Efficacy of intranasal administration of neostigmine in myasthenic patients

Summary The efficacy of intranasally administered neostigmine was tested in 22 patients with generalized myasthenia gravis (MG). Topical therapy to the highly vascularized oropharynx proved to be quickly effective in 5–15 min both clinically and electrophysiologically. Twenty-eight MG patients were then recruited from different centres and their morning doses of oral pyridostigmine were substituted with intranasal neostigmine over a period of 2 or 3 weeks. Intranasal neostigmine proved to be equally efficacious in this regimen. No side-effect was noted even in 4 patients treated in this way for 1 year. Intranasal administration of anti-acetylcholinesterase may be very beneficial: (1) for patients with irregular absorption of oral doses; (2) early in the morning and every time a fast and temporary effect is needed; (3) in bulbar impairment and emergencies, in which a handy atomizer may be life-saving.Presented in part at the XIV World Congress of Neurology, New Delhi, 22–27 October 1989     

Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics

The effects of hemicholinium-3 (HC-3) on spatial discriminaton learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical float (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 g/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 g/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46–460 g/kg/SC) and tetrahydroaminoacridine (THA) (2.2–10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046–1 mg/kg/SC), aceclidine (1–10 mg/kg/SC), oxotremorine (30–100 g/kg/SC) and RS-86 (0.46, 1.0 g/kg/SC) were also effective. Pilocarpine (0.22–2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6–10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The ₂ agonist, clonidine (46, 100 g/kg SC) and the antagonist idazoxan (32, 100 g/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 g/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT_1A agonist 8-OH-DPAT (30, 100 g/kg) or by the benzodiazapine antagonist ZK 93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.     

The effect of papaine on the time course of the end-plate current

Papaine is known to detach cholinesterases from the synaptic cleft. It could be expected that this would result in an increase of the amplitude and half-time of the end-plate current. Thus, the effect of papaine on the end-plate current should be similar to the effect of anticholinesterase methanesulfonyl-fluoride.The end-plate current was recorded in frog skeletal muscle at various levels of membrane potential, before and after papaine was added to the bath.The effect of papaine was an increase of the half-time of the end-plate current, similarly as after treatment of the muscle by methanesulfonylfluoride.It seems that both papaine and methanesulfonyl-fluoride have a similar mechanism of action. In either experimental condition hydrolysis of transmitter is decreased or abolished, which results in an increase of the half-time of the end-plate current.This work was supported by the Research Community of Slovenia     

Junctional and extrajunctional acetylcholine receptors in normal and denervated frog muscle fibres

Summary Ionic channel properties of acetylcholine receptors located in, in the vicinity of, or far away from a frog neuromuscular junction were investigated by noise analysis of drug induced current fluctuations. For drugs applied to the junction, in certain cases two Lorentzian curves were necessary to describe the data. It is postulated that the reason for this observation is that a contribution from perijunctional receptors was being observed. The conductance of a single channel in the junction was independent of the nature of the agonist and had an average value of 17.9 pS (temperature range 8–25°C, solution buffered with Tris). After denervation for 21 days the conductance γ was 7.5 pS at extrajunctional locations. In the close neighbourhood of the junction (perijunctional receptors) values were found between 4 and 19 pS. The mean value of the open channel life-time τ in the endplate exposed to acetylcholine was 2.4 ms at 8–11°C. This value was 0.90 ms with carbachol, 0.50 ms with succinylcholine, 0.28 ms with decamethonium and 0.45 ms with nicotine. The receptors outside the endplate exhibited τ-values which at a given temperature were 2–3 times larger than those at the endplate. Raising the temperature to 23°C reduced all τ-values by factors of 2–3. It is concluded that at least two types of ACh-receptors with different properties exist in the muscle membrane, possibly produced by ACh-receptive units in different states of aggregation. This work was supported by the Deutsche Forschungsgemeinschaft, SFB 38, Project N     

End-plate currents evoked by paired stimuli in frog muscle fibres

Using voltage-clamp techniques spontaneously occuring miniature end-plate currents (mepc) and nerve-evoked end-plate currents (epc) were recorded in frog glycerol-treated or cut muscle preparations. Epcs were induced by pairs of stimuli (the delay of the 2nd stimulus, t being 6 ms–30 s; one pair was delivered every 60–90 s). The decay time constant of the epc (_epc) was longer, the larger its quantal content despite the presence of active acetylcholinesterase (AChE). After treatment with anticholinesterases (prostigmine or armin, an irreversible inhibitor) this increase in _epc became more pronounced. When AChE was fully active the decay of the 1st epc ₁ was slightly faster than the decay of the 2nd epc ₂ only when the interstimulus interval was rather short (t<20 ms). Following treatment with anticholinesterases this difference between ₂ and ₁ could be determined even when t was as long as 30 s. In anticholinesterase-treated preparations was found to be inversely proportional to log t: a 50% increase in the decay time-constant of the 2nd epc occurred with t=120 ms. During continuous stimulation (10 impulses/s) _epc increased from the 1st to the 5–6th responses, but then decreased in parallel with the fall in the epc amplidude. The phenomenon of postsynaptic potentiation we observed could be readily abolished when quantal content was decreased by the presence of magnesium ions, but it was relatively unaffected when the receptor density was decreased by -bungarotoxin (-BuTX).The possible existence is discussed of two kinds of repetitive binding of ACh molecules, first, to free cholinoreceptors (a process which could be inhibited by -BuTX) and, second, to a complex of the cholinoreceptor plus one molecule of ACh (a process which is less sensitive to -BuTX blocking action).     

有机磷农药敌敌畏和对硫磷所致大鼠循环衰竭时的血流动力学特征

目的：在胆碱酯酶抑制剂（ChEI）类有机磷农药敌敌畏、对硫磷所致大鼠循环衰竭模型上，观察循环衰竭前后大鼠血流动力学及心电图变化，旨在阐明有机磷农药中毒引起的循环衰竭的血流动力学特征。方法:健康Wistar雄性大鼠，体重（320±20） g，腹腔注射累积染毒，直至平均动脉压（MBP）降至45 mmHg为循环衰竭标准。观察循环衰竭前后血流动力学指标及心电图变化。结果:2种农药所致大鼠循环衰竭时，收缩压（SBP）、舒张压（DBP）、平均血压（MBP）、心率（HR）、左室内压上升段最大变化速率（+dp/dt_max）、心肌纤维缩短速度（Vpm）以及+dp/dt_max与等容收缩期压力（IP）的比值（+dp/dt_max/IP）均显著低于染毒前，反映心脏舒张功能的左室舒张压（LVDP)、左室内压下降段最大变化速率（-dp/dt_max）、IP均显著高于染毒前（P<0.01）;心电图显示心率缓慢，心律失常。结论:有机磷农药导致大鼠循环衰竭时心率、心脏收缩功能和舒张功能均显著下降，心脏起搏与传导功能受损。     

吡啶斯的明试验对评价垂体hGH储备功能的价值

垂体hGH分泌受中枢神经介质调控。兴奋胆碱能系统可使hGH增加。本文试用胆碱酯酶抑制剂吡啶斯的明兴奋hGH,并与胰岛素兴奋试验进行比较,观察了13名正常青少年和10名垂体性侏儒症患者对两种兴奋试验的反应。结果显示口服吡啶斯的明2mg/kg体重能迅速有效地兴奋垂体hGH释放。其作用较胰岛素兴奋试验更强,是一项值得推荐的判定青少年垂体hGH储备功能的试验。     

甘露醇对动物血清胆碱酯酶的影响

目的：研究甘露醇对小鼠和家兔外周血清胆碱酯酶的影响。方法：取小鼠36只、家兔32只均随机平分为4组。A组给予2.5%敌百虫500 mg·kg 1，小鼠用腹腔注射，家兔用耳缘静脉注射；B组给予20%甘露醇200 mg·kg 1，iv，C组给予10%甘露醇100 mg·kg 1；D组给予等容量0.9%氯化钠注射液，iv。A组于给药10 min，其他组静脉注射30 min后，采血测定血清胆碱酯酶活性。结果：B、C组的小鼠、家兔胆碱酯酶活性明显低于D组，但高于A组。结论：甘露醇可抑制血清胆碱酯酶活性，抑制作用具有剂量依赖性，但抑制作用低于敌百虫。     

急性有机磷杀虫药中毒中间综合征的临床分析

目的探讨急性有机磷杀虫药中毒中间综合征（intermediate syndrome,IMS）的诊断治疗。方法回顾性分析10例IMS患者临床表现和治疗方法。结果有机磷中毒中间综合征的10例患者均出现不同程度呼吸肌麻痹症,及时建立人工气道及机械通气和乙酰胆碱酯酶（AchE）复能剂应用,治愈8例,死亡2例。结论 IMS应早期识别,建立人工气道与机械通气是抢救成功的重要方法。     

Evaluation of Different Laboratory Tests and Activity Indices Reflecting the Inflammatory Activity of Crohn's Disease

In a prospective study we compared the usefulness of various laboratory tests (albumin, alpha-1-proteinase inhibitor (A1PI), cholinesterase (CHE), C-reactive protein, erythrocyte sedimentation rate, hematocrit) and activity indices (CDAI, VHAI) in relation to the disease activity by endoscopic criteria. Except for hematocrit highly significant differences (p < 0.0005) of the mean values of all test results were found for patients without or with slight mucosal lesions compared with patients with severe inflammation of the mucosa. Further analysis of the data indicates the highest test efficiency (84%), sensitivity (80%), and specificity (88.6%) for CHE. CHE showed good correlations to all other tests; the highest correlation was found between CHE and VHAI (r = -0.78). We suggest that a suppression of CHE synthesis mediated by endotoxins and cytokines rather than an increased intestinal loss explains the decreased CHE in severe Crohn's disease. It is concluded from the data that CHE is a useful test to assess the inflammatory activity of Crohn's disease.