the relay helix and indirectly reports on switch 2 movement. This probe suggests that there is an equilibrium between the switch 2 open- and closed-states when the γ-phosphate position is occupied. Actin does not appear to greatly affect this equilibrium directly, but has indirect influence via switch 1. The latter region has been probed by introducing tryptophan residues at positions 239 and 242. The kinetics of the actomyosin ATPase in solution is discussed with respect to recent crossbridge models based on high-resolution crystal structures. To whom correspondence should be addressed: Tel.: +44-(0)-116-229-7048; Fax: +44-(0)-116-229-7018; E-mail: crb5@le.ac.uk     

Immune privilege induced by cotransplantation of islet and allogeneic testicular cells

Objective To induce islet allograft long- term survival through cotransplantation of islet cells with sertoli cells. Methods Testicular sertoli cells were prepared by digestion with collagenase, trypsin an d DNase, and were cultured for 48 hours. Collagenase digested and Ficoll purifi ed donor (Wistar rat) islets were cotransplanted with allogeneic sertoli cells i n the absence of systemic immunosuppression. Terminal deoxynucleotidyl transfer ase- mediated X- dUTP nick- end labeling (TUNEL) was used to label apoptosis of lymphocytes surrounding the islet graft. Results Cotransplantation of islets and 1×10(7) sertoli cells reversed the diabetic sta te for more than 60 days in 100% (6/6) of the chemically diabetic Sprague Dawley rats. Grafts consisting of islets alone or islets plus 1×10(5) sertoli cells survived only for 5-6 days. Apoptosis of lymphocytes surrounding the islets was quite clear. Conclusion Cotransplantation of islets with FasL［+］ sertoli cells induces local immune priv ilege and allows long- term graft survival without systemic immunosuppression.     

Prevalence of osteoporosis and incidence of hip fracture in women - secular trends over 30 years

Background  

The number of hip fractures during recent decades has been reported to be increasing, partly because of an increasing proportion of elderly women in the society. However, whether changes in hip fracture annual incidence in women are attributable to secular changes in the prevalence of osteoporosis is unclear.     

Anthropometric and Dietary Evaluations in a Sample of “Healthy” Mexican Older Adults

The purpose of this study was to describe anthropometric, metabolic, and nutritional characteristics in healthy elderly adults in a primary health care setting. It was conducted through a cross-sectional study of 80 subjects 60 years of age and older. After confirming healthy status, clinical, biochemical, dietetic, and anthropometric evaluations were performed. The findings indicated 22% had anemia, 22% had impaired glucose tolerance, 46% had hypertriglyceridemia, and 51% had hypercholesterolemia. More than 50% had obesity, and almost 80% had a high risk waist circumference measure. Mean energy intake was normal; however, more than 50% of participants did not have adequate intakes of potassium, calcium, magnesium, zinc, folic acid, and vitamins B₁₂ and A. Inadequate food intakes were common. Specific examples are that 16% of the subjects ate no meat/egg, 31% ate no dairy products, 56% ate no legumes, 22% ate no fruits, and 41% ate no vegetables. Additionally, 31% consumed soft drinks. Therefore, we can conclude that elderly people otherwise considered as “healthy” nonetheless had a high proportion of obesity and cardiovascular risk factors. Inadequate dietary patterns were also observed and corresponded with poor micronutrient intake.     

Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy

BACKGROUND & AIMS: Error catastrophe from an increase in mutation rate may be a possible mechanism of action of ribavirin in chronic hepatitis C (CHC). We sought to evaluate the mutagenic potential of ribavirin in vivo and to determine if conserved regions of hepatitis C virus (HCV) NS5B are mutated during ribavirin therapy. METHODS: Thirty-one patients with CHC genotype 1 who participated in a randomized, placebo-controlled trial of ribavirin for 48 weeks were studied. After 48 weeks, patients on placebo were crossed-over to open-label ribavirin for 48 weeks. Viral RNA was extracted from paired, stored sera at day 0 and week 24 during the randomized phase and weeks 48, 52, and 72 during the cross-over phase. The entire NS5B region was sequenced and the mutation rates were calculated. RESULTS: An increase in mutation rate was observed after 4 weeks (4.4 x 10(-2) vs 2.1 x 10(-3) per site/y, P = .02) but not after 24 weeks (4.0 x 10(-3) vs. 5.5 x 10(-3) per site/y, P = .1) in patients who crossed over to ribavirin. Similarly, during the randomized phase no increase in the number of mutations or the mutation rate was observed at week 24 between the ribavirin- and placebo-treated patients 6.6 vs 4.3 x 10(-3) per site/y, respectively (P = .4). No mutations were observed in conserved regions of NS5B. CONCLUSIONS: Ribavirin therapy is associated with an early, transient increase in the mutation rate of HCV. Lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for CHC.     

The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis

A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 +/- 13 to 70 +/- 39 IU/l), decrease in adiponectin (from 9.7 +/- 9.1 to 5.1 +/- 4.5 microg/ml), worsening insulin sensitivity (HOMA Index: from 2.9 +/- 1.8 to 5.5 +/- 5.4), and increase in total hepatic fat (from 30% +/- 32% to 71% +/- 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 +/- 0.7 to 2.9 +/- 1.1) and steatosis (from 0.9 +/- 0.6 to 2.1 +/- 1.3) but no change in fibrosis (from 1.1 +/- 1.2 to 1.2 +/- 1.3). NASH was again present on liver biopsy in 7 patients. CONCLUSION: These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects.     

2型糖尿病患者强化降糖治疗的效果和预测指标

为观察2型糖尿病患者强化降糖治疗的预测指标,强化降糖对糖化血红蛋白（HbA1c）、体重、焦虑／抑郁症状、健康状况的影响,以及强化降糖使HbA1c得到改善的患者的特点,研究者收集来自TRIAD（Translating Research into Action for Diabetes）的数据并分析,对起初采用饮食、运动、口服降糖药治疗、HbA1c〉7．2％、持续治疗或强化治疗（开始或增加口服降糖药种类或开始胰岛素治疗）超过18个月的患者进行检查。     

葛根素对小鼠实验性微循环障碍的改善作用

本文报告了葛根素对肾上腺素(Adr)引起的小鼠肠系膜微循环障碍的影响,并与罂粟碱作比较。结果表明,预先局部滴注0.5%葛根素能够拮抗Adr所致微动脉收缩、流速减慢和流量减少;而局部先滴注Adr造成微循环障碍后,再局部滴注1%葛根素,获得与上类似结果。给小鼠ⅳ葛根素(52 mg/kg)后再局部滴注Adr,可减轻Adr引起的微动脉收缩、流速减慢和流量减少,其作用优于罂粟碱。因此葛根素可改善实验性微循环障碍。