Effectiveness and tolerability of extended-release oxybutynin vs extended-release tolterodine in women with or without prior anticholinergic treatment for overactive bladder

The efficacy and the tolerability of extended-release oxybutynin chloride, 10 mg daily, and extended-release tolterodine tartrate, 4 mg daily, in women with or without prior anticholinergic treatment for overactive bladder (OAB) were compared in a post-hoc analysis of data from the Overactive Bladder: Performance of Extended Release Agents (OPERA) trial. The patient population and study methods have been described previously (Diokno et al., for the OPERA Study Group, Mayo Clin Proc 78:687–695, 2003). Among the group with anticholinergic experience, extended-release oxybutynin was significantly more effective than extended-release tolterodine in reducing micturition frequency at last observation (p=0.052). Complete freedom from urge incontinence was reported by significantly more patients taking oxybutynin than tolterodine at last observation (23.6 vs 15.1%, p=0.038). In addition, among patients completing a full 12 weeks of oxybutynin treatment, significantly greater reductions were observed compared with those taking tolterodine on the primary efficacy variable, number of urge incontinence episodes (p=0.049), and the combined total of urge and non-urge episodes (p=0.012), although the differences between treatment groups were not significant at last observation. In the anticholinergic-naïve group, efficacy and tolerability outcomes were similar across treatments, except that oxybutynin was associated with a significantly lower frequency of micturition at last observation (p=0.035). No efficacy differences favoring tolterodine were observed, and tolerability of the treatments was comparable. Dry mouth (mostly mild to moderate in severity) was reported significantly more often among participants taking extended-release oxybutynin than extended-release tolterodine (32.2 vs 19.2%, p=0.004), but only among those with previous anticholinergic experience. Discontinuation rates were comparably low across groups. The results demonstrate the appropriateness of initiating treatment for OAB with extended-release oxybutynin, particularly in women presenting with incontinence.     

A direct method for studying 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) production by brain in awake animals.

A direct method for measuring the rate of production of neurotransmitter metabolites by the brain of awake monkeys is described. The method utilizes a coupling of a measure of cerebral blood flow with the determination of the difference in concentration of the metabolite under study in arterial and internal jugular bulb blood. A consistent veno-arterial difference for 3-methoxy-4-hydroxyphenethylenglycol (MHPG) has been found. The concentration of MHPG in blood obtained from the right and left venous outflows from brain were not significantly different indicating that blood from either the right or left internal jugular bulb may be used with this method. The rate of production of MHPG by the brain of thw awake monkey is estimated to be 24.1 ng/100 g brain/min. The rate of MHPG production by brain is increased by the administration of piperoxan and decreased by clonidine. Using the experimentally determined rate of production of MHPG by brain and extrapolating to the human it is suggested that a substantial fraction of the total body production of MHPG in man occurs in brain.     

The cholinolytic biperiden in depression

Summary Clinical and experimental work indicates that cholinergic functions might play a role in modulating affactivity in man. In this acute double-blind study either the cholinolytic agent biperiden or placebo infusions were administered to six depressed females. The Janke and Debus self-rating questionnaire (EWL-K), the modified Hamilton depression scale (HAM-D), and the Montgomery and Asberg depression scale (MADRS) were used for documentation of psychopathological change.There was an acute antidepressant effect during infusion of the active drug in comparison to placebo as measured on the global MADRS and EWL-K, but not on the modified HAM-D. Single items such as depressed mood, work and interests (HAM-D), sadness, concentration difficulties, inability to feel (MADR-S), and depressiveness (EWL-K) responded selectively and significantly to the biperiden infusion. It is concluded that cholinergic activity might be involved in the regulation of affectivity in man.     

Correlation between plasma clozapine concentration and heart rate variability in schizophrenic patients

 Forty schizophrenic patients treated with 50–600 mg/day of clozapine as monotherapy and 40 normal control subjects were tested for heart rate variability (HRV) which is mediated by the vagus nerve using acetylcholine as neurotransmitter. As compared to the control subjects, the patients showed essentially reduced HRV parameters which were negatively correlated with the plasma clozapine levels. Therefore, clozapine’s anticholinergic effect is correlated to the plasma clozapine level when measured by the decrease of HRV. We suggest that HRV data might be useful as a predictor for plasma clozapine levels. Received: 9 April 1997/Final version: 21 July 1997     

Assessing declarative memory in schizophrenia using Wisconsin Card Sorting Test stimuli: the Paired Associate Recognition Test

The Paired Associate Recognition Test (PART) was developed to measure declarative memory using Wisconsin Card Sorting Test (WCST) stimuli, so that both tasks could be administered during functional neuroimaging to differentiate memory and executive function, and associated frontal and temporal lobe activation in schizophrenia. The current study was designed to compare PART and WCST performance in schizophrenic patients and to examine effects of medication and symptomatology. The PART, WCST, and standard declarative memory tasks were administered to 30 chronic schizophrenic patients and 30 matched healthy control subjects. Supporting task validity was the finding that patients were equally impaired on the PART and the WCST. Neuroleptics did not appear to affect performance. The effect of anticholinergic medication correlated negatively with WCST performance in a small subsample. Severity of schizophrenia-specific symptoms measured at intake on the Brief Psychiatric Rating Scale correlated negatively with performance on the WCST. These results support the application of the PART and WCST in future functional neuroimaging studies.     

Modulation of Glucose and Growth Hormone Responses to Meals and Exercise in Type 1 Diabetes by Cholinergic Muscarinic Blockade

Anticholinergic drugs suppress nocturnal and exercise-related growth hormone (GH) secretion in Type 1 diabetes; nocturnal GH suppression is associated with a fall in fasting plasma glucose levels. The aim of this study was to assess the effect of GH suppression on glucose levels following a period of meals and exercise in physiological pattern. Six Type 1 diabetic men recruited from the outpatient clinic were studied in random order at least 1 week apart. After an overnight fast subjects received two-thirds of their usual subcutaneous insulin and either 200 mg oral pirenzepine or placebo at time 0 min. Between 90 and 120 min subjects exercised continuously on an ergometric cycle. Standard meals or snacks were eaten at 30, 150, 270, and 390 min. Venous blood was collected from an indwelling cannula between 0 and 570 min. The mean incremental rise in plasma glucose after breakfast (δ peak/_{90 min}) was 2.6 ± 0.5 (mean ±SEM mmol l^?1 (pirenzepine) vs 4.5 ± 0.8 (placebo)), p < 0.05. Following exercise the fall in plasma glucose (δ gluc_{90–240 min}) was 6.4 ± 1.9 (pirenzepine) vs 2.0 ± 1.3 (placebo), p < 0.005. The exercise-related peak rise in GH was 12.6 ± 3.3 (pirenzepine) vs 28.5 ± 6.0 mU l^?1 (placebo), p = 0.08. Excluding one outlying result there was an inverse correlation between the integrated exercise-related increase in GH between 90 and 240 min and the fall in glucose over the corresponding time period (n = 11, r = ?0.75, p = 0.008). In conclusion suppression of exercise-related GH secretion by pirenzepine is associated with a subsequent lowering of plasma glucose levels. The smaller post-prandial glucose rise pre-exercise implies also a direct effect of pirenzepine on meal-related glucose tolerance in Type 1 diabetes.     

Age-related scopolamine effects on social and individual behaviour in rats

The modulation of spontaneous (social and individual) behaviour as a function of the age of the rat (1, 3, 6, 12, 18 and 24 months) and of scopolamine dose (0.1, 0.2, 0.3 and 0.5 mg/kg) was studied. Observations were conducted during the dark phase of the reverse light/dark schedule using a reintroduction procedure. Results showed a marked effect of scopolamine on most of the behavioural patterns considered. Environmental interaction was enhanced whilst agonistic and social active interactions (social grooming) and play fighting were reduced by the drug. A slight hyposensitivity in the youngest rats and a marked hyposensitivity to the drug in the oldest ones were observed. The relationship to biochemical data and human sensitivity on the one hand and to learning and memory tasks and cholinergic specificity on the other hand, are discussed.     

Biochemical and pharmacological effects of fluperlapine on noradrenaline and acetylcholine systems in some rodent,bovine and crustacean preparations

Summary Fluperlapine was compared with clozapine, chlorpromazine, haloperidol and imipramine regarding its effects on some cholinergic and noradrenergic animal systems.Fluperlapine and clozapine showed the most pronounced anticholinergic effects. Fluperlapine was equipotent with clozapine in displacing [³H]-QNB from muscarinic receptors of the calf cerebral cortex (IC₅₀ about 15 nM). In the mydriasis test in the mouse and in the crayfish hindgut bioassay the differences between fluperlapine and clozapine were small.Like the other antischizophrenic drugs tested, fluperlapine displayed a marked affinity for ₁-adrenoceptors (calf cerebral cortex: IC₅₀ about 10 nM) but a neglible affinity for ₂-adrenoceptors in the same tissue. Only clozapine showed a weak affinity for the latter receptor type.Fluperlapine was as effective as imipramine in antagonizing tetrabenazine-induced ptosis in the rat, the antiptotic effect remaining constant after up to ten daily drug administrations. Still, imipramine was stronger than fluperlapine as an inhibitor of the accumulation of [³H]-noradrenaline ([³H]-NA) in rat cerebral cortex slices. Fluperlapine's effects on the spontaneous and the electrically-induced release of [³H]-NA from rat cerebral cortex slices, with and without protriptyline, showed it to be an inhibitor of the reuptake of NA.The results indicate that the pharmacological profile of fluperlapine is similar to that of clozapine, with additional antidepressant properties.     

Amoxapine and amitriptyline

Cognitive effects of brief antidepressant treatments were studied in depressed outpatients assigned double-blind to equipotent doses of amoxapine or amitriptyline in a 12-week double-crossover of 3-week periods of active agent and placebo. The two drugs had different profiles of effects: amitriptyline was associated with faster reaction time on tests of attention and immediate memory, reduced accuracy on an attention task, and impaired long-term memory (after 1 but not 3 weeks); amoxapine slowed performance and increased intraperson variability on a psychomotor coordination task. Amitriptyline facilitated performance in the more depressed patients, and amoxapine in the older patients. Both agents also increased pulse rate and reduced palmar sweating.