Effect of transdermal scopolamine on salivation

The effect of transdermal scopolamine on salivary flow and composition was analyzed in 21 healthy volunteers. The flow rate of whole saliva was significantly lowered by transdermal scopolamine. Significant positive correlations were found between the placebo rate of flow and both the quantity and percentage decreases in response to transdermal scopolamine. The magnesium concentration was significantly increased during transdermal scopolamine administration, whereas the sodium, potassium, and calcium concentrations were not consistently altered. Accordingly, the magnesium secretion rate was unaltered, whereas sodium, potassium, and calcium secretion rates were significantly lowered by transdermal scopolamine administration.     

Alteration of the rat exocrine pancreas after chronic scopolamine administration

N-Methyl scopolamine (NMS) 25 mg kg-1 was given to rats for 14 days as a single daily intraperitoneal injection or by constant infusion through osmotic minipumps placed in the abdominal cavity. The anticholinergic drug reduced significantly body and pancreatic weights, and total pancreatic DNA contents, an indication of tissue growth inhibition. Total enzyme and protein contents were however significantly increased with the drug infusion more efficiently than by the daily injection. It is suggested that pancreatic hypertrophy observed after NMS treatment can be ascribed partially to inhibition of enzyme release elicited by blocking the enteropancreatic reflex causing over a long period enzyme accumulation in the gland. In conclusion, chronic anticholinergic treatment resulted in pancreatic aplasia and hypertrophy and could serve as a good model to study muscarinic receptor modulation in the pancreas.     

The effects of dimenhydrinate, cinnarizine and transdermal scopolamine on performance

We assessed the influence of dimenhydrinate, cinnarizine and transdermal scopolamine on the ability to perform simulated naval crew tasks. The effect of single doses of dimenhydrinate, 100 mg, cinnarizine, 50 mg, and one transdermal scopolamine patch on psychomotor performance was evaluated using a double-blind, placebo-controlled, randomized, crossover design in three separate studies. A total of 60 young naval crew (20 for dimenhydrinate, 15 for cinnarizine and 25 for transdermal scopolamine) underwent a battery of computerized and paper and pencil performance tests, and filled out a questionnaire on side-effects and well-being self-assessment. Dimenhydrinate significantly impaired decision reaction time and auditory digit span. Most of the subjects who took dimenhydrinate also reported a subjective decrease in well-being and general performance abilities. Cinnarizine and transdermal scopolamine did not affect performance abilities. Cinnarizine was free of significant side-effects. Dry mouth was the only significant side-effect of transdermal scopolamine. These findings could be explained by the well-known sedative properties of dimenhydrinate and not by a specific effect on any particular cognitive or motor function. Our results suggest that dimenhydrinate, 100 mg, adversely affects psychomotor function, whereas single doses of cinnarizine, 50 mg, and transdermal scopolamine appear to be free of side-effects on performance and seem to be a preferable anti-seasickness drug for use by a naval crew.     

The effects of transdermal scopolamine on autonomic nervous activity during sleep

We studied the effect of transdermally applied scopolamine (scopolamine-TTS) on autonomic nervous activity during sleep. The double-blind, randomized, crossover study was carried out in six healthy male volunteers by applying 1.5 mg scopolamine-TTS or placebo patch on the retroauricular skin and by monitoring heart rate, cardiac ballistogram, respiration and body movements by using electrocardiogram and static charge sensitive bed.Scopolamine did not decrease the time the subjects desired to sleep (516 min after TTS, 511 min after placebo) or the number of body movements of 3–5 s duration the subjects spontaneously performed during sleep (47 after TTS, 58 after placebo). No adverse effects of scopolamine were reported spontaneously. Scopolamine-TTS slowed the mean heart rate during quiet sleep from 53.2 to 44.9 beats · min^–1, and increased the duration of bradycardia in response to body movements (MIB-reflex) from 12.5 to 14.7 s with a significant difference between scopolamine and placebo effects. The bradycardias were not associated with disturbances in cardiorespiratory or central nervous system functions. The cardiac vagomimetic action of scopolamine-TTS could be explained by low plasma drug concentrations (175 pg/ml) primarily blocking only neuronal inhibitory prejunctional muscarinic receptors which regulate acetylcholine release from the autonomic ganglia and parasympathetic nerve-endings.Because of the central role of acetylcholine in the physiological regulation of sleep, the effect of scopolamine-TTS on sleep merits further investigations.     

The scopolamine model of dementia: determination of central cholinomimetic effects of physostigmine on cognition and biochemical markers in man

Administration of the muscarinic antagonist scopolamine has been proposed as a pharmacological model for Alzheimer's disease. We have attempted to characterize the cognitive deficits produced by the administration of scopolamine (0.2 and 0.4 mg intra muscularly) to normal volunteers. We have also demonstrated reversal of these deficits by the cholinesterase inhibitor physostigmine (1.2 mg intramuscularly). Physostigmine also elevated subjects' plasma ACTH levels, a marker of central cholinergic activity. In the cognitive study, we found that scopolamine impaired subjects' performance on verbal learning, spatial learning and choice reaction time. These changes were associated with subjective sedation as measured by analogue rating scales. Physostigmine attenuated the impairment in verbal learning and reduced subjective sedation. In the biochemical study we examined the effects of the same drug regimes on plasma ACTH levels. Physostigmine administered with a peripherally active cholinergic antagonist (glycopyrrolate 0.2 mg intramuscularly) produced a rise in ACTH level which reached a peak 30 min after drug administration. Such a rise was not apparent when the physostigmine was coadministered with scopolamine. These results suggest that cognitive and neuroendocrine indices of central cholinergic activity such as these may be useful in determining the effectiveness of potential new therapeutic agents for Alzheimer's disease.     

Effects of transdermal scopolamine upon psychological test performance at sea

Summary The effects of transdermal scopolamine upon objective psychological performance assessments and self reports of feeling states, were investigated with volunteer subjects at sea. Scopolamine and placebo patches were administered on consecutive days in a counterbalanced order. Psychological performance was assessed 24 h following each transdermal patch. Choice reaction time and code substitution performance levels were not significantly changed, but letter cancellation errors were significantly more frequent following transdermal scopolamine. Transdermal scopolamine caused significantly more reports of dry mouth. More subjects were also unable to undertake the performance tests following scopolamine than placebo, due to difficulties in focusing on the test materials. However despite deleterious side effects with some personnel, others responded positively to the scopolamine patch. As noted by other workers, responses to the transdermal scopolamine patch seem to be quite variable.Dr. A. C. Parrott is Senior Psychologist at the Institute of Naval Medicine.Surgeon Lt. R. Jones RN, was Medical Officer to HMS Hydra     

石杉碱甲透皮控释制剂督脉经穴给药改善东莨菪碱小鼠记忆障碍作用及机理初探

目的：观察石杉碱甲透皮控释贴片(Hup-ATDDS)督脉穴位给药对东莨菪碱(Scop)致小鼠学习记忆障碍的影响,比较穴位给药与一般部位给药的作用差异,探讨督脉穴位给药机理,为穴位透皮控释给药新途径提供初步实验依据。方法：采用跳台、“Y”迷宫等行为药理学实验方法,观察Hup-ATDDS穴位给药与一般部位给药对Scop小鼠记忆障碍的改善作用,并以小鼠脑胆碱酯酶活性等指标初步探讨穴位给药的作用机理。结果：跳台试验和电迷宫试验表明,Hup-ATDDS督脉百会穴用药后3～6h间有明显的改善学习记忆作用：13．4μg／0．25cm^2组用药后4h为佳,5～6h时作用减弱;26．7μg／0．25cm^2组自药后3h起作用明显,药后4h作用最为显,维持至6h仍有良好作用;Hup-ATDDS26．7μg/0．25cm^2经百会、哑门、大椎、至阳和命门五个穴位给药均有明显的改善学习记忆作用,其中以百会穴组的作用最为显;Hup-ATDDS经百会穴或一般部位(选臀位)给药均有改善学习记忆作用,但以百会穴给药较臀位用药作用更为显,且Hup-ATDDS26．7μg／0．25cm^2组对小鼠脑胆碱酯酶活性有明显抑制作用。结论：Hup-ATDDS督脉穴位给药的改善记忆作用优于一般部位给药;其改善学习记忆作用可能是由于抑制脑CHE活性,改善胆碱能系统功能所致。     

牛磺酸对东莨菪碱所致记忆获得性障碍模型小鼠的改善作用

目的观察牛磺酸对东莨菪碱所致模型小鼠学习记忆及对其脑组织M胆碱受体结合力的影响。方法将昆明小鼠随机分组,设立正常对照组,东莨菪碱模型组及阳性对照药(吡拉西坦)组,牛磺酸小剂量组(0.3g·kg-1),中剂量组(0.75g·kg-1),大剂量(1.875g·kg-1)组,分别灌胃给药,于d5,除正常对照组腹腔注射生理盐水外,其它各组注射东莨菪碱1mg·kg-1,20min后进行Morris水迷宫测试,测试5d后处死,取其脑组织进行M受体结合力测定。结果在行为学实验中,牛磺酸各剂量组游出时间与模型组相比有明显缩短(P<0.05),并可以提高模型小鼠M胆碱受体的结合力。结论牛磺酸对东莨菪碱所致模型小鼠学习记忆障碍及M受体有一定的改善作用。     

Relation between behaviorally augmented tolerance and upregulation of muscarinic receptors in the CNS: Effects of chronic administration of scopolamine

The present experiment was planned to provide information about relations between behaviorally augmented tolerance and accompanying upregulation of muscarinic receptors (mAChR) (physiological tolerance) in the CNS during chronic administration of the cholinergic antagonist scopolamine. Analyses of the data on mAChR binding established significant upregulation (B_max) had occurred in the cortex, hippocampus, and striatum of animals treated with scopolamine, but not of those in the saline or methylscopolamine groups. There were no treatment effects in affinity (K_D). The effect of scopolamine administered before a behavioral test session was to cause an acute decrease in FR₅ responding to water reinforcement, and hence in resulting water consumption. Animals immediately compensated for this decrement by higher response rates during a free drinking (FDR) period which followed. When scopolamine was injected between the FR₅ and FDR periods, FR₅ responding increased to compensate for the drug's effect on the FDR. There was evidence that physiological tolerance also occurred as indicated by a more slowly developing trend toward recovery of levels of behavioral responding related to mAChR upregulation, although full recovery to pretreatment baselines did not occur within the 25 days of chronic treatments. The results as a whole are consistent with a multifactorial model of tolerance development, to which both behavioral and neurochemical processes contribute.     

Spotlight on rivastigmine transdermal patch: in dementia of the Alzheimer's type

Rivastigmine, a cholinesterase inhibitor, is available as a transdermal patch (Exelon? patch, Rivastach? patch, Prometax? patch) for the treatment of mild to moderate Alzheimer's disease. Rivastigmine transdermal patch was effective, in terms of improving cognitive and global function, and generally well tolerated in patients with mild to moderate dementia of the Alzheimer's type in a large, well designed trial. Most adverse events associated with rivastigmine patch were mild to moderate in severity, with the patch generally better tolerated than oral rivastigmine, especially in terms of cholinergic gastrointestinal adverse events. The patch also had good skin adhesion and a favourable skin tolerability profile in this study, with most application-site reactions being mild in severity. Additionally, in a safety and tolerability study, rivastigmine patch, regardless of concomitant memantine therapy, was generally well tolerated in patients switching from oral donepezil therapy. Thus, current evidence suggests that rivastigmine transdermal patch is an effective treatment option for patients with Alzheimer's disease, with the potential for improving compliance and providing sustained clinical benefit because of its ease of use and generally favourable tolerability profile.     

The effects of transdermal scopolamine and four dose levels of oral scopolamine (0.15, 0.3, 0.6, and 1.2 mg) upon psychological performance

Four dose levels of oral scopolamine (0.15 mg, 0.3 mg, 0.6 mg, 1,2 mg), transdermal scopolamine, and placebo, were investigated for their effects upon a battery of psychological performance measures in normal subjects. Oral scopolamine produced significant linear dose-related decrements on tasks involving continuous attention, continuous performance, memory storage for new information, and on self-rated feelings of alertness and sociability. Transdermal scopolamine produced significant performance impairments on these same assessment measures. Resting heart rate levels were significantly reduced by all scopolamine conditions. Side effects (dry mouth, dizziness) were frequent following transdermal scopolamine and the higher oral dose conditions. The overall effects of the transdermal scopolamine patch were broadly equivalent to the effects of 0.8 mg oral scopolamine. This oral dose equivalence for transdermal scopolamine is higher than expected, and possible reasons for this are discussed.     

G-CSF对东莨菪碱痴呆模型大鼠认知及ChAT表达的影响

目的观察粒细胞集落刺激因子(G-CSF)对东莨菪碱所致大鼠认知障碍和Ch AT表达的影响。方法24只10月龄Wistar雄性大鼠随机分为三组:空白组(N组)、东莨菪碱组(S组)和G-CSF干预组(G组),分别腹腔注射生理盐水2 ml(N组)、氢溴酸东莨菪碱1 mg/kg(S组)、腹腔注射氢溴酸东莨菪碱1 mg/kg后皮下注射GCSF 50μg/kg,连续5 d。每天给药后3 h进行水迷宫测试其空间学习记忆能力改变,末次水迷宫实验后4%高聚甲醛灌注取脑组织用免疫组化方法观察Ch AT阳性细胞表达。结果行为学变化:各组大鼠第5天潜伏期和游泳距离较第1天短(P<0.05),N组和G组大鼠第5天潜伏期和游泳距离均较S组短(P<0.05)。Ch AT表达变化:N组和G组大鼠海马Ch AT阳性细胞个数均较S组多(P<0.05)。结论 G-CSF可以有效改善东莨菪碱所引起的大鼠认知功能障碍。     

Effects of transdermal scopolamine on pulmonary function, symptoms and bronchial hyperresponsiveness to methacholine

This study is a result of two consecutive double-blind, placebo-controlled, cross-over studies. In the first study, we evaluated therapeutic effects of a single transdermal scopolamine patch (Scopoderm® TTS, size 2.5 cm², Ciba Geigy) on forced expiratory volume in one second (FEV₁), reversibility, peak expiratory flow (PEF) and symptoms in ten patients with reversible airways disease (ΔFEV₁9% predicted). During the study, blood and urine samples were taken from the patients and analysed for scopolamine levels. The drug was adequately taken up from the patch into the systemic circulation. However, no significant clinical effects, nor correlations between the scopolamine levels and the outcome parameters were observed. Because of the possibility of sub-therapeutic doses in the first study, a second study with two transdermal scopolamine patches was performed in ten patients with bronchial hyperresponsiveness to methacholine. The blood and urine concentrations of free scopolamine were doubled compared to the first study. There were still no statistically significant effects on FEV₁, PEF, symptoms, and bronchial hyperresponsiveness, yet most of the patients now reported adverse side effects. We conclude that transdermal administration of scopolamine is not clinically useful in asthma and chronic obstructive pulmonary disease. Even application of two patches does not result in therapeutically effective levels at the muscarinic receptors in the lung, yet causes several side effects.     

侧脑室注射东莨菪碱对吗啡依赖大鼠戒断反应的抑制作用

目的 观察非选择性毒蕈碱（M）受体拮抗剂东莨菪碱、选择性M1受体拮抗剂哌拉唑嗪以及选择性M2受体拮抗剂美索四氨对吗啡戒断反应的影响。方法 采用吗啡依赖大鼠模型侧脑室注射上述药物,并用腹腔注射纳洛酮诱发戒断反应,记录60min内戒断症状。结果 侧脑室注射东莨菪碱（25,50μg)、派拉唑嗪（20μg)和美索四氨（25μg)可明显抑制由纳洛酮诱发戒断反应,东莨菪碱减轻吗啡戒断症状呈明显量效关系。结论 侧脑室注射东莨菪碱能减轻吗啡戒断反应,提示中枢胆碱能神经毒碱（M）受体在吗啡依赖和耐受过程中起重要作用。     

Vacuous jaw movements induced by sub-chronic administration of haloperidol: interactions with scopolamine

The present series of experiments was conducted to investigate the vacuous jaw movements induced by sub-chronic administration of haloperidol (HP). In the first experiment, daily injection of 0.4 mg/kg HP for 10 days increased vacuous jaw movements and decreased rearing behavior. The second and third experiments investigated the interaction between the effects of HP and the anticholinergic drug scopolamine. Co-administration of 0.5 mg/kg scopolamine with 0.4 mg/kg HP for 9 days reduced vacuous jaw movements and increased rearing responses relative to rats that received HP alone. Co-administration of HP with 0.25 mg/kg scopolamine for 9 days increased rearing relative to rats that received HP alone, but there was no effect of the lower dose of scopolamine on vacuous jaw movements. Administration of 0.5 mg/kg scopolamine plus 0.4 mg/kg HP on days 11–14 to rats that had received HP alone for 10 days reversed the effect of HP on rearing, but not on vacuous jaw movements. Rats that had received HP plus scopolamine for 10 days showed dramatic increases in vacuous jaw movements when scopolamine was withdrawn. Because vacuous jaw movements are produced within the first few days of administration, reduced by administration of scopolamine, and exacerbated by withdrawal of scopolamine, the pharmacological characteristics of these movements do not appear to bear a close relation to those of tardive dyskinesia in humans. The present results are consistent with the hypothesis that vacuous jaw movements in rats share some characteristics with Parkinsonian symptoms.     

小剂量东莨菪碱透皮治疗增加心肌梗死急性期心脏迷走神经张力

目的：研究心肌梗死急性期经皮给予小剂量东莨菪碱能否增加心脏迷走神经的张力。方法：68例首次急性心肌梗死（AMI）患，窦性心律，未用任何影响窦房结的药物，随机分为东莨菪碱组和安慰组，双盲法给药。治疗前后用数字化24h Holter记录测定心率变异性时域参数和频域参数，用苯肾上腺素法测定压力反射敏感性。结果：治疗前心率变异性参数和压力反射敏感性在两组间无明显差异。经皮东莨菪碱治疗明显增加心率变异的时域参数，包括RR间期标准差均值（SDNN），RR间期均值标准差（SDANN）和相邻RR间期差值的均方根（rMSSD)，以及频域参数，包括总功率谱（TP，0－0.40Hz)、低频（LF，0.04-0.15Hz)和高频（HF，0.15-0.40Hz)及压力反射敏感性。结论：心肌梗死急性期应用小剂量东莨菪碱透皮治疗可显增加心脏迷走神经压力，改善自主神经失衡。     

Design of triptorelin loaded nanospheres for transdermal iontophoretic administration

Triptorelin is a decapeptide analog of luteinizing hormone releasing hormone, currently used for the treatment of sex-hormones dependents diseases. The aim of this work was to prepare triptorelin-loaded nanospheres useful for transdermal iontophoretic administration. Nanospheres were prepared with the double emulsion/solvent evaporation technique. The effect of three parameters on the encapsulation efficiency has been determined: the role of the pH of the internal and external aqueous phases, the nature of the organic solvent and the effect of three different poly(lactide-co-glycolide) (PLGA) co-polymers. Particle size, zeta potential and release kinetics were also determined. The encapsulation efficiency varied from 4 to 83% reaching the maximum value when both the internal and the external water phases were brought to pH 7 (isoelectric point of the peptide), methylene chloride was used as solvent of the copolymers and PLGA rich in free carboxylic groups was employed. The release profiles obtained with this co-polymer were characterized by the absence of burst effect. This behavior as well as the high encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the co-polymer. This supports the already expressed theory that the release of peptides and proteins from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. The obtained nanoparticles, regarding their size, amount encapsulated and zeta potential, were shown to be suitable for transdermal iontophoretic administration.     

The scopolamine model as a pharmacodynamic marker in early drug development

Rationale  

Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process.     

Elevated T-maze as an animal model of memory: effects of scopolamine

The elevated T-maze (ETM) is a putative model for the assessment of anxiety and memory in rodents. This study was designed to further evaluate the utility of the ETM in the study of memory processes. We compared the performance of rats in the ETM, the water maze (WM) and the two-way avoidance task (TWA), after pretreatment with scopolamine (SCO; 0.3 or 1.2 mg/kg i.p.). In the ETM, rats were first trained to meet the criterion of remaining inside the enclosed arm for 300 seconds. Seventy-two hours after training, a retrieval test session was performed. At the lower dose, SCO impaired performance in the retrieval session on all three tasks, whereas in the training session an effect was noted only on the WM task. At the higher dose, SCO impaired the performance of rats in the training sessions for ETM and WM, but not TWA. In a fourth experiment using the elevated plus-maze, SCO showed anxiolytic-like effects at the higher dose only. In conclusion, the effects of SCO in rats submitted to the ETM were dose dependent, with the lower dose exerting a selective effect detected only on retrieval, whereas the higher dose induced motor effects that disrupted inhibitory avoidance acquisition, resulting in impaired retrieval. The results are discussed in terms of the utility of the ETM in the study of drug effects and the neurobiological mechanisms underlying anxiety, learning and memory.