Olivia Leoni

N-Methyl-di-aspartate receptors modulate neurotransmitter release and peristalsis in the guinea pig isolated colon ☆

To assess the role of NMDA receptors in modulating neurotransmitter release in the myenteric plexus, we studied the effects of L-glutamic acid and NMDA on endogenous acetylcholine and noradrenaline overflow (assayed by HPLC) from the guinea pig isolated distal colon. L-Glutamic acid and NMDA enhanced electrically evoked acetylcholine and noradrenaline overflow and these effects were reversed by selective NMDA receptor antagonists. The possible functional significance of these findings was studied by measuring the efficiency of the colonic peristaltic reflex in the presence of NMDA receptor agonists. NMDA inhibited propulsion velocity at all concentrations tested, this effect being antagonized by (+/-)-2-amino-5-phosphonopentanoic acid and virtually abolished in sympathetically denervated animals. In conclusion, the inhibitory effect of NMDA on peristalsis, being almost entirely dependent on the integrity of sympathetic pathways, could be, at least in part, due to NMDA-induced noradrenaline release.

An approach for the estimation of drug prescribing using the defined daily dose methodology and drug dispensation data

AbstractObjective: To test the hypothesis that comparison of defined daily dose (DDD) and drug user data may help to estimate drug exposure in a defined population and provide information about drug prescribing patterns. Methods and results: First, comparison of DDD figures with the number of apparent drug users (ADU, i.e., individuals for whom at least one prescription of the drug had been dispensed during a given time period) is demonstrated to correspond to the product of the prescribed daily dose (PDD) and the proportion of days in which the drug had been taken (days of treatment/days in a time period, D). The resulting equation (DDD/day)/ADU in a time period=PDD × D is then applied to the analysis of different sets of drug dispensation data. Examples show that this approach may be helpful to monitor drug prescribing patterns over time. Moreover, in definite situations, it may provide reliable estimates of either PDD or D. Conclusions: Comparison of DDD and drug user data is suggested to be a cost-effective strategy to monitor drug prescribing patterns from an epidemiological perspective, which may be useful to researchers involved in drug utilisation studies as well as to health authorities for monitoring and regulatory purposes.

Tonic modulation of neurotransmitter release in the guinea-pig myenteric plexus: effect of μ and κ opioid receptor blockade and of chronic sympathetic denervation ☆

We have studied the effects of mu- and kappa-opioid receptor blockade on endogenous acetylcholine and noradrenaline overflow from the myenteric plexus of the guinea-pig isolated colon. Cyprodime (putative mu-selective antagonist) and nor-binaltorphimine (kappa-selective antagonist) had a concentration-dependent facilitatory effect on both acetylcholine and noradrenaline overflow. Moreover, in colonic specimens obtained from sympathetically denervated animals, the effect of opioid antagonists on acetylcholine overflow was significantly higher with respect to normal preparations. Evidence is thus given in favour of an involvement of mu- and kappa-opioid receptor pathways in the tonic modulation of neurotransmitter release at the colonic level. Enhanced sensitivity to the effect of mu and kappa antagonists after chronic sympathetic denervation is strongly suggestive for the existence of a functional link between opioid and adrenergic pathways in this model.

Acetylcholine detection by a modified HPLC-ED method improves the assessment of cholinergic function in the myenteric plexus of the guinea-pig colon.

Because of the low basal output, measurement of acetylcholine (ACh) release from enteric neurons usually requires cholinesterase inhibition, a condition which is known to interfere with feed-back mechanisms regulating ACh release. In this study, we resorted to a highly sensitive HPLC-ED method to determine the minimum requirement of physostigmine to achieve reliable quantitation of spontaneous endogenous ACh overflow from the guinea-pig isolated colon. Furthermore, in order to assess the degree of interference by physostigmine with cholinergic function, we assessed the effect of scopolamine and oxotremorine (in the presence of physostigmine) on spontaneous ACH overflow (to detect the presence of autoreceptors) and also measured the efficiency of the peristaltic reflex with different physostigmine concentrations. Spontaneous endogenous ACh overflow was detectable only with physostigmine concentrations > or = 10 nM. ACh overflow increased with increasing physostigmine concentrations (10 nM-10 microM range). Scopolamine significantly enhanced the facilitatory effect of physostigmine concentrations > or = 10 nM; conversely, oxotremorine inhibited ACh overflow. Peristaltic efficiency was not significantly affected by physostigmine concentrations < or = 300 nM. In conclusion, this modified HPLC-ED method allows ACh detection with minimal physostigmine concentrations (10-30 nM), which do not interfere with peristaltic activity, do not saturate autoreceptor feed-back mechanisms and therefore improve the assessment of cholinergic function in colonic enteric neurons.

A 1-Year Study of Drug Prescriptions and Adverse Drug Reactions in Psychiatric Hospital Practice

Drug prescribing habits and adverse drug reaction occurrence were investigated in a psychiatric hospital ward for chronic resident patients, and the usefulness of a drug prescription and adverse event (AE) routine monitoring programme in this setting was assessed. A computerized data base was established and updated bimonthly with clinical data concerning each patient. In particular, information about drug prescriptions was routinely obtained from the clinical records, stored in the data base and periodically retrieved and analysed. The ward doctors were required to report on a form the AEs, which were subsequently examined by a panel of clinical pharmacologists and hospital consultants, to assess their relationship with drug treatments. Moreover, the data base was periodically scrutinized, to search for further AEs. Drug prescription monitoring, besides providing valuable information about drug utilization, allowed identification of some questionable issues (e.g. polypharmacy, low frequency of treatment revisions). The AE monitoring system proved to be effective and the participation of the ward doctors was satisfactory. It is concluded that in this psychiatric hospital setting a drug prescription and AE routine monitoring programme can provide useful information and promote improvement of the quality of care.

Increased reporting of adverse reactions to ACE inhibitors associated with limitations to drug reimbursement for angiotensin-II receptor antagonists.

Abstract. Background and aim: From February 1998 to September 1999, the Italian Ministry of Health limited angiotensin-II type-1 (AT1) receptor antagonist reimbursement only to patients who necessitated discontinuation of angiotensin converting enzyme (ACE) inhibitor treatment due to cough or angioedema. We assessed the consequences of this decision on the reporting of ACE inhibitor-associated adverse drug reactions (ADRs). Methods: ACE inhibitor-associated ADRs reported to the national pharmacovigilance system in 1997–2000 in the district of Varese (northern Italy, more than 820,000 inhabitants) were retrieved and analysed. The dispensation of ACE inhibitors and AT1 receptor antagonists reimbursed by the National Health System was also examined. Results: There were 228 reports of ACE inhibitor-associated ADRs, and cough was the ADR reported in 93.4% of cases. There were no reports of cough in 1997, 50 in 1998, 156 in 1999 and 7 in 2000. In 1998–1999, the dispensation of ACE inhibitors showed little variation, while that of AT1 receptor antagonists grew about twofold. Conclusions: There was a clear correlation between ACE inhibitor-associated ADR reporting and limitation to AT1 receptor antagonist reimbursement status. Drug reimbursement policies should thus be added to the list of factors that may bias ADR reporting, and health authorities should be aware of this potential bias when defining specific measures to regulate prescription and use of new drugs.

The Role of European Healthcare Databases for Post-Marketing Drug Effectiveness, Safety and Value Evaluation: Where Does Italy Stand?

Enormous progress has been made globally in the use of evidence derived from patients’ clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.