Anti-circumsporozoite protein antibodies measure age related exposure to malaria in Kataragama, Sri Lanka

Antibodies to two peptides DDAAD and (NANP)40 representing the repetitive sequence of circumsporozoite antigens (CS protein) of P. vivax and P. falciparum respectively were measured in a cohort of 149 and 107 individuals respectively at four, 6 monthly blood surveys performed on residents of Kataragama, a P. vivax malaria endemic region in southern Sri Lanka. The prevalence of antibodies to the CS protein of both species was relatively low being less than 20% to either peptide in the population as a whole, this being consistent with the low entomological inoculation rates in the area. A marked age related prevalence pattern was evident, with the prevalence of antibodies increasing with age to reach between 25 to 30% in the 25-50 year age group in both P. vivax and P. falciparum. The population had had a life long exposure to P. vivax malaria but not to P. falciparum, an epidemic of which occurred in this region a few months prior to the beginning of this study. Nevertheless, the age-related prevalence of these antibodies was identical with respect to the two species. This suggests that the age-related prevalence pattern reflected differences in inoculation rates between the age groups due to differences in exposure to inoculation rather than an age acquired response resulting from a cumulative experience over several years. An analysis of antibody prevalence in individuals showed first, that sporozoite inoculations must have been clustered rather than homogeneously distributed in the population and secondly, that sero-conversion did not correlate with malaria infections in these individuals.     

Side reactions in solid phase synthesis of histidine-containing peptides

The flow-polyamide synthesis of a histidine-containing sequence (Ac-YDNVLDHLTGR) produced two major impurities which were isolated through Sample Displacement Chromatography and characterized by Fast Atom Bombardment-mass analysis. The impurities correspond to the sequence Ac-YDNVLDH, and to a peptide with the Asp residue cyclized to a succinimide. The latter side-reaction took place during the acetylation procedure, and demands attention where capping procedures are planned in the synthesis of Asp-His sequences.     

Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

1 To assess the effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics, plasma ethosuximide concentrations after a single oral dose (500  mg) of the drug were compared in 12 healthy control subjects and 10 epileptic patients receiving chronic therapy with phenobarbitone, phenytoin and/or carbamazepine.
2 Compared with controls, epileptic patients showed markedly shorter ethosuximide half-lives (29.0±7.8 vs 53.7±14.3  h, means±s.d., P< 0.001) and higher apparent oral clearance (CL/ F) values (15.3±3.8 vs 9.2±1.9  ml  kg⁻¹  h⁻¹, P< 0.001). The apparent volume of distribution ( V/F) of ethosuximide was slighty lower in the patients than in controls (0.6±0.1 vs 0.7±0.1  l  kg⁻¹, P< 0.05).
3 These findings provide evidence that ethosuximide elimination is increased by enzyme inducing anticonvulsants, the effect probably being mediated by stimulation of cytochrome CYP3A activity.
4 The enhancement of ethosuximide clearance in patients comedicated with enzyme inducing anticonvulsants is likely to be clinically relevant. Higher ethosuximide dosages will be required to achieve therapeutic drug concentrations in these patients.     

Dose—response effect of famotidine on patterns of gastro-oesophageal reflux

The present study attempts to assess the alteration in patterns of gastro-oesophageal reflux as assessed by 24-h oesophageal pH monitoring by varying degrees of H2-receptor blockade with famotidine. Subjects were 12 patients with complaints of daily heartburn who demonstrated at least 6% of acid mucosal contact time by 24-h ambulatory oesophageal pH monitoring. All subjects had a positive Bernstein test, and nine of the 12 subjects had erosive oesophagitis. The study was conducted as a double-blind crossover design utilizing 40 mg nocte, 20 mg b.d., and 40 mg b.d. and placebo treatments. Results indicated that all treatments significantly reduced the 24-h percentage acid contact time (P less than 0.05) compared to placebo. The two b.d. treatment regimens also significantly (P less than 0.05) reduced the number of episodes lasting longer than 5 min. Only the b.d. regimens successfully lowered the percentage of upright acid exposure. All treatments significantly (P less than 0.01) reduced the percentage of supine acid contact time, as well as the number of episodes lasting more than 5 min. It is concluded that gastro-oesophageal reflux disease may well require a b.d. dosing regimen with famotidine in order to achieve optimal mucosal healing and day time symptom control.     

Selection of Food Allotment for New Zealand White Rabbits in Developmental Toxicity Studies

Selection of Food Allotment for New Zealand White Rabbits inDevelopmental Toxicity Studies. CLARK, R. L., ANTONELLO, J.M., WENGER, J. D., DEYERLE-BROOKS, K., AND DUCHAI, D. M. (1991).Fundam. Appl. Toxicol. 17, 584–592. In three initial studies,female rabbits were fed 125, 150, or 230 g of Purina CertifiedRabbit Chow No. 5322 ("regular" chow) per day or 150 g/day ofPurina Certified High Fiber Rabbit Chow ("high fiber" chow)for at least 5 weeks prior to artificial insemination and untilDay 28 of gestation when fetuses were removed and examined.Animals allotted 230 g/day of regular chow ate approximately180 g/day and gained more weight than the 150 g/day group untilDay 14 of gestation after which food consumption declined andbody weight decreased. Animals fed 150 g/day regular chow ateall food provided until after Day 22 of gestation when foodconsumption decreased dramatically in some animals. Animalsin the 125 g/day regular chow and 150 g/day high fiber chowgroups ate essentially all food provided throughout gestation.Ad lib feeding in the 230 g/day groups was associated with adversereproductive consequences consisting of decreased numbers ofimplants and live fetuses and decreased fetal weight. In onestudy involving 3 groups fed 125 and 150 g/day regular chowand 150 g/day high fiber chow, reproductive parameters weresimilar in all 3 groups. However, fetal weight in the 150 g/dayregular chow group was 50% more variable than the other groupsin association with more variable maternal body weight changelate in gestation in that group. In subsequent studies using125 g/day, there has consistently been fewer animals going offfeed late in gestation and a decrease in fetal weight varianceof approximately 60% compared to previously when the standarddaily allotment was 150 g/day. These results establish thata daily allotment of 125 g regular chow is sufficient and preferableto 150 g/day regular chow for animals which are to be terminatedon Day 28 of gestation as in developmental toxicity studies.A diet of 150 g/day "high fiber" chow offered no advantage over125 g/day regular chow which itself has an adequately high fibercontent.     

Application of the Tukey Trend Test Procedure to Assess Developmental and Reproductive Toxicity: I. Measurement Data

Developmental and reproductive (DAR) toxicity studies typicallyinclude a series of increasing doses of a compound and a zerodose control. Given this framework, Tukey et al. (Biometrics,41, 295–;301, 1985) proposed a procedure (referred toas either the Tukey trend or TCH test procedure) for detectinga nonzero trend in response to increasing doses of the testcompound. The procedure considers three candidate dosage scalingsto ensure high power against relatively common dose-responsepatterns and appreciable power against most reasonable patterns.For toxicologic effects with near monotonic dose-response patterns,simulation studies have shown the TCH test to be overall morepowerful than pairwise comparison procedures. The TCH test canbe applied sequentially, eliminating the highest dose each timea statistically significant trend is observed, until a no-statistical-significance-of-trenddose is reached. This is the highest dose through which thereis no statistically trustworthy evidence of the compound's impacton the response. Since DAR toxicity usually exhibits a progressive(monotonic) dose-response, we advocate routine use of Tukey'strend test for the evaluation of treatment effects in thesestudies. In this article, we discuss the procedure in detailand apply it to fetal body weight, a continuous measurementvariable, from a developmental toxicity study.     

Clinical Experience with a Single Catheter for Mapping and Ablation of Pulmonary Vein Ostium

Introduction: The aim of this single center study is to evaluate the safety and the efficacy of performing pulmonary vein isolation (PVI) using a single high-density mesh ablator (HDMA) catheter.
Methods: A total of 17 consecutive patients with paroxysmal (10 patients) or persistent atrial fibrillation (7 patients) and no heart disease were enrolled. A single transseptal puncture was performed and the HDMA was placed at each PV ostium identified with anatomic and electrophysiological mapping. Pulsed radiofrequency (RF) energy was delivered at the targeted temperature of 58°C with maximum power of 80 watts. No other ablation system was utilized. The primary objective of the study was acute isolation of the targeted PV, and the secondary objective was clinical efficacy and safety of PVI with HDMA for atrial fibrillation (AF) prevention. Patients were followed at intervals of 1, 3, 6, and 12 months.
Results: PVI was attempted with HDMA in 67/67 PVs. [Correction made after online publication October 27, 2008: PVs changed from 6/67 to 67/67] Acute success rate were: 100% (16/16) for left superior PV, 100% (16/16) for left inferior PV, 100% (17/17) for right superior PV, 100% (1/1) for left common trunk and 47% (8/17) for right inferior PV. Total procedure time was 200 ± 36 minutes (range 130–240 minutes) and total fluoroscopy time was 42 ± 18 minutes (range 23–75 minutes). During a mean follow-up of 11 ± 4 months, 64% of patients remained in sinus rhythm (8/10 paroxysmal AF and 3/7 for persistent AF). No complications occurred either acutely or at follow-up.
Conclusions: PV isolation with HDMA is feasible and safe. The midterm efficacy in maintaining sinus rhythm is higher in paroxysmal than in persistent patients.     

PREVALENCE OF ALCOHOL PROBLEMS AMONG ADULT SOMATIC IN-PATIENTS IN NAPLES

The aim of this cross-sectional study was to determine the prevalenceof alcohol problems among adult somatic in-patients in urbanhospitals of Naples. The patients were screened with a structuredquestionnaire regarding life style. After discharge, the patientrecords were examined and the hospital discharge diagnoses wereregistered. A patient was considered having an alcohol problemif one or more of the following criteria were fulfilled: (1)a Michigan Alcoholism Screening Test score at or above five;(2) a self-reported daily consumption for at least 2 years ofat least 60g of ethanol for males and 36g for females; (3) analcohol-related discharge diagnosis. The prevalence of patientswith alcohol problems was significantly (P < 0.01) higheramong male (43.8%, 95% confidence limits. 37.6–50.2%)than among female patients (14.8%, 95% confidence limits. 9.6–21.4%).There were no significant differences among the different typesof somatic departments regarding the prevalence of alcohol problemswhen gender was considered. Patients with alcohol problems differedsignificantly from those without alcohol problems regardinga number of variables: the former drank significantly more alcohol,smoked for more years, and had a higher prevalence of alcoholproblems in the family. It is concluded that alcohol problemsamong in-patients are as prevalent in Naples as in other industrializedcountries, that it is often not registered among discharge diagnoses,and that the problems are more prevalent in males than in females,irrespective of the type of department.     

On the Use of a Dual-Scale Model to Improve Understanding of a Pharmaceutical Freeze-Drying Process

The evolution of product temperature and of residual ice content in the various vials of a batch during a freeze-drying process can be significantly affected by local conditions around each vial. In fact, vapor fluid dynamics in the drying chamber determines the local pressure that, taking into account the heat flow from the shelf and, eventually, radiation from chamber surfaces, is responsible for the sublimation rate and product temperature. These issues have to be taken into account when using mathematical simulation to predict the evolution of the product as a consequence of the operating conditions (recipe design), as well as during the scale-up of a recipe obtained in a small-scale equipment to a large-scale unit. In this framework, a dual-scale model can significantly improve the understanding for pharmaceuticals freeze-drying processes: it couples a three-dimensional model, describing the fluid dynamics in the chamber, and a second mathematical model, either mono- or bi-dimensional, describing the drying of the product in each vial. Thus, it can be profitably used to gain knowledge about process dynamics, and to improve the design of the equipment, as well as the performance of the control system of the process. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4337-4350,