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.     

Autonomic actions and interactions of mianserin hydrochloride (Org. GB 94) and amitriptyline in patients with depressive illness

The clinical pharmacology of mianserin hydrochloride was studied in patients suffering from a primary depressive illness after steady-state plasma concentration of the drug had been achieved. The results were compared with those found with amitriptyline in both open and double-blind studies. The two drugs are equally effective in their antidepressive effect. Mianserin hydrochloride appears to be free of anticholinergic effects as assessed by the measurement of salivary volume, pupil diameter and the interactions with guanethidine and thymoxamine on the pupil. No peripheral adrenergic interaction as studied by the tyramine dose-pressor-response test were observed in patients treated with mianserin hydrochloride (20 mg three times daily).     

Scopolamine induces impairments in the recognition of human facial expressions of anger and disgust

Rationale Recent psychopharmacological studies lend support to the notion of partially dissociable neuronal systems dedicated to processing specific emotions. For example, GABA-ergic enhancement after an acute dose of the benzodiazepine, diazepam, produces specific impairments in anger and fear recognition. However, it is unclear if these impairments are a general property of benzodiazepines and other drugs that produce a similar profile of neurocognitive impairment to benzodiazepines, such as the anticholinergic, scopolamine.Objective We investigated the effects of scopolamine and the benzodiazepine, lorazepam, on emotion-recognition accuracy.Methods A double-blind independent group design was used with 48 healthy volunteers to compare the effects of scopolamine and lorazepam with an inactive placebo on a commonly used emotion-recognition task. Control measures included an episodic memory task and subjective mood ratings.Results Anger and disgust recognition accuracy was impaired after scopolamine. In contrast, lorazepam produced no impairment in emotion-recognition despite producing similar levels of sedation and anterograde amnesia to scopolamine.Conclusions Scopolamine-induced cholinergic hypofunction selectively impaired the recognition accuracy of disgust and anger facial expressions. The effects of scopolamine on emotion-recognition are similar to those found in Huntington’s disease patients. Furthermore, the impairments in anger and fear recognition previously observed with diazepam do not appear to be a general property of benzodiazepines. This suggests that alterations in emotional processing involving changes in the ability to recognize threat-related emotions (particularly, fear and anger) may not be a principal mechanism underlying anxiolysis or paradoxical aggression seen with benzodiazepines.     

Effects of scopolamine on radial maze performance in rats

The behaviour of male Wistar rats given repeated daily injections of scopolamine (0.5 mg/kg) over a 14 day acquisition period was compared with that of controls treated with isotonic saline on an 8-arm radial maze. Following this were 2 test days when the group learning the task under scopolamine received saline and vice-versa. Scopolamine significantly impaired acquisition of the radial maze task, but animals rapidly improved when tested without scopolamine. Animals trained on the task without scopolamine were significantly impaired when treated with it. Those animals using non-spatial strategies were relatively resistant to the effects of scopolamine. The results are discussed in terms of the similarity of effect of hippocampal lesions and anticholinergic drug treatment, and in relation to recent theories concerning the role of the hippocampus in spatial memory.     

Cutaneous blood flow and local sweating after systemic atropine administration

Localized cutaneous vasodilation (flush) is seen following systemic atropine administration. To verify calculated enhanced dry heat loss with actual changes in cutaneous blood flow, four men were studied in both control and atropine (0.025 mg·kg^–1;im) experiments (T _a=30°C,T _dp=7°C) during moderate exercise (55% O₂ peak). Esophageal temperature (T _es) and arm sweating ( ) by local dewpoint were measured continously. Skin (forearm) blood flow (FBF) was measured twice each minute by venous occlusion plethysmography. Injection of atropine (2 mg) caused an increased sensitivity (+85%,p<0.01) in FBF toT _es with no change in the vasodilator threshold. An elevatedT _es onset (0.3°C,p<0.05) for sweating occurred with no change in the sensitivity of toT _es (–27%,p<0.20). No elevation in either forearm or occurred before the onset of vasodilation, however, both mean skin ( ) and local arm temperatures were higher in the atropine experiments after 15 min of exercise. Systemic atropine resulted in higher cutaneous vasodilation at the same core temperature with the local skin temperature following passively. The effect of systemic atropine in stimulation of increased cutaneous vasodilation is suggested to result by a combination of central and local responses which may be mediated through the release of vasoactive sustances.     

非水毛细管电泳拆分抗胆碱能药物对映体

目的建立非水毛细管电泳拆分体系拆分抗胆碱能药物。方法以有机溶剂甲醇为分离介质,磷酸和氢氧化钠为支持电解质,采用带负电荷的环糊精作手性选择剂,对几种抗胆碱能药物进行了毛细管电泳拆分,并探讨了影响拆分的因素。结果以带负电荷的环糊精HDMSβCD为手性添加剂,在含有20mmol·L-1H3PO4和10mmol·L-1NaOH的甲醇介质中,成功分离了6种抗胆碱能手性药物。结论该方法具有操作简单、重现性好、分析时间短等优点,值得推广应用。     

Anticholinergic Drug Use and Negative Outcomes Among the Frail Elderly Population Living in a Nursing Home

AimIncreasing evidence from experimental studies and clinical observations suggests that drugs with anticholinergic properties can cause physical and mental impairment. The aim of the present study was to evaluate the relationship between the use of drugs with anticholinergic activity and negative outcomes in older nursing home residents.MethodsWe used data from the database of the U.L.I.S.S.E project (Un Link Informatico sui Servizi Sanitari Esistenti per l'Anziani), a prospective multicenter observational study. Patients from 31 facilities in Italy were assessed at baseline and at 6 and 12 months by trained personnel, using the Minimum Data Set for Nursing Home (MDS-NH). The only exclusion criterion was age younger than 65 years. The Anticholinergic Risk Scale (ARS), a list of commonly prescribed drugs with potential anticholinergic effects, was used to calculate the anticholinergic load.ResultsA total population of 1490 patients was analyzed; almost half of the sample (48%) was using drugs with anticholinergic properties. The population of patients with ARS 1 or higher had a higher comorbidity index (P < .003) and greater cognitive impairment (CPS 5–6) (P < .007). They were more likely to suffer from heart failure, Parkinson disease, depression, anxiety, and schizophrenia. In multivariate analysis, a higher score in the ARS scale was associated with a greater likelihood of functional decline (described as the loss of ≥1 ADL point) (odds ratio [OR] 1.13; confidence interval [CI] 1.03–1.23), to a higher rate of falls (OR 1.26; CI 1.13–1.41), and to a higher incidence of delirium (OR 1.16; CI 1.02–1.32) during a 1-year follow-up.ConclusionsThe use of medications with anticholinergic properties is common among older nursing home residents. Our results suggest that among older nursing home residents the use of anticholinergic drugs is associated with important negative outcomes, such as functional decline, falls, and delirium.     

The antidiarrheal and spasmolytic activities of Phyllanthus emblica are mediated through dual blockade of muscarinic receptors and Ca2+ channels

Aim of the study

This study was aimed at providing the possible mechanisms for the medicinal use of Phyllanthus emblica in diarrhea.

Materials and methods

The in vivo studies were conducted in mice, while isolated rabbit jejunum and guinea-pig ileum were used for the in vitro experiments.

Results

The crude extract of Phyllanthus emblica (Pe.Cr), which tested positive for alkaloids, tannins, terpenes, flavonoids, sterols and coumarins, caused inhibition of castor oil-induced diarrhea and intestinal fluid accumulation in mice at 500-700 mg/kg. In isolated rabbit jejunum, Pe.Cr relaxed carbachol (CCh) and K⁺ (80 mM)-induced contractions, in a pattern similar to that of dicyclomine. The preincubation of guinea pig-ileum with Pe.Cr (0.3 mg/mL), caused a rightward parallel shift in the concentration-response curves (CRCs) of acetylcholine without suppression of the maximum response. While at the next higher concentration (1 mg/mL), it produced a non-parallel rightward shift with suppression of the maximum response, similar to that of dicyclomine, suggesting anticholinergic and Ca²⁺ channel blocking (CCB)-like antispasmodic effect. The CCB-like activity was further confirmed when pretreatment of the tissue with Pe.Cr, shifted the CRCs of Ca²⁺ to the right with suppression of the maximum response, similar to nifedipine or dicyclomine. The activity-directed fractions of Pe.Cr showed a combination of Ca²⁺ antagonist and anticholinergic like components in all fractions but with varying potency.

Conclusion

These results indicate that the Phyllanthus emblica fruit extract possesses antidiarrheal and spasmolytic activities, mediated possibly through dual blockade of muscarinic receptors and Ca²⁺ channels, thus explaining its medicinal use in diarrhea.     

β2受体激动剂联合抗胆碱能药物治疗慢性阻塞性肺疾病临床观察

目的观察β2受体激动剂联合抗胆碱能药物治疗慢性阻塞性肺疾病临床疗效。方法将192例慢性阻塞性肺疾病患者随机分为试验组和对照组各96例。对照组予常规治疗,试验组在对照组治疗基础上,使用β2受体激动剂和抗胆碱能药物进行治疗。观察2组临床疗效及肺功能指标[1s内用力呼气容积（FEV1）和FEV1与肺活量预测值比值（FEV1／FVC）及最大用力呼气流量（PEF）]改善情况。结果试验组总有效率为91．7％高于对照组的71．1％,差异有统计学意义（P〈0．05）。治疗后,试验组FEV1、FEV1／FVC和PEF水平均高于治疗前及对照组,差异均有统计学意义（P〈0．05）。结论β2受体激动剂联合抗胆碱能药物治疗慢性阻塞性肺疾病效果显著,且能有效改善患者的肺部功能,提高患者的生活质量,值得临床推广应用。