Role of dopamine in pilocarpine induced motor seizures.

Secondarily generalised motor seizures of limbic origin (hereafter referred to as "limbic" motor seizures) were induced in rats by injecting a high dose of the muscarinic agonist pilocarpine intraperitoneally. This model was used to investigate the involvement of central dopaminergic systems in the development and spread of these seizures. Pilocarpine was found to induce motor seizures in rats in a dose dependent manner. From this study 200 mg/kg and 600 mg/kg pilocarpine i.p. were taken to be threshold convulsant and convulsant doses respectively. Pretreatment with the D1 partial agonist SKF 38393 (30 mg/kg i.p.) caused 100 % of animals tested to convulse in response to 200 mg/kg pilocarpine, and this effect was blocked by the D, antagonist SCH 23390 (0.25 mg/kg i.p.). By contrast, the Dj agonist LY 171555 (0.5 mg/kg s.c.) protected rats against a convulsant dose of pilocarpine, and this action was abolished by the D2 receptor blocker metoclopramide (1.25 mg/kg i.p.). Neither SCH 23390 nor metoclopramide on their own affected seizures induced by 600 mg/kg and 200 mg/kg pilocarpine respectively. These results clearly demonstrated that D, and D2 dopamine receptors function in opposition to regulate seizure activity in this model. Stereotaxic injection of drugs via chronically implanted guide cannulae demonstrated that the proconvulsant action of SKF 38393 could be duplicated by injecting the drug into the substantia nigra (2.5 ?g in 0.5 ?1 bilaterally), and that this action was blocked by pretreatment with SCH 23390 (0.25 mg/kg i.p.). Intranigral injection of the D1 antagonist SCH 23390 (1 ?g in 0.5 ?l bilaterally) protected rats against a convulsant dose of pilocarpine. Intranigral injection of the D2 agonist LY 171555 (1 fig in 0.5 ?1) had no effect on seizures induced by a convulsant dose of pilocarpine. In the striatum, it was confirmed that injection of LY 171555 (1 ?g in 1 ?l bilaterally) into the rostral parts of the caudate is anticonvulsant. However, another I D2 agonist, RU 24213 (1 ?g in 1 ?l bilaterally), failed to protect rats against a convulsant dose of pilocarpine. Systemically injected RU 24213 (4.5 mg/kg s.c.) had no effect on the convulsant action of 600 mg/kg pilocarpine. These data suggest a subpopulation of D2 receptors is responsible for mediating the anticonvulsant response. With regards to D1 receptors in the striatum, the antagonist SCH 23390 (1 ?g in 1 ?l bilaterally) protected rats from a convulsant dose of pilocarpine when injected throughout the rostro-caudal axis of the caudate and into the nucleus accumbens. By contrast, both SKF 38393 (0.1, 1 and 2.5 ?g in 1 ?l bilaterally) and another D1 partial agonist CY 208-243 (0.1 and 1 ?g in 1 ?l bilaterally) had no effect on seizure threshold when injected into the caudate. Both drugs were similarly ineffective when injected into the nucleus accumbens (1 ?g in 1 ?l bilaterally). Early studies indicated that excessive mechanical damage to the cortex may be associated with a lack of seizure protection of intrastriatal LY 171555. This was confirmed when intrastriatal injection of LY 171555, into animals with kainic acid- induced cortical lesions, was found not to be anticonvulsant, as compared with unlesioned controls. Thus it appeared that intact corticostriatal connections were essential for intrastriatal LY 171555 to be anticonvulsant. In vivo microdialysis studies were conducted in conscious, freely moving rats, to investigate changes in striatal dopaminergic transmission associated with seizures induced by pilocarpine. A highly disorganised pattern of dopamine release coincided with the onset of convulsions, with the magnitude of the disruption parallelling the severity of the seizures. It was unclear however whether this phenomenon was part of the mechanism underlying seizure propagation, or whether it was an adaptive response. By contrast, the metabolite homovanillic acid significantly increased, but only did so after seizures had developed, suggesting this might be a compensatory mechanism to contain the seizure. Similar microdialysis studies were done to measure striatal aspartate and glutamate releases during pilocarpine induced seizures, although it is questionable whether the method used necessarily measures amino acid release from a transmitter pool, since it was not always stimulated by high K+; what was apparent was that SKF 38393 significantly decreased aspartate release, with a more modest reduction in glutamate output. In view of the fact that excitatory activity in the striatum is anticonvulsant, a reduction in this activity is consistent with a lowering of seizure threshold

Systematic review of the safety of medication use in inpatient, outpatient and primary care settings in the Gulf Cooperation Council countries

Background Errors in medication use are a patient safety concern globally, with different regions reporting differing error rates, causes of errors and proposed solutions. The objectives of this review were to identify, summarise, review and evaluate published studies on medication errors, drug related problems and adverse drug events in the Gulf Cooperation Council (GCC) countries. Methods A systematic review was carried out using six databases, searching for literature published between January 1990 and August 2016. Research articles focussing on medication errors, drug related problems or adverse drug events within different healthcare settings in the GCC were included. Results Of 2094 records screened, 54 studies met our inclusion criteria. Kuwait was the only GCC country with no studies included. Prescribing errors were reported to be as high as 91% of a sample of primary care prescriptions analysed in one study. Of drug-related admissions evaluated in the emergency department the most common reason was patient non-compliance. In the inpatient care setting, a study of review of patient charts and medication orders identified prescribing errors in 7% of medication orders, another reported prescribing errors present in 56% of medication orders. The majority of drug related problems identified in inpatient paediatric wards were judged to be preventable. Adverse drug events were reported to occur in 8.5–16.9 per 100 admissions with up to 30% judged preventable, with occurrence being highest in the intensive care unit. Dosing errors were common in inpatient, outpatient and primary care settings. Omission of the administered dose as well as omission of prescribed medication at medication reconciliation were common. Studies of pharmacists’ interventions in clinical practice reported a varying level of acceptance, ranging from 53% to 98% of pharmacists’ recommendations. Conclusions Studies of medication errors, drug related problems and adverse drug events are increasing in the GCC. However, variation in methods, definitions and denominators preclude calculation of an overall error rate. Research with more robust methodologies and longer follow up periods is now required.Peer reviewe

Adverse Drug Reactions in Children—A Systematic Review

Adverse drug reactions in children are an important public health problem. We have undertaken a systematic review of observational studies in children in three settings: causing admission to hospital, occurring during hospital stay and occurring in the community. We were particularly interested in understanding how ADRs might be better detected, assessed and avoided