The prevalence of impulsive compulsive behaviors in patients treated with apomorphine infusion: a retrospective analysis / Prevalência de comportamentos impulsivo-compulsivos em pacientes tratados com infusão de apomorfina: análise retrospectiva

ABSTRACT Background: Impulsive compulsive behaviors (ICBs) can affect a significant number of Parkinson's disease (PD) patients. Objective: We have studied brain samples from a brain bank of PD patients who received apomorphine via continuous infusion in life to assess the prevalence and outcome of ICBs. Methods: A search on the Queen Square Brain Bank (QSBB) database for cases donated from 2005 to 2016 with a pathological diagnosis of idiopathic PD was conducted. Notes of all donors who used apomorphine via continuous infusion for at least three months were reviewed. Clinical and demographic data were collected, as well as detailed information on treatment, prevalence and outcomes of ICBs. Results: 193 PD cases, 124 males and 69 females, with an average age at disease onset of 60.2 years and average disease duration of 17.2 years were reviewed. Dementia occurred in nearly half of the sample, depression in one quarter, and dyskinesias in a little over 40%. The prevalence of ICBs was 14.5%. Twenty-four individuals used apomorphine infusion for more than three months. Patients on apomorphine had younger age at disease onset, longer disease duration, and higher prevalence of dyskinesias. The prevalence of de novo ICB cases among patients on apomorphine was 8.3%. Apomorphine infusion was used for an average of 63.1 months on an average maximum dose of 79.5 mg per day. Ten patients remained on apomorphine until death. Conclusions: Apomorphine can be used as an alternative treatment for patients with previous ICBs as it has low risk of triggering recurrence of ICBs.

RESUMO Antecedentes: Comportamentos impulsivo-compulsivos (CICs) podem acometer uma parcela significativa de indivíduos com doença de Parkinson (DP). Objetivo: Nós estudamos amostras de tecido cerebral de uma população de pacientes com DP de um banco de cérebros que receberam apomorfina por infusão contínua em vida, com a finalidade de avaliar a prevalência e o desfecho dos CICs. Métodos: Uma pesquisa no banco de dados do Banco de Cérebros de Queen Square foi conduzida à procura de doações recebidas entre 2005 e 2016 com diagnóstico anatomopatológico de DP idiopática. Os prontuários de todos os doadores que usaram apomorfina por infusão contínua por um período mínimo de três meses foram revisados. Dados clínicos e demográficos foram coletados, assim como informações detalhadas sobre o tratamento, prevalência e desfecho dos CICs. Resultados: 193 casos de DP, 124 do sexo masculino e 69 do sexo feminino, com idade média de início da doença de 60,2 anos e tempo médio de duração da doença de 17,2 anos, foram revisados. Aproximadamente metade dos casos apresentaram demência, um quarto depressão, e um pouco mais de 40% discinesias. A prevalência de CICs foi 14,5%. Vinte e quatro indivíduos usaram infusão de apomorfina por mais de três meses. Os pacientes que usaram apomorfina apresentaram DP mais cedo, maior duração da doença, e uma maior prevalência de discinesias. A prevalência de novos casos de CICs entre pacientes usando apomorfina foi de 8,3%. Infusão de apomorfina foi usada em média por 63,1 meses a um dose máxima média de 79,5 mg por dia. Dez pacientes permaneceram usando apomorfina até o óbito. Conclusões: Apomorfina pode ser usada como opção de tratamento alternativo para pacientes que apresentarem CICs no passado considerando seu baixo risco de causar recorrência de CICs.

Effect of dopamine and its receptors on the development of visual deprivation myopia / 国际眼科杂志(Guoji Yanke Zazhi)

@#Myopic population of China is already nearly 600 million, the rate of teenager myopic occupies the first place in the world, myopia hsa already became one of the main diseases that endangers our adolescent's health. Dopamine is the main catecholamine in retina. Many studies have found that increasing the content of dopamine can effectively inhibit the development of myopia. Form-deprivation myopia is a classical method of myopia modeling. By observing the influence of dopamine and its receptors on the development of form-deprivation myopia, its role in the development of myopia can be reflected, and it is of great significance to guide and control the occurrence and development of myopia. In this paper, the effects of dopamine and its receptors on the development of form-deprivation myopia were reviewed in order to provide reference for the prevention and treatment of myopia.

Pruebas Terapéuticas Con Fines Diagnósticos En Trastornos Del Movimiento / Therapeutic Tests For The Diagnosis Of Movement Disorders

Resumen El diagnóstico en medicina tiene su piedra angular en la obtención de la historia clínica y la exploración física; sin embargo, en algunas de las patologías el uso de pruebas diagnósticas es de gran utilidad como apoyo para confirmar o descartar una enfermedad. Las pruebas diagnósticas incluyen una amplia variedad de procedimientos y dentro de estas se incluyen las pruebas terapéuticas, también llamadas desafíos o retos, en los que se administra una sustancia activa para evaluar la respuesta y apoyar la impresión diagnóstica. En el contexto de los trastornos del movimiento las pruebas terapéuticas más frecuentemente utilizadas son la de levodopa, apomorfina y etanol. En esta revisión se presenta, describe y discute el alcance y utilidad de estas.

Abstract The diagnosis in medicine has its cornerstone in obtaining the clinical history and in the physical examination. However, in some of the pathologies the use of diagnostic tests is very useful as a support to confirm or rule out a disease. Diagnostic tests include a wide variety of procedures and these include therapeutic tests, also called challenges, in which an active substance is administered to evaluate the response and support the presumptive diagnosis. In the context of movement disorders, the most frequently used therapeutic tests are those with levodopa, apomorphine and ethanol. In this review we present, describe and discuss the scope and usefulness of these challenges.

Apomorphine in the treatment of Parkinson's disease: a review / O uso da apomorfina no tratamento da doença de Parkinson: revisão da literatura

ABSTRACT Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.

RESUMO A optimização do tratamento da doença de Parkinson idiopática se faz um desafio, pois tem impacto direto na qualidade de vida do paciente. O melhor esquema terapêutico é o que permite o melhor controle motor com os menores efeitos adversos, através de terapêutica individualizada. A apomorfina é o único medicamento antiparkinsoniano que pode ser comparável à potência da levodopa no controle dos sintomas motores. Trata-se de um agonista dopaminérgico empregado na terapia de resgate em pacientes com flutuações motoras e também contribui para a melhora de muitos sintomas não motores. A via subcutânea, com injeções intermitentes, ou com infusão contínua, parece ser a melhor opção pela eficácia e tolerabilidade. Essa revisão resume aspectos históricos, estrutura da molécula, mecanismo de ação, indicação, contra-indicação e efeitos colaterais, compara a terapia de infusão com apomorfina com outros tratamentos, como a terapia oral, estimulação cerebral profunda e infusão enteral contínua de levodopa/carbidopa gel, e fornece instruções práticas de como iniciar o tratamento.

Consenso de la Asociación Colombiana de Neurología sobre el uso de apomorfina en la enfermedad de Parkinson / Colombian Association of Neurology Consensus on the use of Apomorphine in Parkinson's disease

La apomorfina es un agonista dopa que se viene usando desde hace más 25 años en el tratamiento de la enfermedad de Parkinson avanzada con complicaciones motoras complejas, por lo cual sigue siendo de gran importancia en el tratamiento de esta etapa de la enfermedad. En el siguiente escrito, realizado por el Comité de Movimientos Anormales de la Asociación Colombiana de Neurología, se hace una revisión respecto a la medicación, su eficacia y el papel en el manejo de la enfermedad de Parkinson, así como una comparación entre las diferentes terapias avanzadas disponibles hoy en día. De la misma manera el Comité hace recomendaciones sobre las indicaciones, elección de candidatos y protocolos para el inicio de las diferentes formas de administración (intermitente e infusión continua) para optimizar el uso de esta terapia y facilitar la adherencia al tratamiento. Por otra parte, se revisan los efectos adversos relacionados con la terapia y se hacen recomendaciones sobre el manejo de las mismas, el seguimiento que se debe hacer a los pacientes que reciban apomorfina y las claves en el tratamiento a largo plazo. long term.

Apomorphine is a dopamine agonist that has been used for more than 25 years in the treatment of advanced Parkinson's disease with complex motor complications, becoming an important treatment option for this stage of the disease. In the following document, written by the movement disorders committee of the Colombian Association of Neurology, an extensive review is made about this medication, its efficacy and role in the management of Parkinson's disease as well as a comparison between the different advanced therapies available today. Additionally, recommendations about the indications, election of candidates and protocols for choosing between the different forms of administration (intermittent and continuous infusion) are establish according current evidence in order to help clinicians to optimize the use of this therapy and facilitate adherence to treatment. On the other hand, adverse effects related to the therapy are reviewed and recommendations are made about their management, as well as a protocol to follow-up patients receiving apomorphine and keys in the long term.

Role of Dopamine Receptors on Electroencephalographic Changes Produced by Repetitive Apomorphine Treatments in Rats

Repeated psychostimulants induce electroencephalographic (EEG) changes, which reflect adaptation of the neural substrate related to dopaminergic pathways. To study the role of dopamine receptors in EEG changes, we examined the effect of apomorphine, the dopamine D1 receptor antagonist, SCH-23390, and the D2 receptor antagonist, haloperidol, on EEG in rats. For single and repeated apomorphine treatment groups, the rats received saline or apomorphine for 4 days followed by a 3-day withdrawal period and then apomorphine (2.5 mg/kg, i.p.) challenge after pretreatment with saline, SCH-23390, or haloperidol on the day of the experiment. EEGs from the frontal and parietal cortices were recorded. On the frontal cortex, apomorphine decreased the power of all the frequency bands in the single treatment group, and increased the theta (4.5~8 Hz) and alpha (8~13 Hz) powers in the repeated treatment group. Changes in both groups were reversed to the control values by SCH-23390. On the parietal cortex, single apomorphine treatment decreased the power of some frequency bands, which were reversed by haloperidol but not by SCH-23390. Repeated apomorphine treatment did not produce significant changes in the power profile. These results show that adaptation of dopamine pathways by repeated apomorphine treatment could be identified with EEG changes such as increases in theta and alpha power of the frontal cortex, and this adaptation may occur through changes in the D1 receptor and/or the D2 receptor.

Cavernous nerve reconstitution with the use of bone marrow stem cells and erectile function evaluation: an experimental animal study / Avaliação da função erétil após a reconstituição do nervo cavernoso com o uso de células-tronco de medula-óssea: estudo experimental em ratos

Objective: To assess the influence of adult stem cells from bone marrow of rats in the regeneration of cavernous nerve, taking the return of erectile function as a parameter in animals subjected to the apomorphine-induced test of erection. Methods: Forty-eight male Wistar-EPM rats, aged between nine and ten weeks, and weighing approximately 250 g were used. They were randomly divided into four study Groups containing 12 animals each, as follows: Group I: surgical exposure of the cavernous nerves bilaterally without injury; Group II: bilateral surgical injury of the cavernous nerve of approximately 3 mm, without reconstruction; Group III: bilateral surgical injury of the cavernous nerves of approximately 3 mm, and bilateral reconstruction with silicone guiding tubes containing saline solution inside; Group IV: bilateral surgical injury of the cavernous nerves of approximately 3 mm, and bilateral reconstruction with silicone guiding tubes filled with adult stem cells. Four weeks after surgery, the animals were injected with apomorphine for induction of erection. Results: In Group I there was complete erectile response in all animals (100% ? 12 out of 12). On the other hand, none of the animals in Group II presented erection after the use of apomorphine. Five of the twelve animals of Group III (41.7%) and nine of the 12 animals of Group IV (75%) had erections after the stimulus. When we compared the frequency of restoration of erection in the four Groups, Group IV was shown to have a similar performance to Group I (p = 0.217), while Group III animals had a frequency of erections inferior to those in Group I (p = 0.005). Moreover, comparison of results of Groups III and IV versus Group II showed that the frequency of erections was statistically higher in the first two Groups (p = 0.037 and p < 0.001, respectively). Finally, Group IV presented a tendency to a larger number of erections when compared to Group III (75 versus 41.7%) but this difference was not statistically significant (p = 0.098). Conclusion: This study shows that adult stem cells from bone marrow, filling silicone guiding tubes, may promote the regeneration of cavernous nerves and restore erectile function in an animal model.

Objetivo: Avaliar a influência de células-tronco adultas da medula óssea de ratos na regeneração do nervo cavernosos lesado, tomando-se como parâmetro o retorno da função erétil nos animais submetidos ao teste de ereção induzido pela apomorfina. Métodos: Quarenta e oito ratos Wistar-EPM machos, com idades entre nove e dez semanas, pesando aproximadamente 250 g, foram usados e randomicamente subdivididos em quatro grupos de estudo contendo 12 animais cada. Os grupos experimentais foram divididos em: Grupo I: exposição cirúrgica bilateral do nervo cavernoso sem lesão do mesmo. Grupo II: lesão cirúrgica bilateral do nervo cavernoso de aproximadamente 3 mm, sem reconstrução. Grupo III: lesão cirúrgica bilateral dos nervos cavernosos de aproximadamente 3 mm, e reconstrução bilateral com sondas-guia de silicone contendo solução salina em seu interior. Grupo IV: lesão cirúrgica bilateral dos nervos cavernosos de aproximadamente 3 mm, e reconstrução bilateral com sondas-guia de silicone semeadas com células-tronco adultas em seu interior. Quatro semanas após a cirurgia, os animais foram injetados com apomorfina para indução da ereção. Resultados: No grupo I observou-se resposta erétil completa em todos os animais (100% ? 12 em 12). Por outro lado, nenhum dos animais do grupo II apresentou ereções após a administração de apomorfina. Cinco dos doze animais do grupo III (41,7%) apresentaram ereções, enquanto nove dos 12 animais do grupo IV (75%) evidenciaram ereções após o estímulo. Quando foram comparadas as frequências de restauro de ereção nos quatro grupos, demonstrou-se que Grupo IV teve um comportamento semelhante ao Grupo I (p = 0,217), ao passo que os animais do Grupo III apresentaram frequência de ereções inferiores aos do Grupo I (p = 0,005). Por outro lado, a comparação dos resultados entre os Grupos III e IV versus o Grupo II demostrou que a frequência de ereções foi estatisticamente superior nos dois primeiros Grupos (p = 0,037 e p < 0,001, respectivamente). Finalmente, o Grupo IV apresentou tendência a maior número de ereções quando comparado ao Grupo III (75 versus 41,7%), mas essa diferença não foi estatisticamente significante (p = 0,098). Conclusão: O presente estudo demonstra que células-tronco adultas da medula óssea, semeadas em sondas-guia de silicone, favorecem a regeneração dos nervos cavernosos e promovem o restabelecimento da função erétil em um modelo animal.

The effect of apomorphine on visual discrimination learning and reversal learning in rats / 中华行为医学与脑科学杂志

Objective Using apomorphine, a potent dopamine receptor agonist and rotating T-maze, the effect of apomorphine on the visual discrimination learning and reversal learning in rats was investigated. Methods All rats were trained in a visual discrimination task (food reward and light stimulus) in rotating T-maze. After reaching the acquisition criterion, rats were trained in a reversal task (food reward and without light stimulus) in the same maze. During the period of visual discrimination task, apomorphine was administrated either 30 minutes prior to learning or after learning immediately. Results The results showed that apomorphine, which was given either 30 minutes prior to visual discrimination learning or after learning, could impair the acquisition of discrimination learning( 259.20±26.29 and 264.00±16.97, compared to 168.00±16.97 and 163.20±20.08) and apomorphine, which was given only after visual discrimination learning, could impair the acquisition of reversal learning (451.20±39.44 compared to 360.00±29.39). Conclusion The results showed that apomorphine, which was given either 30 minutes prior to visual discrimination learning or after learning, could impair the acquisition of discrimination learning and apomorphine, which was given only after visual discrimination learning, could impair the acquisition of reversal learning.

Effects of a New Antipsychotic Drug (YKP1447) on Impaired Prepulse Inhibition Induced by Apomorphine and Phencyclidine in Rats / 대한정신약물학회지

OBJECTIVE: Schizophrenia, a devastating mental disorder, displays a wide range of cognitive impairments including attentional impairment. Prepulse inhibition (PPI), in which a startle response to a loud acoustic noise is reduced by a preceding auditory stimulus of a lower intensity, is impaired in schizophrenic patients and rats injected with apomorphine (APO) or phencyclidine (PCP) mimicking attentional deficits in schizophrenics. Here we examined therapeutic efficacy of a newly developed atypical antipsychotic compound (YKP1447;YKP) on PPI impairment induced by various doses of APO and PCP. METHODS: This study was composed of 3 experiments. YKP (0.5-15 mg/kg) or vehicle (VEH) was administered 15 min before the injection of APO (0.5 mg/kg, Exp1) or PCP (2.0 mg/kg, Exp2:1.5 mg/kg, Exp3). They were then tested for PPI in which a mix of startle stimulus and prepulse was presented. RESULTS: APO or PCP treatment effectively impaired PPI in tested animals (VEH/APO or VEH/PCP). Impaired PPI in APO group was reversed in animals that were pretreated with YKP (5-10 mg/kg) (Exp1). However YKP treatment was not effective in PCP group (Exp2-3). CONCLUSION: High concentration of YKP pretreatment had antipsychotic effect on APO-induced impairment in attentional function suggesting that the compound could potentially be used to treat cognitive impairment due to increased dopaminergic receptorbinding.

Effect of Jintong Capsule on the Mice Models of Tourette Syndrome / 中国康复理论与实践

@#Objective To observe effect of Jintong capsule on model mice of tourette syndrome (TS).Methods TS models of mouse were established by intraperitoneal injection of amphetamine (AMP) or subcutaneous injection of apomorphine (APO). The animals were randomly divided into the normal control group, model group, Jintong capsule large dose group, Jintong capsule small dose group and haloperidol control group. The spontaneous movements and grasping action of model animals were observed and the contents of dopamine and its products of metabolism in striatum of animals were detected.Results The abnormal hyperactivity and the content of dopamine of Jintong capsule groups in striatum of AMP model mice were lower than that of the model group ( P< 0.05 ), and the grasping time of Jintong capsule groups in APO model mice shorten compare with the control group ( P<0.05).Conclusion Jintong capsule can ameliorate hyperactivity behaviors of these two animal models, and decrease the content of dopamine in striatum.

Effects of Newer Antipsychotic Drugs on Apomorphine-Induced Climbing Behavior in Mice / 대한정신약물학회지

OBJECTIVE: Chlorpromazine equivalence was used to chart relative potencies of typical antipsychotic agents and it has been known to be in a linear relationship with dopamine D2 receptor affinity. After the introduction of these newer antipsychotic drugs, the role of other neurotransmitter systems than dopamine has been emphasized, and it is difficult to attribute the diverse effect of these drugs to common mechanism. Recently, several equivalent dose guidelines have been published for newer antipsychotic drugs. In this study, antagonism of apomorphine-induced climbing behavior was used to investigate the relationship between the clinically determined equivalent doses and behavioral effects measured by animal model of several newer antipsychotic drugs. METHOD: Several newer anti-psychotic drugs were administered 20 min before apomorphine injection. After apomorphine injection, climbing behavior was assessed for up to 20 min by visual inspection. The doses that had inhibited 50% of the control group behavior was defined to be Half-Effective Doses (HED) and calculated from the regression line. The relationship between the HED and clinical Minimum Effective Doses (MED) published elsewhere was investigated using linear regression analysis. RESULT: All the antipsychotic drugs antagonized the apomorphine-induced climbing behavior in a dose-dependent manner. Statistically significant correlation between HED and MED was found (Spearman's rho=0.96, p<0.001), and statistically significant linear relationship was also found (F=76.2, df=1, 4, p=0.001; r2=0.950). CONCLUSION: Antipsychotics inhibit apomorphine-induced climbing behavior by D2 antagonism. Therefore, the result suggests that the common mechanism underlying the therapeutic effects of newer antipsychotics might be related with dopamine D2 antagonism. However, the equivalent doses used in this study focused mainly on psychotic and behavioral symptoms, so that they are not qualified to embrace multi-dimensional therapeutic effects of newer antipsychotics. Investigation of the relationship between the equivalent doses focused on each symptom domain and the effects on diverse neurotransmitter system would broaden our knowledge of mechanism of action of newer antipsychotics.

Cerebral Proerectile Effect of Apomorphine and Vasoactive Agents in Anesthetized Rats / 대한비뇨기과학회지

PURPOSE: To establish central control of a penile erection, the centrally elicited erectile effects of apomorphine hydrochloride and various vasoactive agents were investigated after intracerebroventricular administration. MATERIALS AND METHODS: Anesthetized male Sprague-Dawley rats were used for the study. After intracerebroventricular administration of normal saline(NS), apomorphine hydrochloride(AH), prostaglandin E1(PGE1), sodium nitroprusside(SNP), phenylephrine hydrochloride(PE) and phentolamine(PT) under a stereotaxic setting, the intracavernosal pressure(ICP), systolic femoral artery pressure(FAP), heart rate(HR), time to first response, duration and number of erectile response and adverse reactions were evaluated for 60 minutes. To show if the centrally elicited erection by agents in native setting were effective, the above criteria were re-evaluated after a bilateral pelvic neurotomy and bilateral orchiectomy. RESULTS:Cerebral proerectile effects were elicited by AH with no significant changes in the FAP and HR, but with PGE1, SNP, PE and PT significant changes in both the FAP and HR were observed. The ICP/FAP ratio was highest with SNP at 0.75+/-0.08. The mean time to first response was shortest with AH at 18.1+/-5.1min. The mean duration was longest with AH at 39.4+/-10.9min. The number of responses was highest with AH at 2.7+/-1.1. Adverse reactions, such as stretching, yawning and ejaculation, were simultaneously observed during increases in the ICP. In the case of a bilateral pelvic neurotomy or bilateral orchiectomy, these elicited erectile responses disappeared. CONCLUSIONS: Vasoactive agents, such as SNP, PGE1 and PE, had a cerebral proerectile effect, but AH showed more an evidently potent proerectile effect in the aspects of ICP, time to first response and duration of erectile response. Testosterone and the pelvic nerve are suggested to be essential for a central proerectile response.

The Effects of Various Stressful Conditions on Erection and Manifestation of Oxytocin Positive Neuron of Apomorphine in Mice / 대한비뇨기과학회지

PURPOSE: The aim of this study was to demonstrate whether various stressful conditions have effects on the erection and manifestation of oxytocin positive neurons of the paraventricular nucleus (PVN) in mice. MATERIALS AND METHODS: Thirty, 10-weeks old mice were divided into 4 groups: control (A), stress only (B), apomorphine only (C) and apomorphine with stress treated (D) groups. Chronic restraint and forced swimming stresses were induced. Apomorphine (80ug/kg) was subcutaneously injected every 3 days, and after 14 days the brains of the mice were extracted, and treated with immunohistochemistry. The data were analyzed by optical density and Student's t-test. RESULTS: One of group D was died of excessive stress. The erection rates of groups C, D, A and B were 80, 64, 20 and 0%, respectively. The number of oxytocin-positive neurons in the PVN of groups C, A, D and B were 215, 205, 201 and 190, respectively (p=0.07). The optical density of the oxytocin-positive neurons of the erection group was significant higher than that of the non-erection group (125 vs. 105, p<0.01). CONCLUSIONS: The erectile function was decreased under stressful condition, which was improved by administration of apomorphine. Apomorphine has a relationship with the oxytocin-positive neurons in the PVN; therefore, it is one of the important factors in inducing an erection.

The Clinical Trial of Apomorphine Hydrochloride SL(Uprima(r)) in Patients with Erectile Dysfunction / 대한비뇨기과학회지

PURPOSE: The clinical efficacy and safety of apomorphine hydrochloride SL, a new centrally acting oral agent for the management of the male erectile dysfunction (ED), were evaluated. MATERIALS AND METHODS: Sixty consecutive patients with ED, who visited the Male Sexual Dysfunction Clinic at Pusan National University Hospital, between April and December 2002, were evaluated by open labelled and uncontrolled randomized methods. Apomorphine hydrochloride SL (Uprima(r)), 4-8 3mg tablets, was prescribed on each visit, which was administered sublingually according to the standard patient guidelines. An overall evaluation of erectile function was performed using the international index of erectile function (IIEF) and global efficacy assessment questions (GAQ). RESULTS: The age distribution of the 51 cases was 22 to 76 years, with a mean of 47.6+/-10.6 years. During the mean follow-up period of 26.2+/-18.6 days, ranging from 7 to 156 days, the sum of the IIEF symptom scores changed significantly, from 11.2+/-6.7, at the baseline, to 17.0+/-8.2, on the 3rd visit (p>0.05). The IIEF scores were significantly improved in the Q3 and Q4, at 45.7% and 59.8%, respectively(p0.05). The improvements in the IIEF scores revealed in psychogenic and mild grade ED were statistically significance (p<0.05). Selectivity as a treatment regimen was shown in only 5 cases (8.3%). Adverse reactions were noted in 7 cases (13.7%), but were self-limited, and resulted in only 1 (1.9%) drop-out due to dizziness. CONCLUSIONS: Apomorphine hydrochloride SL is suggested would be a proper oral agent in patients with psychogenic or mild degree organic ED.

Advances on pharmacotherapy for erectile dysfunction / 医学研究生学报

It is reported that plenty of men,especially the aged,have been bothering in penile erectile dysfunction(ED).There are series of treatments for ED.Oral erectogenic agents have become the first-line treatment options,including drugs that act on the central and peripheral nervous systems,testosterone,traditional Chinese medicine and so on.Sidenafil,apomorphine and yohimbine are the only three oral therapies currently available for the treatment of this disorder.The second therapy includes intracavernosum injection,transurethral medications,transdermal medications etc.Intracavernosum injection of PGE 1 is an effective approach at the present.With the rapid understanding of erectile physiology and etiology of ED and the introduction of new effective oral agents,the future of pharmacotherapy for ED will extend.In this review,we have highlighted the advances in current treatments and therapeutic approaches in male erectile dysfunction.

Apomorphine induced c-fos expression in the striatum of 6-OHDA-lesioned rats / 中国药理学通报

Aim To observe the c-fos expression in the caudate-putman of 6-OHDA-lesioned rats after Apomorphine intraperitoneal injection and to investigate the inherent mechanism of it. Methods Rats received a unilateral injection of 6-OHDA into SNc. The abnormal rotations induced by Apomorphine (APO) were investigated 1、7、14 d and 21 d after lesion.Meanwhile dopaminergic derogation and c-fos expression were observed with Nissl body staining,eletronicmicroscopic and immunocytochemistry methods. Results The number of dopaminergic neurons decreased gradually in the lesioned site and its eletronicmicroscopic structure was damaged. When over 80% dopaminergic neurons were lossed , contralateral rotations surpassed 7 r?min~(1) and c-fos expressed in the ipsilateral striatum. Conclusion APO induces c-fos expression in the ipsilateral striatum. Intrinsic relations may exist between dopaminergic neurons deletion and c-fos expression

A Synergistic Effect of Apomorphine on Sildenafil Induced Penile Erection in Conscious Rabbits / 대한비뇨기과학회지

PURPOSE: The aim of this study was to demonstrate that the combined systemic administration of apomorphine (APO) and sildenafil have a synergistic effect on the erection in conscious rabbits. MATERIALS AND METHODS: The erections of the male New Zealand White rabbits (2-3kg, n=12) were assessed by measuring the length of the uncovered penile mucosa (LUPM) and duration of the erection, both before and after the intravenous administration of agents. After the injection of APO (0, 0.05, 0.1, 0.4mg/kg), sildenafil was administered intravenously in a dose-response manner (0.5, 1, 5mg/kg), followed by measurements for 0-120 minutes. In additional experiments, the effect of increasing the dosages of sildenafil, combined with APO, on blood pressure were evaluated. RESULTS: The intravenous administration of sildenafil caused a concentration dependent increase in the LUPM. There was a statistically significant increase in the LUPM with the administration of APO compared with no administration. The dosages of sildenafil and APO showing the greatest efficacy of sildenafil potentiation were 1mg/kg and 0.1 mg/kg, respectively. The intravenous administration of APO at a dose of 0.1mg/kg was more effective than those of 0.05 and 0.4mg/kg, with dosages of sildenafil of 0.5 and 1mg/kg. There was no additional increase in the duration of erection on the administration of APO. The intravenous administration of sildenafil caused a concentration dependent decrease in blood pressure, but there was no additional decrease on administration of the APO. CONCLUSIONS: We have shown that apomorphine elicits a stronger response on the erection induced by sildenafil in conscious rabbits, with no additional decrease in blood pressure.

Proerectile Effects of Selective alpha1 Blockers: A Comparative Study with Rat Model / 대한비뇨기과학회지

PURPOSE: The purpose of this study was to investigate the pro-erectile potential of various urethral alpha blockers using pharmacological or electrical induction of erection in anesthesized rats. MATERIALS AND METHODS: To evaluate the influence on centrally mediated erection, intravenous administeration of terazosin, doxazosin(3, 10, 30microgram/kg), and tamsulosin (0.3, 1, 3microgram/kg), followed by submaximal subcutaneous apomorphine(50microgram/kg) administration, mean arterial pressure(MAP) and intracavernosal pressure(ICP) were recorded over 30 minutes in male anesthesized rats. The time to first response, peaks within 30 minutes, maximal ICP, area under the curve, percentage of ICP/MAP were compared. To evaluate the influence on peripherally induced erections, various doses of alpha antagonists and submaximal cavernous nerve stimulation(0.5ms, 2V, 10Hz) were combined. The ICP increase and ICP/MAP percentage were also compared. RESULTS: Although various dose response relationships were shown, all three alpha blockers enhanced erectile activity triggered by apomorphine. In terms of time to first response and peaks within 30 minutes, the proerectile effects of terazosin was most prominent whereas those of tamsulosin was minimal, requiring larger doses. In combining with cavernous nerve stimulation, doxazosin and tamsulosin showed moderate proerectile activity, but the highest dose of terazosin was required to enhance ICP increase induced by cavernous nerve stimulation. Despite their pressure lowering effects, all tested alpha adrenergic blockers significantly enhanced the ICP/MAP percentage. CONCLUSIONS: The present finding clearly indicated that alpha 1 selective antagonists can enhance erectile capacity when combined with central or peripheral stimuli for erection.

Pharmacokinetics, Efficacy, and Safety of Selective Inhibitors of Phosphodiesterase Type 5 and Sublingual Apomorphine for the Treatment of Erectile Dysfunction / 대한남성과학회지

Oral pharmacotherapy has become the first-line therapy for the majority of patients with erectile dysfunction (ED) of broad-spectrum etiology since the introduction of oral sildenafil, a potent, selective inhibitor of phosphodiesterase type 5 (PDE5). More than 3 years following the launch of sildenafil have made us informed fully about the mechanism of sildenafil, its clinical efficacy and safety, and appropriate use of the drug. Recently, the efficacy and tolerability of another potent, selective inhibitors of PDE5, vardenafil and tadalafil have been reported one after another and their phase 3 clinical studies worldwide have just finished. The PDE5 inhibitors are contraindicated in patients taking nitrates and may be restricted in others. The recent introduction of sublingual (SL) apomorphine, a centrally acting dopaminergic agonist with known erectogenic effects, could provide patients and clinicians with an additional option in the treatment of ED, although its efficacy and safety need to be verified further by worldwide clinical studies. We are in face of the era of multiple oral agents available for the treatment of ED. Due to the complex nature of individual patient-oriented goals and the multifactorial nature of ED, choices are needed that can be adapted to the requirements and responses of the individual patients. In this review, an overview of the pharmacokinetics, efficacy and safety of the oral PDE5 inhibitors, sildenafil, vardenafil and tadalafil, and sublingual apomorphine are provided.

The Behavioral Changes and the Patterns of Dopamine NeuronalDegeneration after Intrastriatal 6-hydroxydopamine Injection in Rat

BACKGROUND: The terminal destruction of the striatal dopaminergic axon can produce the retrograde degeneration of nigral dopaminergic neurons. An analyses of the postsynaptic dopamine D1 & D2 receptors and the DOPAC/DA level, revealed that this model mimics the early course of Parkinson's disease in humans. We evaluated the time course of the retrograde dopaminergic neuronal degeneration and the pattern of dopaminergic neuronal loss in the substantia nigra after various doses of 6-hydroxydopamine (6-OHDA) injections in the striatum of rats. METHODS: Different doses of 6- OHDA (0.0, 1.25, 2.5, 5, 10 ug/ul in 3.5 ul of saline) were unilaterally injected into the right striatum of rats using a stereotaxic frame. Structural and functional deficits were quantified and compared using apomorphine-induced rotations and tyrosine hydroxylase-immunoreactive (TH-IR) cell numbers in the substantia nigra pars compacta (SNpc) at 3, 6, 9 weeks after lesioning. RESULTS: Striatal 6-OHDA lesions produced dose-dependent decreases in TH-IR cell numbers in SNpc at 3 weeks (-3.8%, 17.9%, 41.2%, 58.5%, 69.9% cell loss compared with the contralesional side respectively), where the ventrolateral portion of the SNpc were more affected. As time progressed, nigral cell loss was significantly increased in all dosage groups and the lesion extended to the medial side of the SNpc and the ventral tegmental area. Apomorphine-induced rotations did not correlate well with nigral TH-IR cell loss. CONCLUSIONS: Intrastriatal injections of 6-OHDA, results in time-dependent and dose-dependent progressive degeneration of nigral dopaminergic neurons. We conclude that this rat model can be useful for the evaluation of further neuroprotective and neurotrophic therapies.