Muscarinic acetylcholine receptor M1 mediates prostate cancer cell migration and invasion through hedgehog signaling / 亚洲男科学杂志(英文版)

The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 (CHRM1) expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 (GLI1), patched 1 (PTCH1), and sonic hedgehog (SHH) expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hedgehog signaling pathway.

Gintonin facilitates catecholamine secretion from the perfused adrenal medulla

The present study was designed to investigate the characteristics of gintonin, one of components isolated from Korean Ginseng on secretion of catecholamines (CA) from the isolated perfused model of rat adrenal gland and to clarify its mechanism of action. Gintonin (1 to 30 µg/ml), perfused into an adrenal vein, markedly increased the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. The gintonin-evoked CA secretion was greatly inhibited in the presence of chlorisondamine (1 µM, an autonomic ganglionic bloker), pirenzepine (2 µM, a muscarinic M₁ receptor antagonist), Ki14625 (10 µM, an LPA₁/₃ receptor antagonist), amiloride (1 mM, an inhibitor of Na⁺/Ca²⁺ exchanger), a nicardipine (1 µM, a voltage-dependent Ca²⁺ channel blocker), TMB-8 (1 µM, an intracellular Ca²⁺ antagonist), and perfusion of Ca²⁺-free Krebs solution with 5mM EGTA (a Ca²⁺chelater), while was not affected by sodium nitroprusside (100 µM, a nitrosovasodialtor). Interestingly, LPA (0.3~3 µM, an LPA receptor agonist) also dose-dependently enhanced the CA secretion from the adrenal medulla, but this facilitatory effect of LPA was greatly inhibited in the presence of Ki 14625 (10 µM). Moreover, acetylcholine (AC)-evoked CA secretion was greatly potentiated during the perfusion of gintonin (3 µg/ml). Taken together, these results demonstrate the first evidence that gintonin increases the CA secretion from the perfused rat adrenal medulla in a dose-dependent fashion. This facilitatory effect of gintonin seems to be associated with activation of LPA- and cholinergic-receptors, which are relevant to the cytoplasmic Ca²⁺ increase by stimulation of the Ca²⁺ influx as well as by the inhibition of Ca²⁺ uptake into the cytoplasmic Ca²⁺ stores, without the increased nitric oxide (NO). Based on these results, it is thought that gintonin, one of ginseng components, can elevate the CA secretion from adrenal medulla by regulating the Ca²⁺ mobilization for exocytosis, suggesting facilitation of cardiovascular system. Also, these findings show that gintonin might be at least one of ginseng-induced hypertensive components.

Additive interaction of intrathecal ginsenosides and neostigmine in the rat formalin test / 대한마취과학회지

BACKGROUND: The authors evaluated the effect of intrathecal mixture of ginsenosides with neostigmine on formalin-induced nociception and made further clear the role of the spinal muscarinic (M) receptors on the activity of ginsenosides. METHODS: A catheter was located in the intrathecal space of male Sprague-Dawley rats. Pain was evoked by injection of formalin solution (5%, 50 microl) to the hindpaw. Isobolographic analysis was done to characterize drug interaction between ginsenosides and neostigmine. The antagonism of ginsenosides-mediated antinociception was determined with M1 receptor antagonist (pirenzepine), M2 receptor antagonist (methoctramine), M3 receptor antagonist (4-DAMP), M4 receptor antagonist (tropicamide). The expression of muscarinic receptor subtypes was examined with RT-PCR. RESULTS: Intrathecal ginsenosides and neostigmine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed an additive interaction between ginsenosides and neostigmine in both phases. Intrathecal pirenzepine, methoctramine, 4-DAMP, and tropicamide reversed the antinociception of ginsenosides in both phases. M1-M4 receptors mRNA detected in spinal cord of naive rats and the injection of formalin decreased the expression of M1 receptor mRNA, but it had no effect on the expression of other three muscarinic receptors mRNA. Intrathecal ginsenosides little affected the expression of all of muscarinic receptors mRNA in formalin-injected rats. CONCLUSIONS: Intrathecal ginsenosides additively interacted with neostigmine in the formalin test. Furthermore, M1-M4 receptors exist in the spinal cord, all of which contribute to the antinocieption of intrathecal ginsenosides.

Síntomas de discontinuación luego de suspensión abrupta de olanzapina / Discontinuation symptoms following olanzapine abrupt withdrawal

Extended use of atypical neuroleptics in clinical practice, may be explained by their effectiveness as antipsychotics and also with recent approvals for therapeutic benefits of this drugs beyond psychotic disorders. Receptor adaptation mechanisms rises critical issues about treatment discontinuation strategies. Clinical data of two patients who have required the use of atypical antipsychotics are discussed. In both cases, abrupt discontinuation of the drug occurred followed by the emergence of extrapyramidal symptoms. Adaptation mechanisms in synaptic structures would be responsible for this phenomena and the subsequent amelioration of this extrapyramidal symptoms when initial treatment is replaced. The authors concluded that atypical antipsychotics, as other psychotropic agents shouldn't be abruptly discontinued even when they are replaced by other drugs from the same family.

El uso de los antipsicóticos atípicos ha ido aumentando con el tiempo entre otras cosas, por el hecho de que se están usando no sólo para los cuadros psicóticos sino que también para otras patologías. Como con otros fármacos que actúan a nivel de receptores deben considerarse los mecanismos de adaptación receptorial que se producen con su uso. Lo anterior es de suma importancia cuando pensamos en la discontinuación del tratamiento y en sus formas de hacerlo. En este trabajo presentamos dos casos clínicos de pacientes que han requerido el uso de antipsicóticos atípicos. En ambos casos se ha realizado una suspensión brusca del fármaco lo que ha generado la aparición de síntomas extrapiramidales, que en nuestra opinión, son explicados por mecanismos de adaptación a nivel sináptico y que han disminuido con el reinicio del tratamiento inicial. Debemos tener presente que estos fármacos no deben ser discontinuados en forma súbita aun cuando sean remplazados por otros de la misma familia.

Mechanism of Smad 3 signaling pathway and connective tissue growth factor in the inhibition of form deprivation myopia by pirenzepine / 中南大学学报(医学版)

OBJECTIVE@#To observe the inhibitive effect of pirenzepine on form deprivation myopia in guinea pigs and to explore the mechanism of Smad3 signaling pathway and connective tissue growth factor (CTGF) in the inhibition of myopia by pirenzepine.@*METHODS@#Forty 1-week-old guinea pigs of either sex were randomly divided into 4 groups: a control group (Group I), a form deprivation group (Group II), a pirenzepine ophthalmic solution group (Group III), and a sodium chloride ophthalmic solution group (Group IV). Translucent blinders were used in the right eyes of Group II, III and IV. The left eyes were not given any treatment as the normal control group. Covered eyes of Group III and IV were given 3% pirenzepine ophthalmic solution and 0.1% azone ophthalmic solution respectively twice every day. Six weeks later, refraction and axial length were measured at the end of the experiment, and immunohistochemistry and Western blot were used to analyze the expression levels of Smad3 and CTGF in the sclera of all 4 groups.@*RESULTS@#There was no significant difference between Group III and I in relative refraction and changes of axial length (P>0.05). The difference of Group II and IV compared with Group I was statistically significant (P0.05), while the difference in Group II, IV and I was significant (P0.05).@*CONCLUSION@#Pirenzepine ophthalmic solution can inhibit the development of form deprivation myopia. Pirenzepine may affect Smad3 signaling pathway in the sclera by inhibiting the development of form deprivation myopia.

An increase in intracelluar free calcium ions modulated by cholinergic receptors in rat facial nucleus / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Ca(2+) in the central nervous system plays important roles in brain physiology, including neuronal survival and regeneration in rats with injured facial motoneurons. The present research was to study the modulations of intracellular free Ca(2+) concentrations by cholinergic receptors in rat facial nucleus, and the mechanisms of the modulations.</p><p><b>METHODS</b>The fluorescence intensity of facial nucleus in Fluo-3 AM loaded acute brainstem slices was detected by applying intracellular free Ca(2+) measurement technique via confocal laser scanning microscope. The changes of fluorescence intensity of facial nucleus indicate the average changes of intracellular free Ca(2+) levels of the neurons.</p><p><b>RESULTS</b>Acetylcholine was effective at increasing the fluorescence intensity of facial nucleus. Muscarine chloride induced a marked increase of fluorescence intensity in a concentration dependent fashion. The enhancement of fluorescence intensity by muscarine chloride was significantly reduced by thapsigargin (depletor of intracellular Ca(2+) store; P < 0.01), rather than Ca(2+) free artifical cerebrospinal fluid or EGTA (free Ca(2+) chelator; P > 0.05). And the increase of fluorescence intensity was also significantly inhibited by pirenzepine (M(1) subtype selective antagonist; P < 0.01) and 4-DAMP (M(3) subtype selective antagonist; P < 0.01). In addition, fluorescence intensity was markedly increased by nicotine. The enhancement of fluorescence intensity by nicotine was significantly reduced by EGTA, nifedipine (L-type voltage-gated Ca(2+) channel blocker), dihydro-beta-erythroidine (alpha4beta2 subtype selective antagonist), and in Ca(2+) free artificial cerebrospinal fluid (P < 0.01), but not in the presence of mibefradil (M-type voltage-gated Ca(2+) channel blocker) or thapsigargin (P > 0.05).</p><p><b>CONCLUSIONS</b>The data provide the evidence that muscarinic receptors may induce the increase of intracellular free Ca(2+) levels through the Ca(2+) release of intracellular Ca(2+) stores, in a manner related to M(1) and M(3) subtypes of muscarinic receptors in rat facial nucleus. Nicotine may increase intracellular free Ca(2+) concentrations via the influx of extracellular Ca(2+)+ mainly across L-type voltage-gated Ca(2+) channels, in a manner related to the alpha4beta2 subtype of nicotinic receptors.</p>

Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1: [revisão] / Adjunctive therapies to glycaemic control of type 1 diabetes mellitus: [review]

Desde o Diabetes Control and Complications Trial (DCCT), a terapia insulínica intensiva tem sido direcionada para alcançar valores de glicemia e hemoglobina glicada (HbA1c) tão próximos do normal quanto a segurança permita. Entretanto, a hiperglicemia (especialmente a hiperglicemia pós-prandial) e a hipoglicemia continuam a ser um problema no manejo do diabetes tipo 1. O objetivo de associar outras drogas à terapia insulínica é diminuir a glicemia pós-prandial. A terapia adjunta pode ser dividida em três grupos, conforme seu mecanismo de ação: 1. Aumento da ação da insulina (metformina e tiazolidinedionas); 2. Alteração da liberação de nutrientes no trato gastrintestinal (acarbose e amilina); 3. Outros modos de ação [pirenzepina, fator de crescimento insulina-símile (IGF-1) e peptídeo semelhante ao glucagon 1 (GLP-1). Muitos desses agentes mostraram, em estudos de curto prazo, diminuição de 0,5 por cento a 1 por cento na HbA1c, diminuir a hiperglicemia pós-prandial e as doses diárias de insulina.

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1 percent, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Prevention and Treatment of School Myopia

Myopia is the most common refractive error throughout the world. Exact and relative etiologies of myopia have not been investigated in detail, although the high prevalence rate of myopia in school children has been well documented. Patients with myopia must endure the physical and financial burden of spectacles or contact lenses throughout their lives. The National Eye Institute estimated that the costs of refractive eye examinations amount to $1 billion annually, with another $1.5 billion spent on eyeglasses each year. The age of onset of myopia is frequently between 5 to 15 years. There has been a dramatic increase in the prevalence rates of myopia over the past decades in Korea and other parts of Asia. The prevalence rate was 8~15% in 1970s, 23% in 1980s, 38% in 1990s, and 46.2% in 2000s in Korean school children. The remarkable increase in Asian school children suggests that life style risk factors during the school periods may have a great impact on the development of school myopia and the overall population prevalence rate of myopia. Because the gene pool has not changed significantly over the past decades, the rapid increase of the prevalence rates of myopia has been attributed to increases in near-work activities and environmental factors. Atropine is effective in preventing myopia by a non-accommodative mechanism. Atropine is a broad-band muscarinic antagonist that binds to all five identified muscarinic receptors. Animal and clinical studies have shown that the M1-selective muscarinic antagonist, pirenzepine, is effective in reducing axial length enlargement and preventing myopia.

Ganho de peso em pacientes em uso de olanzapina e antipsicóticos típicos: um ensaio clínico randomizado / Weight gain in patients in use of olanzapine and typical antipsychoctics: a randomized clinical trial

Objetivos: O propósito deste estudo foi avaliar o ganho de peso com Olanzapina e os Antipsicóticos de Primeira Geração (APGs). Método: Estudo aberto, multicêntrico, naturalístico, randomizado, comparando Olanzapina com APGs, desde a hospitalização e durante nove meses de acompanhamento. Os avaliadores dos desfechos estavam cegos para a droga de alocação. As doses dos Antipsicóticos (APs) foram determinadas pelos médicos de acordo com sua prática clínica. As medidas de peso foram realizadas mensalmente. Resultados: 197 pacientes foram alocados para Olanzapina (n=104) e APGs (n=93). A proporção de pacientes com ganho de peso clinicamente relevante (aumento >_ 7 por cento do peso inicial) foi maior com Olanzapina (66,7 por cento) que APGs (50,0 por cento). O ganho de peso tendei a formar platô em cerca de 6 meses. O aumento médio no peso foi de 8,6 kg (18,96 Ibs) no grupo olanzapina e 5,4 kg (11,90 Ibs) com APGs. Os fatores associados com ganho de peso foram idade, índice de Massa Corporal (IMC) inicial e duração da doença. 0 peso e IMC iniciais foram os melhores determinantes para ganho de peso pela regressão linear. Conclusão: Ambos, olanzapina e APGs estão associados com ganho de peso. Quando comparada com APGs, olanzapina parece induzir maior ganho de peso. 0 tratamento com APs contribui para o ganho de peso de modo apenas parcialmente compreendido. Outros fatores, como efeito genético e comportamento estão claramente envolvidos com o ganho de peso

Effect of pirenzepine ophthalmic solution on form-deprivation myopia in the guinea pigs / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Nonselective muscarinic receptor antagonist, atropine, was believed to inhibit myopic progression. The purpose of this study was to determine the efficacy, through topical administration, of the M1-selective muscarinic antagonist pirenzepine in preventing experimentally induced form-deprivation myopia in guinea pigs.</p><p><b>METHODS</b>Fifty-three guinea pigs, which underwent monocular deprivation with their eyelids sutured, were divided into 6 groups. Three groups were treated with 1%, 2% or 4% pirenzepine ophthalmic solutions; the fourth group with atropine; the fifth with saline and the last group left untreated. Ocular refraction, in vivo biometric measurements and wet eye weight were collected before and after the experiment. All the eyes were finally enucleated for histopathological examination to evaluate the possible toxic effects on ocular structures.</p><p><b>RESULTS</b>Animals untreated or treated with saline produced (-2.31+/-1.47) D and (-2.25+/-0.88) D of axial myopia respectively. Those treated with 1% pirenzepine ophthalmic solution produced relative myopia of (-1.63+/-0.48) D, and those under the treatment of 2% and 4% pirenzepine ophthalmic solution only developed a relative myopia of (-0.89+/-0.42) D and (-0.70+/-0.41) D (F=9.56, P<0.05). The significant reduction in myopia in 2% and 4% pirenzepine treated animals was caused by significantly less vitreous chamber elongation and axial elongation of the deprived eyes [2% group: (0.009+/-0.052) mm, 4% group: (0.006+/-0.078) mm] when compared with untreated, saline treated or 1% pirenzepine treated guinea pigs (0.057+/-0.056) mm, (0.064+/-0.053) mm and (0.033+/-0.035) mm, respectively]. Histological examinations revealed no obviously toxic effects on the eyes treated with pirenzepine.</p><p><b>CONCLUSION</b>Topical administration of the M1-selective muscarinic antagonist, pirenzepine, can prevent induced form-deprivation myopia in guinea pigs by inhibiting axial elongation without obvious damage to ocular tissues.</p>

Estratégias terapêuticas na esquizofrenia resistente: avaliação naturalística de três novos antipsicóticos / Therapeutic strategies for resistant schizophrenia: a naturalistic evaluation of three new antipsychotics

A clozapina ainda é o único agente comprovadamente eficaz no tratamento da esquizofrenia refratária. Entretanto o conceito de resistência, visto de forma ampla, abrange síndromes mais leves, e os novos antipsicóticos podem ser alternativa no tratamento. São apresentados aqui três estudosðpiloto realizados em um hospital público, o Instituto Municipal Nise da Silveira, localizado no Rio de Janeiro (RJ). Onze pacientes foram tratados com olanzapina. No estudo com risperidona foram incluídos oito pacientes. O tempo de seguimento dos dois estudos foi de seis meses. Análise dos dados foi feita com teste nãoðparamétrico, o Wilcoxon. Para tratamento com clozapina foram selecionados nove pacientes, todos devidamente monitorados do ponto de vista hematológico. O tempo de acompanhamento foi de 12 meses, e os resultados, analisados por meio do teste t pareado. Todos os pacientes tinham diagnóstico de esquizofrenia (CIDð10), e, para avaliação psicopatológica, usaram-se a PANSS e a BPRS nos seguintes tempos: admissão, terceiro, sexto e 12§ meses de tratamento. Com olanzapina, seis pacientes (54 por cento) atingiram o critério de melhora e apresentaram significativas diminuições do escore total, sintomas positivos e negativos (fator anergia) da BPRS. No tratamento com risperidona verificaram-se diminuições não-significantes da pontuação total e sintomas positivos da BPRS. Com clozapina, os nove pacientes apresentaram uma diminuição de 26 por cento a 86 por cento da pontuação total da BPRS. Adicionalmente os valores das subescalas de sintomas positivos, negativos e de psicopatologia geral da PANSS apresentaram reduções significativas após 12 meses. Apesar de suas limitações, este estudo aponta para a utilização dos novos antipsicóticos na abordagem farmacológica da esquizofrenia resistente e ressalta a necessidade de uma visão mais ampla do conceito de resistência ao tratamento antipsicótico

Muscarine M2 Receptor-mediated Presynaptic Inhibition of GABAergic Transmission in Rat Meynert Neurons

Cholinergic modulation of GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) by the activation of muscarine receptors was investigated in mechanically dissociated rat nucleus basalis of the Meynert neurons using the conventional whole-cell patch recording configuration. Muscarine (10microM) reversibly and concentration-dependently decreased mIPSC frequency without affecting the current amplitude distribution. Muscarine action on GABAergic mIPSCs was completely blocked by 1microM methoctramine, a selective M2 receptor antagonist, but not by 1microM pirenzepine, a selective M1 receptor antagonist. NEM (10microM), a G-protein uncoupler, attenuated the inhibitory action of muscarine on GABAergic mIPSC frequency. Muscarine still could decrease GABAergic mIPSC frequency even in the Ca2+-free external solution. However, the inhibitory action of muscarine on GABAergic mIPSCs was completely occluded in the presence of forskolin. The results suggest that muscarine acts presynaptically and reduces the probability of spontaneous GABA release, and that such muscarine-induced inhibitory action seems to be mediated by G-protein-coupled M2 receptors, via the reduction of cAMP production. Accordingly, M2 receptor-mediated disinhibition of nBM neurons might play one of important roles in the regulation of cholinergic outputs from nBM neurons as well as the excitability of nBM neurons themselves.

Olanzapina: comentários e sugestões ao protocolo preliminar do Ministério da Saúde / Olanzapine: prelimminary official guidelines for Brazilian mental health services ð critical appraisal and suggestions

Após breve revisão da literatura, examina-se criticamente a proposta preliminar (Anexo I da Portaria SAS 347, de 21/09/2000) da Secretaria de Assistência à Saúde do Ministério da Saúde, que contém diretrizes para o emprego clínico da olanzapina em pacientes esquizofrênicos refratários com mais quatro anos de enfermidade no Sistema Único de Saúde. A relevância e a oportunidade da iniciativa terapêutica da clozapina na esquizofrenia refratária, além do baixo perfil de efeitos adversos extrapiramidais e cognitivos, com utilidade comprovada nos sintomas positivos e quadros agudos esquizofrênicos equivalente ao haloperidol, sugere-se a dispensa de um procedimento prêvio para a obtenção formal de consentimento e uma ampliação dos critérios de inclusão de forma a alcançar, segundo ordem de prioridade, pacientes com outras formas de intolerância grave aos antipsicóticos convencionais além de discinesia tardia; pacientes refratários intolerantes ou com contra-indicação à clozapina; esquizofrênicos crônicos não-refratários graves; esquizofrênicos agudos; e pacientes com outras nosologias, em que o uso de atípico com boa tolerância possa se constituir na melhor escolha (transtornos esquizoafetivos, mania aguda, distúrbios psicóticos do comportamento em pacientes com mal de Alzheimer, psicose intercorrente no tratamento com drogas dopaminérgicas no mal de Parkinson). Por se tratar de medicamento de alto custo, impeditivo de uma prescrição livre e generalizada, sugere-se eventual gerenciamento de cotas por região, além do procedimento de autorização e acompanhamento de resultados, a ser feito pelos comitês locais de especialistas previstos pela Portaria. Por razões de segurança, a retirada cuidadosa da medicação em curso (antipsicóticos e anticolinérgicos) é recomendada, com as doses iniciais protocolares de olanzapina partindo de 10mg e não de 5mg, como proposto

The Mechanism of Antiallodynic Effect of Intrathecal Morphine in Neuropathic Pain Induced by Spinal Nerve Ligation / 대한마취과학회지

BACKGROUND: Although the efficacy of morphine in a neuropathic pain state is somewhat controversial, intrathecally administered morphine reversed the mechanical allodynia in a previous animal study. Using a behavioral test, we investigated the mechanism of the antiallodynic action of intrathecal morphine by administering opioids, alpha2 adrenergic and cholinergic receptor antagonists in a rat model of neuropathic pain induced by a spinal nerve ligation injury. METHODS: Male Sprague Dawley rats were prepared with a tight ligation of the left lumbar 5th and 6th spinal nerves and insertion of a chronic lumbar intrathecal catheter. Morphine 1 microgram was administered intrathecally to attenuate the mechanical allodynia. Naloxone 10 microgram, yohimbine 30 microgram, prazosin 30 microgram, atropine 10 microgram, pirenzepine 10 microgram, and methoctramine 10 microgram was administered intrathecally before and after the injection of morphine in order to investigate the reversal of an increased allodynic threshold by morphine. The allodynic thresholds for the left hindpaw withdrawal to von Frey hairs were assessed and converted to %MPE. RESULTS: A reduction of mechanical allodynia by intrathecal morphine was produced. Naloxone pretreatment, but not posttreatment, reversed the antiallodynic effect of intrathecal morphine (P < 0.01). All alpha2 adrenergic and cholinergic receptor antagonists used here did not reverse it. CONCLUSIONS: The results suggest that the reversal mechanism of mechanical allodynia by intrathecal morphine appears to be mediated mostly by the opioid receptor system, but not the alpha2 adrenergic and cholinergic receptor systems, at the spinal level in a rat model of a spinal nerve ligation injury.

Mechanism of epibatidine-induced catecholamine secretion in the rat adrenal gland

The present study was attempted to investigate the characteristics of epibatidine on secretion of catecholamines (CA) from the isolated perfused model of the rat adrenal gland, and to establish the mechanism of action. Epibatidine (3X10(-8) M) injected into an adrenal vein produced a great inhibition in secretory response of CA from the perfused rat adrenal gland. However, upon the repeated injection of epibatidine (3X10(-8) M) at 15 min-intervals, CA secretion was rapidly decreased after second injection of epibatidine. However, there was no statistical difference between CA secretory responses of both 1st and 2nd periods by the successive administration of epibatidine at 120 min-intervals. Tachyphylaxis to releasing effects of CA evoked by epibatidine was observed by the repeated administration. Therefore, in all subsequent experiments, epibatidine was not administered successively more than twice only 120 min-intervals. The epibatidine-induced CA secretion was markedly inhibited by the pretreatment with atropine, chlorisondamine, pirenzepine, nicardipine, TMB-8, and perfusion of Ca2+/-free Krebs solution containing EGTA, while was not affected by diphenhydramine. Moreover, the CA secretion evoked by ACh for 1st period (0apprx4 min) was greatly potentiated by the simultaneous perfusion of epibatidine (1.5X10(-8) M), but followed by time-dependently gradual reduction after 2nd period. The CA release evoked by high potassium (5.6+/-10(-8) M) for 1st period (0apprx4 min) was also enhanced by the simultaneous perfusion of epibatidine, but those after 2nd period were not affected. Taken together, these experimental data suggest that epibatidine causes catecholamine secretion in a calcium dependent fashion from the perfused rat adrenal gland through activation of neuronal cholinergic (nicotinic and muscarinic) receptors located in adrenomedullary chromaffin cells. It also seems that epibatidine-evoked catecholamine release is not relevant to stimulation of histaminergic receptors.

Muscarinic receptor subtype controlling the carbachol-induced muscle contraction in guinea pig gastric antrum

Stimulation of muscarinic receptors by carbachol (CCh) in the circular smooth muscle of the guinea pig gastric antrum causes muscle contraction. In the present study, muscarinic receptor subtype controlling the muscle contraction in response to CCh was studied using putative muscarinic receptor antagonists. Isometric force of the isolated circular muscle strips was measured in an organ bath. CCh contracted the muscle in a dose-dependent way, and each of the three muscarinic receptor antagonists, 4-diphenylacetoxy-N-methylpeperdine methiodide (4-DAMP), methoctramine and pirenzepine shifted the concentration-response curves to the right without significantly reducing the maximum force. The affinities of the muscarinic antagonists (pA2 values) obtained from Schild plot analysis were 10.15, 7.05 and 6.84 for 4-DAMP, methoctramine and pirenzepine, respectively. These results suggest that the M3-subtype mainly mediate the muscle contraction in response to CCh in guinea pig gastric antrum.

Brain spect imaging in Huntington's disease before and after therapy with olanzapine: case report

Olanzapine, an atypical antipsychotic drug, was administered to a patient with Huntington's disease (HD) with marked choreiform movements. Brain SPECT with (99m)Tc-HMPO was performed before and after treatment. Brain SPECT imaging has been performed in patients with HD in order to determine the status of basal ganglia perfusion. The use of brain SPECT with (99m)Tc-HMPAO before and after treatment in patients with HD has not been yet reported. The marked hypoperfusion of the basal ganglia on brain SPECT performed before therapy with olanzapine improved significantly after treatment.

Meta-análise para avaliar a eficácia e a segurança da olanzapina comparada ao haloperidol no tratamento da esquizofrenia: achados preliminares / Meta-analysis for evaluate the efficacy and safety of olanzpine compared to haloperidol in the treatment of schizophenia: preliminary findings

O objetivo deste estudo foi avaliar, através de meta-análise, a eficácia clínica a curto prazo (seis semanas) e a segurança da olanzapina em comparaçäo como haloperidol e placebo, a luz dos dados obtidos a partir dos ensaios clínicos controlados. A busca realizada através do MEDLINE em CD ROM, das referências bibliográficas tanto dos artigos de revisäo quanto dos estudos primários, bem como o contato com o fabricante, resultaram em três ensaios randomizados, controlados, duplo-cegos comparando a olanzapina com haloperidol/placebo e um envolvendo a comparaçäo com placebo isoladamente. Os resultados clinicamente relevantes foram extraídos, quais sejam, (I) a proporçäo de pacientes que deixaram de alcançar pelo menos 40 por cento de melhora da Brief Psychiatric Rating Scale, (II) a proporçäo de pacientes que abandonaram o tratamento devido a efeitos adversos e (IV) o número de pacientes que necessitaram de medicaçäo antiparkinsoniana em decorrência dos sintomas extrapiramidais. Insucesso terapêutico, definido como a incapacidade de alcançar pelo menos 40 por cento de melhora da psicopatologia, esteve presente em 48 por cento dos pacientes tratados com olanzapina, em comparaçäo com 64 por cento daqueles tratados com haloperidol. Seria necessário tratar 6 pacientes com olanzapina para prevenir um insucesso terapêutico previsto para ocorrer nos pacientes tratados com haloperidol (OR=0,53, IC 95 por cento = 0,44-0,64, p<0,00001). Ocorreram significantemente menos interrupçöes prematuras do tratamento por ineficácia nos pacientes tratados com olanzapina do que nos foram tratados com haloperidol, respectivamente 20,7 por cento e 30,5 por cento (OR=0,60, IC 95 por cento = 0,49-0,62, p<0,00001). A interrupçäo prematura do tratamento devida a efeitos adversos foi mais frequente nos pacientes tratados com haloperidol do que naqueles tratados com olanzapina, respctivamente, 7 por cento e 4 por cento (OR = 0,58, IC 95 por cento = 0,39-0,85, p = 0,005). O uso de anticolinérgicos foi necessário em apenas 15 por cento dos pacientes tratados com olanzapina, em comparaçäo com 49 por cento daqueles tratados com haloperidol (OR = 0,19, IC 95 por cento = 0,15-0,23, p<0,0001). Em conclusäo, a olanzapina parece ser mais eficaz como antipsicótico do que o haloperidol. Ademais, parece mais segura, uma vez que promoveu menos interrupçöes por efeitos adversos e exigiu significantemente menos medicaçöes antiparkinsonianas

Comparison of the efficacy and acceptability of atypical antipsychotic drugs: a meta-analysis of randomized, placebo-controlled trials.

Knowing the clinical differences of olanzapine, quetiapine, and risperidone would be of benefit for choosing an atypical antipsychotic drug. In order to compare their efficacy and acceptability, we conducted a meta-analysis of published, randomized, placebo-controlled trials by comparing the response and dropout rates of an atypical antipsychotic drug group and those of a placebo group. After a comprehensive search of study reports, the response and dropout rates of patients treated with an atypical antipsychotic drug and those treated with placebo were extracted on the intention-to-treat basis. The effect size with 95 per cent confidence interval (CI) of pooled data comparing the response and dropout rates of an atypical antipsychotic drug group and those of a placebo group were calculated by using the Peto method. The response-rate effect sizes (95% CIs) of olanzapine, quetiapine, and risperidone were 1.75 (1.06 to 2.89), 1.71 (1.20 to 2.42), and 3.28 (1.98 to 5.44), respectively. The dropout-rate effect sizes (95% CIs) of olanzapine, quetiapine, and risperidone were 0.55 (0.35 to 0.88), 0.65 (0.46 to 0.91), and 0.39 (0.24 to 0.62), respectively. In conclusion, olanzapine, quetiapine, and risperidone are more effective and more acceptable than placebo in treating schizophrenic patients. However, they are not different from each other in the respect of efficacy and acceptability. The cost of these agents should play an important role in choosing an atypical antipsychotic drug.