RESUMO
Background: In Italy, since the beginning of the COVID-19 pandemic, patients testing positive for SARS-CoV-2 through nasopharyngeal swab have reported taste and smell alterations. As these symptoms are quite uncommon in other respiratory infections, their specificity and prevalence are useful features for the differential diagnosis of COVID-19. The objective was to describe taste and smell alterations in patients diagnosed with SARS-CoV-2 infection and to define the onset of those disorders during the clinical course of the disease. Study design: Cross-sectional study. Methods: This study was conducted on adult patients testing positive for SARS-CoV-2 infection through nasopharyngeal swab at a Local Healthcare Trust in Northern Italy between April 27th and May 27th, 2020. In order to investigate the clinical course, the onset of the first symptoms, smell and/or taste alterations, a phone-based questionnaire was administered during the programming of the second nasopharyngeal swab. Results: We recruited 168 patients; the mean age was 52 years old, and 94 (56.0%) were female. Among the 135 symptomatic patients, 87 (64.4%) reported taste and smell alterations. Patients with a mild clinical course showed the highest prevalence for taste and smell disorders (76.6%), which were also associated with a more benign clinical course of the disease (P = 0.0166). Furthermore, in 33 (37.9%) of these patients, changes in smell and taste perception appeared before the acute phase of the disease. Among the 14 patients with a severe clinical course of SARS-CoV-2 infection, 8 reported a variation of taste and smell perception before the hospitalization, with a median of 4 days (IQR 2-7). Conclusions: Smell and taste disorders can be listed among the first symptoms of SARS-CoV-2 infection and may anticipate the acute phase of the disease. Noteworthy, they seem to be associated with a more benign clinical course.
Assuntos
COVID-19 , Transtornos do Olfato , Estudos Transversais , Atenção à Saúde , Feminino , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Transtornos do Olfato/diagnóstico , Transtornos do Olfato/epidemiologia , Transtornos do Olfato/etiologia , Pandemias , SARS-CoV-2 , PaladarRESUMO
Abstract: In line with previous case-reports, the study conducted by Hoom Choi ascertained the effectiveness of the HPV vaccine as a promising approach in the therapeutic management of ano-genital warts. The uncertain length of time and the varying effectiveness of traditional treatments encourage a reduction in the use of them and the development of a therapeutic use of HPV-vaccination. While the efficacy, safety profile and effects of the HPV vaccination in preventing ano-genital warts is well-know, therapeutic HPV vaccination has not been evaluated in a Randomized Prospective Trial, to date, and has not received a formal approval and an off-label indication for the treatment of those lesions. For these reasons, RCTs or cohort studies are warranted.
Assuntos
Alphapapillomavirus , Condiloma Acuminado , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Condiloma Acuminado/prevenção & controle , Humanos , Infecções por Papillomavirus/prevenção & controle , Estudos Prospectivos , Vacinas SintéticasRESUMO
Over the past decade, an increasing prevalence of infections caused by non-fermenting Gram-negative bacteria has been reported in many countries. Among these bacteria, Pseudomonas aeruginosa and Acinetobacter baumannii have been associated with high mortality and treatment failures. Treatment options for multidrug-resistant P. aeruginosa and A. baumannii infections are limited to carbapenems in most cases. The mechanisms of carbapenem resistance have been identified in P. aeruginosa and other Gram-negative non-fermenters, including enzyme production, overexpression of efflux pumps, porin deficiencies, and target- site alterations. This article reviews the in vitro activity of doripenem and compares it with that of imipenem and meropenem against a large collection of non-fermenting Gram-negative bacilli, obtained in worldwide surveillance studies between 2000 and 2010. A detailed examination of the available data demonstrate that doripenem has more potent in vitro antibacterial activity against P. aeruginosa and Acinetobacter species compared to other carbapenems. Furthermore, doripenem has a limited ability to select for carbapenem-resistant mutants in vitro.
Assuntos
Antibacterianos/farmacologia , Bacillus/efeitos dos fármacos , Carbapenêmicos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Doripenem , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade MicrobianaRESUMO
This article summarizes the recommendations drawn up by the Italian Society of Chemotherapy regarding the proper use of antimicrobial agents for infectious diseases.
Assuntos
Antibacterianos/uso terapêutico , Infecções/tratamento farmacológico , Antibacterianos/normas , Análise Custo-Benefício , Farmacorresistência Bacteriana , Resistência a Múltiplos Medicamentos , Humanos , Itália , Sociedades CientíficasRESUMO
The incidence of invasive fungal infections (IFIs) caused by both common and uncommon opportunistic fungi is increasing along with emerging fungal resistance. Since traditional agents (amphotericin B, fluconazole, itraconazole) are limited by an inadequate spectrum of activity, drug resistance or toxicity, there is a great interest in the development of new antifungal agents for treatment of IFIs in high-risk populations. In recent years a number of systemic antifungal drugs have become available and options for treatment of IFIs have expanded. A new generation of triazole agents (voriconazole, posaconazole, isavuconazole, ravuconazole and albaconazole), with a broad spectrum of activity and sufficient improvements in potency to overcome resistance have emerged and represent an alternative to conventional antifungals for the prevention and treatment of IFIs. This article focuses on the microbiology, pharmacology, clinical efficacy and safety of the new antifungal triazole generation.
Assuntos
Antifúngicos/farmacologia , Micoses/tratamento farmacológico , Triazóis/farmacologia , Farmacorresistência Fúngica/fisiologia , HumanosRESUMO
A series of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (CFMs), previously described as noncompetitive AMPA-type glutamate receptor antagonists, more potent than GYKI 52466. New synthesized compounds proved to be able to protect against seizures induced by means of auditory stimulation in DBA/2 mice and compound 8f the most active of the series showed anticonvulsant properties comparable to GYKI 52466.
Assuntos
Anticonvulsivantes/síntese química , Benzodiazepinas/síntese química , Receptores de AMPA/antagonistas & inibidores , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Benzodiazepinas/farmacologia , Avaliação Pré-Clínica de Medicamentos , Camundongos , Convulsões/prevenção & controle , Relação Estrutura-AtividadeRESUMO
DNA single-strand breakage and activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Recently, we proposed that during an acute model (pleurisy), cellular injury is mediated by peroxynitrite formation and consequent PARS activation. Here, we investigated whether in vivo melatonin treatment inhibits cellular injury induced by peroxynitrite production and PARS activation in macrophages collected from rats subjected to carrageenan-induced pleurisy. Macrophages harvested from the pleural cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123. Furthermore, carrageenan-induced pleurisy caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS, and reduction of cellular levels of NAD+. In vivo treatment with melatonin [12.5 or 25 or 50 mg/kg, intraperitoneally (i.p.), 30 min before carrageenan] significantly reduced peroxynitrite formation in a dose-dependent manner and prevented the appearance of DNA damage, decrease in mitochondrial respiration, loss of cellular levels of NAD+, and PARS activation. Our study supports the view that the antioxidant and anti-inflammatory effect of melatonin is also correlated with the inhibition of peroxynitrite production and PARS activation. In conclusion, melatonin may be a novel pharmacological approach to prevent cell injury in acute inflammation.
Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Melatonina/farmacologia , Ácido Peroxinitroso/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Doença Aguda , Animais , Carragenina/toxicidade , Dano ao DNA , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , NAD/metabolismo , Pleurisia/induzido quimicamente , Pleurisia/tratamento farmacológico , Pleurisia/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Studies were performed on the mechanisms of the protective effects of free-radical scavengers against gentamicin-mediated nephropathy. Administration of gentamicin, 100 mg/kg s.c., for 5 days to rats induced marked renal failure, characterised by a significantly decreased creatinine clearance and increased blood creatinine levels, fractional excretion of sodium Na(+), lithium Li(+), urine gamma glutamyl transferase and daily urine volume. A significant increase in kidney myeloperoxidase activity and lipid peroxidation was observed in gentamicin-treated rats. Immunohistochemical localisation demonstrated nitrotyrosine formation and poly(ADP-ribose)synthase activation in the proximal tubule from gentamicin-treated rats. Renal histology examination confirmed the tubular necrosis. N-acetylcysteine (10 mg/kg i.p. for 5 days) caused normalisation of the above biochemical parameters. In addition, N-acetylcysteine treatment significantly prevents the gentamicin-induced tubular necrosis. These results suggest that (1) N-acetylcysteine has protective effects on gentamicin-mediated nephropathy, and (2) the mechanisms of the protective effects can be, at least in part, related to interference with peroxynitrite-related pathways.
Assuntos
Acetilcisteína/farmacologia , Sequestradores de Radicais Livres/farmacologia , Gentamicinas/administração & dosagem , Insuficiência Renal/prevenção & controle , Tirosina/análogos & derivados , Animais , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Malondialdeído/metabolismo , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/fisiopatologia , Tirosina/efeitos dos fármacos , Tirosina/metabolismoRESUMO
The minimum inhibitory concentration (MIC) and postantibiotic effect (PAE) of marbofloxacin, enrofloxacin, difloxacin and ciprofloxacin were evaluated in vitro against 43 feline-source Bordetella bronchiseptica strains. All strains tested were susceptible to marbofloxacin and enrofloxacin (MIC90 0.5mg/l), while 93 and 84% of the strains were susceptible, respectively, to ciprofloxacin and difloxacin with MIC(90) values of, respectively, 1 and 8mg/l. The PAE was studied in 10 strains by exposure of bacteria to marbofloxacin, enrofloxacin, difloxacin and ciprofloxacin at 5 and 10 times minimum inhibitory concentration (MIC) for 1 and 2h. Regrowth was determined by measuring the viable counts after drug removal by a 10(3) dilution procedure. PAEs increased as a function of concentration and exposure time. The mean duration of PAEs varied between 1.1 and 8.2h, showing the following order: marbofloxacin>enrofloxacin>ciprofloxacin>difloxacin. These data are encouraging since fluoroquinolones have a possible role in the clinical treatment of B. bronchiseptica infections, and the strong PAE caused by quinolones may contribute to the in vivo efficacy of these drugs.
Assuntos
Anti-Infecciosos/farmacologia , Bordetella bronchiseptica/efeitos dos fármacos , Ciprofloxacina/análogos & derivados , Ciprofloxacina/farmacologia , Fluoroquinolonas , Quinolonas/farmacologia , Animais , Anti-Infecciosos/uso terapêutico , Infecções por Bordetella/tratamento farmacológico , Infecções por Bordetella/microbiologia , Infecções por Bordetella/veterinária , Doenças do Gato/tratamento farmacológico , Doenças do Gato/microbiologia , Gatos , Ciprofloxacina/uso terapêutico , Enrofloxacina , Feminino , Masculino , Testes de Sensibilidade Microbiana/veterinária , Quinolonas/uso terapêuticoRESUMO
Oxidative stress has been suggested as a potential mechanism in the pathogenesis of lung inflammation. The pharmacological profile of n-acetylcysteine (NAC), a free radical scavenger, was evaluated in an experimental model of lung injury (carrageenan-induced pleurisy). Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity that contained many neutrophils (PMNs), an infiltration of PMNs in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate, tumor necrosis factor alpha, and interleukin 1beta. All parameters of inflammation were attenuated by NAC treatment. Furthermore, carrageenan induced an up-regulation of the adhesion molecules ICAM-1 and P-selectin, as well as nitrotyrosine and poly (ADP-ribose) synthetase (PARS), as determined by immunohistochemical analysis of lung tissues. The degree of staining for the ICAM-1, P-selectin, nitrotyrosine, and PARS was reduced by NAC. In vivo NAC treatment significantly reduced peroxynitrite formation as measured by the oxidation of the fluorescent dihydrorhodamine-123, prevented the appearance of DNA damage, an decrease in mitochondrial respiration, and partially restored the cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. A significant alteration in the morphology of red blood cells was observed 24 h after carrageenan administration. NAC treatment has the ability to significantly diminish the red blood cell alteration. Our results clearly demonstrate that NAC treatment exerts a protective effect and clearly indicate that NAC offers a novel therapeutic approach for the management of lung injury where radicals have been postulated to play a role.
Assuntos
Acetilcisteína/farmacologia , Sequestradores de Radicais Livres/farmacologia , Proteínas I-kappa B , Pulmão/fisiopatologia , Pleurisia/tratamento farmacológico , Tirosina/análogos & derivados , Animais , Western Blotting , Carragenina/toxicidade , Dano ao DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Eritrócitos/efeitos dos fármacos , Eritrócitos/ultraestrutura , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Malondialdeído/metabolismo , Inibidor de NF-kappaB alfa , Neutrófilos/fisiologia , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Selectina-P/metabolismo , Peroxidase/metabolismo , Pleurisia/induzido quimicamente , Pleurisia/patologia , Pleurisia/fisiopatologia , Poli(ADP-Ribose) Polimerases/metabolismo , Ratos , Ratos Sprague-Dawley , Tirosina/metabolismoRESUMO
Retigabine (D-2319, 0.5-20 mg/kg i.p.) antagonised dose dependently audiogenic seizures in DBA/2 mice. Retigabine at 0.5 mg/kg i.p., a dose that per se did not affect the occurrence of audiogenic seizures significantly, potentiated the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice. The degree of additivity for the effect induced by retigabine was greatest for diazepam, phenobarbital, phenytoin and valproate, less for carbamazepine and lamotrigine and least for felbamate. The increase in anticonvulsant activity was usually associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment (drugs plus retigabine), was more favourable than the same drug plus vehicle. Since retigabine had no significant influence on the total and free plasma levels of the anticonvulsant drugs, pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. However, the possibility that retigabine modifies the clearance of the anticonvulsant drugs from the brain cannot be excluded. Retigabine had no significant effect on the hypothermic effects of the anticonvulsants tested. In conclusion, retigabine showed an additive effect when administered in combination with classical anticonvulsants, most notably diazepam, phenobarbital, phenytoin and valproate.
Assuntos
Anticonvulsivantes/farmacologia , Carbamatos/farmacologia , Fenilenodiaminas/farmacologia , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/toxicidade , Temperatura Corporal/efeitos dos fármacos , Carbamatos/toxicidade , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Atividade Motora/efeitos dos fármacos , Fenilenodiaminas/toxicidade , Convulsões/sangueRESUMO
The synthesis and anticonvulsant activity of 1-aryl-7,8-methylenedioxy-1,2,3,5-tetrahydro-4H-2,3-benzodiazepin-4-(thi)ones (4a-d) and their 3-N-alkylcarbamoyl derivatives (4e-h) are reported. The new compounds possess marked anticonvulsant properties, comparable to those of the dehydro analogues 3 and higher than that of GYKI 52466 (1). Noteworthy, compound 4c shows a longer-lasting anticonvulsant activity. Electrophysiological experiments show that derivative 4c is less effective than 1 and 3c to reduce the KA-evoked currents in cerebellar granule neurons.
Assuntos
Anticonvulsivantes/síntese química , Benzodiazepinas , Receptores de AMPA/antagonistas & inibidores , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Camundongos , Camundongos Endogâmicos DBARESUMO
This review focuses on the most recent research findings on adverse reactions caused by quinolone antibiotics. Reactions of the gastrointestinal tract, the central nervous system (CNS) and the skin are the most often observed adverse effects. Occasionally major events such as phototoxicity, cardiotoxicity, arthropathy and tendinitis occur, leading to significant tolerability problems. Over the years, several structure-activity and side-effect relationships have been developed, in an effort to improve overall antimicrobial efficacy while reducing undesirable side-effects. In this article we review the toxicity of fluoroquinolones, including the newer derivatives such levofloxacin, sparfloxacin, graepafloxacin and the 7-azabicyclo derivatives, trovafloxacin and moxifloxacin. A special attention is given to new data on mechanistic aspects, particularly those regarding CNS effects. In recent years extensive in vivo and in vitro experiments have been performed in an attempt to explain the neurotoxic effects of quinolones sometimes observed under therapeutic conditions. However, the molecular target or receptor for such effects is still not exactly known. Several mechanisms are thought to be responsible. The involvement of gamma-aminobutyric acid (GABA) and excitatory amino acid (EAA) neurotransmission and the kinetics of quinolones distribution in brain tissue are discussed. In addition, quinolones may interact with other drugs--theophylline and nonsteroidal antiflammatory drugs (NSAID(s))--in producing CNS effects This article provides information about the different mechanisms responsible of quinolones interaction with NSAID(s), methylxanthines, warfarin and antiacids.
Assuntos
Anti-Infecciosos/efeitos adversos , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Digestório/efeitos dos fármacos , Interações Medicamentosas , Fluoroquinolonas , Humanos , Pele/efeitos dos fármacos , Relação Estrutura-Atividade , Xantinas/farmacologiaRESUMO
OBJECTIVE: To investigate the effects of M40403, a synthetic mimetic of superoxide dismutase (SOD), on collagen-induced arthritis (CIA) in rats. METHODS: CIA was elicited in Lewis rats by intradermal injection of 100 microl of an emulsion of bovine type II collagen (CII) in Freund's incomplete adjuvant at the base of the tail. A second injection was given on day 21. RESULTS: Immunization induced an erosive arthritis of the hind paws. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws by days 24-26 after the first injection, with a 100% incidence by days 27. Severity progressed over a 35-day period. Radiography revealed soft tissue swelling and focal resorption of bone, together with osteophyte formation in the tibiotarsal joint. Histopathologic features included erosion of the articular cartilage at the joint margins and subchondral bone resorption associated with bone-derived multinucleated cell-containing granulomatous lesions. Treatment with M40403 (2-10 mg/kg/day) starting at the onset of arthritis (day 25) ameliorated the clinical signs on days 26-35 and improved the histologic findings in the joint and paw. Immunohistochemical analysis for nitrotyrosine (a marker of peroxynitrite formation) and poly(ADP-ribose) polymerase (PARP; a nuclear enzyme activated by DNA single-strand damage) revealed positive staining in the inflamed joints of CII-treated rats, suggestive of the formation of peroxynitrite and DNA damage, both of which were markedly reduced by M40403 treatment. Radiographic evidence of protection from bone resorption, osteophyte formation, and soft tissue swelling was apparent in the tibiotarsal joints of M40403-treated rats. Arthritic rats treated with M40403 gained weight at the same rate and to the same extent as normal, nonarthritic rats. CONCLUSION: This study shows that a low molecular weight mimetic of SOD, M40403, attenuates the degree of chronic inflammation, tissue damage, and bone damage associated with CIA in the rat, and supports the possible use of SOD mimetics as therapeutic agents for the management of chronic diseases such as rheumatoid arthritis.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Compostos Organometálicos/farmacologia , Tirosina/análogos & derivados , Animais , Anti-Inflamatórios não Esteroides/química , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrografia , Colágeno , Colágeno Tipo XI , Modelos Animais de Doenças , Interleucina-1/biossíntese , Interleucina-1/sangue , Articulações/metabolismo , Articulações/patologia , Masculino , Manganês , Peso Molecular , Compostos Organometálicos/química , Proteínas/metabolismo , Ratos , Ratos Endogâmicos Lew , Superóxido Dismutase/química , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/metabolismo , Aumento de Peso/efeitos dos fármacosRESUMO
A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13).
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Pirrolidinonas/síntese química , Pirrolidinonas/uso terapêutico , Convulsões/tratamento farmacológico , Estimulação Acústica , Animais , Anticonvulsivantes/química , Benzimidazóis/química , Avaliação Pré-Clínica de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos DBA , Pirrolidinonas/química , Relação Estrutura-AtividadeRESUMO
A series of 2,3-benzodiazepine derivatives has been previously described as noncompetitive AMPA-type glutamate receptor antagonists potentially useful for treatment of epilepsy. To further explore the structure-activity relationships of AMPA antagonists, a series of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) was synthesized starting from the corresponding bicyclic 1-aryl-3, 5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. In addition, they antagonize the AMPA-induced seizures, and their anticonvulsant activity is reversed by pretreatment with aniracetam, thus suggesting the involvement of AMPA receptors. The pharmacological studies revealed that the 11H-[1,2,4]triazolo[4, 5-c][2,3]benzodiazepin-3(2H)-ones (6) herein reported show anticonvulsant activity comparable to that of their bicyclic precursors. Furthermore, an HPLC study put in evidence that these tricyclic derivatives 6 were converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.
Assuntos
Anticonvulsivantes/síntese química , Benzodiazepinas/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de AMPA/antagonistas & inibidores , Estimulação Acústica , Regulação Alostérica , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacocinética , Benzodiazepinas/farmacologia , Cromatografia Líquida de Alta Pressão , Eletrochoque , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Atividade Motora/efeitos dos fármacos , Pentilenotetrazol , Pirrolidinonas/uso terapêutico , Convulsões/tratamento farmacológico , Convulsões/etiologia , Relação Estrutura-Atividade , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol PropiônicoRESUMO
1. The aim of the present study was to investigate the effects of cloricromene, a coumarine derivative, in rats subjected to collagen-induced arthritis. 2. Collagen-induced arthritis (CIA) was induced in Lewis rats by an intradermal injection of 100 microl of the emulsion (containing 100 microg of bovine type II collagen) (CII) and complete Freund's adjuvant (CFA) at the base of the tail. On day 21, a second injection of CII in CFA was administered. 3. Lewis rats developed an erosive hind paw arthritis when immunized with CII in CFA. Macroscopic clinical evidence of CIA first appeared as peri-articular erythema and oedema in the hind paws. The incidence of CIA was 100% by day 27 in the CII challenged rats and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone together with osteophyte formation in the tibiotarsal joint and soft tissue swelling. 4. The histopathology of CIA included erosion of the cartilage at the joint margins. Treatment of rats with cloricromene (10 mg kg(-1) i.p. daily) starting at the onset of arthritis (day 23), delayed the development of the clinical signs at days 24 - 35 and improved histological status in the knee and paw. 5. Immunohistochemical analysis for iNOS, COX-2, nitrotyrosine and for poly (ADP-ribose) synthetase (PARS) revealed a positive staining in inflamed joints from collagen-treated rats. The degree of staining for iNOS, COX-2, nitrotyrosine and PARS were markedly reduced in tissue sections obtained from collagen-treated rats, which had received cloricromene. 6. Radiographic signs of protection against bone resorption and osteophyte formation were present in the joints of cloricromene-treated rat. 7. This study provides the first evidence that cloricromene, a coumarine derivative, attenuates the degree of chronic inflammation and tissue damage associated with collagen-induced arthritis in the rat.
Assuntos
Artrite/prevenção & controle , Cromonar/farmacologia , Colágeno/administração & dosagem , Tirosina/análogos & derivados , Animais , Artrite/induzido quimicamente , Artrite/patologia , Peso Corporal/efeitos dos fármacos , Bovinos , Cromonar/análogos & derivados , Ciclo-Oxigenase 2 , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Membro Posterior/diagnóstico por imagem , Membro Posterior/patologia , Interleucina-1/metabolismo , Isoenzimas/efeitos dos fármacos , Isoenzimas/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/sangue , Poli(ADP-Ribose) Polimerases/metabolismo , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismo , Radiografia , Ratos , Ratos Endogâmicos Lew , Índice de Gravidade de Doença , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismo , Tirosina/efeitos dos fármacos , Tirosina/metabolismoRESUMO
In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed positive staining in lungs from carrageenan-treated iNOS-WT mice. Lung tissue sections from carrageenan-treated iNOS-WT mice showed positive staining for poly adenosine diphosphate (ADP)-ribose synthetase that was mainly localized in alveolar macrophages and in airway epithelial cells. The intensity and degree of staining for nitrotyrosine and poly-ADP-ribose synthetase were markedly reduced in tissue sections from carrageenan-treated iNOS-KO mice. The inflamed lungs of iNOS-KO mice also showed an improved histologic status. Furthermore, a significant reduction in the suppression of energy status, in DNA strand breakage, and in decreased cellular levels of nicotinamide adenine dinucleotide (NAD(+)) was observed ex vivo in macrophages harvested from the pleural cavity of iNOS-KO mice subjected to carrageenan-induced pleurisy. Taken together, our results clearly show that iNOS plays an important role in the acute inflammatory response.
Assuntos
Pulmão/patologia , Óxido Nítrico Sintase/fisiologia , Pleurisia/patologia , Tirosina/análogos & derivados , Animais , Carragenina , Células Cultivadas , Dano ao DNA , Ativação Enzimática , Exsudatos e Transudatos/química , Exsudatos e Transudatos/citologia , Imuno-Histoquímica , Peroxidação de Lipídeos , Pulmão/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Knockout , Neutrófilos/patologia , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Peroxidase/metabolismo , Pleura/patologia , Pleurisia/metabolismo , Pleurisia/fisiopatologia , Poli(ADP-Ribose) Polimerases/metabolismo , Tirosina/metabolismoRESUMO
The anticonvulsant activity of riluzole against sound-induced seizures was studied in the DBA/2 mouse model. Riluzole (0.1-4 mg kg(-1), intraperitoneal (i.p.)) produced dose-dependent effects with ED(50) values for the suppression of tonic, clonic and wild running phases of 0.72, 1.38 and 2.71 mg kg(-1), respectively. Riluzole also protected DBA/2 mice from seizures induced by an intracerebroventricular (i.c.v.) injection of N-methyl-D-aspartate (NMDA) with ED(50) values of 3.03 and 5.0 mg kg(-1) for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of riluzole to the right (ED(50)=6.53 against tonus and 9.34 mg kg(-1) vs. clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED(50) of riluzole against the tonic component of audiogenic seizures from 0.72 to 1.97, and that against clonus from 1.38 to 2.77 mg kg(-1). Riluzole was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/kainate receptor agonist (ED(50)=1.80 and 3.35 mg kg(-1), against tonus and clonus, respectively). Pretreatment with aniracetam, a positive allosteric modulator of AMPA/kainate receptors, shifted the dose-response curve of riluzole to the right (ED(50)=1.78 against tonus and 2.58 mg kg(-1) vs. clonus). The data indicate that riluzole is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of riluzole depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.
Assuntos
Anticonvulsivantes/farmacologia , Receptores de AMPA/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Riluzol/farmacologia , Estimulação Acústica , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Receptores de Glicina/efeitos dos fármacos , Receptores de Glicina/metabolismo , Convulsões/prevenção & controleRESUMO
BACKGROUND: Small intestine permeability is frequently altered in inflammatory bowel disease and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJ) and adherence (1,2). The role of hydrogen peroxide (H2O2), and nitric oxide (NO) and PARS in the permeability and structure of small intestine TJ is not clearly understood. MATERIALS AND METHODS: In vitro study, MDCK (Madin-Darby Canine Kidney) cells were exposed to H2O2 (100 microM for 2h), or zymosan (200 microl of stock solution 1 mg/ml for 4h), in the presence or absence of a treatment with poly(ADP-ribose) synthetase (PARS) inhibitor 3-aminobenzamide (3-AB: 3 mM) or with n-acetylcysteine (NAC 10 mM). In vivo study, wild-type mice (WT) and mice lacking (KO) of the inducible (or type 2) nitric oxide synthase (iNOS) were treated with zymosan (500 mg/kg, suspended in saline solution, i.p.). In addition INOSWT mice were treated with 3-AB (10 mg/kg, i.p.) or with NAC (40 mg/kg, i.p.) 1 hour and 6 h after zymosan administration. RESULTS: Exposure of MDCK cells to hydrogen peroxide caused a significant impairment in mitochondrial respiration that was associated with a reduction of cells adherence as well as derangement of the junctional proteins. A significant increase of nitrate and nitrite levels, stable metabolites of nitric oxide (NO), were found in MDCK supernatant after zymosan incubation. NO production was associated with a significant reduction of cell adherence and impairment of occludin protein. Pre-treatment of the cells with 3-AB or with NAC caused a significant prevention of H2O2-mediated occludin junctional damage as well as reduced the NO-induced occludin damage. In addition, H2O2 and NO are able to induce a significant derangement of beta-catenin and Zonula Ocludence-1 (ZO-1). We found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the terminal ileal TJs in zymosan-treated iNOSWT mice compared with permeable TJ in the control animals. Zymosan-treated iNOSKO mice showed a significant increase of tight junctional permselectivity. There were no differences in strand count or strand depth in the ilea from control or treated animals. In addition, a significant disrupted immunofluorescence signal for occludin, ZO-1 and beta-catenin was observed in the terminal ilea of zymosan-treated iNOSWT mice. In ileal fragments from zymosan-treated iNOSKO mice, we found less irregular distribution patterns of occludin, ZO-1 and beta-catenin. Similarly NAC or 3-AB treatments were able to prevent zymosan-induced damage of junctional proteins in iNOSWT mice. CONCLUSION: In conclusion, this study demonstrates that the alteration of permselectivity is most likely induced by ROS and PARS activation.