Development of monolithic matrix type transdermal patches containing cinnarizine: Physical characterization and permeation studies

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated

Histamine Excites Rat GABAergic Ventral Pallidum Neurons via Co-activation of H1 and H2 Receptors / 神经科学通报·英文版

The ventral pallidum (VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion. Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamic-derived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.

Hearing function after betahistine therapy in patients with Ménière's disease / Função auditiva após terapia com beta-histina em pacientes com doença de Ménière

ABSTRACT INTRODUCTION: Preventing or reversing hearing loss is challenging in Ménière's disease. Betahistine, as a histamine agonist, has been tried in controlling vertigo in patients with Ménière's disease, but its effectiveness on hearing problems is not known. OBJECTIVE: To examine the effect of betahistine on hearing function in not-previously-treated patients with Ménière's disease and to define possible contributors in this regard. METHODS: A total of 200 not-previously-treated patients with definite unilateral Ménière's disease received betahistine by mouth (initial dose, 16 mg three times a day; maintenance dose, 24-48 mg daily in divided doses). Changes in indicators of hearing status before and six months after treatment were documented. Hearing loss was considered as the mean hearing level >25 dB HL at five frequencies. RESULTS: The mean duration of disease was 3.37 years. Six months after treatment the mean hearing level decreased by 6.35 dB compared to that at the baseline (p < 0.001). Both patients' age and the duration of disease correlated negatively with the improvement in hearing function. Post treatment hearing loss was independently associated with age, the initial hearing level and the chronicity of disease. The corresponding optimal cut-off points for predicating a persistent hearing loss 6 months after treatment were 47 years, 38 dB HL, and 1.4 years, respectively. CONCLUSION: Oral betahistine was significantly effective in preventing/reversing hearing deterioration in patients with Ménière's disease. Age, the hearing level on admission, and the disease duration were independent predictors of hearing status after treatment.

Resumo Introdução: Prevenir ou reverter a perda auditiva é um desafio na doença de Ménière. A betahistina, um agonista de histamina, tem sido testada no controle de vertigem em pacientes com doença de Ménière, mas sua eficácia em problemas de audição ainda não é conhecida. Objetivo: Analisar o efeito da betahistina na função auditiva em pacientes com doença de Ménière não tratados previamente, e definir possíveis contribuintes a esse respeito. Método: Um total de 200 pacientes sem tratamento prévio, e com diagnóstico definido de doença de Ménière unilateral, recebeu beta-histina por via oral (dose inicial de 16 mg três vezes ao dia; dose de manutenção de 24-48 mg por dia, em doses divididas). Alterações dolimiar auditivo antes e após seis meses de tratamento foram documentadas. Considerou-se como perda auditiva uma média do nível de audição > 25 dB NA em cinco frequências. Resultados: A média de duração da doença foi de 3,37 anos. Seis meses após o tratamento, a média do limiar auditivo diminuiu em 6,35 dB, em comparação com o valor da linha de base (p < 0,001). Tanto a idade dos pacientes quanto a duração da doença apresentaram correlação negativa com a melhora da função auditiva. A perda auditiva após o tratamento foi independentemente associada à idade, ao nível inicial de audição e à cronicidade da doença. Os pontos de corte ótimos correspondentes para prever uma perda auditiva persistente seis meses após o tratamento foram 47 anos, 38 dB HL e 1,4 ano, respectivamente. Conclusão: A betahistina oral foi significantemente eficaz na prevenção/reversão da deterioração auditiva em pacientes com doença de Ménière. Idade, nível de audição na admissão e duração da doença foram fatores preditivos independentes da condição auditiva após o tratamento.

Interações medicamentosas potenciais com benzodiazepínicos em prescrições médicas de pacientes hospitalizados / Potential drug interactions with benzodiazepines in medical prescriptions of hospitalized patients

A prática de associações medicamentosas é comum em pacientes hospitalizados, Esta prática é muitas vezes necessária, principalmente em pacientes psiquiátricos, uma vez que, juntamente com as doenças neuropsiquiátricas, podem ocorrer outras comorbidades, Entretanto, esta prática pode favorecer a ocorrência de interações medicamentosas com consequente potencialização de diferentes efeitos adversos, Diante deste quadro, o presente trabalho teve como objetivo avaliar a ocorrência de potenciais interações medicamentosas com os benzodiazepínicos, prescritos aos pacientes internados na Clínica Psiquiátrica do Hospital Regional de Assis ? SP, a fim de gerar informações que contribuam para a eficácia do tratamento estabelecido ao paciente, Para isso, foi realizada uma análise de 100 prescrições médicas, nas quais foram avaliadas as possibilidades de ocorrência de interações medicamentosas entre os diferentes fármacos da classe dos benzodiazepínicos administrados concomitantemente, bem como com outras classes de fármacos, Por meio deste estudo, verificou-se que das 100 prescrições médicas analisadas 93 apresentaram a possibilidade de ocorrência de interações farmacológicas entre benzodiazepínicos e com outras classes de fármacos, totalizando 356 possíveis interações, Desse total, destacam-se as associações dos benzodiazepínicos com os antipsicóticos, anti-histamínicos, antiepilépticos e antidepressivos, as quais podem potencializar a manifestação de inúmeros efeitos adversos, em destaque, a exacerbação do efeito depressor do sistema nervoso central, com repercussões que podem variar desde a manifestação clínica leve até risco de êxito letal, Neste contexto, busca-se com este trabalho contribuir para uma melhor compreensão, reconhecimento e intervenção precoce ou profilática em situações clínicas decorrentes de interações farmacológicas entre diferentes classes de fármacos com os benzodiazepínicos...

The practice of drug combinations is common in hospitalized patients. This practice is often necessary, especially in psychiatric patients, since other comorbidities may occur in parallel with neuropsychiatric disorders. However, this practice may favor the occurrence of drug interactions with consequent increase of different adverse effects. Facing this situation, the present study aimed to evaluate the occurrence of potential drug interactions with benzodiazepines prescribed to hospitalized patients at the Psychiatric Clinic of the Hospital Regional de Assis - SP, in order to generate information that contributes to the effectiveness of the treatment provided to patient. To this end, an analysis of 100 medical prescriptions was performed, in which were evaluated the possibility of drug interactions between the different medications from the class of benzodiazepines concomitantly administered, as well as other classes of drugs. By means of this study, it was verified that the 100 analyzed prescriptions 93 presented the possibility of different pharmacological interactions between benzodiazepine, and with other classes of drugs, totaling 356 possible interactions. Of this total stand out the associations of benzodiazepines with antipsychotics, antihistamines, antiepileptics and antidepressants, which can enhance the expression of numerous adverse effects, highlighted the exacerbation of depressant effect on the central nervous system, with effects that can range from mild clinical manifestation until risk of lethal outcome. In this context, it seeks in this work to contribute to a better understanding, recognition and early or prophylactic intervention in clinical situations arising from interactions between different pharmacological classes of drugs with benzodiazepines...

Cleansing the world of the germ of laziness: hygiene, sanitation, and the Javanese population in Suriname / Limpando o mundo do germe da preguiça: higiene, saneamento e população javanesa no Suriname

In 1915 the Rockefeller Foundation took its hookworm eradication campaign to Suriname, but was soon disappointed because of opposition from its main target group: the Javanese. Moreover, authorities and planters objected to the construction of latrines because of the costs and their belief that the Javanese were “unhygienic”. In describing the labor migration from Java to Suriname, I show that this “lack of hygiene” was closely related to the system’s organization. I argue that uncleanliness was the consequence of harmful socio-economic and ecological conditions. Secondly I suggest that even though the Foundation did not manage to cleanse Suriname of hookworm, its educational efforts, its emphasis on prevention, and its training of local health workers probably had more impact than Rockefeller officials thought.

Em 1915, a Fundação Rockefeller levou sua campanha de erradicação da ancilostomíase ao Suriname, logo sofrendo a oposição de seu principal alvo, os javaneses. Autoridades e proprietários rurais também reagiram à instalação de latrinas devido aos custos implicados e à crença de que os javaneses eram “anti-higiênicos”. Ao descrever a migração de trabalhadores de Java para o Suriname, mostro que a “falta de higiene” ligava-se à organização do sistema. Argumento que a sujeira era consequência de condições ecológicas e socioeconômicas danosas. Sugiro ainda que, embora a Fundação não tenha livrado o Suriname da anciolostomíase, seus esforços educacionais, sua ênfase na prevenção e o treinamento de profissionais de saúde locais tiveram maior impacto do que o imaginado pelos funcionários da agência norte-americana.

Sangrado gastrointestinal en pacientes hospitalizados / Gastrointestinal bleeding in hospitalized patients

El sangrado gastrointestinal es una complicación potencial del paciente que se hospitaliza. Como las descripciones iniciales en cuidados intensivos relacionaban el sangrado por úlceras de estrés con alta mortalidad, la investigación fue creciente en los pacientes críticos. No sucedió lo mismo con los hospitalizados y los trabajos disponibles son escasos. Los principales factores de riesgo se han descrito en los críticos (ventilación mecánica más de 48 horas y coagulopatía). La eficacia de la terapia no se ha demostrado en aquellos en la sala general. La evidencia indirecta muestra utilidad marginal de estos medicamentos en la prevención del sangrado gastrointestinal. En los casos críticos hay abundante información pero la interpretación es confusa. Se ha documentado una tasa alta de formulación para prevenir el sangrado en los hospitalizados, la mayoría sin indicación clara, lo cual puede exponer al paciente a eventos adversos innecesarios y gastos adicionales al sistema de salud. Se recomiendan estrategias para implementación de guías para el uso racional de estos fármacos...

Gastrointestinal bleeding is a potential inpatient complication. Research has extensively focused in critically ill patients due to initial descriptions of high mortality related to bleeding due to stress ulceration. On the other hand, research evaluating GI bleeding in inpatients is scarce with few available reports. The main risk factors have been described in critically ill patients (requiring mechanical ventilation for more than 48 hours and coagulopathy). Treatment efficacy has not been demonstrated in patients hospitalized in the general ward. Indirect evidence show marginal usefulness of these medications in gastrointestinal bleeding prevention. There is plentiful data on critically ill patients but with confusing interpretation. It has been documented that preventive medicines are often prescribed to avoid bleeding in inpatients, with no clear indication in most cases, exposing the patient to unnecessary adverse events and additional costs for the healthcare system. Implementation guidelines are recommended for the rational use of these medicines...

Reabilitação vestibular com realidade virtual na doença de Ménière / Vestibular rehabilitation with virtual reality in Ménière's disease

A tecnologia de realidade virtual fornece uma grande variedade de estímulos que geram conflitos sensoriais em diferentes níveis de dificuldades e em ambiente seguro. OBJETIVO: Verificar o efeito de um programa de reabilitação vestibular do equilíbrio corporal com estímulos de realidade virtual em pacientes com doença de Ménière. Forma de estudo: Estudo clínico observacional. MÉTODO: Quarenta e quatro pacientes, com idade entre 18 e 60 anos e doença de Ménière definida, distribuídos em dois grupos - experimental (GE) e controle (GC) - fizeram uso de betaistina e dieta alimentar; o grupo experimental foi submetido adicionalmente a 12 sessões de reabilitação com realidade virtual da BRU TM. Os pacientes responderam ao Dizziness Handicap Inventory (DHI), à escala analógica de tontura e realizaram a posturografia com realidade virtual antes e após a intervenção. RESULTADOS: Após a intervenção, o GE apresentou valores significantemente menores do DHI (p < 0,001) e da escala analógica de tontura (p = 0,012) e valores significantemente maiores da área do limite de estabilidade (p = 0,016), em comparação com o GC. CONCLUSÃO: A reabilitação do equilíbrio corporal com estímulos de realidade virtual é eficaz na melhora da tontura, da qualidade de vida e do limite de estabilidade de pacientes com doença de Ménière.

Virtual reality technology can provide a wide range of sensory stimuli to generate conflicts of varying degrees of complexity in a safe environment. OBJECTIVE: To verify the effect of a virtual realitybased balance rehabilitation program for patients with Menière's disease. METHOD: This observational clinical study included 44 patients aged between 18 and 60 years diagnosed with Menière's disease submitted to a controlled randomized therapeutic intervention. The case and control groups took betahistine and followed a diet. Case group subjects underwent 12 rehabilitation sessions with virtual reality stimuli in a Balance Rehabilitation Unit (BRU TM). Patients were assessed based on DHI scores, the dizziness visual analogue scale, and underwent posturography with virtual reality before and after the intervention. RESULTS: After the intervention, the case group showed significantly lower scores in DHI (p < 0,001) and in the dizziness visual analog scale (p = 0.012), and had significantly greater limit of stability areas (p = 0.016) than controls. CONCLUSION: Virtual reality-based balance rehabilitation effectively improved dizziness, quality of life, and limit of stability of patients with Menière's disease.

Teste do soro autólogo em urticária crônica espontânea na criança / Autologous serum skin test in children with chronic spontaneous urticaria

Objetivos: Verificar a reatividade ao teste do soro autólogo em crianças com urticária crônica espontânea e analisar a relação entre o teste do soro autólogo, as características clínicas e o tratamento utilizado nesses pacientes. Método: Este estudo transversal analisou resultados de testes cutâneos com soro autólogo dos pacientes. Foram incluídas crianças com urticária crônica espontânea nos últimos 12 meses, submetidas ao teste do soro autólogo entre agosto/2001 a junho/2012. Soro autólogo (0,05 mL) foi injetado via intradérmica e reações interpretadas após 30 minutos. Medicações que pudessem suprimir a resposta cutânea foram suspensas por 7 dias antes da realização do teste cutâneo. Todos os pacientes foram investigados detalhadamente para urticária crônica e outras doenças. As crianças foram consideradas não responsivas ao tratamento se submetidas ao uso oral de anti-histamínicos em doses habituais, com persistência dos sintomas por no mínimo 3 meses. Resultados: Foram incluídos 57 pacientes (61,4% meninos), com mediana de 10,6 anos (3,7-17,1 anos). Trinta pacientes (53%) apresentaram teste do soro autólogo positivo e 21 destes (70%) não responderam ao tratamento habitual (p < 0,001). Pacientes com teste do soro autólogo positivo apresentaram maior frequência de sintomas, com 1,5 episódios/mês (p = 0,04). Quatorze por cento das crianças apresentaram níveis altos de anticorpo antiperoxidase e 16,6% níveis altos de anticorpo antitireoglobulina. Houve relação significativa entre os altos títulos de anticorpo antiperoxidase com a positividade ao teste do soro autólogo (p = 0,02). Conclusões: A frequência de reatividade ao teste do soro autólogo foialta, sugerindo que o teste deve ser realizado rotineiramente em crianças com urticária crônica espontânea. Pacientes com teste do soro autólogo positivo apresentaram maior chance de não responder ao tratamento habitual.

Objectives: To investigate reactivity to the autologous serum skin test in children with chronic spontaneous urticaria and to analyze the relationship between test results and clinical characteristics and treatment response in these patients. Method: This cross-sectional study analyzed the results of skin tests performed with autologous serum obtained from the patients. Children showing chronic spontaneous urticaria in the past 12 months and subjected to autologous serum skin testing between August 2001 and June 2012 were included. Autologous serum (0.05 mL) was injected intradermally and reactions interpreted after 30 minutes. Medications that could suppress skin response were with held for 7 days prior to skin testing. All patients underwent a thorough workup for chronic urticaria and other illnesses. Children were considered non-responsive if chronic spontaneous urticaria persisted for at least 3 months under regular doses of oral anti-histamines. Results: Fifty seven children were included (61.4% males), with a median age of 10.6 years (3.7-17.1 years). Thirty patients (53%) had positive autologous serum skin tests; of these, 21 (70%) did not respond to treatment (p < 0.001). Patients with a positive autologous serum skin test showed.

Preconditioning of the response to ischemia/ reperfusion-induced plasma leakage in hamster cheek pouch microcirculation

OBJECTIVE: Ischemic preconditioning and some drugs can protect tissues from injury by preserving microcirculation. This study evaluated vascular permeability in a hamster cheek pouch preparation using either short ischemic periods or bradykinin as preconditioning stimuli followed by 30 min of ischemia/reperfusion. METHOD: Sixty-six male hamsters were divided into 11 groups: five combinations of different ischemic frequencies and durations (one, three or five shorts periods of ischemia, separated by one or five minutes) with 10 min intervals between the ischemic periods, followed by 30 min ischemia/reperfusion; three or five 1 min ischemic periods with 10 min intervals between them followed by the topical application of histamine (2 µM); bradykinin (400 nM) followed by 30 min of ischemia/reperfusion; and three control groups (30 min of ischemia/reperfusion or histamine or bradykinin by themselves). Macromolecular permeability was assessed by injection of fluorescein-labeled dextran (FITC-dextran, MW= 150 kDa; 250 mg/Kg body weight), and the number of leaks/cm2 was counted using an intravital microscope and fluorescent light in the cheek pouch. RESULTS: Plasma leakage (number of leaks/cm²) was significantly reduced by preconditioning with three and five 1 min ischemic periods, one and three 5 min ischemic periods and by bradykinin. Histamine-induced macromolecular permeability was also reduced after three periods of 5 min of ischemia. CONCLUSION: Short ischemic periods and bradykinin can function as preconditioning stimuli of the ischemia/reperfusion response in the hamster cheek pouch microcirculation. Short ischemic periods also reduced histamineinduced macromolecular permeability.

Human umbilical artery smooth muscle exhibits a 2-APB-sensitive capacitative contractile response evoked by vasoactive substances and expresses mRNAs for STIM, Orai and TRPC channels

After depletion of intracellular Ca2+ stores the capacitative response triggers an extracellular Ca2+ influx through store-operated channels (SOCs) which refills these stores. Our objective was to explore if human umbilical artery smooth muscle presented this response and if it was involved in the mechanism of serotonin- and histamine-induced contractions. Intracellular Ca2+ depletion by a Ca2+-free extracellular solution followed by Ca2+ readdition produced a contraction in artery rings which was inhibited by the blocker of Orai and TRPC channels 2-aminoethoxydiphenyl borate (2-APB), suggesting a capacitative response. In presence of 2-APB the magnitude of a second paired contraction by serotonin or histamine was significantly less than a first one, likely because 2-APB inhibited store refilling by capacitative Ca2+ entry. 2-APB inhibition of sarcoplasmic reticulum Ca2+ release was excluded because this blocker did not affect serotonin force development in a Ca2+-free solution. The PCR technique showed the presence of mRNAs for STIM proteins (1 and 2), for Orai proteins (1, 2 and 3) and for TRPC channels (subtypes 1, 3, 4 and 6) in the smooth muscle of the human umbilical artery. Hence, this artery presents a capacitative contractile response triggered by stimulation with physiological vasoconstrictors and expresses mRNAs for proteins and channels previously identified as SOCs.

Betahistine in the treatment of tinnitus in patients with vestibular disorders / Betaistina no tratamento do zumbido em pacientes com distúrbios vestibulares

Betahistine is a medicine used to treat vestibular disorders that has also been used to treat tinnitus. AIM: To assess the effects of betahistine on tinnitus in patients with vestibular disorders. MATERIAL AND METHOD: Retrospective data were collected from patient records for individuals presenting with vestibular dysfunction and tinnitus. Patients included had received betahistine 48 mg/day and clinical outcomes were compared with a control group comprising individuals who were unable to receive betahistine due to gastritis, ulcers, pregnancy, asthma or hypersensitivity to the drug. Patients underwent control of any aggravating factors and also standard vestibular exercises as a basis for treatment. The intensity, frequency and duration of tinnitus were assessed on the first day of dosing and after 120 days of treatment. Clinical improvement was defined as a total or partial reduction of tinnitus after treatment. RESULTS: Clinical improvement was observed in 80/262 (30. 5 percent) of patients treated with betahistine and 43/252 (17. 1 percent) of control patients. Betahistine significantly (p<0. 0001) improved tinnitus in treated individuals. CONCLUSIONS: The daily dosage of 48 mg of betahistine during 120 consecutive days is useful to reduce or eliminate tinnitus in patients with vestibular disorders.

A betaistina é um medicamento utilizado no tratamento de distúrbios da função vestibular, que também tem sido utilizado para tratar o zumbido. OBJETIVO: Avaliar o efeito da betaistina sobre o zumbido de pacientes com distúrbios vestibulares. MATERIAL E MÉTODO: Foram coletados dados retrospectivos de pacientes com vestibulopatia e zumbido. Os pacientes incluídos receberam 48 mg/dia de betaistina ao dia e os resultados clínicos foram comparados com os de um grupo controle, que incluiu indivíduos impossibilitados de receber betaistina devido à gastrite, úlceras, gravidez, asma ou hipersensibilidade ao medicamento. Os pacientes realizaram controle de fatores agravantes e exercícios de reabilitação vestibular, como tratamento de base para a vestibulopatia. A intensidade, frequência e duração do zumbido foram avaliadas no primeiro dia e após 120 dias de tratamento. A melhora clínica foi definida pela redução total ou parcial do zumbido após o tratamento. RESULTADOS: Observou-se melhora clínica do zumbido em 80/262 (30,5 por cento) dos pacientes tratados com a betaistina e em 43/252 (17,1 por cento) pacientes do grupo controle. A betaistina melhorou significativamente (p<0.0001) o zumbido nos indivíduos tratados. CONCLUSÃO: A dose de 48 mg/dia de betaistina durante 120 dias consecutivos é útil na redução ou eliminação do zumbido de pacientes com distúrbios vestibulares.

Substance P and its receptors are involved in the effect of histamine H3 receptor agonist, IMETIT on nasal allergic symptoms in guinea pigs / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To explore the influence of histamine H3 receptor agonist, IMETIT and simultaneous use of IMETIT and H1-receptor antagonist, Loratadine, on the symptoms of allergic rhinitis (AR) and substance P(SP) secretion and expression of SP receptor (SP-R) mRNA in AR model in guinea pigs.</p><p><b>METHODS</b>Guinea pigs were divided randomly into 4 groups: AR group (group A), IMETIT group (group B), Loratadine group (group C) and IMETIT+Loratadine group (group D). The severity of AR was assessed by determining the extent of three markers of allergic symptoms (sneezing, nasal rubbing and nose blocking). The changes in the nasal mucosa were studied by pathological methods. The expression of positive cell of SP was detected by immunohistochemistry. SP-R mRNA expression in nasal mucosa was used to do reverse transcriptive-polymerase chain reaction (RT-PCR). Statistical analysis was performed using a SPSS 13.0 software.</p><p><b>RESULTS</b>In Group B, the mean (x ± s) number of sneeze [(15.0 ± 1.3) times], scratching nose [(16.5 ± 2.3) times] and respiratory frequency [(76.3 ± 4.1) times/min] were significantly improved than those in group A [(23.5 ± 2.6) times, (26.1 ± 4.1) times and (66.5 ± 5.8) times/min, respectively), P value were 0.000, 0.000 and 0.001, respectively]. The numbers of SP-positive cells [(11.6 ± 3.6)/HP] and SP-R mRNA expression (0.64 ± 0.04) in group B were reduced significantly compared to group A [(27.1 ± 9.7)/HP, (0.83 ± 0.03), P value were 0.000, 0.000, respectively]. Sneeze [(10.0 ± 2.3) times], scratching nose [(11.8 ± 1.7) times] and respiration [(90.0 ± 5.0) times/min] in Group D were improved significantly than those in group B (P value were 0.000, 0.002 and 0.000, respectively). SP-positive cells [(2.0 ± 1.7)/HP] and SP-R mRNA expression (0.52 ± 0.06) in Group D compared with group B were also significantly reduced (P value were 0.012 and 0.000, respectively). Pathological changes in guinea pig nasal mucosa in group B, group D were alleviated than those in group A. The combination of IMETIT and Loratadine had a synergistic effect on these effects (F value were 11.59, 8.28, 5.61, 5.48, 6.50, respectively, P value were 0.002, 0.008, 0.025, 0.027, 0.017).</p><p><b>CONCLUSIONS</b>IMETIT and the combination of IMETIT with Loratadine can effectively relieve the symptoms of AR in guinea pigs, its mechanism may be relevant to reduce SP secretion and the expression of SP-R mRNA, and the two has a synergistic effect. It may be useful as a novel therapeutic approach in nasal allergy.</p>

Nueva alternativa terapéutica en profilaxis de migraña con histamina como agonista de receptores H3 / New therapeutic alternatives in migraine prophylaxis using histamine H3 receptor agonists

Antecedentes: La histamina subcutánea a bajas concentraciones puede ser una alternativa terapéutica en la profilaxis de la migraña al interactuar con receptores H3 y limitar la excesiva respuesta inflamatoria. Objetivo: Presentar los resultados de la administración de histamina bajas dosis en la profilaxis de la migraña, colectados durante 15 años. Métodos: Se aplicaron diferentes diseños de administración de histamina subcutánea (10 μg/ml en solución de Evans) dos veces a la semana, con una administración inicial de 1μg (0.1 ml) e incremento gradual hasta 10 μg (1.0 ml) durante 12 semanas. Se realizaron estudios comparativos con placebo, valproato sódico y topiramato. Se utilizó la prueba de Anova de rangos de Friedman para evaluar las diferencias entre los resultados. Resultados: Los datos registrados durante las 12 semanas de tratamiento revelaron que en el grupo con histamina las variables estudiadas tuvieron una disminución significativa comparada con el control (p<0.001), con una reducción de la frecuencia de cefalea (50%), intensidad del dolor (51%), duración de ataques de migraña (45%), así como en el consumo de analgésicos (52%). Conclusiones: El estudio aporta evidencia sobre la seguridad y eficacia de la histamina aplicada por vía subcutánea a dosis de 1 a 10 μg dos veces a la semana. Representa una nueva alternativa terapéutica y proporciona las bases clínicas y farmacológicas para el uso de agonista H3 histaminérgicos en la profilaxis de la migraña.

BACKGROUND: Subcutaneous histamine at low concentrations interacts with H3-receptors and may constitute a new therapeutic drug in migraine prophylaxis. It acts by limiting the excessive inflammatory response involved in migraine pathophysiology. OBJECTIVE: Describe the results of a 15-year trial administering histamine at low concentrations. METHODS: Different study designs were used with subcutaneous histamine (10 microg/ml in Evan's solution) twice weekly, with an initial administration of microg (0.1 ml) and gradually increasing the dose to 10 microg (1.0 ml) over a 12-week period together with placebo, sodium valproate and topiramate. A Friedman-type rank ANOVA test was used to assess the difference between basal values and different design outcomes. RESULTS: Data recorded during the 12-week period showed a significant reduction in variables from both treatment groups (histamine) compared with basaline stage results (p < 0.001). The histamine group reported a reduction of headache frequency (50%), decrease in pain intensity (51%), length of migraine attacks (45%) and painkiller use (52%). CONCLUSIONS: The present study provides evidence on the safety and efficiency of subcutaneous histamine administered at a dose of 1-10 microg twice weekly. This treatment constitutes a new therapeutic alternative, and provides a clinical and pharmacological basis for the use of H3 histaminergic agonists in migraine prophylaxis.

Otimizando o componente farmacológico da terapia integrada da vertigem / Optimizing the pharmacological component of integrated balance therapy

A farmacoterapia é opção importante no tratamento das vestibulopatias periféricas. OBJETIVO: Identificar a medicação que otimiza a terapia integrada da vertigem (TIV) na doença de Ménière e em outras vestibulopatias periféricas. MATERIAL E MÉTODO: Estudo de casos em que pacientes com doença de Ménière ou outras vestibulopatias periféricas receberam TIV com betaistina, cinarizina, clonazepam, flunarizina, Ginkgo biloba ou sem medicação durante 120 dias. RESULTADOS: Na doença de Ménière, TIV com qualquer um dos medicamentos foi mais eficaz do que TIV sem medicação, após 60 dias; a betaistina foi mais efetiva que todas as outras drogas, após 60 e 120 dias. Nas outras vestibulopatias periféricas, diferenças significantes foram observadas entre TIV com betaistina, cinarizina, clonazepam ou flunarizina e TIV sem medicação após 60 dias e todas as drogas foram mais efetivas que TIV sem medicação após 120 dias; betaistina, cinarizina ou clonazepam foram igualmente efetivos e betaistina foi mais efetiva que flunarizina e Ginkgo biloba. Os tratamentos foram bem tolerados. CONCLUSÕES: TIV incluindo medicação é mais efetiva que sem medicação na doença de Ménière ou em outras vestibulopatias periféricas. Betaistina foi o medicamento mais efetivo na doença de Ménière e tão eficaz quanto cinarizina ou clonazepam em outras vestibulopatias periféricas.

Drug treatment is an important option for the treatment of peripheral vestibular diseases. AIM: To identify the drug component associated with optimal integrated balance therapy (IBT) for MénièreÆs disease or other peripheral vestibular disorders. MATERIALS AND METHODS: Analysis of a series of patients with MénièreÆs disease patients or patients with other peripheral vestibular disorders that received IBT involving either no medication or betahistine, cinnarizine, clonazepam, flunarizine or Ginkgo biloba during 120 days. RESULTS: In MénièreÆs disease, significant differences were observed for all drug therapies (60 days) versus no medication; betahistine was significantly more effective than all other drugs at 60 and 120 days. For non-MénièreÆs disorders, significant differences were observed among betahistine, cinnarizine, clonazepam and flunarizine and no medication after 60 days; all drug therapies were significantly more effective than no medication after 120 days; betahistine, cinnarizine or clonazepam were equally effective and betahistine was more effective than flunarizine and EGb 761. All treatment options were well tolerated. CONCLUSIONS: Drug therapies were more effective than no medication in the IBT for patients with MénièreÆs disease or other peripheral vestibular disorders. Betahistine was the most effective medication for patients with MénièreÆs disease and was as effective as cinnarizine and clonazepam for other peripheral vestibular disorders.

The effect of central histamine H3 receptor on breathing activity of asthmatic guinea pigs / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.</p><p><b>METHODS</b>Anesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.</p><p><b>RESULTS</b>(1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.</p><p><b>CONCLUSION</b>Brain histamine H3 receptors may be related to asthmatic respiratory responses.</p>

An ab initio study of histamine agonists.

A systematic theoretical study on histamine agonists and their interaction with H1 and H2 receptor models has been carried out utilizing ab initio molecular orbital technique. The effect of substituents on histamine agonists' charge distribution and their agonistic activity has been studied in detail. Drug-receptor interaction models have been studied at the Hartree Fock level of theory with a split valence basis set keeping the cost and efficiency of the calculation in mind. The study indicates that the agonistic activity is controlled either by receptor conformation or by steric hinderances caused by the substituents. The monocationic form of histamine does not appear to be a necessity for a proton relay process which is similar to the one proposed earlier by Weinstein and coworkers. The study also indicates some importance of common cellular ions in neurotransmitter properties of histamine.

Central serotonergic and histaminergic modulation of peripheral inflammation and nociception in rats.

Possible central serotonergic and histaminergic modulation of acute peripheral inflammation was investigated in rats, adopting the formaldehyde-induced acute pedal inflammation as an experimental model. Intracerebroventricular (icv) administration of central inhibitory neurotransmitter, serotonin and its precursor, 5-hydroxytryptophan (5-HTP) attenuated the oedema volume and exudate protein content alongwith augmentation in pain threshold. On the contrary, cyproheptadine, a 5-HT-receptor antagonist and selective serotonin synthesis inhibitor, parachlorophenylalanine (PCPA) produced oedema augmenting and pro-nociceptive effects besides elevating the protein content of the exudate. Centrally administered histamine attenuated pedal oedema, nociception as well as protein concentration in oedema fluid. Cimetidine, an H2 histaminergic receptor blocker did not produce any significant effect on inflammation.

Study of structure-activity relationships for neurotransmitters using molecular electric field mapping: histamine and some of its H2-receptor agonists.

Molecular electric field mapping has been carried out to study structure-activity relationships for neutral and cationic forms of histamine and some of its agonists which are thiazole derivatives. Optimised geometries and Mulliken charges at the atomic sites were obtained using the PM3 method. Electric field values near the N3-H bond in histamine and those near substituents at the C2 position in the agonists have been found to correlate reasonably well with observed activities. Electric fields near the sulphur atom in thiazoles indicate that involvement of this site in hydrogen bonding with the H2-receptor is unlikely.