Synthesis of ferulic acid derivatives and their inhibition of cholinesterase inhibitory activity / 中国药科大学学报

@#Ferulic acid (FA), a natural product of phenylpropanoids containing phenolic hydroxyl groups, has a wide range of pharmacological activities and some therapeutic effect on Alzheimer's disease (AD).Using FA as the raw material, the ferulic acid carbamate aniline derivatives were first synthesized by 4-step esterification reaction, splicing carbamate active functional groups, hydrolysis reaction and amide condensation.These FA derivatives were evaluated for in vitro cholinesterase inhibition activity by the Ellman method.A total of 15 novel FA derivatives were designed and synthesized, and their structures were confirmed by 1H NMR, 13C NMR and ESI-MS.Cholinesterase activity tests showed that compounds 5c, 5f, 5j, 5g, 5m possessed good acetylcholinesterase inhibition activity.Except for 5l, 5m, almost all compounds have inhibition activity on butyrylcholinesterase, which is much higher than that on acetylcholinesterase.In conclusion, compounds 5c, 5f, 5j and 5g can be used as potential anti-AD inhibitors targeting cholinesterase..

Clinical correlates of hypotension in patients with acute organophosphorus poisoning / 世界急诊医学杂志（英文）

@#BACKGROUND: The aim of the present study is to describe the clinical correlates of hypotension and its associated outcomes in patients with acute organophosphorus poisoning (AOPP). METHODS: In this retrospective cohort study, we analyzed data pertaining to 871 patients with AOPP who were treated at two hospitals. Data from hypotensive and non-hypotensive patients were compared to identify clinical correlates of hypotension. We also evaluated the association between clinical parameters (including hypotension) and in-hospital mortality. RESULTS: The incidence of hypotension in AOPP patients was 16.4%. Hypotensive patients showed significantly higher in-hospital mortality (1.1% vs. 39.9%, P<0.001). Advanced age (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.08-1.44), history of diabetes (OR 2.65, 95% CI 1.14-5.96), and increased white blood cell count (OR 1.06, 95% CI 1.03-1.09), plasma cholinesterase (OR 0.91, 95% CI 0.84-0.94), plasma albumin (OR 0.88, 95% CI 0.85-0.92), serum amylase (OR 1.01, 95% CI 1.01-1.02), and blood pH (OR 0.64, 95% CI 0.54-0.75) were significantly associated with hypotension. After adjusting for potential confounders, hypotension was associated with increased in-hospital mortality (hazard ratio 8.77-37.06, depending on the controlled variables). CONCLUSIONS: Hypotension is a common complication of AOPP and is associated with increased in-hospital mortality. Advanced age, history of diabetes, and changes in laboratory parameters were associated with hypotension in AOPP patients.

Mosquito Larvicidal Potential of Tropical Seaweeds: Acetylcholinesterase Inhibitory Effects of Bryopsis pennata, Padina australis and Sargassum binderi on Aedes aegypti (L.) and Aedes albopictus Skuse

@#Introduction: Inhibition of the cholinesterase’s function leads to paralysis and death. This mechanism is served as a common mode of action of insecticide. The three tropical seaweeds, namely Bryopsis pennata, Padina australis and Sargassum binderi were reported for its potential mosquito larvicidal effect. In the present study, these seaweeds were evaluated for their potential as a cholinesterase inhibitor in the mechanism of larvicidal action. Methods: Acetylcholinsterase (AChE) inhibition assay was carried out based on the colorimetric method using a microplate reader. Phytochemical content of the seaweed extracts was screened by using liquid chromatography-mass spectroscopy (LC-MS). Results: Green seaweed B. pennata showed the strongest inhibition effect towards in vitro AChE by using tissue homogenates of Aedes aegypti (IC50 value = 0.84 mg mL-1) and Aedes albopictus as the enzyme source (IC50 value = 0.92 mg mL-1). The pattern of Lineweaver-Burk plots revealed that B. pennata was a mixed type inhibitor of AChE, as the readings of Km, Vmax, Ki and Ki’, indicates that it had a strong inhibition ability with high binding affinity towards both free enzyme and enzyme-substrate complex. Conclusion: These findings suggest the compound(s) in B. pennata extract serves as a promising source that could be developed into a mosquito larvicidal agent with AChE inhibition effect.

The prescribing cascade and medication therapy management between cholinesterase inhibitors and anticholinergic drugs / 中国药学杂志

OBJECTIVE: To discuss about one patient with Alzheimer′s disease and urinary incontinence and to investigate the prescribing cascade between cholinesterase inhibitors and anticholinergic drugs further more. METHODS: Clinical pharmacists participated in a medication therapy management program aiming at one patient with Alzheimer′s disease and urinary incontinence. By doing this they successfully identified and interrupted a prescribing cascade. Then some constructive advices were provided to doctors and patients on the rational administration of drugs. RESULTS: The drug treatment plan was adjusted by clinical pharmacists and doctors after evaluating the benefits and risks about the use of cholinesterase inhibitors and anticholinergic drugs in the elderly patient with chronic disease. And this change directly led to a significant relief of urinary incontinence in the patient. CONCLUSION: The use of cholinesterase inhibitors in Alzheimer′s patients increases the risk of urinary incontinence, and at the same time additional use of anticholinergic drugs in the treatment of urinary incontinence can further damage the cognition.Therefore, clinical pharmacists and doctors should pay great attention to the prescribing cascade of cholinesterase inhibitors and anticholinergic drugs. To identify and interrupt prescribing cascades is important when clinical pharmacists and doctors are prescribing prescriptions for elderly patients with chronic diseases. They must work closely for the optimization of prescriptions and the improvement of medication safety in elderly patients.

Recent Advances in Diagnosis and Treatment of Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder in which neuronal loss causes cognitive decline and other neuropsychiatric problems. It can be diagnosed based on history, examination, and appropriate objective assessments, using standard criteria such as the Diagnostic and Statistical Manual of Mental Disorders or the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA). Brain imaging and biomarkers are making progress in the differential diagnoses among the different disorders. The cholinesterase inhibitors, donepezil, rivastigmine and galantamine and N-methyl-D-aspartate receptors antagonist memantine are approved by the US Food and Drug Administration for AD. Recently some acetylcholinesterase inhibitors gained approval for the treatment of severe AD and became available in a higher dose formulation or a patch formulation. Optimal care in AD is multifactorial and it should include early diagnosis and multidisciplinary care with pharmacological and nonpharmacological interventions including exercise interventions, cognitive interventions and maintenance of social networks.

Relation of breast cancer and malathion aerial spraying in Arica, Chile / Relación entre cáncer mamario y aspersiones aéreas con malatión en Arica, Chile

Breast cancer mortality has been increasing in Arica Chile where it has surpassed the national rates 11 times between 1990 and 2010. The city of Arica was sprayed with the organophosphrous pesticide malathion in order to control the Mediterranean fly 33 years ago. Moreover we have demonstrated that a malathion treatment induces the formation of breast carcinomas in Sprague Dowley female rats. The objective of this work was to find a relationship between malathion aerial spraying and the increased mortality rate due to breast cancer that has been observed in Arica in recent years. We extracted city data bases with all breast cancer cases diagnosed from 1995 to 2005 from the Dr. Juan Noe Crevani Hospital of Arica city and Ernesto Torres Hospital of Iquique. The number of patients was 100 in Arica and 58 in Iquique, nearby city that has never been sprayed with malathion which had a similar population than Arica in those years. The statistical analysis of the characteristics of the sample related to breast cancer risk showed that there is no significant difference between women from Arica and from Iquique. Nevertheless the patients with more times of exposure to malathion were 5.7-times more likely to be diagnosed with breast cancer (OR= 5.7; p<0.02). In addition, metastases were found in 30.5 percent of the malathion-exposed group and only in 16 percent in the group never exposed (p<0.05). This study suggests that the increase in the mortality rate due to breast cancer occurring in Arica has a significant correlation with the exposure to malathion sprayed over the city more than 30 years ago.

La mortalidad por cáncer de mama ha ido aumentando en Arica Chile, donde ha sobrepasado las tasas nacionales 11 veces entre los años 1990 y 2010. La ciudad de Arica recibió aspersiones del pesticida organofosforado malatión, con el fin de controlar la mosca mediterránea, por primera vez hace 33 años. Por otra parte hemos demostrado que un tratamiento con malatión induce la formación de carcinomas mamarios en ratas hembras Sprague Dowley. El objetivo de este trabajo es encontrar una relación entre las aspersiones con malatión y el aumento en la tasa de mortalidad por cáncer de mama que se ha observado en Arica en los últimos años. Se extrajeron de bases de datos, los casos de cáncer mamario diagnosticados entre 1995 y 2005, en los Hospitales Dr. Juan Noé Crevani de Arica y Ernesto Torres de Iquique. El número de pacientes diagnosticados con cáncer de mama fue 100 en Arica y 58 en Iquique, ciudad que nunca fue fumigada con malatión y con una población similar a la de Arica durante esos años. El análisis estadístico de las características de la muestra, en relación a los factores de riesgo de cáncer mamario, mostró que no hay diferencia significativa entre las mujeres de Arica y de Iquique. Sin embargo, las mujeres con mayor tiempo de exposición al malatión fueron 5,7 veces más propensas a ser diagnosticadas con cáncer de mama (OR = 5,7, p <0.02). Además el 30,5 por ciento del grupo expuesto a malatión presentó metástasis y en el grupo no expuesto sólo el 16 por ciento (p <0.05). Este estudio sugiere que el aumento de la tasa de mortalidad por cáncer de mama que se ha producido en Arica tiene una correlación significativa con la exposición al malatión esparcido sobre la ciudad hace más de 30 años.

Evidence-Based Treatment of Alzheimer's Disease

The pharmacological treatment of Alzheimer's disease is based on symptomatic therapy of cognitive decline and behavioral problems. Numerous therapies have been investigated for the treatment and prevention of Alzheimer's disease. We reviewed the current evidence-based medical research and guidelines of treatment for Alzheimer's disease. The use of cholinesterase inhibitors (ChEI) and N-methyl-D-aspartate (NMDA) inhibitors can bring about significant but modest therapeutic improvement. There is insufficient evidence to recommend vitamine E, estrogen, ginko biloba, or nonsteroidal anti-inflammatory drugs (NSAIDs) for the prevention or treatment of Alzheimer's disease. This article reviews the available data on current pharmacological treatments through evidence-based medicine.

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Índex of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 ± 4.8 percent, 92.3 percent ± 22.8 percent of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Two fast screening methods (GC-MS and TLC-ChEI assay) for rapid evaluation of potential anticholinesterasic indole alkaloids in complex mixtures

The pharmacotherapyfor Alzheimer's disease (AD) includes the use of acetylcholinesterase inhibitors (AChEI). Recent investigations for novel AD therapeutic agents from plants suggested that Tabernaemontana genus is a promising source of novel anticholinesterasic indole alkaloids. In this work two fast screening techniques were combined in order to easily identify novel cholinesterase inhibitors (ChEI). Gas chromatography-mass spectrometry (GC-MS) of the less polar alkaloidic fractions obtained from the acid-base extraction of the stalk of T. laeta revealed thirteen monoindole alkaloids, four of them confirmed by co-injection with previously isolated alkaloids. The others were tentatively identified by mass fragmentation analysis. By gas chromatography with flame ionization detection (GC-FID) and using isatin as internal standard, affinisine and voachalotine were determined as major compounds. These fractions and fourteen previously isolated alkaloids, obtained from root bark of T. laeta and T. hystrix were investigated for acetyl (AChE) and butyrylcholinesterase (BuChE) inhibitory activities by the modified Ellman's method in thin layer chromatography(TLC-ChEI). Results showed selective inhibition of the alkaloids heyneanine and Nb-methylvoachalotine for BuChE, and 19-epi-isovoacristine for AChE, whereas olivacine, affinisine, ibogamine, affinine, conodurine and hystrixnineinhibited both enzymes. In addition to confirming that monoterpenoid indole alkaloids can be novel therapeutic agents for AD, this is the first report of the ChEI activity of olivacine, a pyridocarbazole alkaloid.

Dentre os tratamentos da doença de Alzheimer (DA) está o uso de inibidores da enzima acetilcolinesterase. Pesquisas recentes visando a descoberta de novos agentes terapêuticos naturais para esta doença sugerem que o gênero Tabernaemontana é uma fonte promissora de alcalóides indólicos anticolinesterásicos. Neste trabalho, duas técnicas de análise em mistura foram associadas de modo a identificar facilmente novos inibidores colinesterásicos. A cromatografia em fase gasosa acoplada a espectrometria de massas (CG-EM) das frações alcaloídicas apolares, obtidas da extração ácido-base do caule de T. laeta, revelou a presença de treze alcalóides monoindólicos, quatro deles confirmados por co-injeção com padrões previamente isolados. Os outros alcalóides foram tentativamente identificados pelo padrão de fragmentação de massas. Por cromatografia em fase gasosa com detecção por ionização de chama (CG-DIC) e utilizando isatina como padrão interno, affinisina e voachalotina foram identificadas como substâncias majoritárias. As frações alcaloídicas obtidas e os quatorze alcalóides previamente isolados das raízes de T. laeta e T. hystrix foram analisados quanto à atividade inibitória das enzimas acetil (AChE) e butirilcolinesterase (BuChE) pelo método de Ellman em cromatografia em camada delgada (CCD-ChEI). Os resultados revelaram uma inibição seletiva dos alcalóides heyneanina e Nb-metilvoachalotina para BuChE e de 19-epi-isovoacristina para AChE, enquanto que olivacina, affinisina, ibogamina, affinina, conodurina e hystrixnina inibiram ambas as enzimas. Além de confirmar que alcalóides indólicos monoterpênicos são agentes terapêuticos promissores para o tratamento da DA, este é o primeiro relato da atividade anticolinesterásica de olivacina, um alcalóide piridocarbazólico.

Clinical Course of Small Vessel Dementia Patients According to Cholinesterase Inhibitor Treatment

BACKGROUND: Small vessel dementia (SVD) is the most frequent cause of vascular dementia and is regarded a distinct clinical entity. However, the data on the natural course of SVD and drug trials specifically aiming SVD have been sparse. The aim of this study was to answer the following three questions: 1) How does SVD progress? 2) Does cholinesterase inhibitor therapy improves cognitive symptoms and daily activity of life (ADL) in SVD? 3) Is there any clinical difference among the subtypes of SVD? METHODS: According to cholinesterase inhibitor medications, patients with SVD were retrospectively analyzed using Hyoja Dementia registry. In this study, effects of treatment were assessed by comparing the scores of Korea version Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), Functional Independence Measure (FIM) at the base line with those at endpoints. RESULTS: After 12 months, the mean MMSE, CDR, FIM scores improved significantly in the cholinesterase inhibitor treatment group, compared with that in no-treatment group. In no-treatment group, annual decline of MMSE was 2.7, compared with 0.3 increment in the treatment group. White matter type of SVD showed worst prognosis compared with other types. CONCLUSIONS: This study suggests that SVD has more benign clinical course than previously reported, and cholinesterase inhibitor improves cognitive and ADL functions in SVD. Among the subtypes of SVD, the white matter type may have poor prognosis.

Drug Therapy for Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD afflicts 0.3 to 0.5 million people in Korea, and the number is projected to increase to 2 million by the year of 2050. This article provides a brief overview of the most popular drug therapies in the treatment of AD including cholinesterase inhibitors (AchEIs) (donepezil, galantamine, rivastigmine), NMDA receptor antagonist (memantine), acetyl-l-carnitine, antioxidant vitamins, and Ginko biloba. Based on a review of relevant papers in the literature, this article presents pharmacological and clinical safety profiles of these agents and prescribing tips as well as a final summary on the effectiveness, safety, and alerts for clinicians. AchEIs as well as memantine will continue to play an important role in the treatment armamentarium for AD, even though newer strategies are being explored. There is not enough evidence supporting the continuous use of other drugs such as acetyl-l-carnitine, antioxidant vitamins, and Ginko biloba for the treatment of AD.

Comparison of Antiallodynic Effects between Intrathecal Cholinesterase Inhibitors and NMDA Antagonists on Two Neuropathic Pain Rat Models / 대한마취과학회지

BACKGOUND: Cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists reduce the mechanical allodynia in neuropathic pain models. In this study our aim was to compare the antiallodynic effects between intrathecal cholinesterase inhibitors and NMDA antagonists on two well-characterized neuropathic pain rat models. METHODS: Male Sprague Dawley rats were anesthetized and either had the left L5 and L6 spinal nerves ligated (SNL group) or Freund complete adjuvant (FCA) administrated to the sciatic nerve (FCA group) in order to cause neuropathic pain. A catheter was implanted into the intrathecal space for drug administration. After obtaining baseline values, edrophonium (3-100microgram), neostigmine (0.3-10microgram), AP-5 (0.3-3microgram) and MK-801 (1-30microgram) were administered intrathecally to each group. The allodynic left hind paw withdrawal thresholds to von Frey hairs were assessed and converted to % MPE. Antiallodynic effects on the two groups were compared by analyzing dose-response curves and ED 50 values. Motor weakness was also checked. RESULTS: Intrathecal edrophonium, neostigmine, AP-5 and MK-801 had a dose-dependent antiallodynic effect on the two neuropathic pain models. Comparing the antiallodynic effect dose response curves, intrathecal cholinesterase inhibitors had lower ED 50 with steep slopes in the SNL model, whereas intrathecal NMDA antagonists had lower ED 50 in the FCA model, but there were no statistically significant differences between the two models. CONCLUSIONS: Intrathecal cholinesterase inhibitors and NMDA antagonists have relatively better antiallodynic effects on the SNL and FCA neuropathic pain rat models, respectively.

Antagonism of morphine-induced central respiratory depression by donepezil in the anesthetized rabbit

Morphine is often used in cancer pain and postoperative analgesic management but induces respiratory depression. Therefore, there is an ongoing search for drug candidates that can antagonize morphine-induced respiratory depression but have no effect on morphine-induced analgesia. Acetylcholine is an excitatory neurotransmitter in central respiratory control and physostigmine antagonizes morphine-induced respiratory depression. However, physostigmine has not been applied in clinical practice because it has a short action time, among other characteristics. We therefore asked whether donepezil (a long-acting acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease) can antagonize morphine-induced respiratory depression. Using the anesthetized rabbit as our model, we measured phrenic nerve discharge as an index of respiratory rate and amplitude. We compared control indices with discharges after the injection of morphine and after the injection of donepezil. Morphine-induced depression of respiratory rate and respiratory amplitude was partly antagonized by donepezil without any effect on blood pressure and end-tidal C0(2). In the other experiment, apneic threshold PaC0(2) was also compared. Morphine increased the phrenic nerve apnea threshold but this was antagonized by donepezil. These findings indicate that systemically administered donepezil partially restores morphine-induced respiratory depression and morphine-deteriorated phrenic nerve apnea threshold in the anesthetized rabbit.

Two Cases of Discontinuation Syndrome Following Cessation of Cholinesterase Inhibitors

Discontinuation syndrome is a cluster of symptoms that appear when a patient terminates long-term medication. We report 2 patients with Alzheimer's disease who developed significant behavioral disturbances after the cessation of cholinesterase inhibitors. Although the clinical profile of discontinuation syndrome in cholinesterase inhibitors are yet poorly defined, it may be of importance to consider this syndrome when patients develop significant behavioral disturbances after these agents are stopped, and if more severe reactions are expected, retrial of these agents may be prudent.

Hypersexuality in Dementia

PURPOSE: Hypersexual behavior such as increased libido, change in sexual orientation or disinhibition had been reported in dementia. Mechanism and treatment measures were reviewed. METHOD: A medline search was undertaken for papers written by English since 1970. RESULTS: Careful evaluation of past medical and sexual history should be undertaken as well as review of medication. SSRIs may be the first line because they are relatively safe. And then antiandrogens, estrogens or gonadotropin releasing hormone analogues can be tried. Effect of atypical antipsychotics or acetylcholinesterase inhibitors were also suggested. CONCLUSIONS: Symptoms of hypersexuality in dementia often cause feelings of embarrasment and become immense burden to relatives and healthworkers. Some pharmacological agents were promising. For example, combination of cimetidine or spironolactone and a cholinesterase inhibitor can be useful.

Pharmacological Treatment Strategies for Alzheimer's Disease

Alzheimer's disease(AD) is one of the most common causes of mental deterioration in elderly individuals, accounting for around 45~60% of the overall cases of dementia over 65 years of age. Although there is presently no "cure" for AD, a large number of potential therapeutic interventions have emerged to correct cholinergic dysfunctions. Currently, cholinergic therapy, particularly cholinesterase inhibition, represents the most realistic approach to the symptomatic treatment of AD. Modest efficacy for mild to moderate AD has been shown in well-designed clinical trials for tacrine, donepezil, rivastigmine, and galantimine. Among other treatment options, estrogen replacement therapy in postmenopausal women is under active investigation, but recent studies showed somewhat disappointing results. Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs are beneficial in the treatment and prevention of AD. But prednisone and COX-2 inhibitor, celecoxib showed no clinical benefit in recent studies. Alpha-tocopherol and gingko biloba showed some beneficial effect in delaying the progression of AD and enhancing cognitive functions. Immunization with beta amyloid peptide was considered to be the only method to prevent and halt disease progression in patients with AD. Recently, phase II clinical trial using synthetic beta amyloid peptide (AN-1792) was discontinued because some patients showed neuro-inflammation which may be caused by autoimmune responses.

Organophosphate Cholinesterase Inhibitor (Diisopropylfluorophosphate) Induces Acetylcholinesterase-mediated Nicotinic Receptor Facilitation

BACKGROUND: Cholinesterase inhibitors (ChEIs) which have been widely used clinically are known to have diverse actions on the neuromuscular synaptic transmissions, suggesting that inhibiting cholinesterase (ChE) might not be their only mode of action. ChEIs interact with the nicotinic acetylcholine receptor (nAChR) macromolecule as a weak agonist, and as a modulator inducing desensitization and blockade at high concentrations. In a previous study, we reported that carbamate ChEIs, Pyridostigmine and Physostigmine could facilitate the ionic influx through nAChRs, when precluding the Ach-hydrolyzing effect of acetylChE (AChE) by applying carbachol as an agonist. The facilitation of the nAChR function was supposed to be achieved by AChE-mediated nAChR modulation and possibly by the up-regulation of nAChRs. METHODS: In this study, we analyzed the effect of irreversible organophosphate ChEI, diisopropylfluorophosphate (DFP) on the function of muscular nAChRs in TE671 cells, quantifying carbachol-induced intracellular 22 Na+ influx through nAChRs, using radioassay. RESULTS: Preincubation of cells with 1 mM DFP at 37 degrees C for 10 min as well as the simultaneous application of carbachol and DFP, decreased the carbachol-induced influx dose-dependently.However, preincubation of cells with 10 micrometer DFP potentiated the influx to 132.5+/-7.4% CPM. Moreover, Najar Tx completely inhibited the potentiated 22 Na + influx. CONCLUSIONS: Organophosphate ChEI can facilitate nAChR functions at low concentrations with a yet discovered mechanism, which is supposed to necessitate cellular metabolism, and be possibly mediated by AChE. The inhibition of DFP on nAChR functions at high concentration is attributable to its remained curare-like actions and direct cellular toxicity.

Two Cases of Pisa Syndrome Due to Cholinestrase Inhibitor

The Pisa syndrome is a rare extrapyramidal side effect with twisting and bending characteristics of the upper trunk, neck, and head, usually caused by neuroleptic treatment. However, there have been no reports of Pisa syndrome in cholinesterase inhibitor therapy. We report 2 female patients of Alzheimer's disease with Pisa syndrome after cholinesterase inhibitor ther-apy. The postural disturbance in these patients was completely resolved after the cessation of the cholinesterase inhibitor. Although the pathophysiology of Pisa syndrome appears to be extremely complicated and poorly understood, it may be of importance to consider the relationship between acetylcholine and Pisa syndrome. Therefore, the present cases provide a novel viewpoint on the underlying mechanism of the Pisa syndrome and the role of acetylcholine in the movement disorder.

Interaction between Neostigmine and Morphine in the Neuropathic Pain Model / 대한마취과학회지

BACKGROUND: Spinally administered neostigmine, but not morphine, has been well known to reverse the mechanical allodynia in human and animal studies. The efficacy of morphine in neuropathic pain state is somewhat controversial. Using an isobolographic analysis, we examine the spinal interaction between neostigmine and morphine in a rat model of neuropathic pain. METHODS: Male Sprague Dawley rats were prepared with tight ligation of left lumbar 5th and 6th spinal nerves and chronic lumbar intrathecal catheter. Intrathecal dose response curves were established for the antiallodynic effect of neostigmine (0.3, 1.0, 3.0, and 10 microgram) and morphine (0.3, 1.0, 3.0, and 10 microgram) alone to obtain the ED50 for each agent. ED50 fractions (1/2, 1/4, 1/8, and 1/16) of drug combination of neostigmine-morphine were administered. Allodynic thresholds for left hindpaw withdrawal to von Frey hairs application were assessed and converted to %MPE. The ED50 of neostigmine-morphine combinations was established and isobolographic analysis of the drug interaction was carried out. RESULTS: Intrathecal neostigmine and morphine alone produced dose-dependent reductions of tactile allodynia. ED50 values are 0.43 microgram (0.21~0.86 microgram) for neostigmine and 0.39 microgram (0.07~2.01 microgram) for morphine. The log dose responses were plotted from the peak effect of %MPE in each group of neostigmine and morphine. The experimental ED50 1.34E-2 microgram (2.1E-4-0.85 microgram) for neostigmine and morphine combination was found to be significantly below the theoretical additive ED50 value 0.41 microgram (P<0.05). CONCLUSION: The results suggest that intrathecal neostigmine and morphine alone produce a dose dependent antagonism on touch evoked allodynia and intrathecal neostigmine is synergistic at the spinal level when combined with intrathecal morphine in a rat model of neuropathy.

The Effect of Selective Muscarinic Receptor Antagonists on Antiallodynic Action in a Rat Model of Neuropathic Pain / 대한마취과학회지

BACKGROUND: Peripheral nerve injury may produce a syndrome consisting of spontaneous pain, allodynia and hyperpathia. In previous study, we examined the antiallodynic action produced by intrathecal (i.t.) cholinesterase inhibitors (ChEi) in a neuropathic pain rat model and the reversal of antiallodynic state by i.t. atropine, muscarinic antagonist, but not by nicotinic antagonist mecamylamine. The purpose of this study was to determine the selective antagonistic action of four subtypes of muscarinic receptor on antiallodynic state by i.t. ChEi in a rat model of neuropathic pain. METHODS: Sprague Dawley rats were prepared with tight ligation of left L5/L6 spinal nerves with 6-0 black silk and chronic lumbar intrathecal catheters. After obtaining the baseline hindpaw withdrawal scores, edrophonium (100 microgram) or neostigmine (10 microgram) was administered intrathecally. Tactile allodynia was measured using von Frey filaments and allodynic threshold was calculated by the up-down method. Allodynic changes were tested at 15, 30, 45, 60, 90, 120 and 180 minutes. To examine the reversal of antiallodynia and to compare the antagonizing action of antiallodynic state produced by i.t. administration of ChEi, non-selective muscarinic receptor antagonists atropine (10 microgram), M1 antagonist pirenzepine (3 microgram), M2 antagonist methoctramine (3 microgram), M3 antagonist 4-DAMP (3 microgram) and M4 antagonist tropicamide (3 microgram) were injected intrathecally respectively 5 minutes prior to the injection of edrophonium or neostigmine. RESULTS: Antiallodynia produced by i.t. edrophonium was reversed by pretreatment with i.t. methoctramine, 4-DAMP, tropicamide and pirenzepine (P<0.05). On the contrary, antiallodynic state made by i.t. neostigmine was not antagonized by methoctramine, 4-DAMP and tropicamide. M1 antagonist pirenzepine had a moderate, statistically significant (P<0.05) effect on reversal of increased allodynic threshold while atropine showed a complete antagonism. CONCLUSION: These experiments suggest that antialllodynic action of cholinesterase inhibitors is likely due to mediation of spinal muscarinic system and M1 receptor subtype is more likely involved in this mechanism.