New metallophamaceutic reduced renal injury induced by non-steroidal anti-inflammatory

Abstract Purpose To evaluate the effect of Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), a novel nitric oxide donor, able to modulate the histological changes caused by the NASID (meloxicam). Methods Wistar rats were assigned into three groups (n=6 rats/group): Sham group (saline solution), NSAID group (meloxicam - 15 mg/kg) and Rut-bpy group (100 mg/kg of Rut-bpy associated with 15mg/kg of meloxicam). At the end of experiments, kidneys were removed for histological study, fractal dimension and lacunarity in all animals. Results At the histological examination, all animals (six animals - 100 %) in the NSAID group had membrane thickening and other changes (necrosis, acute tubular congestion and vascular congestion); on the other hand, only one animal (16.6 %) of the Rut-bpy group had congestion. The fractal dimension and lacunarity were greater in the control and Rut-bpy group than in NSAIDs group (p<0.05). Conclusion Rut-bpy may prevent renal histological changes in rats caused by meloxicam.

Síntese e estudos espectroscópicos de organometálicos de rutênio-areno contendo fármacos anti-inflamatórios e derivados como ligantes / Synthesis and spectroscopic studies of ruthenium-arene organometallics bearing anti-inflammatory drugs and derivatives as ligands

Compostos organometálicos do tipo rutênio-areno têm sido estudados no transcurso dos últimos anos em razão do potencial que apresentam para o tratamento de doenças dentre as quais se destaca o câncer. Neste contexto, o presente trabalho teve como principal objetivo o estudo de organometálicos de Ru(II)-p-cimeno contendo como ligantes fármacos anti-inflamatórios não esteroides (FAINEs) ou seus derivados piridinaamida (FAINE-amida). Foram realizadas as sínteses de duas classes de compostos de fórmulas gerais [RuCl(p-cimeno)L] e [RuCl2(p-cimeno)Lam] em que L = ibuprofeno, naproxeno ou indometacina e Lam = derivado amida desses FAINES, respectivamente. A composição e estrutura dos compostos foram elucidadas principalmente com base em análise elementar, espectrometria de massas (ESI-MS), espectroscopia de ressonância magnética nuclear (1H RMN, 13C RMN, HSQC, HMBC) e espectroscopia vibracional ATR/FT-IR. Os dados indicaram que todos os fármacos-ligantes utilizados estabilizam a unidade Ru(II)-areno, sendo que os carboxilatos coordenam-se ao Ru(II) de modo bidentado por ambos os átomos de oxigênio, enquanto que a coordenação dos derivados amida ocorre pelo nitrogênio do anel piridínico. No entanto, em contraste ao comportamento em solventes não-coordenantes como clorofórmio, estudos em solução indicaram que a presença de dimetilsulfóxido promove dissociação do fármaco ligante acompanhada pela coordenação do solvente (gradual, no caso de L, ou imediata total no caso de Lam). Resultados preliminares de estudos de espectroscopia de fluorescência sugerem interação dos compostos de Ru(II)-areno-indometacina com albumina de soro humano (HSA)

Ruthenium-arene organometallics have been investigated in recent years due to the potential for treatment of diseases among which cancer is highlighted. In this context, the main objective of the present work is the study of organometallics of Ru(II)-p-cymene bearing non steroidal anti-inflammatory drugs (NSAIDs) or their pyridine-amide (NSAIDamide) as ligands. Two classes of compounds of general formula [RuCl(p-cymene)L] and [RuCl2(p-cymene)Lam], in which L = ibuprofen, naproxen or indomethacin and Lam = amide derivative of these NSAIDs, respectively have been synthesized. The composition and the structure of these compounds have been elucidated mainly based on elemental analysis, mass spectrometry (ESI-MS), nuclear magnetic resonance spectroscopy (1H RMN, 13C RMN, HSQC, HMBC) and vibrational spectroscopy (ATR/FT-IR). The data indicate that all the used drug-ligands stabilize the Ru(II)-arene framework, being that the carboxylates coordinate Ru(II) in bidentate mode through both oxygen atoms while the coordination of the amide derivatives occurs via nitrogen atom of the pyridine ring. However, in contrast to the behavior in non-coordinating solvents such as chloroform, studies in solution indicate that the presence of dimethylsulfoxide promotes dissociation of the drug ligand accompanied by the coordination of the solvent (gradual, for L, or total immediate for Lam). Preliminary results from fluorescence spectroscopy suggest interaction of the Ru(II)-arene-indomethacin compounds with human serum albumin (HSA)

N-acetyl-L-cysteine and cysteine increase intracellular calcium concentration in human neutrophils

N-acetyl-L-cysteine (NAC) and cysteine have been implicated in a number of human neutrophils' functional responses. However, though Ca²⁺ signaling is one of the key signalings contributing to the functional responses of human neutrophils, effects of NAC and cysteine on intracellular calcium concentration ([Ca²⁺]ᵢ) in human neutrophils have not been investigated yet. Thus, this study was carried out with an objective to investigate the effects of NAC and cysteine on [Ca²⁺]ᵢ in human neutrophils. We observed that NAC (1 µM ~ 1 mM) and cysteine (10 µM ~ 1 mM) increased [Ca²⁺]ᵢ in human neutrophils in a concentration-dependent manner. In NAC pre-supplmented buffer, an additive effect on N-formyl-methionine-leucine-phenylalanine (fMLP)-induced increase in [Ca²⁺]ᵢ in human neutrophils was observed. In Ca²⁺-free buffer, NAC- and cysteine-induced [Ca²⁺]ᵢ increase in human neutrophils completely disappeared, suggesting that NAC- and cysteine-mediated increase in [Ca²⁺]ᵢ in human neutrophils occur through Ca²⁺ influx. NAC- and cysteine-induced [Ca²⁺]ᵢ increase was effectively inhibited by calcium channel inhibitors SKF96365 (10 µM) and ruthenium red (20 µM). In Na⁺-free HEPES, both NAC and cysteine induced a marked increase in [Ca²⁺]ᵢ in human neutrophils, arguing against the possibility that Na⁺-dependent intracellular uptake of NAC and cysteine is necessary for their [Ca²⁺]ᵢ increasing activity. Our results show that NAC and cysteine induce [Ca²⁺]ᵢ increase through Ca²⁺ influx in human neutrophils via SKF96365- and ruthenium red-dependent way.

Efeito protetor do Nitrosil-Rutênio (Cis[Ru(bpy)2SO3NO]+(PF6) em modelos experimentaisde lesões gástricas em camundongos – envolvimento da via NO/GCS/KATP

Lesões gástricas relacionadas ao consumo excessivo de antiinflamatórios não esteroidais (AINEs) e etanol possuem um importante papel na gastroenterologia clínica. Fármacos com ação anti-secretória gástrica, como os inibidores da bomba de prótons, representam a principal opção na terapia destas patologias. Objetivo: Avaliar o efeito do doador de NO nitrosil-rutênio (Rut-NO) na defesa da mucosa gástrica em modelos experimentais de lesão gástrica em camundongos e a participação da guanilato ciclase solúvel (GCs) e dos canais de KATP neste efeito. Métodos: Protocolo1-Camundongos swiss foram pré-tratados com Rut-NO (3mg/Kg, v.o), rutênio (2.3mg/Kg, v.o) ou nitroprussiato (NPS) na dose de 10mg/kg, v.o, meia hora antes da administração por gavagem de etanol 50%. Em outro grupo, os animais foram pré-tratados com ODQ (10mg/Kg, v.o) ou glibenclamida (10mg/Kg,i.p) trinta minutos ou 1h antes, respectivamente dos tratamentos citados anteriormente.Depois de 1h, os animais foram sacrificados e os estômagos removidos para a avaliação das lesões gástricas por planimetria computadorizada. Além disso, fragmentos de tecido foram removidos para análise microscópica e dosagem de glutationa (GSH) e malondialdeído (MDA)...

Gastric lesions associated to excessive consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol have an important role in clinical gastroenterology. The drugs with gastric antisecretory action, suchas proton pump inhibitors, represent the main option in the treatment of these pathologies. Aim: To evaluate the effect of NO donor nitrosyl-ruthenium (Rut-NO) in gastric mucosal defense in experimental models of gastric damage in mice, as wellthe involvement of soluble guanylate cyclase (sGC) and KATPchannels in this effect. Methods: Protocol 1-mice were pre-treated with Rut-NO (3mg/Kg, vo), ruthenium (2.3mg/Kg, p.o) or nitroprusside (SNP) at a dose of 10mg/kg, p.o, half an hour before administration by gavage of 50% ethanol. In another group, the animals were pre-treated with ODQ (10mg/kg, po) or glibenclamide (10mg/kg, ip) thirty minutes or 1 hour prior, respectively,the treatments mentioned above. After 1h, the animals were sacrificed and the stomachsremoved for evaluation of gastric lesions by computerized planimetry. In addition, fragments of tissue were removed for microscopic analysis and measurement of glutathione (GSH) and malondialdehyde (MDA) levels...

Efeito protetor do complexo de rutênio (II) (cis-[RuCl(qui)(bpy)2]PF6) contra a lesãogástrica induzida por naproxeno: possível papel regulador da enzima guanilato ciclase solúvel

Os AINEs são um dos principais agentes que contribuem para a patogênese da úlcera gastrintestinal e representam um importante fator etiológico por serem comum enteutilizados na prática clínica. Objetivo: Avaliar o efeito protetor do complexo de rutênio (II)(cis-[RuCl(qui)(bpy)2]PF6), contra a lesão gástrica induzida por na proxeno (NPX) em camundongos. Métodos: Foram utilizados camundongos Swiss (18-22g). Mensuramos os níveis de GMPc incubando amostras de tecidos gástricos com DMSO, com o complexo de Ru (II) e com ODQ, 30 μm de cada composto, por 5 minutos. Os grupos avaliados foram: grupo controle que recebeu CMC, grupo veículo, em que foi administrado NPX (300 mg/kg)e o que recebeu complexo de Ru (II), todos por gavagem. Os animais foram tratados com o complexo de Ru (II), nas doses de 0,3, 3 e 30 mg/kg. Após 30 minutos, seguiu-se com a indução da lesão com NPX. Seguindo o mesmo protocolo,avaliou-se o efeito do composto em estudo e de seus precursores, na dose de 3mg/kg, por gavagem.Verificou-se o efeito do composto na adesão e rolamento leucocitários; seguindo os protocolos descritos, tanto o rolamento quanto a adesão foram avaliados 3h após a indução de gastropatia e de modulação com ODQ (10 mg/kg) por gavagem. Analisou-se o efeito do complexo de Ru (II)em artérias mesentéricas de ratos wistar(200-250g) pré-contraídas com fenilefrina(PHE)(0,3 μM). Simulou-sea ligação entre o composto e a enzima GCs a partir de recursos disponíveis em site que contém banco de dados de proteínas...

NSAIDs contribute to the pathogenesis of gastrointestinal ulcers and represent an important etiologic factor because iscommonly used in clinical practice. Aim:To evaluate the protective effect of the ruthenium complex (II) (cis-[RuCl(qui)(bpy)2]PF6), against the gastric damageinduced by naproxen(NPX)in mice. Methods: Swiss mice were used (18-22g). Measure the GMPc levels incubating samples of gastric tissues with DMSO, with the complex of RU (II) and with ODQ, 30 μm of each compound, for 5 minutes. The groups evaluated were: control group that received CMC, group vehicle, in which was administered NPX (300 mg/kg) and who received complex of RU (II), all by gavage. The animals were treated with the complex of RU (II), in the doses of 0.3, 3 and 30 mg/kg. After 30 minutes, was followed with the induction of the lesion with NPX. Following the same protocol, it was evaluated the effect of the compound and its precursors, in dose of 3mg/kg, by gavage. It was verified theeffect of compound in accession and leukocyte bearing; following the protocols described, both the bearing for accession were evaluated 3h after the induction of gastropathy and modulation with ODQ (10 mg/kg) by gavage. It examined the effect of the complex of RU (II) in mesenteric arteries of Wistar rats (200-250 g) pre-contracted with phenylephrine (PHE) (0.3 μM). Simulated-If the connection between the compound and the enzyme GCs from resources available in the site that contains the database of proteins...

Antiplasmodial activity of iron(II) and ruthenium(II) organometallic complexes against Plasmodium falciparum blood parasites

This work reports the in vitro activity against Plasmodium falciparumblood forms (W2 clone, chloroquine-resistant) of tamoxifen-based compounds and their ferrocenyl (ferrocifens) and ruthenocenyl (ruthenocifens) derivatives, as well as their cytotoxicity against HepG2 human hepatoma cells. Surprisingly with these series, results indicate that the biological activity of ruthenocifens is better than that of ferrocifens and other tamoxifen-like compounds. The synthesis of a new metal-based compound is also described. It was shown, for the first time, that ruthenocifens are good antiplasmodial prototypes. Further studies will be conducted aiming at a better understanding of their mechanism of action and at obtaining new compounds with better therapeutic profile.

Fontes de obtenção de medicamentos para tratamento de hipertensão arterial no Brasil: análise da Pesquisa Nacional de Saúde, 2013 / Sources for obtaining drugs for hypertension in Brazil: results from the National Health Survey, 2013

RESUMO: Objetivo: Analisar as diferenças sociodemográficas dos indivíduos adultos hipertensos, em relação às fontes de obtenção de medicamentos para tratar hipertensão arterial no Brasil. Métodos: Análise secundária dos dados oriundos da Pesquisa Nacional de Saúde, 2013; os desfechos considerados nas análises foram representados pelas fontes de obtenção de medicamentos para tratar a hipertensão arterial. Resultados: Foram entrevistados 10.017 indivíduos. A grande maioria dos hipertensos em uso de medicamentos (74,0%) utiliza uma fonte única de obtenção de medicamentos 7,3% (IC95% 6,4 - 8,4) referiu obter todos os medicamentos por meio dos planos de saúde privados; 22,7% (IC95% 21,0 - 24,4) em farmácias do sistema público de saúde; 21,8% (IC95% 20,2 - 23,4) no Programa Farmácia Popular do Brasil; e 29,5% (IC95% 27,7 - 31,4) exclusivamente pelas farmácias comerciais. A obtenção no sistema público de saúde como fonte única diminuiu com o avanço da idade, apresentou-se menor nas pessoas de cor da pele branca, diminuiu fortemente com o aumento da escolaridade e evidenciou-se menor entre os residentes na região Norte do país; no Programa Farmácia Popular do Brasil, a fonte única de obtenção também foi menor para as pessoas com maior escolaridade. A obtenção nas farmácias comerciais esteve associada positivamente com um perfil do sexo masculino, de maior escolaridade, de idade mais elevada, tendo declarado cor da pele branca. A ocorrência de mais de uma fonte de obtenção mostrou-se associada positivamente ao aumento da idade e inversamente ao aumento da escolaridade. Conclusões: Os resultados possibilitaram identificar diferentes estratégias para obtenção de medicamentos usados no tratamento da hipertensão, de modo a explicar como são obtidos os medicamentos no país e qual o impacto das políticas públicas nesse setor.

ABSTRACT: Objective: To analyze the sociodemographic differences among adults with hypertension regarding the sources for obtaining drugs for hypertension treatment in Brazil. Methods: This is a secondary analysis of data from the National Health Survey 2013; the outcomes considered for the analysis were the sources for obtaining drugs for treating high blood pressure. Results: The great majority (74%) of patients with hypertension taking drugs use a single source for obtaining them, 7.3% (95%CI 6.4 - 8.4) reported getting all the drugs through private health plans, 22.7% (95%CI 21.0 - 24.4) by pharmacies of the public health system, 21.8% (95%CI 20.2 - 23.4) by the Popular Pharmacy Program, and about one-third (29.5%; 95%CI 27.7 - 31.4) exclusively by commercial pharmacies. Having the public health system as the single source for obtaining the drugs was found to decrease with age, was lower in white people, decreased strongly with increase in education, and was lower for residents in the North region. Exclusive obtainment through the Popular Pharmacy Program was lower for people with higher education. Obtainment in commercial pharmacies was positively associated with being male, with higher education level, being older, and having white skin color. Obtainment using more than one source was positively associated with increasing age and inversely associated with higher education levels. Conclusions: The results allowed the identification of a trajectory of patients in obtaining drugs for the treatment of hypertension, aiming at explaining how the drugs are obtained and the impact of public policies in this sector in the country.

Estudo de propriedades físico-químicas de metalofármacos de dirutênio com anti-inflamatórios não esteroides / Study of physico-chemical properties of diruthenium metallodrugs with non-steroidal anti-inflammatory drugs

Complexos de rutênio, em razão da menor toxicidade e por poderem exibir atividade citotóxica ou antimetastática, tem sido considerados como alternativas potencialmente promissoras aos complexos de platina para tratamento de câncer. Nosso grupo de pesquisa tem investigado a interação de íons metálicos com fármacos anti-inflamatórios não esteroides (FAINEs) e já obteve sucesso na preparação de metalofármacos de dirutênio(II,III)-FAINEs, os quais se mostraram promissores com relação à atividade frente a modelos de glioma. Com a finalidade de contribuir para o entendimento das propriedades físico-químicas desses complexos, o presente trabalho teve como principal objetivo analisar propriedades consideradas particularmente essenciais a um potencial candidato a fármaco, tais como, estabilidade no estado sólido, lipofilicidade, solubilidade aquosa e dissolução intrínseca. Um complexo inédito de fórmula [Ru2Cl(feno)4], em que feno = fenoprofenato, foi sintetizado e caracterizado por meio de análise elementar, espectroscopia eletrônica, espectroscopia vibracional, difratometria de raios X, análise térmica e espectrometria de massas. Os complexos já testados anteriormente para atividade biológica, [Ru2Cl(ibp)4], ibp = ibuprofenato, e [Ru2(cet)4Cl], cet = cetoprofenato, foram analisados quanto à estabilidade no estado sólido por meio da determinação isotérmica de variação de massa. As lipofilicidades desses dois complexos, juntamente com a dos fármacos de origem e a do precursor sintético [Ru2(O2CH3)4Cl], foram avaliadas pelo método shake flask, e suas solubilidade aquosas foram investigadas em presença de co-solventes alcoólicos. Investigou-se ainda a velocidade de dissolução intrínseca do [Ru2Cl(ibp)4] que se encontra em estágio avançado de estudos biológicos. Os resultados obtidos trazem novas informações sobre o comportamento térmico dos complexos e sobre suas características biofarmacêutica

Ruthenium complexes, mainly due to the lower toxicity and the cytotoxic and anti-metastatic activities, have been considered as potentially promising alternatives to platinum drugs for cancer treatment. Our research group has investigated the interactions of diruthenium metal cores with anti-inflammatory non-steroidal drugs (NSAIDs) and succeeded in preparing diruthenium(II,III)-NSAIDs metallodrugs which show promising activity against glioma models. With the aim of elucidating the physico-chemical properties of these complexes, the major objective of the present work was to investigate properties which are considered as essential for a potential candidate to drug, e.g., stability in the solid state, lipophilicity, aqueous solubility and intrinsic dissolution. A new complex of formula [Ru2Cl(feno)4], where feno = fenoprofen, was synthesized and characterized by elemental analysis, electronic spectroscopy, vibrational spectroscopy, X-rays difractommetry, thermal analysis and mass spectrometry. The complexes previously tested for biological properties, [Ru2Cl(ibp)4], ibp = ibuprofenate, and [Ru2(cet)4Cl], cet = cetoprofenate, were inv estigated for the stability in the solid state by isothermal thermogravimetry. The lipophilicity of the se complexes, as well as those of the parent drugs and of the precursor [Ru2(O2CH3)4Cl], was evaluated by the shake flask method, and their aqueous solubility in the presence of alcohol co-solvents was investigated. In addition, the intrinsic dissolution rate was determined for [Ru2Cl(ibp)4], which is undergoing advanced biological studies. The results provide important new information on the thermal behavior of the complexes and also on their biopharmaceutical propertie

Toxicology and tissue distribution of Ruthenium (II) CO-releasing molecules and its interaction with endogenous substances / 药学学报

Carbon monoxide has been proved to be an important signal molecule in body. Transition metal carbonyl compounds are solidified form of carbon monoxide. Numerous studies have shown that Ruthenium carbonyl carbon monoxide releasing molecules have a strong pharmacological activity. In this paper, five Ruthenium (II) carbonyl CORMs 1-5 were synthesized and their toxicology, tissue distribution and interaction with blood endogenous substances were investigated. The results showed CORMs' IC50 to fibroblasts are ranged from 212.9 to 2089.2 micromol x L(-1). Their oral LD50 to mouse is between 800 to 1600 mg x kg(-1). After repeated administration, CORMs 1 and CORMs 5 haven't shown an obvious influence to rats' liver and kidney function, but caused the injury to liver and kidney cells. The in vivo distribution result revealed the majority of CORMs were distributed in blood, liver and kidney, only a small part of CORMs distributed in lung, heart and spleen. They could scarcely cross the blood-brain barrier and distribute to brain. The non-CO ligands in structure have an obvious relevance to their in vivo absorption and distribution. Interestingly, CORMs could enhance the fluorescence of bovine serum albumin, and this enhancement was in direct proportion with the concentration of CORMs. Under different conditions, interaction of CORMs with glutathione got different type of products, one is Ruthenium (II) tricarbonyl complexes, and Ruthenium (II) dicarbonyl complexes.

Hydrolytic property and solution stability of NAMI derivative containing nicotinamide / 中国中药杂志

<p><b>OBJECTIVE</b>To study the influence of ligand structure on hydrolysis and solution stability of NAMI derivatives.</p><p><b>METHOD</b>NAMI type compound 1, trans- [RuCl4 (DMSO) (nica)] Na x 2DMSO (nica, nicotinamide) were prepared. Their hydrolytic mechanism, kinetics and stability were investigated by UV-Vis spectrophotometer.</p><p><b>RESULT</b>Similar to NAMI, compound 1 undergoes two well-separated steps chloro-hydrolysis (I chloro-hydrolysis and II chloro-hydrolysis) (step reaction) in pH 7.4 buffer solution; while dimethyl sulfoxide (DMSO) hydrolyze in pH 5.00 acetic buffer solution. The k(obs) and t1/2 for each hydrolytic reaction were determined.</p><p><b>CONCLUSION</b>The stability of compound 1 in acidic solution is much more stable than that of in neutral solution. Nicotinamide in place of imidazole can decrease chloro hydrolytic rate of NAMI derivatives obviously, while the influence on the DMSO hydrolytic process is not so remarkable.</p>

Effects of Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), a novel nitric oxide donor, in L-NAME-induced hypertension in rats / Efeitos do Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), um novo doador de óxido nítrico, na hipertensão induzida com L-NAME em ratos

PURPOSE: To evaluate the effect of Rut-bpy (Cis-[Ru(bpy)2(SO3)(NO)]PF 6), a novel nitric oxide donor in Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. METHODS: Twenty-four male Wistar rats were randomly assigned to four groups (n=6), named according to the treatment applied (G1-Saline, G2-Rut-bpy, G3-L-NAME and G4-L-NAME+Rut-bpy). L-NAME (30 mg/Kg) was injected intraperitoneally 30 minutes before the administration of Rut-bpy (100 mg/Kg). Mean abdominal aorta arterial blood pressure (MAP) was continuously monitored. RESULTS: Mean arterial blood pressure (MAP) in G3 rats rose progressively, reaching 147±16 mmHg compared with 100±19 mm Hg in G1 rats (p<0.05). In G4 rats, treated with L-NAME+Rut-bpy, MAP reached 149+11 mm Hg while in G2 rats, treated with Rut-bpy, MAP values were 106±11 mm Hg. In G1 rats these values decreased progressively reaching 87+14 mm Hg after 30 minutes. An important finding was the maintenance of the MAP throughout the experiment in G2 rats. CONCLUSION: Rut-bpy does not decrease the MAP in L-Name induced hypertensive rats. However, when it is used in anesthetized hypotensive rats a stable blood pressure is obtained.

OBJETIVO: Avaliar o efeitos do Rut-bpy (Cis-[Ru (bpy)2(SO3)(NO)] PF6), um novo doador de óxido nítrico, em ratos hipertensos induzidos pelo éster metílico de N-nitro-L-arginina (L-NAME). MÉTODOS: Vinte e quatro ratos Wistar machos foram distribuídos aleatoriamente em quatro grupos (n = 6), nomeados de acordo com o tratamento aplicado (G1-Salina, G2-Rut-bpy, G3-L-NAME e G4-L-NAME+Rut -bpy). L-NAME (30 mg / Kg) foi injetado por via intraperitoneal 30 minutos antes da administração de Rut-bpy (100 mg / kg). A pressão arterial média (PAM) da aorta abdominal foi monitorada continuamente. RESULTADOS: A pressão arterial média (PAM) em ratos do grupo G3 subiu progressivamente, chegando a 147 ±16 mm Hg, em comparação com 100 ±19 mm Hg em ratos do G1 (p <0,05). Em ratos G4, tratados com L-NAME + Rut-bpy, a PAM atingiu 149±11 milímetros de Hg, enquanto no G2 (ratos tratados com Rut bpy) os valores da PAM foram 106 ±11 mm Hg. No G1 esses valores decresceram progressivamente, atingindo 87±14 mm Hg após 30 minutos. Um achado importante foi a manutenção da PAM durante todo o experimento em ratos do grupo G2. CONCLUSÃO: O uso de Rut bpy não diminui a PAM em ratos hipertensos por L-NAME. No entanto, quando ele é usado em ratos anestesiados, hipotensos, uma pressão arterial estável é obtida.

New nitric oxide donors based on ruthenium complexes

Nitric oxide (NO) donors produce NO-related activity when applied to biological systems. Among its diverse functions, NO has been implicated in vascular smooth muscle relaxation. Despite the great importance of NO in biological systems, its pharmacological and physiological studies have been limited due to its high reactivity and short half-life. In this review we will focus on our recent investigations of nitrosyl ruthenium complexes as NO-delivery agents and their effects on vascular smooth muscle cell relaxation. The high affinity of ruthenium for NO is a marked feature of its chemistry. The main signaling pathway responsible for the vascular relaxation induced by NO involves the activation of soluble guanylyl-cyclase, with subsequent accumulation of cGMP and activation of cGMP-dependent protein kinase. This in turn can activate several proteins such as K+ channels as well as induce vasodilatation by a decrease in cytosolic Ca2+. Oxidative stress and associated oxidative damage are mediators of vascular damage in several cardiovascular diseases, including hypertension. The increased production of the superoxide anion (O2-) by the vascular wall has been observed in different animal models of hypertension. Vascular relaxation to the endogenous NO-related response or to NO released from NO deliverers is impaired in vessels from renal hypertensive (2K-1C) rats. A growing amount of evidence supports the possibility that increased NO inactivation by excess O2- may account for the decreased NO bioavailability and vascular dysfunction in hypertension.

Treatability of resin effluents by electrochemical oxidation using batch recirculation reactor

Electro oxidation processes are developed throughout the world for ambient temperature destruction of organic wastes. Several of these processes are based on mediated electrochemical oxidation. This article presents the experimental results of electro chemical study based on mediated electrochemical oxidation process conducted for synthetic organic ion exchange resin materials. Investigation was carried out using the traditional noble metal oxide coated anode, ruthenium oxide-titanium and the mediator used for the experiment was ferrous sulphate, with sodium chloride as supporting electrolyte. The concentration of sodium chloride was maintained at 5, 8, 12 gm/L. The experiment was carried out in batch recirculation reactor with varied current densities for various flow rates. The study highlighted that in batch reactor set up the best effect of total organic content reduction was found to occur at 3.75 A/dm[2] with flow rate of 20 L/h. The simulated studies were carried out for different volumes of effluent and current densities. A graphical analysis was made between the experimental and simulated values and it was found that both the values are very close

The Effect of Prolonged Water Exposure on the Epidermal Permeability Barrier / 대한피부과학회지

BACKGROUND: Water exposure is considered an important causative factor of irritant contact dermatitis. It is also known that water exposure can disrupt the stratum corneum (SC). However, there are only a few morphologic studies on the effect of water contact on the skin. OBJECTIVE: The aim of our study was to investigate the effects of prolonged water exposure on the permeability barrier and the ultrastructure of the SC intercellular lipids. METHODS: After prolonged water exposure of hairless mouse skin in vivo for 24, 36, 48, and 72 hrs respectively, the permeability barrier function was assessed by transepidermal water loss (TEWL) measurement, and the ultrastructure of SC by electron microscopy using osmium tetraoxide and ruthenium tetraoxide postfixation and calcium ion capture cytochemistry. Additionally, the lipid composition was evaluated using confocal microscopy with nile red stain and the integrity of the SC assessed using a lanthanum tracer. RESULTS: After prolonged water exposure, water caused a significant increase in TEWL with disappearance of the calcium gradient, but this did not significantly influence the recovery rate of TEWL. The intercellular lipids were disrupted, and multiple lacunae containing abnormal delaminated materials within the intercellular spaces were observed. Lanthanum tracer penetrated into the intercellular space of the SC. There was a progressive decrease in nile red staining with neutral lipid content. With increasing exposure to water, these results were more evident. CONCLUSION: Our results provide a better understanding of the disruptive effect of prolonged water exposure on barrier lipids, the penetration-enhancing effect of water and the increased susceptibility to irritants, with regard to duration of water exposure.

The Effect of High Dose Systemic Steroid and its Long-term Usage on the Skin Barrier of Hairless Mice / 대한피부과학회지

BACKGROUND: Prolonged exposure of topical and systemic corticosteroid to skin can result in well-recognized cutaneous abnormalities including cutaneous atrophy, easy bruisibility, increased skin fragility, and increased risk of infection. Skin barrier impairment is also reported as a steroid-induced side effect. A major function of the skin is the formation of a permeability barrier between the external milieu and the organism. Recent studies have shown that chronic corticosteroid negatively impacts epidermal barrier function. As well as this topical corticosteroid not only has antiproliferative actions but also inhibits the differentiation of the epidermis, resulting in structural defects in the epidermis. OBJECT: We wanted to determine whether high dose systemic steroid injection would display adverse effects, specifically on; epidermal functions, permeability barrier homeostasis and stratum corneum integrity and cohesion. The basis for such changes was also to be determined. MATERIAL AND METHODS: Systemic steroid was administered by injecting each hairless mouse, 8-10 week of age, intraperitoneally with 0.3 mg triamcinolone acetonide, two times per week for five weeks. For the controlled hairless mice, 0.9% normal saline was administered by the same method of injection. Every week, transepidermal water loss (TEWL) was checked and skin biopsies were taken. Skin specimens were prepared for electron microscopy using both 0.25% ruthenium tetroxide and 4% osmium tetroxide postfixation. For light microscopy staining hematoxylin-eosin and ion capture cytochemistry was used. RESULTS: The results were as follows; 1. From about 1 week onwards, high dose systemic steroid usage produced visible cutaneous changes and significantly increased the TEWL in the group of 0.3 mg triamcinolone acetate injected hairless mice compared with the control. 2. Light microscopic observations of the steroid-injected hairless mice showed gradual thinning of the epidermis from about 2 weeks onwards, compared with the control. Loss of stratum corneum was also observed in the steroid injected hairless mice. 3. The ruthenium tetroxide staining of high dose systemic steroid treated specimens revealed that the lipid bilayer was impaired and fragmented from about 3 weeks. Intercellular spaces were widened and the lipid bilayer either disappeared or showed damage when compared with the control. 4. From about 3weeks onwards. electron microscopic studies revealed, not only a marked decrease in the number of lamellar bodies, but also an abnormal transformation of lamellar bodies in the steroid injected hairless mice compared with the control. 5. Throughout the five weeks, the calcium gradient gradually disappeared in the 0.3mg triamcinolone injected hairless mice compared with the control. Consequently, high dose systemic steroid use results in barrier dysfunction and morphological abnormalities.

Tratamiento de los melanomas malignos uveales posteriores con placas espiesclerales radioactivas cargadas con rutenio: experiencia en Venezuela / Radiotherapeutic treatment in posterior uveaol malignant melanoma using ruthenium applicators: Venezuelan experience

Se presentan los resultados del tratamiento con placas epiesclerales radioactivas cargadas con ruthenio106 (106Ru/106Rh) a 11 pacientes portadores de melanoma maligno uveal posterior. Se aplicó una dosis calculada de acuerdo a la altura del tumor. El grado de regresión de la lesión se correlacionó de una forma estadísticamente significativa con la dosis al ápex del tumor. Se evitó la enucleación en el 90,9 por ciento de los pacientes. Nuestros resultados demuestran que el tratamiento con placas epiesclerales radioactivas cargadas con Ruthenio106 es un método efectivo en el control del melanoma maligno uveal posterior

The Effect of Barrier Recovery using Topical Steroid and Systemic Steroid after Acetone-application in Hairless Mice / 대한피부과학회지

BACKGROUND: Acetone disrupts the cutaneous permeability barrier through the removal of stratum corneum lipids. This pertubation of barrier integrity stimulates a variety of homeostatic repair that ultimately results in the normalization of barrier function. OBJECT: To measure the effect of steroid on the barrier recovery of acetone applied skin. MATERIAL AND METHODS: The flank skin of 8~10 week old hairless mice was treated with acetone and then topical and systemic steroids were applied. Transepidermal water loss(TEWL) was checked after 0, 3, 6, 12 and 24 hours. Electron and light microscopic examination and ion capture cytochemistry were performed after 3, 6, 12 and 24 hours after systemic and topical steroids had been applied. RESULTS: The results were as follows ; 1) During 3~6 hours after experiment, the recovery rate of TEWL was most prominent in the group of acetone applied animal than other groups. 2) After 12 hours after acetone applied, formation of new stratum corneum was found in the groups of acetone applied or acetone applied skin with topical steroid application. But loss of stratum corneum was observed in the groups of high or low dose steroid injection. 3) Ruthenium tetroxide staining of acetone alone or topical steroid treated specimens after 12 hours experiment revealed that the lipid bilayer was partly impaired and fragmented. Intercellular spaces were widening and the lipid bilayer disappeared or was damaged in the groups of high or low dose steroid injection. 4) Six hours after acetone application, pattern of calcium distribution had been partially reestabilished in the group of acetone alone or topical steroid treated animals. But calcium content was still sparse and decreased from the stratum granulosum to basale in the groups of high or low dose steroid injection. CONCLUSION: In summary the present study demonstrates that steroid treatment acutely delays recovery rate of TEWL, inhibits normalization of calcium gradient or epidermal lipid synthesis that leads to abnormalities in permeability barrier homeostasis.

Comparação da eficiência dos eletrodos de carbono, titânio e TiRuO2 na desinfecção de águas / Comparision of eficiency of the carbon, titanium and TiRuO2 electrodes in water desifection

A desinfecção de águas de abastecimento é de vital importância para a saúde pública. Porém processos convencionais de desinfecção, por requererem a dição de substâncias à água, podem gerar compostos tóxicos como é o caso dos trialometanos formados quando o cloro entra em contato com substãncias orgãnicas presente na água. O tratamento eletrolítico pode ser um substituto para o processo de cloração com a vantagem de não requerer a adição de nenhuma susbstância ao processo. O tratamento eletrolítico é facilmente automatizável, versátil, requer pouco espaço para sua implantação e tem baixo custo operacional.O presente trabalho visou comparar o efeito do tratamento eletrolítico com eletrodos de carbono, titânio e titânio recoberto por óxido de titânio e óxido de rutênio(TiRuO2) na viabilidade do Bacillus subtilis. Suspensões de B. subtilis foram determinados: o número de células viáveis, o pH e a temperatura. Os resultados permitiram concluir que o eletrodo de carbono reduz a viabilidade do bacilo em 99,999 por cento em 30 min de eletrólise, ao passo que os eletrodos de titânio e TiRuO2 não possibilitaram uma redução significativa até 45 min depois do tratamento

The Effect of Bentonite and Glycolic Acid on the Stratum corneum

BACKGROUND: Bentonite clay, which is a major component of mud pack, has been used for various purposes in cosmetics. Glycolic acid is known to be effective in the treatment of acne. Al-though those products are used widely, information on the mode of action and effects on the skin are little and controversial till now. OBJECTIVE: To investigate whether bentonite alone, or bentonite with glycolic acid in mixed formulation affect the stratum corneum leading to alteration on cutaneous barrier function and whether those products alter the lipid lamellae and desmosomes of corneocytes. MATERIALS AND METHODS: Mud pack-type ointment of bentonite, bentonite and 5% glycolic acid formulation, bentonite and 10% glycolic acid formulation were applied on the volar fore-arm of the five healthy men and flank skin of five 6-8 week old hairless mice. Transepidermal water loss and capacitance were measured. Electron microscopic examination after ruthenium tetroxide postfixation was performed on the flank skin of the mice. RESULTS: Transepidermal water loss(TEWL) increased immediately and normalized 4 to 6 hours later after removal of vapor permeable membrane in both mouse and human. Capacitance did not show any evidence of change in the water content of the stratum corneum. Electron microscopic examination revealed that lipid lamellae and desmosome of corneocytes were not de-graded, but lamellar body secretion and partially electron-lucent material was-increased in 10% glycolic acid and bentonite mixture-treated area. CONCLUSION: Barrier function of stratum corneum is not disturbed by bentonite and glycolic acid formulations at the concentration used. Barrier structures are not disrupted, but lamellar body secretion and partially electron-lucent material was increased by bentonite and glycolic acid formulations at higher concentration.

Histochemical Electron Microscopic Findings of Traumatic Cataract in Rabbits by Ruthenium Red

Glycosaminoglycans (GAGs)are essential components of the extracellular matrix of various tissues.They have been known to regulate cellular and extracellular environments for cell survival and differentiation in various physiologic and pathologic conditions.The present study was conducted to identify the distribution of GAGs in subepithelial cortical fibers of normal and traumatic cataractous lens of rabbits. Traumatic cataract was made by piercing the anterior lens capsule with 25-gauge sharp needle and the rabbits were killed at different time intervals (1, 2, 3 and 4 weeks).From the enucleated eyes subepithelial lens cortical fibers were obtained.A normal rabbit lens was used for the control. The specimens were stained with 0.05%ruthenium red (RR)and processed for histochemical electron microscopy. RR reactive materials were identified as fine granular or filamentous structures.In normal rabbit lens they were present mainly along the surface of lens epithelial cells, the surface of the subepithelial cortical fibers. In cataractous rabbits lens, strong RR positive reactions were observed along the surface of the lens epithelial cells and subepthelial cortical fibers as well as at the intercortical fiber spaces and even within its micro-organelles. This investigation resulted in an illustration of the ultrastructural distribution of GAGs in normal and traumatic cataractous lens of rabbit.this may suggest altered GAG distribution may closely related to the formation of lens opacity.