Anxiolytic effects of N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, a pyrroloformamide isolated from a marine Streptomyces sp., in adult zebrafish by the 5-HT system.

General anxiety disorders are among the most prevalent mental health problems worldwide. The emergence and development of anxiety disorders can be due to genetic (30-50%) or non-genetic (50-70%) factors. Despite medical progress, available pharmacotherapies are sometimes ineffective or can cause undesirable side effects. Thus, it becomes necessary to discover new safe and effective drugs against anxiety. This study evaluated the anxiolytic effect in adult zebrafish (Danio rerio) of a natural pyrroloformamide (PFD), N-(4,5-dihydro-5-oxo-1,2-dithiolo-[4,3,b]-pyrrole-6-yl)-N-methylformamide, isolated from a Streptomyces sp. bacterium strain recovered from the ascidian Eudistoma vannamei. The complete structure of PFD was determined by a detailed NMR analysis, including 1H-13C and 1H-15N-HBMC data. In addition, conformational and DFT computational studies also were performed. A group of fishes (n = 6) was treated orally with PFD (0.1, 0.5 and 1.0 mg/mL; 20 µL) and subjected to locomotor activity and light/dark tests, as well as, acute toxicity 96 h. The involvement of the GABAergic and serotonergic (5-HT) systems was investigated using flumazenil (a silent modulator of GABA receptor) and 5-HT1, 5-HT2A/2C and 5-HTR3A/3B receptors antagonists, known as pizotifen, granisetron and cyproheptadine, respectively. PFD was nontoxic, reduced locomotor activity and promoted the anxiolytic effect in zebrafish. Flumazenil did not inhibit the anxiolytic effect of the PFD via the GABAergic system. This effect was reduced by a pretreatment with pizotifen and granisetron, and was not reversed after treatment with cyproheptadine. Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.Communicated by Ramaswamy H. Sarma.

Pyrroloformamide (PFD), isolated from the marine Streptomyces sp. associated ascidian Eudistoma vannamei, showed no toxicity in adult zebrafish but reduced its locomotor activity.The structural elucidation of PFD was determined by the analysis of 1D and 2D NMR and HRESIMS data.The density functional theory (DFT) study confirmed the existence of two conformers as determined by NMR spectra.The serotonergic system modulated the anxiolytic effect of PFD via the 5-HT receptor in adult zebrafish.Molecular docking and dynamics studies confirmed the interaction of PFD with the 5-HT receptor.

Development of immediate release Rupatadine fumarate 10 mg tablets: A Quality by Design (QbD) approach.

Objective: The main objective of this research is to develop an immediate release Rupatadine fumarate 10 mg tablets formulation by direct compression, through a Quality by Design approach in Costa Rica. Methods: According to a Quality by Design approach; Target Product Profile, Quality Target Product Profile, and the Critical Quality Attributes were defined. In the preformulation study, compatibility tests were carried out between the raw materials. The Critical Material Attributes were established using Quality Risk Management. Three formulation prototypes were prepared by direct compression and its Critical Process Parameters were defined. The analysis of the prototypes was realized in terms of organoleptic properties, identification, potency, content uniformity, dissolution, disintegration, friability and loss by drying. Results: All the prototypes showed a white or slightly pink surface, potency between 90.0 -110.0 % of the labeling, an acceptance value for the content uniformity lower than the specification (AV < 15), the dissolved amount of active pharmaceutical ingredient was greater than 85.0 % at 30 minutes, friability less than 1.0 %, a disintegration time less than 15 minutes and moisture content less than 2.0 %. Conclusions: The approaching of a Quality by Design model to the current development allowed to obtain satisfactory results in the three formulation prototypes. The excipients to be used can be lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, magnesium stearate, stearic acid, and PVP K-30.

Pharmacological Characterization of Mouse Hind Paw Edema Induced by Parachartergus fraternus Venom.

Stings from the wasp Parachartergus fraternus occur throughout Latin America, and edema followed by pain is the main symptom presented by victims. This often limited inflammatory event has not been characterized for this species. In this work, we identified the mechanisms and possible mediators involved in this response. P. fraternus venom (100, 200, and 400 µg/kg) was injected into the hind paws of mice, and edema was evaluated at intervals of 10 min for up to 60 min and at 120, 240, and 1440 min using a digital plethysmometer. The peak of edema was observed at 10 min with a dose of 200 µg/kg. A reduction in edema was observed with indomethacin (58.1%), celecoxib (44.5%), MK886 (30.8%), and dexamethasone (53.2%). Loratadine, cimetidine, and cyproheptadine treatment reduced the edema by 54.2%, 63.9%, and 84.4%, respectively, compared with the control. Captopril and L-NAME inhibited 42.5% and 69.8%, respectively, of the edema. These results showed that the edema induced in mice by P. fraternus venom occurs early and is mediated by arachidonic acid derivatives, vasoactive amines, and nitric oxide. Together, these mediators amplify the inflammatory process, with emphasis on histamine and serotonin in triggering the edematogenic response, being more effective the use of cyproheptadine in the therapeutic approach.

In vivo and in silico anti-inflammatory mechanism of action of the semisynthetic (-)-cubebin derivatives (-)-hinokinin and (-)-O-benzylcubebin.

(-)-Cubebin (CUB), isolated from seeds of Piper cubeba, was used as starting material to obtain the derivatives (-)-hinokinin (HK) and (-)-O-benzyl cubebin (OBZ). Using paw edema as the experimental model and different chemical mediators (prostaglandin and dextran), it was observed that both derivatives were active in comparison with both negative (5% Tween® 80 in saline) and positive (indomethacin) controls. The highest reduction in the prostaglandin-induced edema was achieved by OBZ (66.0%), while HK caused a 59.2% reduction. Nonetheless, the dextran-induced paw edema was not significantly reduced by either of the derivatives (HK or OBZ), which inhibited edema formation by 18.3% and 3.5%, respectively, in contrast with the positive control, cyproheptadine, which reduced the edema by 56.0%. The docking analysis showed that OBZ presented the most stable ligand-receptor (COX-2 - cyclooxygenase-2) interaction in comparison with CUB and HK.

Rupatadine oral solution in children with persistent allergic rhinitis: A randomized, double-blind, placebo-controlled study.

BACKGROUND: Allergic rhinitis (AR) is one of the most common chronic diseases in childhood. No large, multicentre clinical trials in children with persistent allergic rhinitis (PER) have previously been performed. Rupatadine, a newer second-generation antihistamine, effective and safe in adults, is a promising treatment for children with AR. The aim of the present study was to evaluate the efficacy and safety of a new rupatadine oral solution in children aged 6-11 yr with PER. METHODS: A multicenter, randomized, double-blind, placebo-controlled study was carried out worldwide. Patients between 6 and 11 yr with a diagnosis of PER according to ARIA criteria were randomized to receive either rupatadine oral solution (1 mg/ml) or placebo over 6 wk. The primary efficacy end-point was the change from baseline of the total nasal symptoms score (T4SS) after 4 wk of treatment. RESULTS: A total of 360 patients were randomized to rupatadine (n = 180) or placebo (n = 180) treatment. Rupatadine showed statistically significant differences vs. placebo for the T4SS reduction both at 4 (-2.5 ± 1.9 vs. -3.1 ± 2.1; p = 0.018) and 6 wk (-2.7 ± 1.9 vs. -3.3 ± 2.1; p = 0.048). Rupatadine also showed a statistically better improvement in the children's quality of life compared with placebo. Adverse reactions were rare and non-serious in both treatment groups. No QTc or laboratory test abnormalities were reported. CONCLUSIONS: Rupatadine oral solution (1 mg/ml) was significantly more effective than placebo in reducing nasal symptoms at 4 and 6 wk and was well tolerated overall. This is the first large clinical report on the efficacy of an H1 receptor antagonist in children with PER in both symptoms and quality of life.

Safety and efficacy of cyproheptadine for treating dyspeptic symptoms in children.

OBJECTIVE: To present our experience using cyproheptadine, a potent serotonin antagonist used to stimulate appetite, to treat dyspeptic symptoms in children. STUDY DESIGN: This was a retrospective open-label study conducted to evaluate the safety and efficacy of cyproheptadine in children with refractory upper gastrointestinal symptoms (eg, nausea, early satiety, vomiting, retching after fundoplication, abdominal pain). Response was graded as resolution if symptoms resolved and medication was discontinued, as significant improvement if symptoms resolved with no further interventions, and as failure with any other outcome. RESULTS: A total of 80 children (65% females) aged <12 years (mean age, 10 years) were included. Response to therapy was reported in 55% of patients. Multivariate analysis revealed better response in children and females (P = .04 and .03, respectively). No associations were found between response to therapy response and gastric emptying, antroduodenal manometry, functional dyspepsia, vomiting, and use of cyproheptadine as first therapy. Early vomiting (occurring within 1 hour after starting a meal) responded better than late vomiting (P = .03), and patients with retching after undergoing Nissen fundoplication had an 86% response rate. Twenty-four patients (30%) complained of side effects, all mild, including somnolence (16%), irritability and behavioral changes (6%), increased appetite and weight gain (5%), and abdominal pain (2.5%), but only 2 of these patients discontinued therapy. Multivariate analysis demonstrated an association between side effects and lack of response to therapy (P = .04), but no associations with age and sex. CONCLUSION: Cyproheptadine is safe and effective for treating dyspeptic symptoms in children, particularly in young children and those with early vomiting and retching after fundoplication.

A randomized, double-blind, placebo-controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis.

OBJECTIVE: To determine whether the administration of cyproheptadine was able to induce weight gain in patients with cystic fibrosis. METHODS: We performed a double-blind, placebo-controlled trial in two centers in Brazil. Twenty-five patients with cystic fibrosis between 5 and 18 years completed the study. Patients were randomized into two groups, to receive either cyproheptadine 4 mg three times per day for 12 weeks or placebo. All data were collected at the beginning and at the end of the study period and included weight, height and spirometry. RESULTS: Average weight gain was 0.67 kg in the placebo group and 1.61 kg in the cyproheptadine group (p = 0.036). Body mass index (BMI) decreased 0.07 kg/m(2); in the placebo group and increased 0.46 kg/m(2); in the intervention group (p = 0.027). The change in BMI for age (z score) was -0.19 in the placebo group and +0.20 in the cyproheptadine group (p = 0.003). BMI z score decreased 0.19 in the placebo group and increased 0.2 in the cyproheptadine group (p = 0.003). Changes in pulmonary function were not statistically different. CONCLUSION: Use of cyproheptadine in cystic fibrosis patients was well tolerated, showing a significant weight gain and a significant increase in BMI after 12 weeks. A clinically relevant effect size for weight/age (z score) and body mass index for age (z score) was found. Such findings suggest that the prescription of cyproheptadine can be an alternative approach for patients who need nutritional support for a short period of time.

Ensaio clínico randomizado, duplo-cego e controlado por placebo de ciproheptadina para estímulo do apetite na fibrose cística / A randomized, double-blind, placebo-controlled trial of cyproheptadine for appetite stimulation in cystic fibrosis

OBJETIVO: O objetivo deste estudo foi determinar se a administração de ciproheptadina é capaz de induzir ganho de peso em pacientes com fibrose cística. MÉTODOS: Foi realizado um estudo duplo-cego, controlado com placebo em dois centros no Brasil. Vinte e cinco pacientes com fibrose cística entre 5 e 18 anos completaram o estudo. Os pacientes foram randomizados em dois grupos, para receber ciproheptadina 4 mg três vezes por dia durante 12 semanas ou placebo. Todos os dados foram coletados no início e no final do período de estudo e incluíram peso, altura e espirometria. RESULTADOS: O ganho de peso médio foi de 0,67 kg e 1,61 kg nos grupos placebo e ciproheptadina, respectivamente (p = 0,036). O índice de massa corporal (IMC) diminuiu 0,07 kg/m² no grupo placebo e aumentou 0,46 kg/m² no grupo intervenção (p = 0,027). A mudança no IMC para a idade (escore z) foi de -0,19 no grupo placebo e 0,20 no grupo ciproheptadina (p = 0,003). O IMC escore z diminuiu 0,19 no grupo placebo e aumentou 0,2 no grupo ciproheptadina (p = 0,003). Alterações na função pulmonar não foram estatisticamente diferentes. CONCLUSÃO: O uso de ciproheptadina em pacientes com fibrose cística foi bem tolerado, apresentando um ganho de peso significativo e um aumento no IMC após 12 semanas. Foi encontrado um tamanho de efeito clinicamente relevante para o peso/idade (escore z) e IMC para idade (escore z). Tais achados sugerem que a prescrição de ciproheptadina pode ser uma abordagem alternativa para pacientes que precisam de suporte nutricional por um curto período de tempo.

OBJECTIVE: To determine whether the administration of cyproheptadine was able to induce weight gain in patients with cystic fibrosis. METHODS: We performed a double-blind, placebo-controlled trial in two centers in Brazil. Twenty-five patients with cystic fibrosis between 5 and 18 years completed the study. Patients were randomized into two groups, to receive either cyproheptadine 4 mg three times per day for 12 weeks or placebo. All data were collected at the beginning and at the end of the study period and included weight, height and spirometry. RESULTS: Average weight gain was 0.67 kg in the placebo group and 1.61 kg in the cyproheptadine group (p = 0.036). Body mass index (BMI) decreased 0.07 kg/m² in the placebo group and increased 0.46 kg/m² in the intervention group (p = 0,027). The change in BMI for age (z score) was -0.19 in the placebo group and +0.20 in the cyproheptadine group (p = 0.003). BMI z score decreased 0.19 in the placebo group and increased 0.2 in the cyproheptadine group (p = 0.003). Changes in pulmonary function were not statistically different. CONCLUSION: Use of cyproheptadine in cystic fibrosis patients was well tolerated, showing a significant weight gain and a significant increase in BMI after 12 weeks. A clinically relevant effect size for weight/age (z score) and body mass index for age (z score) was found. Such findings suggest that the prescription of cyproheptadine can be an alternative approach for patients who need nutritional support for a short period of time.

Quantification of cyproheptadine in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry in a bioequivalence study.

A rapid, sensitive and specific method to quantify cyproheptadine in human plasma using amitriptyline as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using a diethyl-ether/dichloromethane (70/30; v/v) solvent. After removing and drying the organic phase, the extracts were reconstituted with a fixed volume of acetonitrile/water (50/50 v/v)+0.1% of acetic acid. The extracts were analyzed by high performance liquid chromatography coupled to electrospray tandem mass spectrometry (LC-MS/MS). Chromatography was performed isocratically using an Alltech Prevail C18 5 µm analytical column, (150 mm x 4.6 mm I.D.). The method had a chromatographic run time of 4 min and a linear calibration curve ranging from 0.05 to 10 ng/mL (r2 > 0.99). The limit of quantification was 0.05 ng/mL. This HPLC/MS/MS procedure was used to assess the bioequivalence of cyproheptadine in two cyproheptadine + cobamamide (4 mg + 1 mg) tablet formulations (Cobactin® [cyproheptadine + cobamamide] test formulation supplied from Zambon Laboratórios Farmacêuticos Ltda. and Cobavital® from Solvay Farma (standard reference formulation)). A single 4 mg + 1 mg [cyproheptadine + cobamamide] dose of each formulation was administered to healthy volunteers. The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval. Since the 90% CI for Cmax and AUCs ratios were all within the 80-125% bioequivalence limit proposed by the US Food and Drug Administration, it was concluded that the cyproheptadine test formulation (Cobactin®) is bioequivalent to the Cobavital® formulation for both the rate and the extent of absorption of cyproheptadine.

Síndrome serotonínico pediátrico: reporte de un caso / Serotonin syndrome pediatric: case report

El síndrome serotonínico es un cuadro neurológico agudo debido a hiperactividad serotoninérgica, por la interacción de drogas que refuerzan o mimetizan la acción del neurotrasmisor. La incidencia del síndrome de serotonina es ascendente por la disponibilidad creciente de fármacos serotoninérgicos como los antidepresivos. Por ello es importante que los médicos reconozcan y manejen adecuadamente el síndrome serotonínico. Este reporte de caso se refiere a una intoxicación accidental por el neuroléptico atípico olanzapina en un niño de 2 años, quien desarrolló manifestaciones clínicas como agitación, sudoración, mioclonías, clonus espontáneo e hipertermia, considerados como criterios diagnóstico del cuadro. La terapia consistió en descontaminación interna con lavado gástrico, carbón activado y sulfato de sodio, ciproheptadina, propranolol y furosemida. Su evolución fue satisfactoria. En nuestro país hay disponibilidad de la mayoría de los fármacos causales y tienen amplio uso, por lo que es probable el subregistro del síndrome. De allí la importancia de este reporte de caso

Serotonin syndrome is an acute neurologic picture due to serotonergic hyperactivity, due to the interaction of drugs that enhance or mimic the action of the serotonin. The incidence of serotonin syndrome is rising because of the growing availability of serotonergic drugs such as antidepressants. It is therefore important that clinicians recognize and manage appropriately this syndrome. This case report refers to an accidental poisoning by the atypical neuroleptic olanzapine in a 2 year old boy who developed clinical manifestations such as agitation, sweating, myoclonus, spontaneous clonus and hyperthermia, considered as diagnostic criteria for the syndrome. Therapy consisted of internal decontamination with gastric lavage, activated charcoal and sodium sulfate, cyproheptadine, propranolol and furosemide. The clinical outcome was satisfactory. In our country the majority of the causal drugs are easily available and widely employed, for which reason it is probable that this syndrome is under registered. Hence the importance of this case report

Futura study: evaluation of efficacy and safety of rupatadine fumarate in the treatment of persistent allergic rhinitis.

UNLABELLED: Allergic rhinitis affects 10-30% of the population, negatively impacting one's quality of life and productivity. It has been associated with sinusitis, otitis media, sleep disorders, and asthma. Rupatadine is a second generation antihistamine with increased affinity to histamine receptor H1; it is also a potent PAF (platelet-activating factor) antagonist. It starts acting quite quickly, offers long lasting effect, and reduces the chronic effects of rhinitis. AIM: this study aims to assess the efficacy and safety of rupatadine in the treatment of persistent allergic rhinitis. MATERIALS AND METHOD: this is a multi-centric open prospective study. This study included 241 patients from 13 centers in Brazil and was held between October of 2004 and August of 2005. Signs and symptoms of rhinitis and tolerance to medication were analyzed after one and two weeks of treatment. RESULTS: reduction on general scores from 8.65 to 3.21 on week 2 (p<0.001). All signs and symptoms improved significantly in the first day of treatment (p<0.001), except for nasal congestion and secretion, which improved from the second day of treatment (p<0.001). Adverse events occurred in 19.9% of the cases, 27.7% on week 1. CONCLUSION: rupatadine effectively controls persistent allergic rhinitis; it is safe and presents low incidence of side effects.

Futura study: evaluation of efficacy and safety of rupatadine fumarate in the treatment of persistent allergic rhinitis / Estudo futura: avaliação da eficácia e segurança do fumarato de rupatadina no tratamento da rinite alérgica persistente

Allergic rhinitis affects 10-30 percent of the population, negatively impacting one's quality of life and productivity. It has been associated with sinusitis, otitis media, sleep disorders, and asthma. Rupatadine is a second generation antihistamine with increased affinity to histamine receptor H1; it is also a potent PAF (platelet-activating factor) antagonist. It starts acting quite quickly, offers long lasting effect, and reduces the chronic effects of rhinitis. AIM: this study aims to assess the efficacy and safety of rupatadine in the treatment of persistent allergic rhinitis. MATERIALS AND METHOD: this is a multi-centric open prospective study. This study included 241 patients from 13 centers in Brazil and was held between October of 2004 and August of 2005. Signs and symptoms of rhinitis and tolerance to medication were analyzed after one and two weeks of treatment. RESULTS: reduction on general scores from 8.65 to 3.21 on week 2 (p<0.001). All signs and symptoms improved significantly in the first day of treatment (p<0.001), except for nasal congestion and secretion, which improved from the second day of treatment (p<0.001). Adverse events occurred in 19.9 percent of the cases, 27.7 percent on week 1. CONCLUSION: rupatadine effectively controls persistent allergic rhinitis; it is safe and presents low incidence of side effects.

A rinite alérgica acomete 10 a 30 por cento da população, interferindo na qualidade de vida e na capacidade produtiva. Está associada à sinusite, otite, roncopatias e asma. A Rupatadina é um anti-histamínico de segunda geração, com elevada afinidade ao receptor histamínico H1 e potente inibição do fator ativador plaquetário (PAF). Tem rápido início de ação, longa duração e reduz os efeitos crônicos da rinite. OBJETIVO: Avaliar a eficácia e segurança da rupatadina no tratamento da rinite alérgica persistente. MATERIAL E MÉTODO: Estudo multicêntrico, aberto, prospectivo. Foram selecionados 241 pacientes em 13 centros no Brasil durante o período de outubro de 2004 a agosto de 2005. Foram analisados os sinais e sintomas da rinite e a tolerabilidade após 1 e 2 semanas. RESULTADOS: Redução do escore geral de 8,65 para 3,21 na semana 2 (p<0,001). Todos os sinais e sintomas melhoraram significativamente, e no primeiro dia de tratamento (p<0,001), com exceção da obstrução e secreção nasal, a partir do segundo dia (P<0,001). A frequência de eventos adversos foi 19,9 por cento, sendo 27,7 por cento na 1ª semana. CONCLUSÕES: A rupatadina é eficaz no controle da rinite alérgica persistente, é segura e apresenta baixos índices de efeitos colaterais.

Germinating seeds of the mung bean, Vigna radiata (Fabaceae), as a model for the preliminary evaluation of cytotoxic effects of drugs

Cytotoxic properties of plant extracts and drugs being developed for cancer treatment are usually evaluated by a variety of in vivo and in vitro tests carried out in animal or plant based models. In the present study we have evaluated the possibility of using the germinating mung beans (Vigna radiata), for rapid and inexpensive screening of drugs exhibiting cytotoxic properties. Mung beans were allowed to germinate either in tap water or in different drug solutions, and parameters like percent germination, increase in radicle length, change in seedling weight and mitotic index of apical root meristems were determined at two time intervals coinciding with the time at which the radicle length in control group was 1.0 to 1.5 cm (time 0, T0) and 48 h later (T48). Methanol extract of Calotropis procera latex as well as drugs like podophyllotoxin, cyclophosphamide, cyproheptadine and aspirin produced a dose-dependent inhibitory effect on seed germination, seed weight gain, radicle growth and mitotic index in the radicle meristems. The inhibitory effect of some of the drugs tested was associated with reduction in water imbibition. Some of the drugs at higher concentrations allowed seed germination to take place but produced radicle decay and seedling weight loss. Our study shows that germinating V radiata beans could be used as a convenient model for the preliminary screening of drugs exhibiting cytotoxic properties.(AU)

Germinating seeds of the mung bean, Vigna radiata (Fabaceae), as a model for the preliminary evaluation of cytotoxic effects of drugs

Cytotoxic properties of plant extracts and drugs being developed for cancer treatment are usually evaluated by a variety of in vivo and in vitro tests carried out in animal or plant based models. In the present study we have evaluated the possibility of using the germinating mung beans (Vigna radiata), for rapid and inexpensive screening of drugs exhibiting cytotoxic properties. Mung beans were allowed to germinate either in tap water or in different drug solutions, and parameters like percent germination, increase in radicle length, change in seedling weight and mitotic index of apical root meristems were determined at two time intervals coinciding with the time at which the radicle length in control group was 1.0 to 1.5 cm (time 0, T0) and 48 h later (T48). Methanol extract of Calotropis procera latex as well as drugs like podophyllotoxin, cyclophosphamide, cyproheptadine and aspirin produced a dose-dependent inhibitory effect on seed germination, seed weight gain, radicle growth and mitotic index in the radicle meristems. The inhibitory effect of some of the drugs tested was associated with reduction in water imbibition. Some of the drugs at higher concentrations allowed seed germination to take place but produced radicle decay and seedling weight loss. Our study shows that germinating V radiata beans could be used as a convenient model for the preliminary screening of drugs exhibiting cytotoxic properties.

Determination of rupatadine in pharmaceutical formulations by a validated stability-indicating MEKC method.

A stability-indicating MEKC was developed and validated for the analysis of rupatadine in tablet dosage forms, using nimesulide as internal standard. The MEKC method was performed on a fused-silica capillary (50 microm id; effective length, 40 cm). The BGE consisted of 15 mM borate buffer and 25 mM anionic detergent SDS solution at pH 10. The capillary temperature was maintained at 35 degrees C and the applied voltage was 25 kV. The injection was performed using the hydrodynamic mode at 50 mbar for 5 s, with detection by photodiode array detector set at 205 nm. The method was linear in the range of 0.5-150 microg/mL (r2=0.9996). The specificity and stability-indicating capability of the method were proven through degradation studies inclusive by MS, and showing also that there was no interference of the excipients and no increase of the cytotoxicity. The accuracy was 99.98% with bias lower than 1.06%. The LOD and LOQ were 0.1 and 0.5 microg/mL, respectively. The proposed method was successfully applied for the quantitative analysis of rupatadine in pharmaceutical formulations, and the results were compared to a validated RP-LC method, showing non-significant difference (p>0.05).

A 12-week placebo-controlled study of rupatadine 10 mg once daily compared with cetirizine 10 mg once daily, in the treatment of persistent allergic rhinitis.

BACKGROUND: With the current increasing incidence of allergies worldwide, new treatments showing efficacy and long term safety are needed for chronic conditions such as persistent allergic rhinitis (PER). New generation H1-antihistamines have demonstrated anti-allergic properties, which could possibly enhance their effectiveness in long-term periods of treatment. OBJECTIVE: To investigate the efficacy of rupatadine, in controlling symptoms of PER over a 12-week period. METHODS: A randomized, double blind, parallel-group, placebo-controlled study was carried out in patients aged older than 12 years with PER. Main inclusion criteria were: instantaneous total symptom score (i6TSS) >or=45, nasal obstruction score or=2 as moderate during the first visit. The primary efficacy endpoint was the 12-week average change from baseline of the patients' i6TSS. RESULTS: In all, 736 patients were selected. Of them, 543 (73.8%) were randomized in three different groups: placebo (n = 185), cetirizine (n = 175) and rupatadine (n = 183). Rupatadine (P = 0.008) but not cetirizine (P = 0.07) statistically reduced the baseline i6TSS vs placebo (47.8%, 44.7% and 38.8%, respectively), after 12 weeks. Onset of action was observed at the first 24 h for both treatments (rupatadine vs placebo, P = 0.013; cetirizine vs placebo, P = 0.015). Furthermore, instantaneous total nasal symptoms score (iTNSS) (including nasal blockage) mean change from baseline showed a significant reduction with rupatadine 10 mg in comparison with placebo, along all treatment duration of 12 weeks. Study treatments were well tolerated. CONCLUSION: Rupatadine significantly relieves symptoms of PER, providing a rapid onset of action and maintains its effects over a long period of 12-weeks.

Spatial-specific action of serotonin within the leech midbody ganglion.

Serotonin is a conspicuous neuromodulator in the nervous system of many vertebrates and invertebrates. In previous experiments performed in the leech nervous system, we compared the effect of the amine released from endogenous sources [using selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine] with that of bath-applied serotonin. The results suggested that the amine does not reach all its targets in a uniform way, but produces the activation of an interneuronal pathway that generated specific synaptic responses on different neurons. Taking into account that the release of the amine is often regulated at the presynaptic level, we have investigated whether autoreceptor antagonists mimic the SSRIs effect. We found that methiothepin (100 microM) produced similar effects than fluoxetine. To further test the hypothesis that endogenous serotonin produce its effect by acting locally at specific sites, we analyzed the effect of iontophoretic applications of serotonin. We found a site in the neuropil of the leech ganglia where serotonin application mimicked the effect of the SSRIs and the 5-HT antagonist. The results further support the view that the effect of serotonin exhibits a spatial specificity that can be relevant to understand its modulatory actions.

New antihistamines: a critical view.

OBJECTIVES: To perform a critical evaluation of the more recent H1 antihistamines and the various terms used to describe them, based on a review of evidence on their role in the treatment of allergic disorders. SOURCES OF DATA: Original articles, reviews and consensus documents published from 1998 to 2006 and indexed in the MEDLINE and PubMed databases. Keyword: antihistamines. SUMMARY OF THE FINDINGS: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1 receptors and because of their lower penetration of the central nervous system (CNS), having fewer sedative effects as a result. Whilst second-generation antihistamines are in general better tolerated than their predecessors, some adverse effects, principally cardiotoxicity, have been observed with some of them. Over the last 20 years, new compounds with different pharmacokinetic properties have been synthesized. The majority of these exhibit anti-inflammatory properties that are independent of their action on the H1 receptor. More recent improvements, generally in the form of active metabolites, led to the use of the term third-generation antihistamines. This term emerged spontaneously, with no clear definition of its meaning or clinical implications, creating great confusion among healthcare professionals. CONCLUSION: On the basis of the evidence on H1 antihistamines, none of them deserve the title "third-generation antihistamine." As the Consensus Group on New Generation Antihistamines concluded, to merit this definition, a new class of antihistamines would have to demonstrate distinct clinical advantages over existing compounds and fulfill at least three prerequisites: they should be free from cardiotoxicity, drug interactions and effects on the CNS.