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Background: Overactive bladder is a common disorder that affects approximately 34 million adults in the United States. Anticholinergic (antimuscarinic) agents are the most widely used pharmacological option for overactive bladder., Objective: This study set out to identify and characterize the influence of a number of intrinsic characteristics on the pharmacokinetics of the anticholinergic agent trospium chloride (Sanctura(®)) 60 mg extended release (XR), and to evaluate the correlation between trospium chloride exposure and key efficacy and safety outcomes in subjects and patients., Study Design: Pharmacokinetic data were obtained from three studies in which a total of 349 subjects received trospium chloride XR for up to 12 weeks. Plasma trospium chloride concentration data were pooled and a population pharmacokinetic model was derived using non-linear mixed-effects modelling. Demographic factors were assessed for influence on the model. The correlation between trospium chloride exposure and key efficacy variables was evaluated. Correlations between exposure and safety outcomes were also assessed., Intervention: Trospium chloride XR 60 mg once daily for 10 days in healthy volunteers or trospium chloride 60 mg XR once daily for either 2 weeks or 12 weeks in patients with overactive bladder., Results: The best population pharmacokinetic model was determined to be a two-compartment model with zero-order release into the depot compartment and first-order absorption. Body surface area (BSA) was the only covariate to significantly (P < 0.05) impact trospium chloride 60 mg XR pharmacokinetics. Significant relationships (P < 0.05) were observed between exposure [maximum plasma concentration (C(max)) and the area under the plasma concentration-time curve from time zero to 24 h (AUC(24))] and efficacy outcomes in the <65-year age group for change in average number of voids/day, change in number of incontinence episodes, and change in urgency severity, and in the ≥65-year age group statistical significance (P < 0.05) was achieved for C(max), but not for AUC(24), for these same three efficacy measures. Statistically significant relationships (P < 0.004) were also observed between exposure and both dry mouth and constipation, with increased benefit and increased incidence of adverse events (AEs) associated with higher concentrations; the correlation coefficients were low against the aggregate of AEs of interest (0.19 for AUC(24) and 0.18 for C(max)), indicating only mild strength of association., Conclusion: This population pharmacokinetic analysis demonstrated that the only demographic characteristic associated with trospium chloride pharmacokinetics was BSA. Thus, treatment of most patients with overactive bladder with once-daily trospium chloride 60 mg XR should not require consideration of key intrinsic demographic parameters. Furthermore, while efficacy and tolerability outcomes were found to be correlated with trospium chloride exposure, the strength of the association was modest in this study.

Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M(1)) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.

Antimuscarinic agents are the treatment of choice for overactive bladder syndrome. Due to the development of novel delivery systems, extended-release formulations of oxybutynin, tolterodine, and trospium chloride are now available. In addition to the convenience of once-daily dosing, the new formulations of these commonly prescribed agents have improved their therapeutic index, striking a better balance between efficacy and tolerability.

Background and Purpose: Statins reduce the risk of stroke recurrence, but the benefits of statins in improving outcome of acute stroke patients have not been well explored., Methods: We assessed potential effects of statins initiated before or within 4 weeks of stroke on 90-day outcome. Favorable outcomes were National Institutes of Health Stroke Scale (NIHSS) score < or =2 at 12 weeks and modified Rankin Scale (mRS) < or =2., Results: Before stroke, 129 patients were receiving statins, 123 initiated statins within 4 weeks, and 600 patients were not on statins. Multivariate logistic regression analysis demonstrated that poststroke statins were associated with a significant probability of a favorable outcome at 12 weeks [NIHSS (P=0.002; OR, 1.92; CI, 1.27 to 2.91) and mRS (P=0.033; OR, 1.57; CI, 1.04 to 2.38)], whereas prestroke statins demonstrated a trend toward significance., Conclusions: These preliminary results suggest that statin use may improve outcome of acute ischemic stroke.

Background and Purpose: Basic fibroblast growth factor (bFGF) and citicoline (cytidine 5'-diphosphate choline, an endogenous compound that stabilizes membrane function) have demonstrated neuroprotective effects after focal cerebral ischemia. Both agents are candidates for future stroke therapy in humans. For evaluation of synergistic effects of bFGF and citicoline, a low-dose combination of both compounds was tested against each compound alone and placebo., Methods: Four groups of Sprague-Dawley rats (n=12 per group) underwent 90 minutes of focal cerebral ischemia with the use of the suture model of middle cerebral artery occlusion. Animals were randomly and blindly assigned to one of the following treatment groups: placebo, low-dose citicoline (250 mg/kg IP daily for 4 days), low-dose bFGF (10 microg/kg per hour IV for 3 hours), and the combination of both (250 mg/kg citicoline and 10 microg/kg per hour bFGF). Triphenyltetrazolium chloride staining was used after 4 days to determine postmortem infarction. Neurological scores were assessed on a daily basis., Results: The premature mortality rate was 41.7% in the placebo and citicoline groups, 33.3% in the bFGF group, and 25% (P=NS) in the combination group. The mean neurological score on day 4 was 3.1+/-1.6 (placebo), 3.1+/-1.6 (citicoline), 2.9+/-1.5 (bFGF), and 2.4+/-1.4 (combination) (P=NS). The mean volume of infarction was significantly reduced in the combination group (136. 5+/-25.4 mm3) versus placebo (172.6+/-48.9 mm3; P=0.036, Fisher test), versus citicoline alone (186.0+/-35.7 mm3; P=0.005, Fisher test), and versus bFGF alone (176.0+/-49.2 mm3; P=0.023, Fisher test)., Conclusions: These results demonstrate synergistic effects of a low-dose combination of the growth factor bFGF and citicoline after temporary experimental focal cerebral ischemia and furthermore support the effectiveness of a combination treatment regimen for the management of acute stroke.

Background and Purpose: Citicoline, a naturally occurring precursor of phosphatidylcholine, is neuroprotective and is currently being assessed in clinical trials. To evaluate potential synergistic neuroprotective effects of prolonged citicoline treatment and early N-methyl-D-aspartate (NMDA) antagonist therapy, suboptimal treatment regimens of citicoline and MK-801 were tested alone and in combination in a rat model of temporary focal ischemia., Methods: Four groups of Sprague-Dawley rats (n = 12 per group) underwent 90 minutes of temporary middle cerebral artery occlusion (MCAO) with the suture model. Animals were randomly and blindly assigned to one of four treatment groups: (1) saline, vehicle; (2) MK-801, 0.5 mg/kg IV bolus at 60 minutes after MCAO followed by saline 1 mL/kg IP daily for 7 days; (3) saline IV at 60 minutes after MCAO followed by citicoline 250 mg/kg IP daily for 7 days; or (4) both MK-801 and citicoline (daily for 7 days) active treatment. Triphenyltetrazolium chloride staining was used to assess postmortem infarct volume. Neurological scores were determined daily., Results: Premature mortality between days 2 and 4 was 33.3% in group 1, 41.7% in groups 2 and 3, and 25.0% in group 4. Mean corrected infarct volume was significantly reduced in group 4 compared with the others (175.2 +/- 89.3 mm3 in group 1, 179.1 +/- 78.5 mm3 in group 2, 163.9 +/- 73.7 mm3 in group 3, and 84.7 +/- 56.8 mm3 in group 4 [P < .02, ANOVA and P < .05, Scheffé's test for group 1 versus group 4]). Mean infarct volume in animals dying prematurely was significantly (P < .05, Student's t test) larger in group 1 than those surviving for 7 days (247.2 +/- 89.5 versus 139.2 +/- 68.2 mm3), but there was no significant difference in infarct volume in groups 2, 3, and 4 between animals dying prematurely and those surviving for 7 days., Conclusions: These results demonstrate synergistic neuroprotective effects of citicoline and an NMDA antagonist in temporary experimental focal ischemia.

Potential therapeutic effects of cytidine 5-diphosphocholine (citicoline), a key intermediary in the biosynthesis of the membrane phospholipid, phosphatidylcholine, are presumably related to enhanced phospholipid synthesis in the ischemic brain. We evaluated prolonged citicoline treatment in a temporary focal ischemia model. Using the suture occlusion model, we induced 2 hours of temporary ischemia in 30 Sprague-Dawley rats. The rats were randomly and blindly assigned to receive intraperitoneally 500 mg/kg citicoline (HD), 100 mg/kg citicoline (LD) or physiologic saline as the control group once daily for 7 days (n = 10 per group) beginning at the time of reperfusion. Neurological scoring (0-5 scale) was performed daily. After elective sacrifice on day 7, or earlier if death occurred prematurely, the brains underwent 2,3,5-triphenyltetrazolium chloride (TTC) staining for calculation of corrected infarct and edema volume. The mean corrected infarct volume in the HD group was 125 +/- 45.2 mm3 (mean +/- SD), significantly smaller than controls, 243.5 +/- 88.6 mm3 (p < 0.01, Scheffe's-test). The LD group infarct volume was 200.2 +/- 62.8 mm3 (N.S.). The mean amount of brain edema in the HD group was 46.4 +/- 45.6 mm3 was smaller than the controls, 92.3 +/- 54.4 mm3 and the LD group, 84.9 +/- 71.7 mm3 (N.S.). Mortality before day 7 in the HD was 30% while it was 50% in the two other groups. The neurologic score on day 7 was 2.5 +/- 1.8 in the HD group, 3.3 +/- 1.8 in the LD group and 3.4 +/- 1.7 in controls (N.S.). These results demonstrate that extended high dose citicoline treatment significantly reduced infarct volume in this temporary focal ischemia model and that there was a trend toward reducing brain edema and mortality. These effects may be related to membrane stabilization and inhibition of free fatty acid release.

Neurochemical and behavioral studies have elucidated extensive interactions between dopaminergic and cholinergic systems in brain areas associated with movement and cognition. The initial goal of these studies was to evaluate the effect of the anti-Parkinson drug dihydrexidine (DHX), a dopamine D1 full-efficacy agonist, on brain acetylcholine (ACh) release using in vivo microdialysis techniques. Moderate doses of DHX (3 and 10 mg/kg) produced approximately a 50% increase in striatal ACh release that was blocked by the D1 agonist SCH23390 (0.3 mg/kg). A higher dose of DHX (17.5 mg/kg) was less effective in raising striatal ACh, possibly due to D2 receptor activation. In frontal cortex, DHX (10 mg/kg) evoked a more robust increase in ACh release (+200%) that was blocked by SCH23390 (0.3 mg/kg). Since elevations in brain ACh are associated with cognitive improvement, the effectiveness of DHX in a passive avoidance model of learning and memory was also evaluated. These studies revealed a significant improvement in performance by 0.3 mg/kg DHX in scopolamine-induced amnestic rats. These results provided support for the hypothesis that DHX improves cognitive performance as a consequence of ACh release in relevant brain regions. Further, D1 agonists may have novel therapeutic potential in the treatment of dementia.

This randomized, placebo-controlled, double-blind study was designed to evaluate the safety and efficacy of dexfenfluramine (Dfen). Dfen 15 mg BID, and placebo were administered for 12 weeks to 337 moderately obese patients on calorically restricted diets. Patients were monitored for an additional 4 weeks. Efficacy was evaluated in 321 patients who were an average of 52% in excess of ideal body weight. Dfen-treated patients lost significantly more weight than did those treated with placebo (p less-than-or-equal 0.001). Small nonsignificant fluctuations in body weight were observed during the 4-week posttreatment period in both groups. The most common drug-related side effects were diarrhea, asthenia, dry mouth, and thirst (p less-than-or-equal 0.05 compared with placebo). Dexfenfluramine may become a valuable addition to weight loss and weight management programs.

Citicoline is approved in Europe and Japan for use in stroke, head trauma and other neurological disorders. It is presently being evaluated in phase II/III stroke trials in the United States. Exogenous administration of CDP-choline provides both choline and cytidine which access the brain and serve as substrates for the synthesis of phosphatidylcholine, a primary neuronal membrane component; the choline also enhances brain acetylcholine synthesis. Membrane repair and regeneration is necessary for recovery from stroke. Furthermore, citicoline may alleviate free fatty acid-induced toxicity which accompanies ischemic insult. Data from many pre-clinical and clinical trials support the hypothesis that citicoline may be a safe and effective treatment for stroke.

Esmolol, an ultra-short-acting, cardioselective, beta-receptor blocking agent, has been developed for use in clinical conditions requiring controlled beta-receptor blockade. Its esterase-induced rapid metabolic inactivation and resulting brief pharmacologic effect provides control over the magnitude and duration of beta-receptor blockade. In placebo-controlled clinical trials, the effects of infusion of esmolol on the sympathetically mediated hemodynamic responses to stressful events during the perioperative period were evaluated in patients scheduled for surgical procedures under general anesthesia. In patients undergoing either noncardiac or cardiac surgical procedures, esmolol was effective in attenuating tachycardia that is normally seen during induction of anesthesia, laryngoscopy and endotracheal intubation, or sternotomy and aortic dissection by reducing the hemodynamic stress on the heart with negligible adverse effects. This much-desired cardioprotective effect of esmolol will be of special value to patients with coronary artery disease and patients with an unstable cardiovascular status who are undergoing major surgical procedures with general anesthesia.

Sympathomimetics are extensively used clinically as decongestants and bronchodilators in cough, cold, and sinus remedies. However, few studies have addressed the glycemic potentials of these drugs. In this study, the glycemic potentials of pseudoephedrine (PSD), ephedrine (EPD), and phenyl-propanolamine (PPA), the three most commonly used sympathomimetics, were evaluated. PSD caused a dose-dependent delayed hyperglycemia. This was attenuated when procedural stress was reduced. EPD and PPA did not increase the hyperglycemia due to procedural stress. EPD and PPA blunted the hyperglycemia in fed mice after a 2 g/kg oral glucose challenge; PSD had no effect. The effects of PPA and EPD on post-challenge glucose levels may be partially explained by increased insulin/glucose ratios at 15 minutes post-challenge. These studies indicate that there are differences in the glycemic effects among the sympathomimetics in stressed mice.

Pseudoephedrine hydrochloride was evaluated at two dosage levels in six normal healthy males, at rest and during submaximal exercise. Although there appeared to be a dose-related rise and during submaximal exercise. Although there appeared to be a dose-related rise in resting heart rate, it was not statistically significant. The drug had no effect on the amount of time required to reach 85 per cent maximal predicted heart rates while on the treadmill or on the amount of time required to recover baseline heart rates. Also, there was no drug effect observed on blood pressure at rest, during exercise, or in the recovery period. There was a significant increase in the frequency of sinus arrhythmias after the 120-mg pseudoephedrine dose. There appeared to be no drug effect on postexercise blood glucose and insulin levels.