ABSTRACT
ABSTRACT: Pain is a major symptom in many dental procedures. Studies show consistently that pain, including dental pain, is not effectively treated; management of pain is a critical and challenging component in dentistry. Improvement and efficacy on the treatment depends on knowing which treatments are the most effective. Knowing how well an analgesic works and its associated adverse effects is fundamental to clinical decision. The aim of this review is to provide information to the dentistry field on the treatment of dental pain specifically with COX-2 inhibitors providing a useful guide to dentist on controlling pain. Therefore, nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed analgesic agents in surgical outpatients. Major limitations of NSAIDs are their gastrointestinal (GI) adverse events (perforation, ulceration, and bleeding), impairment of hemostatic function, and renal failure (with long-term therapy). A new class of NSAIDs, COX2 selective inhibitors (Coxibs), have been developed with the aim of reducing the GI adverse events of traditional NSAIDs while maintaining their effective anti-inflammatory and analgesic properties.
RESUMEN: El dolor es un síntoma principal en muchos procedimientos dentales. Los estudios demuestran consistentemente que el dolor, incluido el dolor dental, no se trata de manera efectiva; el manejo del dolor es un componente crítico y desafiante en odontología. La mejora y la eficacia en el tratamiento depende de saber qué tratamientos son los más efectivos. Saber qué tan bien funciona un analgésico y sus efectos adversos asociados es fundamental para la decisión clínica. El objetivo de esta revisión es proporcionar información al campo de la odontología sobre el tratamiento del dolor dental específicamente con los inhibidores de la COX-2, proporcionando una guía útil para el control del dolor por parte del dentista. Por lo tanto, los fármacos antiinflamatorios no esteroideos (AINE) son los agentes analgésicos más comúnmente prescritos en pacientes ambulatorios quirúrgicos. Las principales limitaciones de los AINE son los eventos adversos gastrointestinales (perforación, ulceración y hemorragia), deterioro de la función hemostática e insuficiencia renal (con terapia a largo plazo). Una nueva clase de AINE, los inhibidores selectivos de la COX-2 (Coxibs), se han desarrollado con el objetivo de reducir los eventos adversos gastrointestinales de los AINE tradicionales mientras se mantienen sus propiedades antiinflamatorias y analgésicas efectivas.
Subject(s)
Humans , Palliative Care/methods , Cyclooxygenase Inhibitors/therapeutic use , Isoenzymes/antagonists & inhibitors , Pain/etiology , Pain/drug therapy , Tooth Extraction/adverse effects , Cyclooxygenase 2 , Cyclooxygenase 2 InhibitorsABSTRACT
OBJECTIVE: To assess the knowledge and practice of pediatricians about infants with physiological reflux and gastroesophageal reflux disease. METHODS: 140 pediatricians were interviewed during two scientific events in 2009 and 2010. The questions referred to two clinical cases of infants. One with symptoms of infant regurgitation (physiological reflux) and another with gastroesophageal reflux disease. RESULTS: Among 140 pediatricians, 11.4% (n=16) and 62.1% (n=87) would require investigation tests, respectively for infant regurgitation (physiological reflux) and gastroesophageal reflux disease. A series of upper gastrointestinal exams would be the first requested with a higher frequency. Medication would be prescribed by 18.6% (n=6) in the case of physiological reflux and 87.1% (n=122) in the case of gastroesophageal reflux disease. Prokinetic drugs would be prescribed more frequently than gastric acid secretion inhibitors. Sleeping position would be recommended by 94.2% (n=132) and 92.9% (n=130) of the respondents, respectively for the case of physiological reflux and gastroesophageal reflux disease; however, about half of the respondents would recommend the prone position. Only 10 (7.1%) of the pediatricians would exclude the cow's milk protein from the infants' diet. CONCLUSIONS: Approaches different from the international guidelines are often considered appropriate, especially when recommending a different position other than the supine and prescription of medication. In turn, the interviews enable us to infer the right capacity of the pediatricians to distinguish physiologic reflux and gastroesophageal reflux disease correctly. .
OBJETIVO: Avaliar o conhecimento e a prática de pediatras brasileiros na assistência ao lactente com refluxo fisiológico e doença do refluxo gastroesofágico. MÉTODOS: Foram entrevistados 140 médicos pediatras em dois eventos científicos em 2009 e 2010. As perguntas referiam-se a dois casos clínicos de lactentes, um com quadro compatível com regurgitação do lactente (refluxo fisiológico) e outro com doença do refluxo gastroesofágico. RESULTADOS: Dos 140 participantes, 11,4% (n=16) e 62,1% (n=87) solicitariam exame para lactentes, respectivamente, com refluxo fisiológico e doença do refluxo gastroesofágico. O primeiro exame solicitado com maior frequência seria a radiografia contrastada de esôfago, estômago e duodeno. Medicação seria prescrita por 18,6% (n=26) para o caso de refluxo fisiológico e 87,1% (n=122) para o caso de doença do refluxo gastroesofágico. Procinéticos seriam prescritos com maior frequência do que os redutores da secreção ácida gástrica. Prescrição de posição para dormir fez parte das recomendações de 94,2% (n=132) e 92,9% (n=130) dos entrevistados, respectivamente, para os casos de refluxo fisiológico e doença do refluxo gastroesofágico. Entretanto, cerca da metade dos entrevistados não recomendaria o decúbito dorsal. Prescrição de dieta de exclusão do leite de vaca para um lactente com quadro de doença do refluxo gastroesofágico seria feita por apenas 10 (7,1%) dos participantes. CONCLUSÕES: Condutas diferentes das diretrizes internacionais são frequentemente consideradas adequadas, especialmente quanto à recomendação de posição diferente do decúbito dorsal e prescrição de medicamentos. As respostas permitem inferir a capacidade de correta diferenciação entre refluxo fisiológico e doença do refluxo gastroesofágico. .
Subject(s)
Humans , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Pyrimidines/chemistry , Pyrroles/chemistry , Sulfonamides/pharmacology , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/chemical synthesisABSTRACT
O objetivo deste trabalho foi analisar os motivos das faltas às consultas odontológicas em Unidades de Saúde da Família (USF) e implementar estratégias para sua redução por meio da pesquisa-ação. O estudo foi realizado em 12 USF de Piracicaba/SP, de 01 de janeiro a 31 de dezembro de 2010. A amostra se consistiu de 385 usuários, entrevistados por telefone, sobre os motivos das faltas, além de 12 cirurgiões-dentistas e 12 enfermeiras. Realizaram-se duas oficinas com os profissionais: uma para problematização dos dados coletados nas entrevistas e elaboração de estratégias; e outra após 4 meses, para avaliação. O maior motivo de faltas foi a coincidência do horário de funcionamento das unidades com o de trabalho dos usuários. Dentre as estratégias ressaltou-se a realização de palestras sobre saúde bucal, educação permanente nas reuniões de equipe, capacitação dos Agentes Comunitários de Saúde, participação em grupos terapêuticos e parcerias entre Equipe de Saúde Bucal e equipamentos sociais da comunidade. A adoção de prontuário único foi a estratégia desafiadora encontrada pelos profissionais. Concluiu-se que as estratégias implementadas levaram à diminuição das faltas em 66,6% e o caráter motivador das oficinas possibilitou a reflexão crítica para o redirecionamento da prática em saúde.
The aim of this study was to analyze the reasons for missed appointments in dental Family Health Units (FHU) and implement strategies to reduce same through action research. This is a study conducted in 12 FHUs in Piracicaba in the State of São Paulo from January, 1 to December, 31 2010. The sample was composed of 385 users of these health units who were interviewed over the phone and asked about the reasons for missing dental appointments, as well as 12 dentists and 12 nurses. Two workshops were staged with professionals: the first to assess the data collected in interviews and develop strategy, and the second for evaluation after 4 months. The primary cause for missed appointments was the opening hours of the units coinciding with the work schedule of the users. Among the strategies suggested were lectures on oral health, ongoing education in team meetings, training of Community Health Agents, participation in therapeutic groups and partnerships between Oral Health Teams and the social infrastructure of the community. The adoption of the single medical record was the strategy proposed by professionals. The strategies implemented led to a 66.6% reduction in missed appointments by the units and the motivating nature of the workshops elicited critical reflection to redirect health practices.
Subject(s)
Cysteine Endopeptidases/metabolism , Enzyme Precursors/metabolism , Plant Proteins/metabolism , Amino Acid Sequence , Biocatalysis , Computer Simulation , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Enzyme Activation , Enzyme Precursors/antagonists & inhibitors , Enzyme Precursors/chemistry , Enzyme Precursors/genetics , Hot Temperature , Hydrogen-Ion Concentration , Hydrolysis , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/genetics , Isoenzymes/metabolism , Kinetics , Leucine/analogs & derivatives , Leucine/chemistry , Leucine/metabolism , Leucine/pharmacology , Models, Molecular , Molecular Sequence Data , Plant Proteins/antagonists & inhibitors , Plant Proteins/chemistry , Plant Proteins/genetics , Protein Conformation , Protein Folding , Protein Stability , Recombinant Proteins/chemistry , Recombinant Proteins/metabolismABSTRACT
Toxoplasmosis is caused by Toxoplasma gondii, which is the main causative agent of abortion in small ruminants. Goats are among the animals that are most susceptible to this protozoon, and the disease that it causes leads to significant economic losses and has implications for public health, since presence of the parasite in products of goat origin is one of the main sources of human infection. Because of the significant economic impact, there is an urgent need to study the prevalence of T. gondii infection among goats in Sertão do Cabugi, which is the largest goat-producing region in Rio Grande do Norte. In the present study, the ELISA assay was used to test 244 serum samples from nine farms, located in four different municipalities in the Sertão do Cabugi region, which is an important goat-rearing region. The results showed that the prevalence of anti-T. gondii antibodies was 47.1% and that there was a significant association between positivity and the variables of age (≥ 34 months), location (Lajes, Angicos and Afonso Bezerra) and farm (all the farms). The avidity test was applied to all the 115 ELISA-positive samples to distinguish between acute and chronic infection. One hundred and three samples (89.6%) displayed high-avidity antibodies, thus indicating that most of the animals presented chronic infection, with a consequent great impact on the development of the goat production system and a risk to human health.
A toxoplasmose é causada pelo Toxoplasma gondii, principal agente causador de aborto em pequenos ruminantes. Os caprinos são uns dos animais mais suscetíveis a esse protozoário, levando a perdas econômicas significativas e implicações para a saúde pública, uma vez que a presença do parasito em produtos de origem caprina é uma das principais fontes de infecção humana. Devido ao impacto econômico significativo torna-se urgente estudar a prevalência da infecção, pelo T. gondii, entre caprinos do Sertão do Cabugi, a maior região produtora de caprinos no Rio Grande do Norte. O presente estudo utilizou o ELISA para testar 244 amostras de soro de 9 fazendas, situadas em 4 diferentes cidades na região do Sertão do Cabugi; uma importante região de criação de cabras. Os resultados mostraram uma prevalência de 47,1% para anticorpos anti- T. gondii e uma significativa associação entre a positividade e as variáveis idade (≥ 34 meses), localização (Lajes, Angicos e Afonso Bezerra e propriedade (todas as fazendas). O teste de avidez foi aplicado a todas as 115 amostras positivas pelo ELISA para discriminar entre infecção aguda e crônica. Cento e três amostras (89,6%) apresentaram anticorpos de alta avidez; indicando que a maioria dos animais estavam em infecção crônica, gerando um grande impacto sobre o desenvolvimento do sistema de produção em cabras e um risco para a saúde humana.
Subject(s)
Female , Humans , Male , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Breast Neoplasms/physiopathology , Colonic Neoplasms/physiopathology , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/pharmacology , Prostaglandin-Endoperoxide Synthases/pharmacology , Prostatic Neoplasms/prevention & control , Apoptosis , Adenomatous Polyposis Coli/prevention & control , Cell Transformation, Neoplastic , Cohort Studies , Epidemiologic Studies , Isoenzymes/antagonists & inhibitors , Membrane Proteins , Neovascularization, Pathologic , Risk FactorsABSTRACT
La fosforilación de la glucosa en los mamíferos, es catalizada por una familia de isoenzimas (hexoquinasas I-IV; HQ) de diferente Km para el azúcar. En los hepatocitos y células b-pancreáticas se encuentra la glucoquinasa (GQ; HQ IV) de Km elevado (12-20 mM). Hemos observado que GQ está presente en el intestino delgado y podría contribuir a la producción de lactato durante la absorción del azúcar. En este trabajo se determinó el efecto de la dieta (ratarina R; 60% de glucosa G; sacarosa S; almidón A; caseína C), suministrada ad libitum, sobre las actividades de HQ y GQ en homogenatos de hígado y mucosa intestinal de rata. El suministro de glucosa (5%) en el agua de beber (SG) también fue evaluado en las dietas con R y G. Las actividades de HQ (Glucosa 1 mM) y la capacidad fosforilativa total (CFT: Glucosa = 100 mM) se determinaron enzimáticamente. GQ se estimó por diferencia. En el grupo control (R) y en S, A y C, la GQ hepática fue un 85% de la CFT, mientras que en G, GSG y RSG un 66%. La HQ intestinal alcanzó en los grupos R, GSG, A y C un 87% y en RSG un 30% de la CFT. La GQ en G, S, aumentó, pero una menor magnitud. La presencia de GQ en el intestino delgado y su expresión diferencial de acuerdo a la dieta, abren la posibilidad de que dicho órgano contribuya al metabolismo inicial de la glucosa procedente de la dieta y provea al hígado de un precursor (lactato) muy eficaz para sus procesos anabólicos.
Glucose phosphorylation in mammals, is catalyzed by a family of isoenzymes (hexokinases I- IV; HQ) of different Km for the sugar. In hepatocytes and pancreatic b- cells are glucokinase (GQ ; HQ IV) of high Km (12-20 mM). We observed that GQ is present in the small intestine and may contribute to the production of lactate during the absorption of sugar. In this work, the effect of diet (ratarina R, G 60% glucose, sucrose S; starch A; casein C) provided ad libitum , on the activities of HQ and GQ in liver homogenates of rat intestinal mucosa . The supply of glucose (5%) in the drinking water ( SG ) was also evaluated in the diets with R and G. HQ activities (Glucose 1 mM) and phosphorylating full capacity ( CFT : Glucose = 100 mM ) were determined enzymatically . GQ was estimated by difference. In the control group (R) and S, A and C, the GQ liver was about 85% of CFT, whereas G, GSG and RSG 66%. The intestinal HQ reached in the R groups, GSG, A and C by 87% and 30% RSG the CFT. The GQ in G, S , increased , but a lower magnitude. the presence of glucokinase in the small intestine and its differential expression according to diet, open the possibility that this structure contributes to initial metabolism of glucose and provide to the liver a precursor (lactate) very effective for their anabolic processes.
Subject(s)
Animals , Rats , Phosphorylation/physiology , Glucose/analysis , Glucose/chemistry , Isoenzymes/analysis , Isoenzymes/antagonists & inhibitors , Isoenzymes/blood , Dietary Sucrose/analysis , Dietary Sucrose/chemistry , Dietary Sucrose/blood , Blood Chemical Analysis , Dietary Carbohydrates , HematologyABSTRACT
Alkaline phosphatase (ALP) is important in calcification and its expression seems to be associated with the inflammatory process. We investigated the in vitro acute effects of compounds used for the prevention or treatment of cardiovascular diseases on total ALP activity from male Wistar rat heart homogenate. ALP activity was determined by quantifying, at 410 nm, the p-nitrophenol released from p-nitrophenylphosphate (substrate in Tris buffer, pH 10.4). Using specific inhibitors of ALP activity and the reverse transcription-polymerase chain reaction, we showed that the rat heart had high ALP activity (31.73 ± 3.43 nmol p-nitrophenol·mg protein-1·min-1): mainly tissue-nonspecific ALP but also tissue-specific intestinal ALP type II. Both ALP isoenzymes presented myocardial localization (striated pattern) by immunofluorescence. ALP was inhibited a) strongly by 0.5 mM levamisole, 2 mM theophylline and 2 mM aspirin (91, 77 and 84 percent, respectively) and b) less strongly by 2 mM L-phenylalanine, 100 mL polyphenol-rich beverages and 0.5 mM progesterone (24, 21 to 29 and 11 percent, respectively). â-estradiol and caffeine (0.5 and 2 mM) had no effect; 0.5 mM simvastatin and 2 mM atenolol activated ALP (32 and 36 percent, respectively). Propranolol (2 mM) tended to activate ALP activity and corticosterone activated (18 percent) and inhibited (13 percent) (0.5 and 2 mM, respectively). We report, for the first time, that the rat heart expresses intestinal ALP type II and has high total ALP activity. ALP activity was inhibited by compounds used in the prevention of cardiovascular pathology. ALP manipulation in vivo may constitute an additional target for intervention in cardiovascular diseases.
Subject(s)
Animals , Male , Rats , Alkaline Phosphatase/metabolism , Enzyme Inhibitors/pharmacology , Myocardium/enzymology , Alkaline Phosphatase/antagonists & inhibitors , Fluorescent Antibody Technique , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Rats, Wistar , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Four isoenzymes of carbonic anhydrase (CA) were purified from Elephas Irogontherii (steppe elephant) bone (approx 0.3-0.5 million years old) from different locations (outer peripheral, cytosolic, inner peripheral and integral) using Sepharose 4B-L-tyrosine sulphanilamide affinity chromatography and their kinetics properties were investigated and compared with known CA isoenzymes. The purification degree of CAs was monitored by SDS-PAGE. Purification fold for outer peripheral, inner peripheral, cytosolic and integral CA was 395.6, 652.8, 1091 and 429.3 and the molecular mass (as determined by gel filtration chromatography) was 37, 36, 35, and 39 kDa, respectively. The optimal temperature for isozymes was 10-20, 30, 30 and 60 degrees C and optimal pH- was between 7.5-11, 7.5-10, 7.5-10 and 7.5 respectively. K(m) values (at optimum pH and 20 degrees C) for p-nitrophenyl acetate as substrate were 4.83, 6.80, 4.525 and 3.86 mM and the Vmax values for the same substrate were 0.00097, 0.0149, 0.00249 and 0.00072 micromol/L*min, respectively. I50 values of isoenzymes for the inhibitors of CA - sulphanilamide, KSCN, acetazolamide and NaN3 were also determined.
Subject(s)
Acetazolamide/pharmacology , Animals , Bone and Bones/enzymology , Carbonic Anhydrases/isolation & purification , Elephants , Hydrogen-Ion Concentration , Isoenzymes/antagonists & inhibitors , Sodium Azide/pharmacology , Sulfanilamides/pharmacology , Thiocyanates/pharmacologyABSTRACT
IL-1beta is known promote cyclooxygenase-2 (COX- 2) and matrix metalloproteinase-2 (MMP-2) expression. This study focuses on the characterization of the signaling cascade associated with IL-1beta-induced matrix metalloproteinase-2 (MMP- 2) regulation in human chondrocytes. The decrease in collagen levels in the conditioned media was prevented by a broad spectrum MMP inhibitor, suggesting that IL-1beta promotes the proteolytic process leading to MMP-2 activation. IL-1beta-related MMP-2 expression was found to be dependent on prostaglandin E2 (PGE2) production. In addition, the induction of COX-2 and MMP-2 was inhibited by the pretreatment of chondrocytes with a SB203580 or Ro 31-8220, indicating the involvement of protein kinase C (PKC) or p38 mitogen-activated protein kinase (MAPK). However, there is no cross-talk between PKC and p38 MAPK in the IL-1beta-induced MMP-2 activation. Taken together, these results demonstrated that IL-1beta induces MMP-2 expression through the PGE2-dependent mechanism in human chondrocytes.
Subject(s)
Humans , Chondrocytes/drug effects , Dinoprostone/analysis , Matrix Metalloproteinase 2/analysis , Indoles/pharmacology , Interleukin-1/pharmacology , Isoenzymes/antagonists & inhibitors , Nitrobenzenes/pharmacology , Phosphorylation/drug effects , Prostaglandin-Endoperoxide Synthases/metabolism , Protein Kinase C/antagonists & inhibitors , Sulfonamides/pharmacology , Up-Regulation , p38 Mitogen-Activated Protein Kinases/metabolismSubject(s)
Animals , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/therapeutic use , Electroshock/methods , Female , Isoenzymes/antagonists & inhibitors , Male , Mice , Pentylenetetrazole/toxicity , Prostaglandin-Endoperoxide Synthases/metabolism , Seizures/chemically inducedABSTRACT
Parecoxib, a prodrug of valdecoxib, a selective COX-2 inhibitor, has been recently introduced for the treatment of moderate to severe postoperative pain. This prospective, open, multicentric study enrolled 260 patients undergoing orthopaedic, gynaecological, dental and general surgery. Postoperatively, patients were treated with parecoxib, 40 mg IM/IV. There was a statistically significant decrease in the mean pain intensity score (p<0.05). At the end of 24 hours, 89.6% of total cases had a very good to total relief of pain. The mean duration of analgesia was 19.26 hours and mean time of onset of analgesia was 16.25 minutes ranging from 11-20 minutes. The laboratory values were within normal limits. The drug was well tolerated. There was no report of any hypersensitivity reaction. This study suggests that parecoxib, in a dose of 40 mg IM/IV, is an effective and safe option for the management of postoperative pain.
Subject(s)
Adult , Aged , Analgesics, Non-Narcotic/adverse effects , Cyclooxygenase 2 , Female , Humans , Isoenzymes/antagonists & inhibitors , Isoxazoles/adverse effects , Male , Membrane Proteins , Middle Aged , Pain, Postoperative/drug therapy , Postoperative Care , Prostaglandin-Endoperoxide Synthases , Treatment OutcomeABSTRACT
In randomized groups of Wistar rats, the effect inhibitor of selective NASAID over the COX-1, COX-2 and COX-3 the synchronizes inhibition of COX-1 and COX-2, COX-1 and COX-3, COX-2 and COX-3, and COX-1, COX-2 and COX-3 were studied. The conclusions were that the selective inhibition of COX-1, COX-2 and COX-3 no given gastrointestinal damage; the synchronizes inhibition of COX-1 and COX-2 given preferential gastric damage; in contrast the inhibition of COX-2 and COX-3 given massive necrosis preferential in small intestine.
Subject(s)
Animals , Female , Rats , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cyclooxygenase Inhibitors , Gastrointestinal Tract/drug effects , Isoenzymes/antagonists & inhibitors , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/enzymology , Gastrointestinal Tract/enzymology , Gastrointestinal Tract/pathology , Prostaglandin-Endoperoxide SynthasesABSTRACT
PG synthesis plays major role in inflammation. The enzymes responsible for PG synthesis are cox-1 and cox-2. Cox-1 regulates physiological functions in gut and kidney while cox-2 induces inflammation. Selective cox-2 inhibitors have little effect on cox-1 and thus showed better GI tolerability. The efficacy of new drugs is not greater than that of NSAID's by oral route of administration. In the present study new selective cox-2 inhibitors also showed less efficacy than NSAID'S by topical route of administration. However if current studies confirm the reduced GI toxicity this can be the only advantage of these drugs because these drugs showed less efficacy than NSAID'S by oral and topical routes of administration.
Subject(s)
Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Chemistry, Pharmaceutical , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/administration & dosage , Edema/drug therapy , Gels , Isoenzymes/antagonists & inhibitors , Prostaglandin-Endoperoxide Synthases , Rats , Pharmaceutical VehiclesABSTRACT
Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.
Subject(s)
Humans , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chromatography, Affinity , Computer Simulation , Enzyme Inhibitors/pharmacology , Isoenzymes/isolation & purification , Isoenzymes/antagonists & inhibitors , Ketoprofen/pharmacology , Leukocyte Elastase/isolation & purification , Leukocyte Elastase/antagonists & inhibitors , Models, Molecular , Naproxen/pharmacology , Phenylbutazone/analogs & derivatives , Salicylates/pharmacology , Spectrum Analysis, RamanABSTRACT
The effects of a beta-blocker, propranolol, on the enzyme and isoenzyme activities in the heart muscle in vitro and concomitant histopathology of the component cells of the islets of Langerhans were studied in the Wistar rats after treatment with streptozotocin and isoproterenol. The biochemical data indicated that the isoproterenol induced myocardial infarction (MI) precipitates an acute diabetic response in the rat heart. The superimposition of MI in diabetes mellitus caused significant inhibition of phosphofructokinase and hexokinase in the heart muscle. The lactate dehydrogenase depicted shifting of H-type to M-type in diabetes with or without MI. The drugs, when administered in combination, brought distinctive histopathological changes in beta-cells of the pancreatic islets including degranulation, hyalinosis and a near-total destruction; however A and D cells remained more or less unaffected. The effect of propranolol in diabetes mellitus was uncertain but in MI with or without prior diabetes, the drug inversely altered the activities of all the cardiac enzymes, besides stimulating a mild recuperation of the cells of the endocrine parenchyma.