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Selected AbstractsPopulation pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] Double-Blind, Randomized, Placebo-Controlled, Dose-Response Study of the Safety and Efficacy of Botulinum Toxin Type A in Subjects with Crow's FeetDERMATOLOGIC SURGERY, Issue 3 2005Nicholas J. Lowe MD Background Published evidence suggests that botulinum toxin type A (BTX-A) is an effective treatment for crow's feet. However, few dose-ranging studies have been performed. Objectives To assess the safety and efficacy of a single treatment with one of four doses of BTX-A (Botox/Vistabel, Allergan Inc) compared with placebo for the improvement of crow's feet. Methods Subjects received a single bilateral treatment of 18, 12, 6, or 3 U of BTX-A or placebo injected into the lateral aspect of the orbicularis oculi muscle (parallel-group, double,blind design). Investigators and subjects rated crow's feet severity at maximum smile on day 7 and at 30-day intervals from days 30 to 180. Results As observed by both investigators and subjects, all doses of BTX-A resulted in improvements in crow's feet severity when compared with placebo. A dose-dependent treatment effect for efficacy was observed, with higher doses having an increased magnitude and duration of effect. However, a clear differentiation between the 18 U and 12 U doses was not apparent. Few adverse events were reported, with no statistically significant differences between BTX-A and placebo in the incidence of subjects experiencing adverse events. Conclusion BTX-A is safe and effective in decreasing the severity of crow's feet, with 12 U per side suggested as the most appropriate dose. THIS STUDY WAS FUNDED BY ALLERGAN, WHICH WAS ALSO INVOLVED IN THE DESIGN AND CONDUCT OF THE STUDY; COLLECTION, MANAGEMENT, ANALYSIS, AND INTERPRETATION OF THE DATA; AND PREPARATION, REVIEW, AND APPROVAL OF THE MANUSCRIPT. DRS. LOWE AND FRACZEK ARE PAID CONSULTANTS FOR ALLERGAN, DRS. KUMAR AND EADIE ARE EMPLOYEES OF ALLERGAN, AND DRS. LOWE AND KUMAR HOLD STOCK OPTIONS. [source] Comparison of ADA 1997 and WHO 1985 criteria for diabetes in south Indians , the Chennai Urban Population StudyDIABETIC MEDICINE, Issue 12 2000R. Deepa SUMMARY Aims To compare the American Diabetes Association (ADA) fasting criteria and World Health Organization (WHO) 2-h criteria for diabetes in an urban south Indian population. Methods Subjects were drawn from the Chennai Urban Population Study. Of the 1001 subjects studied, 52 (5.2%) were diagnosed as having diabetes according to WHO 2-h criteria and 32 (3.2%) according to the ADA fasting criteria. Results Twenty-five (48%) of the subjects diagnosed with diabetes by the WHO 2-h criteria were not classified as having diabetes by the ADA fasting criteria. Similarly, of the 78 subjects (7.8%) classified as having impaired glucose tolerance (IGT), only eight (10.3%) had impaired fasting glucose (IFG) according to the ADA fasting criteria. The overall agreement between the WHO 2-h criteria and ADA fasting criteria was poor (, = 0.40). Conclusions Use of the ADA fasting criteria results in a lower prevalence rates of diabetes in this lean urban south Indian population. [source] Drinks of the Father: Father's Maximum Number of Drinks Consumed Predicts Externalizing Disorders, Substance Use, and Substance Use Disorders in Preadolescent and Adolescent OffspringALCOHOLISM, Issue 12 2002Stephen M. Malone Background The maximum number of drinks consumed in 24 hr seems to be an interesting phenotype related to alcoholism. The goal of the present study was to determine in an epidemiologic sample whether this measure of drinking history in fathers predicted externalizing behavioral disorders, substance use, and substance abuse in preadolescent and adolescent offspring and whether any such associations would be independent of paternal alcohol dependence diagnoses. Methods Subjects were male and female twins from both age cohorts of the Minnesota Twin Family Study, a population-based longitudinal study, and were approximately 11 or 17 years of age, respectively, upon study enrollment. In both age cohorts, diagnoses of conduct disorder, oppositional defiant disorder, and attention-deficit/hyperactivity disorder served as outcome measures. In addition, measures of lifetime substance use and of the presence of symptoms of substance abuse were derived for the 11-year-old cohort when subjects were approximately 14 years old and diagnoses of substance abuse were derived for the older cohort at age 17. An extension of logistic regression using generalized estimating equations served to assess whether paternal maximum alcohol consumption predicted filial outcome measures. Results Paternal maximum alcohol consumption was consistently associated with conduct disorder, substance use, and substance abuse or dependence in male and female offspring. These associations were not mediated by a primary effect of paternal alcoholism. Conclusions Paternal maximum alcohol consumption was uniquely associated with those offspring characteristics most reliably found in adolescent children of alcoholic parents. This phenotype might supplement DSM diagnoses of alcohol dependence to reduce the number of false positives in genetic research. [source] Application of Insect Repellents by Travelers to Malaria Endemic AreasJOURNAL OF TRAVEL MEDICINE, Issue 4 2006Yvonne Thrower MSc Background The use of insect repellents applied to the skin is always encouraged in those visiting malaria endemic areas. There are a number of factors contributing to the efficacy of insect repellents in the field and an important factor contributing to their longevity relates to the applied dose. This study investigated the dose of insect repellent that travelers might normally apply to the skin. Methods Subjects were asked to apply a product they had purchased to the arms and neck, and the dose applied (mg/cm2) was calculated. The study was conducted using three different populations; 74 travelers to malaria endemic areas visiting pharmacies to purchase repellents before they left the UK, 23 travelers on safari in India, and 24 on safari in Kenya. Results There was a significant difference in the mean applied arm dose of product (mg/cm2) [p < 0.001, analysis of variance (ANOVA)]; UK 1.15 (SD 0.29), India 0.96 (SD 0.23), and Kenya 1.34 (SD 0.54). Higher concentrations were achieved on the neck area. Few of the participants in the field trial used long-sleeved shirts at night. Even using 50% wt/vol repellent products, 32% in the Kenya and 25% in the India, study achieved a dose of active ingredient less than 0.5 mg/cm2. Conclusion These pilot studies would indicate that travelers tend to apply below the optimal concentration of active ingredient of repellent as might be suggested by mathematical models. [source] The Mechanism of Hearing Loss in Paget's Disease of Bone,THE LARYNGOSCOPE, Issue 4 2004Edwin M. Monsell MD Abstract Objectives/Hypothesis The mechanism of hearing loss (HL) in Paget's disease of bone was investigated. The present study was a systematic, prospective, controlled set of clinical investigations to test the hypothesis that there is a general underlying mechanism of HL in Paget's disease of bone and to gain additional insights into the auditory and otologic dynamics of this disease. Specific questions were 1) whether the mechanism is cochlear or retrocochlear and 2) whether the bone mineral density of the cochlear capsule is related to hearing levels. Study Design Several double-blinded, cross-sectional, prospective, correlational studies were conducted in a population of elderly human subjects with skull involvement with Paget's disease versus a control population of elderly subjects free of Paget's disease. Demographic and clinical data were recorded. Longitudinal observations were made in subjects under treatment. Methods Subjects were recruited from a Paget's disease clinic. Pure-tone auditory thresholds, word recognition, and auditory brainstem responses (ABRs) were recorded. The dimensions of the internal auditory canals were measured using computed tomographic (CT) images and digital image analysis. The precision, accuracy, and temporal stability of methods to measure the bone mineral density of the cochlear capsule and an adjacent area of nonotic capsule bone were validated and applied. Correlations were sought between hearing levels and cochlear capsule bone mineral density. Results ABRs were recorded in 64 ears with radiographically confirmed Paget's disease involving the skull. Responses were absent in eight ears, all of which had elevated high pure-tone thresholds. ABRs were interpreted as normal in 56 ears; none were abnormal. The mid-length diameter and minimum diameter of the internal auditory canal of 68 temporal bones from subjects with Paget's disease were found to have no statistically significant relationship to hearing thresholds. The Pearson product-moment correlation coefficients (age- and sex-adjusted) in the group with Paget's disease involving the temporal bone were ,0.63 for left ears and ,0.73 for right ears for high-frequency air conduction pure-tone thresholds (mean of 1, 2, and 4 kHz) versus cochlear capsule density. Correlation coefficients (age- and sex-adjusted) between cochlear capsule density and air-bone gap (mean at 0.5 and 1 kHz) for the affected group were ,0.67 for left ears and ,0.63 for right ears. All correlations between hearing thresholds and cochlear capsule density in pagetic subjects were significant at P < .001. The regressions were consistent throughout the ranges of hearing level. There were no significant correlations between cochlear capsule mean density and hearing level in the volunteer subjects. Conclusions The evidence supports the existence of a general, underlying, cochlear mechanism of pagetic HL that is closely related to loss of bone mineral density in the cochlear capsule. This mechanism accounts well for both the high-frequency sensorineural HL and the air-bone gap. Early identification, radiographic diagnosis of temporal bone involvement, and vigorous treatment with third-generation bisphosponates are important to limit the development and progression of pagetic HL. [source] Intermittent dosing of fluticasone propionate cream for reducing the risk of relapse in atopic dermatitis patientsBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2002J. Hanifin Summary Background One of the most troublesome features of atopic dermatitis (AD) is its chronic relapsing nature, and there is a lack of published evidence on the best treatment strategy for long-term management of the disease. Objectives To compare an intermittent dosing regimen of fluticasone propionate (FP) cream 0·05% (twice per week) with its vehicle base in reducing the risk of relapse when added to regular daily emollient in adult and paediatric subjects with stabilized AD. Methods Subjects (aged 3 months to 65 years) with moderate or severe AD were enrolled into an open-label Stabilization Phase of up to 4 weeks on daily emollients plus FP twice daily. Those subjects who achieved ,treatment success' (Global Assessment Score ,,2, erythema, pruritus, and papulation/induration/oedema scores ,,1) entered the double-blind Maintenance Phase. They continued with regular emollients and were randomized at a 2 : 1 ratio to either intermittent FP or vehicle, once daily 4 days per week for 4 weeks followed by once daily 2 days per week for 16 weeks. Subjects who relapsed on intermittent FP were discontinued from the study. Those who did not relapse continued for an additional 24 weeks on intermittent dosing for safety monitoring. Results A total of 372 (247 paediatric, 125 adult) subjects were enrolled into the Stabilization Phase. Of these, 348 (231 children, 117 adults) were randomized into the Maintenance Phase. Analysis of the primary efficacy parameter showed that subjects receiving intermittent FP cream (twice per week), in addition to regular daily emollients in the Maintenance Phase, were 7·7 times less likely to have an AD relapse than subjects receiving intermittent vehicle cream/emollients [Mantel,Haenszel (MH) estimate of the odds ratio, 95% confidence interval (CI) 4·6, 12·8; P < 0·001]. Paediatric subjects were 8·1 times less likely to have an AD relapse (95% CI 4·3, 15·2; P < 0·001) and adult subjects were 7·0 times less likely to have an AD relapse (95% CI 3·0, 16·7; P < 0·001). For subjects receiving intermittent FP cream/emollient, the median time to relapse could not be estimated as the majority remained controlled at 20 weeks. For those receiving intermittent vehicle/emollient, the median time to relapse was 4·7 weeks. For paediatric and adult groups, this was 5·1 and 4·1 weeks, respectively. Median exposure to FP for all subjects was 337 days. There was only one study drug-related adverse event (acne) and there were no reports of skin thinning or atrophy associated with the use of FP cream in paediatric or adult subjects. Conclusions In paediatric and adult subjects, once stabilized with regular FP treatment, the risk of relapse of AD can be significantly reduced by extended intermittent dosing with FP cream in addition to regular emollient therapy. [source] Effects of inhaled ciclesonide on circulating T-helper type 1/T-helper type 2 cells in atopic asthmatics after allergen challengeCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2006T. Kawayama Summary Background The predominance of T-helper type 2 (Th2) lymphocytes is thought to underlie the pathogenesis of asthma. Allergen inhalation challenge in atopic asthmatic subjects is associated with decreased interferon-, (IFN-,) positive CD4+ and CD8+ lymphocytes in peripheral blood and induced sputum. Objective This study examined the effects of an inhaled corticosteroid on these previously described allergen-induced changes in circulating Th1 and Th2 lymphocytes. Methods Subjects were randomized to 7 days of placebo, 40 or 80 ,g ciclesonide in a crossover study. Airway responses and peripheral blood were measured before and after treatment, and 24 h after allergen challenge. Results Ciclesonide 40 and 80 ,g significantly attenuated the late response and sputum eosinophils at 8 h post-allergen (P<0.05). Circulating IFN-, positive CD4+ lymphocytes decreased after allergen challenge with placebo (P<0.05), and this was inhibited by 40 ,g ciclesonide treatment (P<0.05). There was no effect of allergen inhalation or ciclesonide on IL-4-positive CD4+ lymphocytes or IFN-, and IL-4-positive CD8high lymphocytes. The allergen-induced change of IFN-,/IL-4 ratio on CD4+ cells correlated with the allergen-induced change of peripheral blood eosinophils. Conclusions The results of this study suggest that attenuation of allergen-induced airway responses by ciclesonide may be mediated through regulation of IFN-,-positive CD4+ cells. [source] Improvements in insulin sensitivity and ,-cell function (HOMA) with weight loss in the severely obeseDIABETIC MEDICINE, Issue 2 2003J. B. Dixon Abstract Aims To examine the effect of weight loss on insulin sensitivity and ,-cell function in severely obese subjects of varying glycaemic control. Patients and methods Subjects were 254 (F:M 209:45) patients having adjustable gastric banding for severe obesity, with paired biochemical data from before operation and at 1-year follow up. The homeostatic model assessment method was used to calculate insulin sensitivity (HOMA%S) and ,-cell function (HOMA%B). Subjects were grouped by diabetic status and by pre-weight loss HbA1c. Results Initial mean (sd) weight and body mass index were 128 (26) kg and 46.2 (7.7) kg/m2, respectively, and at 1-year were 101 (22) kg and 36.4 (6.7) kg/m2. The percentage of excess weight lost (%EWL) was 44.3 (14)%. HOMA%S improved from 37.5 (16)% presurgery to 62 (25)% (P < 0.001). %EWL was the only predictor of HOMA%S improvement (r = 0.28, P < 0.001). Subjects with normal fasting glucose, impaired fasting glucose and Type 2 diabetes had a fall, no change and increase in HOMA%B, respectively. The improvement in HOMA%B in subjects with diabetes (n = 39) was inversely related to the time with diabetes (r = ,0.36, P = 0.02). In non-diabetic subjects the HOMA%S,HOMA%B relationship was favourably altered with weight loss, so that for any given HOMA%S there was an increase in HOMA%B (f = 11.8, P = 0.001). This improvement in HOMA%B was positively related to %EWL (r = 0.25, P = 0.019). Discussion There are beneficial changes in both insulin sensitivity and ,-cell function with weight loss. Modern laparoscopic obesity surgery may have an important early role in the management of Type 2 diabetes in obese subjects. [source] A higher-order PDE-based image registration approachNUMERICAL LINEAR ALGEBRA WITH APPLICATIONS, Issue 5 2006Volker Grimm Abstract This paper addresses the problem of image registration with higher-order partial differential equation (PDE) methods. From the study of existing affine-linear and non-linear methods, a new framework is proposed that unifies common image registration methods within a generic formulation. Currently image registration strategies are classified into either affine-linear or non-linear methods subject to the underlying transformations. The new approach combines both strategies to obtain proper approximations which are invariant under global geometrical distortion (shearing), anisotropic resolution (scale changes), as well as rotation and translation. To achieve this favourable property, a modified gradient flow approach is proposed which uses an operator with a kernel consisting of affine-linear transformations. An approximation with finite differences leads to a large singular linear system. The pseudo-inverse solution of this system can be computed efficiently by augmenting the singular system to a regular system. Numerical experiments show the improvements compared to unmodified gradient flow approaches. Copyright © 2005 John Wiley & Sons, Ltd. [source] | ||||||||||