New classes of glaucoma medical treatment

Glaucoma is a progressive degenerative disease of the optic nerve head, characterized by a specific pattern of axonal loss and visual field deterioration. This review aims at introducing the different novel pharmacologic agents for its treatment, as well as their mechanisms. Most glaucoma patients require lifelong care and individualized treatment. Intraocular pressure (IOP), which is regulated by aqueous humor production, outflow via the trabecular meshwork (parasympathomimetics only) and uveoscleral outflow pathways, is currently the only treatable target for glaucoma treatment. Conventional glaucoma medications are categorized as β blockers, α agonists, carbonic anhydrase inhibitors, parasympathomimetics, and prostaglandin analogues. The development of basic research-derived novel classes of pharmacologic agents features novel action mechanisms, which are different from those of conventional medications. New classes of recently approved or clinical trial-tested medications include Rho-kinase inhibitors, nitric oxide donors, adenosine agonists, and prostaglandin analogs targeting E-type prostanoid receptors, etc. Their integration and future development will facilitate the expansion and customization of therapeutic options.

An LC-MS/MS method for the simultaneous determination of lycorine and galanthamine in rat plasma and its application to pharmacokinetic study of Lycoris radiata extract in rats / 华中科技大学学报（医学）（英德文版）

A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometry was developed for the simultaneous determination of lycorine and galanthamine, two major constituents in Lycoris radiata extract, in rat plasma. Liquid-liquid extraction with ethyl ether was carried out using diphenhydramine as the internal standard. The two bioactive alkaloids were separated on a Zorbax SB-C18 reserved-phase column (150 mm × 4.6 mm, i.d., 5 μm) by gradient elution using a mobile phase consisting of methanol with 0.1% formic acid (A) and water with 0.1% formic acid (B) at a flow rate of 0.6 mL/min. All analytes showed good linearity over a wide concentration range (r (2)>0.99) and the lower limit of quantification was 3.00 ng/mL for each analyte. The average extraction recovery of the analytes from rat plasma was more than 82.15%, and the intra-day and inter-day accuracy and precision of the assay were less than 12.6%. The validated method was successfully applied to monitoring the concentrations and pharmacokinetic studies of two Amaryllidaceous alkaloids in rat plasma after an oral administration of Lycoris radiata extract.

Medical management of glaucoma: Principles and practice.

Glaucoma care is more an art than science. The introduction of several new classes of glaucoma medications and the completion of many large randomized clinical trials have not changed this fact. While we now have better choices when initiating glaucoma therapy relative to our predecessors, the principles of glaucoma therapy have not changed much during this period. Debates continue regarding the utility of concepts such as “the monocular therapeutic trial,” “target intraocular pressure (IOP),” and “maximal medical therapy.” Our tools for detecting and following glaucomatous disease have improved but are not precise enough for us to prospectively predict which patients will do better or worse than others. Much attention has been given to disease stage, rate of progression, and compliance with medications but regular patient follow-up, an area that has received little attention, may be among the most important predictors of patient outcomes.

Spasmogenic and spasmolytic activities Onosma griffithii Vatke

Methanolic extract of Onosma grifflthii and its fractions were evaluated for possible effects on rabbits' jejunum preparations. Rabbits of either sex [weight 1.5-2.0 kg] were used in experiments. Studies were carried out on rabbits' jejunum preparations. Crude methanolic extract of Onosma griffithii [Meth.OG] was tried in concentrations of 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 5.0 and 10.0 mg/ml on rabbits' jejunum preparations. Meth.OG was also tried on KCl-induced contractions to explain its possible mode of actions in the presence and absence of atropine [0.03 microM]. Fractions of Meth.OG were tried in similar manner. Calcium chloride curves were constructed for Meth.OG treated tissues that were compared with curves constructed for verapamil in same fashion. Preliminary phytochemical screening of the plant was also performed. Meth.OG increased the amplitude of spontaneous activity of rabbits' jejunum preparations at concentrations of 0.1, 0.3 and 1.0 mg/ml. However, spasmolytic effects were observed at higher concentrations 3.0, 5.0 and 10.0 mg/ml. Mean EC[50] values [mg/ml], respectively, in absence and presence of atropine were 7.5 +/- 0.25 [6.9-8.4, n=6] and 3.0 +/- 0.17 [2.3-3.5, n=6, P<0.05]. Mean EC[50] values, respectively, for effects on spontaneous and KCl-induced contractions were 7.5 +/- 0.25 [6.9-8.4, n=6] and 7.3 +/- 0.35 [6.25-8.2, n=6, p<0.05]. rc-Hexane, chloroform and ethyl acetate fractions showed their respective EC[50] values [mg/ml] 9.7 +/- 0.25 [8.6-10.2, n=6], 4.0 +/- 0.2 [3.5-4.6, n=6] and 1.07 +/- 0.093 [0.78-1.5, n=6]. EC[50] values for calcium chloride curves in presence of 0.3 mg/ml Meth.OG were - 2.27 +/- 0.038 [- 2.4 to - 2.10, n=6] vs. control - 2.78 +/- 0.04 [-2.9 to - 2.6, n=6,P<0.05] Log [Ca[++]]M. Comparing with curves of calcium chloride constructed in presence of 0.1 juM verapamil, the EC[50] [log [Ca[++]] M] values were - 1.82 +/- 0.087 [- 2.0 to - 1.65, n=6] vs. control - 2.64 +/- 0.089 [- 2.9 to - 2.4, n=6] demonstrated a right shift [p<0.05]. Meth.OG tested positive for terpenes, saponins, sterols, flavonoids and carbohydrates. We concluded that the relaxant effect of Meth.OG is exerted through blocking of calcium channels. However,

butanolic and aqueous fractions produced spasmogenic effects that require further work for isolation of pharmacologically active substances

Less tachycardia in adults when using atropine 0.9 mg compared with 1.2 mg plus neostigmine 2.5 mg.

OBJECTIVE: Compare the increase in heart rate in adults after 0.9 vs. 1.2 mg of atropine plus neostigmine 2.5 mg as the non-depolarizing muscle relaxant reversal agent. MATERIAL AND METHOD: A randomized, double blind, controlled trial on 46 adults ASA I-II, undergoing elective gynecological or general surgery with balanced general anesthesia was performed. The subjects were randomized into two groups, After surgery, the study group received 0.9 mg of atropine, while the control group received 1.2 mg of atropine. Both groups received 2.5 mg of neostigmine simultaneously. RESULTS: The heart rate and blood pressure were taken at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, and 30 min after the injection. The increase in heart rate and blood pressure between the two groups were compared. The heart rate (at 3, 4, 5, and 6 min) of patients in the study group increased significantly less than that of patients in the control group. There was no significant difference in blood pressure between groups and no side effects occurred. CONCLUSION: The authors conclude that 0.9 mg of atropine with 2.5 mg neostigmine can be safely used as the reversal agent for a non-depolarizing muscle relaxant, particularly in patients for whom any increase in heart rate would be harmful.

Terapéutica en el glaucoma crónico de ángulo abierto / Therapeutic in the open angle chronic glaucoma

El objetivo fundamental del tratamiento en el glaucoma es evitar la progresión de la neuropatía óptica glaucomatosa. El tratamiento farmacológico está dirigido básicamente a disminuir la producción de humor acuoso en el epitelio ciliar, aumentar su evacuaciòn por la vía uveo escleral o por la vía trabecular. El glaucoma se encuentra entre las primeras causas de ceguera en el mundo. En este trabajo presentamos los medicamentos más recomendados en el glaucoma primario de ángulo abierto...

Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males

OBJETIVO: Investigar se o uso do cloridato de betanecol é uma alternativa útil no manejo clínco da disfunção orgásmica induzida pela clomipramina, relatada por até 96 % dos usuários do sexo masculino. MÉTODOS: Foram estudados 12 pacientes do sexo masculino em remissão completa de transtorno de pânico porém com queixas de disfunção orgásmica grave secundária ao uso da clomipramina. Os pacientes foram aleatoriamente distribuídos ao tratamento com cloridrato de betanecol (20 mg quando necessário) ou placebo em um estudo duplo cego "crossover" de dois períodos. RESULTADOS: Foi observado um benefício claro no período de uso da droga ativa. Não foram observados efeito placebo ou "carry-over" nos pacientes inicialmete alocados ao medicamento ativo. CONCLUSÕES: Os resultados deste estudo sugerem que o cloridato de betanecol, usado em doses únicas, 45 minutos antes da relação sexual, pode ser útil em pacientes do sexo masculino apresentado disfunção orgásmica secundária ao uso da clomipramina.

Neuromuscular blocking effects of an alkaloidal extract from Inula royleana: contractile and electrical studies on amphibian skeletal muscle in vitro.

The neuromuscular blocking properties of an alkaloidal extract from the root of Inula royleana have been investigated in vitro using a combination of mechanical and electrophysiological approaches. Neurogenic twitches of the frog sartorius were profoundly inhibited by concentrations of the extract > or = 20 micrograms/ml, being reduced to 50% of control amplitude in approximately 90 s at a concentration of > or = 20 micrograms/ml. They were partially reversed by neostigmine (6 micrograms/ml), and by prolonged washout of the extract. Muscle surface action potentials, recorded with extracellular electrodes, also declined rapidly in amplitude in the presence of the extract. Direct muscle stimulation during inhibition by the extract elicited contractions and action potentials whose magnitudes were similar to control responses. Resting membrane potentials, and the intracellular input impedance of the skeletal muscle cells, were not significantly changed by the alkaloids. These results indicate that the extract has significant neuromuscular blocking activity of a partially or slowly reversible nature. The block appears to be exerted at the postjunctional end-plate nicotine receptors, thus offering promise for the identification of novel cholinergic receptor antagonist(s).

Colinomiméticos / Terapeutic effects of cholonergic substances

Atualizaçäo sobre a fisiologia, terapêutica e toxicidade dos colinomiméticos sobre o homem.

Partially folded intermediates during trypsinogen denaturation

The equilibrium unfolding of bovine trypsinogen was studied by circular dichroism, differential spectra and size exclusion HPLC. The change in free energy of denaturation was delta GH2O = 6.99 + ou - 1.40 kcal/mol for guanidine hydrochloride and delta GH2O = 6.37 + ou - 0.57 kcal/mol for urea. Satisfactory fits of equilibrium unfolding transitions required a three-state model involving an intermediate in addition to the native and unfolded forms. Size exclusion HPLC allowed the detection of an intermediate population of trypsinogen whose Stokes radii varied from 24.1 + ou - 0.4 angstron to 26.0 + ou - 0.3 angstron 1.5 M and 2.5 M guanidine hydrochloride, respectively. During urea denaturation, the range of Stokes radii varied from 23.9 + ou - 0.3 angstron to 25.7 + ou - 0.6 angstron for 4.0 M and 6.0 M urea, respectively. Maximal intrinsic fluorescence was observed at about 3.8 M urea with 8-aniline-1-naphthalene sulfonate (ANS) binding. These experimental data indicate that the unfolding of bovine trypsinogen is not a simple transition and suggest that the equilibrium intermediate population comprises one intermediate that may be characterized as a molten globule. To obtain further insight by studying intermediates representing different stages of unfolding, we hope to gain a better understanding of the complex interrelations between protein conformation and energetics.

The Additive of Latanoprost 0.005% in Patients with Maximum Tolerated Medical Therapy Regimen

Latanoprost 0.005% which is a currently available ocular hypotensive agent has been known to produce an additional reduction of intraocular pressure when used in combination with beta adrenergic bloker. The aim of this study was to evaluate the additive effect of this drug in patients with maximum tolerated medical therapy regimen. 48 eyes of 32 patients were categorized into 2 groups as to their type of glaucomas(primary open abgle glaucoma(POAG) vs chronic angle closure glauoma(CACG), and pilocarpine use. POAG group showed 22.3, 24.8, 22.7, 21.0, 21.4% and CACG group showed 17.6, 17.1, 15.7, 17.5, 17.8% of ocular hypotensive effect at post treatment 2 weeks, 4 weeks, 3 months, 6 months, 9 to 12 months, respectively and there was no satistically significant difference between two groups. Pilocarpine using group showed 25.5, 30.5, 26.4, 23.4, 17.8% and non-using group showed 20.6, 18.9, 19.0, 18.7, 25.1% of ocular hypotensive effect at each follow up period. Conclusively, latanoprost 0.005% appeared to be a very effective drug in reducing intraocular pressure in patients with maximum tolerated medical therapy regimen without regard to their type of glaucomas, and use of parasympathomimetics.

Utilidad de un procinético cisaprida en el tratamiento abortivo de la migraña / Utility of the prokinetic cisapride in the abortive treatment of migraine

Alrededor de 23 millones de americanos sufren de cefalea migrañosa y más de 11 millones experimentan incapacidad significativa. El tratamiento puede ser de dos tipos; abortivo y profiláctico. Se han utilizado agonistas de los receptores de la serotonina para la mejoría de los síntomas. Cisaprida un fármaco procinético tiene propiedades agonistas en los receptores 5HT2 y en los SHT4. Se estudiaron nueve pacientes 8 del sexo femenino y 1 del masculino con una media de 27 años. Se estableció diagnóstico de cefalea, se valoraron las características de la cefalea y la respuesta al tratamiento con cisaprida. Se valoró la respuesta a los 30, 30-60 y más de 60 min y mostraron que cisaprida disminuyo la cefalea a leve en 67 por ciento, moderada en 22 por ciento y severa 11 por ciento, disminuyo el dolor en el 56 por ciento en menos de 30 min entre 30-60 min el 33 por ciento y el 1 por ciento más de 60 min. El siguiente estudio mostró utilidad de la cisaprida en el tratamiento abortivo de la migraña

Pharmacological analysis of acute morphine dependence in infant rats: close molecular relationship of head-shaking precipitated by opiate antagonists and cholinergic neurotransmission

The influence of drugs affecting different neurotransmitter systems on an acute abstinence heanshaking (AHS) model induced by nalorphine or naloxone was studied in 9-day-old rat pups pretreated (3 h before) with morphine (10mg/kg, i.p.). One hour after the injection of nalorphine (10 mg/kg, i.p.) AHS was stopped by a second dose of morphine (10 mg/kg, i.p.) and reinitiated 1 h later by a higher dose of nalorphine (20 mg/kg, i.p.). In other groups AHS was blocked by spiroperidol (0.1 mg/kg, i.p.), clonidine (0.01 mg/kg, i.p.) or scopolamine (50 mg/kg, i.p.). In these groups a second injection of nalorphine did not reinitiate AHS. In dose-effect curve experiments the AHS induced by naloxone or nalorphine was significantly reduced by previous injections of scopolamine, spiroperidol, metergoline or phentolamine in the corresponding groups. Scopolamine was the only antagonist which displaced the AHS dose-effect curves to the right without affecting the maximal response. Since no common receptors exist for a direct competitive interaction between opiate antagonists and scopolamine, these experiments suggest that a direct molecular relationship exists between the tissue concentration of nalorphine (or naloxone) and the endogenous ACh release during abstinence. Thus, the AHS model in 9-day-old rats clearly differentiates specific from non-specific blockade of the abstinence syndrome, and confirms a distinct or primary role of cholinergic neurotransmission in morphine abstinence

Additive effect of Dapiprazole and Pilocarpine for the Reversal of Mydriasis and Cycloplegia

We assessed the combined effects of dapiprazole, an alpha-adrenergic receptor blocker, with pilocarpine. direct-acting parasympathomimetics, on reversing mydriasis and cycloplegia in 40 eyes (20 subjects) who received 1% tropicamide or 2.5% phenylephrine for pupillary dilation and cycloplegic refraction. These results were compared to 40 eyes (20 subjects) that received dapiprazole alone. The study was divided into four groups, each of which consisted of 20 eyes that received either 1% tropicamide or 0.5% phenylephrine followed by instillation of 0.5% dapiprazole alone or in combination with 2% pilocarpine. A significant difference in the reduction of pupil size and the increase in accommodative amplitude has been observed between the groups that received dapiprazole alone and those received both dapiprazole and pilocarpine(p<0.001). These results suggest that dapiprazole and pilocarpine eyedrops have additive effects on reversing both mydriasis and cycloplegia after instillation of 1% tropicamide or 2.5% phenylephrine for pupillary dilation and cycloplegic refraction.

Teofinila e fenoterol isolados ou combinados com brometo de ipratrópio em DPOC: efeitos a longo prazo medidos por funçäo pulmonar seriada, qualidade de vida e uso adicional de broncodilatador / Theophylline and fenoterol isolated or combined with ipratropium bromide in COPD: long-term effects measured by serial peack expiratory flow rate, quality of life and extra-use of bronchodilator

OBJETIVO: Comparar o efeito do fenoterol e brometo de ipratróprio em doses acima das usuais e teofilina, isolados ou combinados em DPOC. MÉTODOS: foram incluídos pacientes com VEF1 abaixo de 60 por cento do previsto e VEF1/CVF menor do que 70 por cento após broncodilatador (Bd). Tolerância à teofilina foi necessária para inclusäo. Após período basal de três semanas, em que apenas fenoterol em spray usado se necessário era permitido, os pacientes foram alocados de maneira aberta e randomizada para cinco períodos de tratamento de três semanas com: fenoterol (F) 600mcg quatro vezes ao dia; teofilina de liberaçÝo lenta (T) duas vezes ao dia; F 300 mcg e brometo de ipratrópio (BI) 120mcg quatro vezes ao dia ; F 600mcg e T; F300 mcg, BI 120mcg quatro vezes ao dia e T. A resposta foi avaliada por medida seriada do pico de fluxo expiratório (PFE), qualidade de vida, espirometria, teste de caminhada de seis minutos e uso adicional de Bd para controle sintomático. RESULTADOS: Trinta pacientes completaram o estudo. O VEF1 foi de 1,15 mais ou menos 0,37 L. A mediana da resposta ao Bd agudamente foi de 16 por cento. O nível sérico da T foi de 13,8 mais ou menos 2,8 mg/l. Näo ocorreram mudanças significativas na CVF1, VEF1 e distância caminhada. Cada um dos esquemas aumentou o PFE em relaçäo ao período basal (F=5,25-p menor que 0,01), mais nos respondedores ao Bd no laboratório. Os valores do PFE foram menores que o tratamento F. A dispnéia caiu de modo semelhante em todos os grupos, mas sua variaçäo näo se correlacionou com as variaçöes do PFE. Todos os tratamentos resultaram em reduçäo significativa do número de doses extras de Bd (x2=28,06-p menor que 0,05) mais com F+T e F+t+BI e em melhora na qualidade de vida (x2 =19,5-p menor que 0,001), mas sem diferenças entre os tratamentos. CONCLUSÖES: A resposta a broncodilatadores avaliada por medidas de qualidade de vida e dispnéia näo se correlaciona com a resposta funcional avaliada por espirometria e medidas seriadas do PFE. A resposta ao uso regular de betagonista é menor do que a encontrada com teofilina ou a combinaçäo de betagonista e ipratrópio, estes últimos sendo equivalentes. Quando betagonista é combinado com teofilina ou com teofilina e ipratrópio, é vista maior reduçäo no uso de Bd adicional, porém os efeitos colaterais aumentaras; PFE, dispnéia e qualidade de vida permaneceram inalterados.

Noçöes básicas sobre as drogas antiglaucomatosas / Basic notions about antiglaucomatous drugs

Os autores fazem uma revisäo das principais drogas em uso ou em fase de pesquisa para o tratamento do glaucoma. Analisam critérios a serem observados na sua escolha e quais as formas utilizadas na sua administraçäo. Descrevem, também, como estas substâncias atuam na reduçäo da pressäo intra-ocular e na proteçäo do nervo óptico

Pupillary Responses to Dilute Pilocarpine in Brain Death and Comatous Patients

Recently, it is reported that preganglionic oculomotor nerve palsies shows denervational supersensitive pupillary responses to dilute parasympathomimetic agents and this phenomenon is in inverse proportion to consciousness level. We measured pupillary diameters of 10 brain death patients(20 eyes) and 10 comatous patients (20 eyes). After we instilled 0.06% pilocarpine to patients that initial pupillary diameter is over 4.0mm(13 eyes in brain death group, 5 eyes in comatous group), we compared pupillary responses of two groups to evaluate whether this helps diagnosis of brain death. If pupillary diameter was changed over 25%(compared to initial diameter), we considered it positive. In comatous group, no one was positive. But in brain death group, 11 cases were positive(84.6%). It revealed significant difference statistically(P<0.05). Mean change of pupillary diameter to 0.06% pilocarpine was 0.46mm(9.35%) in comatous group, and 2.62mm(47.72%) in brain death group. With above results, we concluded that pupillary response to dilute parasympathomimetic agents is a useful indicator for diagnosis of brain death.