Alzheimer''s disease (AD) and vascular dementia (VaD) share several features such as overactivation of microglial cells, damage induced by free radicals, glutamate and calcium overload. Propentofylline (HWA 285) has shown beneficial effects on all of these common elements, thus favouring its use in both subtypes of dementia. In a multinational, randomized, 12-month, double-blind, parallel-group study 260 out-patients with mild to moderate AD or VaD received 300 mg propentofylline (n = 129) or placebo (n = 131) three times daily 1 h before meals. The efficacy was tested at four independent rater levels (physician, psychologist, relative and patient) with assessments covering three major domains of dementia (global function, cognitive function and activities of daily living). After 12 months, the total patient population showed statistically significant treatment differences in favour of propentofylline for the global measures of dementia (Gottfries-Bråne-Steen scale, GBS, p = 0.001; Clinical Global Impressions, CGI, item I: p = 0.004, item II: p = 0.072) as well as for the cognitive measures (Syndrome Short Test, SKT, p = 0.002) and Mini-Mental State Examination (p = 0.001). The activities of daily living also showed a significant treatment difference in favour of propentofylline (p = 0.002). No significant treatment differences were found for rating scales performed by the patients. At month 12, VaD patients showed treatment differences in favour of propentofylline for the GBS total score (p = 0.006), CGI item I (p = 0.004), GGI item II (p = 0.044) and SKT (p = 0.028). Treatment differences for AD patients were all in favour of propentofylline and reached statistical significance for the SKT (p = 0.018). Propentofylline showed a good safety profile with respect to adverse events, vital signs, ECG and laboratory changes.
Propentofylline, a neuroprotective glial cell modulator, has been shown in preclinical studies to address some of the common pathological processes of Alzheimer’s disease (AD) and vascular dementia (VaD), including glial cell activation and increased production of cytokines, free radicals, and glutamate. To examine whether propentofylline (300 mg t.i.d. taken 1 h before meals) would provide beneficial effects in patients with AD and/or VaD, 901 patients with mild-to-moderate AD and 359 patients with mild-to-moderate VaD were enrolled in four double-blind, placebo-controlled, randomized studies ranging in duration from 6 months to 56 weeks. Propentofylline was found to provide consistent improvements over placebo in efficacy assessments for both AD and VaD patients. In addition, results from a drug withdrawal study suggested that propentofylline does not merely relieve dementia symptoms but slows the progression of the disease itself. Propentofylline had a good safety profile and was generally well tolerated.
The mode of action of propentofylline (a xanthine derivative) suggested that it would have beneficial effects in patients with Alzheimer's disease or vascular dementia. In four double-blind, placebo-controlled, randomized studies, 901 patients with mild to moderate Alzheimer's disease and 359 patients with mild to moderate vascular dementia were treated for up to 12 months (daily dose of propentofylline: 3 x 300 mg taken 1 hr before food). Patients were assessed at regular intervals for efficacy and safety of the drug. Efficacy variables covered cognitive and global functions as well as activities of daily living. Propentofylline showed statistically significant, clinically relevant improvements over placebo in efficacy assessments, both in patients with Alzheimer's disease and in patients with vascular dementia. The drug was also well tolerated. It had no significant effects on laboratory findings and the adverse events that were considered to be related to the study medication were mostly minor, transient, and affected the digestive and nervous systems.
Fexofenadine hydrochloride is a non-sedating antihistamine that is used in the treatment of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. A pooled analysis of pharmacokinetic data from children 6 months to 12 years of age and adults was conducted to identify the dose(s) in children that produce exposures comparable to those in adults for the treatment of seasonal allergic rhinitis. The pharmacokinetic parameter database included peak and overall exposure data from 269 treatment exposures from 136 adult subjects, and 90 treatment exposures from 77 pediatric allergic rhinitis patients. The data were pooled and analysed using NONMEM software, version 5.0. A covariate model based on body weight and age and a power function model based on body weight were identified as appropriate models to describe the variability in fexofenadine oral clearance and peak concentration, respectively. Individual oral clearance estimates were on average 44%, 36% and 61% lower in children 6 to 12 years (n=14), 2 to 5 years (n=21), and 6 months to 2 years (n=42), respectively, compared with adults. Trial simulations (n=100) were carried out based on the final pharmacostatistical models and parameter estimates to identify the appropriate dose(s) in children relative to the marketed dose of 60 mg fexofenadine hydrochloride in adults. The trials were designed as crossover studies in 18 subjects comprising various potential dosing regimens with and without weight stratification. Pharmacokinetic parameter variability was assumed to have a log-normal distribution. Individual weights and ages were simulated using mean (SD) estimates derived from the studies used in this analysis and proportional measurement/model mis-specification errors derived from the analysis were incorporated into the simulation. The results indicated that a 30 mg dose of fexofenadine hydrochloride administered to children 1 to 12 years of age and weighing >10.5 kg and a 15 mg dose administered to children 6 months and older and weighing
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