Effects of prolyl-leucyl-glycinamide and cyclo(leucyl-glycine) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to rats

The effects of melanotropin release-inhibiting factor, a tripeptide (Pro-Leu-Gly-NH₂) derived from the hypothalamus, and its enzymatically stable analog, cyclo(Leu-Gly) on the supersensitivity of dopamine receptors in brain induced by chronic administration of haloperidol to male Sprague-Dawley rats was determined. Oral administration of haloperidol (1.5 mg/kg per day) for 21 days induced supersensitivity of dopamine receptors as shown by enhanced locomotor activity in response to apomorphine, and an increase in the number of binding sites for [³H]spiroperidol in the striatum. Subcutaneous administration of Pro-Leu-Gly-NH₂ or cyclo(Leu-Gly) in doses of 2 mg/kg per day, given prior to the injection of haloperidol, inhibited both the enhanced response to apormorphine as well as the increase in the number of binding sites for [³H]spiroperidol in the striatum. Chronic administration of either of the peptides alone did not modify either the apomorphine-induced response or the binding of [³H]spiroperidol in the striatum. These studies suggest that the hypothalamic peptide, Pro-Leu-Gly-NH₂ and its long-acting analog, cyclo (Leu-Gly) can prevent the development of both behavioral and biochemical supersensitivity of dopamine receptors in brain induced by neuroleptic drugs and that these peptides may be useful in preventing the development of neuroleptic-induced tardive dyskinesia.     

Characteristics of infantile convulsions and choreoathetosis syndrome caused by PRRT2 mutation

Importance:Infantile convulsions and choreoathetosis(ICCA)is a rare neurological disorder.Many affected patients are either misdiagnosed or prescribed multiple antiepileptic drugs.Objective:To explore therapeutic drug treatments and dosages for ICCA in children.Methods:Detailed clinical features(e.g.,past medical history and family history),genetic features,and treatment outcomes were collected from the records of six patients with ICCA.Results:Mean age at paroxysmal kinesigenic dyskinesia(PKD)onset was 8 years 8 months(range,3-12 years);the clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia.All patients had infantile convulsions at less than 1 year of age,and the mean onset age was 5.5 months(range,4-7 months).Two patients had a family history of ICCA,PKD,or benign familial infantile epilepsy.Whole exome sequencing identified the c.649-650insC mutation in PRRT2 in six patients;three mutations were inherited and three were de novo.All patients were prescribed low-dose carbamazepine and showed dramatic improvement with the complete disappearance of dyskinetic episodes after 3 days.They attended follow-up for 5-17 months and were attack-free until the final follow-up.Interpretation:PRRT2 mutations are the primary cause of ICCA.Lowdose carbamazepine monotherapy is effective and well-tolerated in children.     

Safinamide for the treatment of Parkinson’s disease

Introduction: The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms and disease modification.

Areas covered: Motor fluctuations and OFF periods are a significant determinant of quality of life in PD and reducing their duration and severity can significantly improve motor function. This aim may be partly facilitated by the development of effective adjunctive drugs for dopamine replacement. Safinamide (Xadago), which is a first generation anticonvulsant, has pharmacological properties which are of interest in the context of neurodegenerative diseases, leading to research into its potential as an adjunct to levodopa in PD.

Expert opinion: Although its mechanism has not been fully defined, safinamide provides enhanced symptom control of motor function in advanced PD and improves quality of life.     

莫西沙星注射液导致全身皮疹的迟发型过敏反应

目的分析莫西沙星注射液导致全身皮疹的迟发型过敏反应。方法临床药师参与患者应用莫西沙星注射液后第8天出现全身皮疹的迟发型过敏反应的治疗,对其发生原因进行探讨。结果与结论该例患者的皮疹与莫西沙星注射液的相关性极大。莫西沙星注射液导致的迟发型过敏反应,医师、药师及护士应予以高度重视,同时做好药物不良反应的监测。     

Association of diabetes with dyskinesia in older psychosis patients

Rationale Older patients treated with antipsychotics are more likely to develop tardive dyskinesia (TD) than younger individuals. Advanced age is also an important risk factor for diabetes, which may be associated with TD. These observations suggest that older diabetic patients may be particularly vulnerable to developing TD.Objective To examine whether older psychosis patients with diabetes exhibit more severe dyskinesia than well-matched patients without diabetes and to test whether there are differences in dyskinesia severity between diabetic patients treated with conventional versus atypical antipsychotics versus those not taking antipsychotic medications.Method Sixty-one psychosis patients with diabetes and 122 case-matched non-diabetic comparison patients were studied. Observer-based and quantitative instrumental measures were administered to assess prevalence and severity of dyskinesia. Raters were unaware of patients diabetes status.Results Diabetic patients exhibited significantly more severe TD than non-diabetic comparison patients. Groups did not differ in terms of severity of parkinsonism. Significantly more diabetic (27.9%) than non-diabetic (14.6%) patients met research diagnostic criteria for TD. Diabetic patients treated with atypical antipsychotics at the time of assessment had significantly more severe TD than all other patient subgroups, including patients treated with conventional antipsychotics. Results from the instrumental measures of force steadiness were consistent with observer-based severity ratings.Conclusion The deleterious effect of diabetes on TD in the absence of any effect of parkinsonism supports preclinical studies of glucose-related dopamine hyperfunction and has implications for the pharmacologic management of psychosis in patients with pre-existing diabetes.     

Interaction between chronic amphetamine and neuroleptic treatments on oral behavior in rats

The interaction of concurrently administered amphetamine (AMPH) and haloperidol (HAL) on behavior was examined. Rats were divided into four groups: drug naive controls; HAL-treated for 6 months; AMPH-treated for 1 month; and rats administered both continuous HAL for 6 months and concurrent AMPH treatment during the 2nd month of HAL administration. AMPH alone increased locomotor activity, and this effect was blocked by concurrent haloperidol administration; however, the AMPH-induced reduction of body weight was unaltered by concurrent haloperidol treatment. Oral behavior, monitored both by a human observer and a computerized system, was not significantly altered by HAL alone, or by AMPH alone, but increases in tremorous oral behavior appeared in the concurrent administration group 4 months after AMPH treatment was discontinued. These results could have implications for tardive dyskinesia.     

Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities

The development of vacuous chewing movements (VCMs), and changes in glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in extrapyramidal nuclei were examined in rats treated chronically with neuroleptics. Animals were injected with flupenthixol (FLU) or haloperidol (HAL) decanoate for 16, 40 or 48 weeks and were then sacrificed. Another group of rats was treated with FLU or HAL for 48 weeks, and then withdrawn from the neuroleptics for 16 weeks before sacrifice. VCMs were assessed weekly, and the effects of the GABA agonist progabide on VCMs and locomotor activity were examined. GAD and ChAT activities were determined at death. The concentrations of Calbindin D_28K (CaBP) and parvalbumin (PV) were determined in rats receiving 48 weeks of neuroleptic treatment. VCMs first appeared after 8–10 weeks of neuroleptic administration, reached asymptotic rates after 18–20 weeks, and then remained stable for the remainder of the chronic drug administration period. During withdrawal, there was a steady decline in the VCM rate. The GABA receptor agonist progabide reduced VCMs and locomotor activity. Significant decreases in nigral GAD activity were observed after 40, but not after either 16 or 48 weeks of neuroleptic administration. CaBP and PV were unchanged after 48 weeks of neuroleptic treatment. In addition, ChAT activities in 16, 40 or 48 week treated animals did not show consistent changes after either neuroleptic. Chronic neuroleptic administration followed by 16 weeks of withdrawal also did not have any significant effects on GAD or ChAT activity in any of the brain areas examined. The present results demonstrate that decreases in nigral GAD activity do not occur when VCMs have reached near maximal rates. It appears, therefore, that neuroleptic-induced VCMs and decreases in nigral GAD activity are not causally related. Nevertheless, the reduction in VCMs produced by progabide suggests that impaired GA-BAergic mechanisms may be involved in the expression of these abnormal perioral movements.     

张伟辨治原发性纤毛运动障碍经验

原发性纤毛运动障碍是由纤毛结构缺陷引起的多发性异常遗传病,属于临床罕见、疑难疾病。张伟老师认为本病因先天禀赋不足,肺肾亏虚,气运失司,布津不利,津聚为痰,痰凝化热导致,临床治疗以清热化痰、健脾养阴固本为法,获得良好疗效。介绍张老师临床治疗本病的经验及临床典型病案,以期对本病的辨治有所启示。