9 research outputs found
Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350
INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany
Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation:A Multinational Population-Based Cohort Study
INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG
Noradrenergic augmentation strategies in the pharmacological treatment of depression and schizophrenia : An experimental study
The pharmacological treatment of depression and schizophrenia, two major
psychiatric disorders, is largely based on modulation of central
monoaminergic neurotransmission. However, currently available
pharmacological treatment alternatives possess a relatively modest
clinical efficacy, making them less than optimal. The present series of
studies, using in vivo electrophysiological, biochemical and behavioral
techniques in rats, aim at the disclosure of mechanisms whereby an
augmented clinical efficacy of antidepressant, as well as antipsychotic,
drugs may be achieved.
Pindolol, a partial beta-adrenoceptor agonist with affinity for the
serotonin (5-HT) ]A receptor, has been claimed to shorten the clinical
onset of action of selective serotonin reuptake inhibitors (SSRIs); an
effect suggested to result from an antagonistic action of pindolol on
somatodendritic 5-HT1A autoreceptors, reversing the acute, inhibitory,
effect of SSRIs on serotonergic neuronal activity. However, upon systemic
administration, pindolol, in contrast to the selective 5-HT1A receptor
antagonist WAY 100635, was unable to reverse the inhibitory effect of an
SSRI on 5-HT neuronal activity. This observation, in conjunction with
other data from our laboratory, rather indicates that pindolol exerts a
weak agonistic activity on sontatodendritic 5-HT1A autoreceptors and thus
may shorten the delayed onset of action of SSRIs by a mechanism unrelated
to 5-HT1A receptor blockage.
In other experiments, repeated treatment with a noradrenaline reuptake
inhibitor (NRI), was found to cause a gradual increase in noradrenaline
nerve-terminal output and a partial recovery of the initially suppressed
noradrenergic electrophysiological activity during the course of the
treatment, consonant with a partial desensitization of the presynaptic
inhibitory feedback mechanism. Administration of a low dose of an alpha2
-adrenoceptor antagonist enhanced noradrenaline neuronal activity, as
well as nerve-terminal. release, most markedly in chronically, but also
acutely, treated animals; tentatively indicating an advantageous effect
of this drug combination in the treatment of at least some forms of
depression.
Modulation of central serotonergic function is thought to mediate the
clinical action of several classes of antidepressant drugs, and previous
data demonstrate a central noradrenergic regulation of midbrain
scrotonergic neurons. We have now observed that acute administration of
die highly selective NRI reboxetine increases the firing rate of
serotonin neurons in the dorsal raphe nucleus, which, in turn, results in
an enhanced cortical output of serotonin; effects that may have bearing
on the clinical action of selective NRls, Analogous studies of the
effects of NRIs on the function of the mesolimbocortical dopamine system
revealed several effects. Thus, acute administration of reboxetine
increased burst firing, but not basal firing rate, of dopamine neurons in
the ventral tegmental area and concomitantly enhanced doparmine output in
the prefrontal cortex, but not in the nucleus accumbens, This effect of
reboxetine on cortical dopamine release is similar to that caused by
alpha2-adrenoceptor antagonists as well as most atypical antipsychotic:
drugs.
Previous observations have shown that concomitant treatment with an cc,
adrenoceptor antagonist my markedly enhance the effect of a dopamine D2
receptor antagonist, i.e. a classical antipsychotic drug, on prefrontal
dopamine output as well as in the conditioned avoidance response (CAR)
test, a preclinical test of antipsychotic efficacy with high predictive
validity, supporting the observed advantageous clinical antipsychotic
effect of this drug combination. Given the similar effects of alpha2
-adrenoceptor blockage and noradrenaline reuptake inhibition on cortical
dopamine function, we investigated the effect of reboxetine in the same
experimental paradigm. Pretreatment with reboxetine significantly
enhanced the effect of the D 2 receptor antagonist on cortical dopamine
output as well as in the CAR test, without affecting catalepsy scores.
Our data thus indicate that noradrenaline reuptake inhibition may augment
the clinical effect of classical antipsychotic drugs in the treatment of
schizophrenia, tentatively with particular regard to negative and
cognitive symptoms
Effects of saline or mianserin (5 mg/kg, IP) pre-treatment (30 min) on saline – or raclopride (0
1 and 1.0 mg/kg SC) – induced effects on catalepsy (a) 30 min, (b) 60 min, (c) 120 min, and (d) 240 min after saline or raclopride administration. Each bar represents the median catalepsy score (± semi-interquartile range; n = 8 in all groups). Statistical evaluation was performed by means of the Kruskal-Wallis one way analysis of variance (ANOVA), followed by the Mann-Whitney U-test. ANOVA Chi (df = 5) = 11.75, p > 0.05. p < 0.05, p < 0.01, ***p < 0.001 compared with respective control (saline/saline or mianserin/saline).<p><b>Copyright information:</b></p><p>Taken from "Adjunctive treatment with mianserin enhances effects of raclopride on cortical dopamine output and, in parallel, its antipsychotic-like effect"</p><p></p><p>Neuropsychiatric Disease and Treatment 2005;1(4):356-372.</p><p>Published online Jan 2005</p><p>PMCID:PMC2424124.</p><p>© 2005 Dove Medical Press Limited. All rights reserved</p