Asunto(s)
Fenantridinas/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Neumonía/tratamiento farmacológico , SRS-A/antagonistas & inhibidores , Tiazoles/farmacología , Triazinas/farmacología , Animales , Broncoconstricción/efectos de los fármacos , Cobayas , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Masculino , Fenantridinas/uso terapéutico , Neumonía/etiología , Neumonía/fisiopatología , Ratas , Tiazoles/uso terapéutico , Triazinas/uso terapéuticoRESUMEN
The synthesis of a series of substituted heterocyclic alkoxypropionic acids is described. They were evaluated for antiinflammatory effects in two animal models of chronic inflammation; adjuvant arthritis and type II collagen arthritis in the rat. The desired profile of biological activity was characterized by the reduction of inflammation with the coincident restoration toward normal levels of the biochemical markers (acute phase proteins) associated with the inflammatory response, an effect that was not shared by classical nonsteroidal antiinflammatory agents. Romazarit, (Ro 31-3948, 7), 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropio nic acid, was selected for further evaluation. In contrast to NSAIDs, romazarit was inactive in animal models of acute inflammation, and furthermore it did not inhibit the cyclooxygenase enzyme in vitro or in vivo. Inhibition of interleukin-1-mediated events in vitro has been observed.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Oxazoles/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Fenómenos Químicos , Química , Evaluación Preclínica de Medicamentos , Femenino , Oxazoles/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
The biologic effects of a new potential disease-modifying antirheumatic drug, romazarit (Ro 31-3948, 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropio nic acid), have been investigated. In a 5-day adjuvant arthritis model, romazarit inhibited the development of hindpaw inflammation with a minimum effective dose of 30 mg kg-1. Plasma levels of the acute phase reactants seromucoid and haptoglobulin were also significantly reduced. Romazarit was equally effective in adrenalectomized animals, indicating that the compound is not acting via stimulation of the pituitary/adrenal axis. When the developing adjuvant arthritis was extended to 15 days romazarit showed dose-related improvements of all the symptoms of arthritis with a minimum effective dose of 25 mg kg-1. Romazarit caused a dose-dependent (range 20-250 mg kg-1) reduction in both the inflammatory and bony changes occurring during collagen arthritis in the rat, without any significant effect on anticollagen antibody titers except at the highest dose. Collagenase and prostaglandin E2 production in cultures of talus bones taken from rats with collagen arthritis were reduced by romazarit. In vitro romazarit was an extremely weak inhibitor of prostaglandin synthetase activity in both sheep seminal vesicle (IC50 6500 microM) and rat renal medulla (IC50 greater than 300 microM) cell-free preparations. Romazarit showed little or no activity in models of acute inflammation such as rabbit skin edema, carrageenan pleurisy or UV-induced erythema. In both acute and chronic tests romazarit displayed no ulcerogenic potential. In comparison with the structurally similar compound clobuzarit, hepatic changes such as increases in catalase and peroxisome proliferation-associated 80,000 mol.wt. protein were markedly less with romazarit. Clinical studies with romazarit are currently in progress.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis/tratamiento farmacológico , Clofibrato/análogos & derivados , Oxazoles/uso terapéutico , Animales , Huesos/efectos de los fármacos , Huesos/metabolismo , Huesos/patología , Clofibrato/uso terapéutico , Dinoprostona/biosíntesis , Evaluación Preclínica de Medicamentos , Femenino , Cobayas , Masculino , Colagenasa Microbiana/biosíntesis , Conejos , RatasAsunto(s)
Antiinflamatorios no Esteroideos , Edema/prevención & control , Retinoides/farmacología , Adyuvantes Inmunológicos , Animales , Ciclosporinas/farmacología , Dexametasona/farmacología , Edema/inducido químicamente , Edema/patología , Femenino , Pie/patología , Mycobacterium tuberculosis/inmunología , Ratas , Ratas Endogámicas , Pruebas CutáneasRESUMEN
Methods are described for the quantification of certain acute phase reactants (albumin, iron, fibrinogen, seromucoid, haptoglobin, and ceruloplasmin) in small amounts of plasma using the COBAS-BIO centrifugal analyzer. These methods have been applied to determine the concentrations of these acute-phase reactants (APRs) in rat plasma during the first 5 days of adjuvant-induced arthritis. The levels of the APRs alter with the degree of inflammation in a dose-related manner. Administration of the antiinflammatory and antirheumatic drugs (indomethacin, dexamethasone, and clobuzarit [CLOZIC]) during the course of the adjuvant-induced arthritis reduced the inflammatory response as judged by the measurement of oedema. These compounds, however, show differential effects on the profile of APRs as systemic measurements of the inflammatory disease. The present study shows that specific classes of drug have defined effects on acute-phase protein concentration. We believe that the multiple analysis of APR levels during the course of inflammation may help to distinguish between and elucidate the mechanisms of action, of antiinflammatory and antirheumatic drugs.
Asunto(s)
Proteínas de Fase Aguda/sangre , Inflamación/sangre , Adyuvantes Inmunológicos/farmacología , Animales , Ceruloplasmina/sangre , Femenino , Fibrinógeno/análisis , Pie/patología , Haptoglobinas/análisis , Inflamación/patología , Hierro/sangre , Orosomucoide/análisis , Ratas , Ratas Endogámicas , Albúmina Sérica/análisisRESUMEN
Single intra-articular injections of copper II bisglycinate [Cu(II)gly] (30-300 micrograms) into guinea-pig knee joints induce progressive joint degradation which first appears after about 2 weeks and peaks about 12 weeks after injection. The stable complex, copper II bishistidinate (300 micrograms) was without effect. The Cu(II)gly induced syndrome has features more in common with osteoarthritis than rheumatoid arthritis in that erosion occurs in the absence of persistent synovial inflammation. The possibility that the damage may be caused by Cu(II)gly inducing free radical formation within the joint, leading to a self-perpetuating chain reaction is discussed. D-Penicillamine and other drugs were tested for their effects on the histological changes induced 4 weeks after the intra-articular injections of 100 micrograms Cu(II)gly. Few significant effects were observed and these were restricted to D-penicillamine, which caused inconsistent protection, sodium aurothiomalate which protected at a dose causing weight loss and prednisolone which exacerbated joint damage. It is concluded that the variability of the control response will need to be reduced before the model can be used for routine drug evaluation but it may be of value in the study of chronic degradative joint disease.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis/inducido químicamente , Modelos Animales de Enfermedad , Glicina , Compuestos Organometálicos , Animales , Artritis/tratamiento farmacológico , Artritis/patología , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Glicina/administración & dosificación , Cobayas , Histidina/administración & dosificación , Inyecciones Intraarticulares , Articulación de la Rodilla/patología , Masculino , Compuestos Organometálicos/administración & dosificación , Osteoartritis/inducido químicamente , Osteoartritis/tratamiento farmacológico , Osteoartritis/patología , Penicilamina/uso terapéuticoAsunto(s)
Artritis Experimental/metabolismo , Artritis/metabolismo , Huesos/metabolismo , Colágeno/farmacología , Colagenasa Microbiana/metabolismo , Prostaglandinas E/metabolismo , Animales , Técnicas de Cultivo , Dinoprostona , Masculino , Ratas , Astrágalo/anatomía & histología , Astrágalo/metabolismoRESUMEN
Injections of labile copper complexes such as copper II bisglycinate [Cu(II)gly] induce marked inflammatory responses in rats in contrast to stable copper complexes like copper II bishistidinate which are nonirritant. The antirheumatic drugs D-penicillamine, mercaptopyridoxine, thiola and captopril, inhibit Cu(II)gly-induced cutaneous vascular permeability when given intravenously and show oral cupriuretic activity. Inhibition of Cu(II)gly inflammation alone or cupriuretic activity alone do not appear predictive of clinical antirheumatic activity since L-cysteine methylester and trien, which are active in the former and latter tests, respectively, are devoid of clinical antirheumatic activity. Indomethacin and aspirin are inactive in these tests, thus discounting the concept that such drugs act in part through their copper complexes. The mechanisms by which labile copper induces inflammation and by which D-penicillamine-like drugs modulate the response are discussed. It is suggested that copper can generate free radicals in vivo and that D-penicillamine may act by neutralization of labile copper complexes and/or by formation of copper complexes with the capacity to catalyse the dismutation of superoxide anion.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Cobre , Compuestos Organometálicos , Penicilamina/uso terapéutico , Animales , Permeabilidad Capilar , Cobre/orina , Interacciones Farmacológicas , Extremidades , Femenino , Glicina , Histidina , Inflamación/inducido químicamente , Inflamación/fisiopatología , Masculino , Ratas , Ratas Endogámicas , Piel/irrigación sanguínea , Enfermedades de la Piel/inducido químicamente , Enfermedades de la Piel/fisiopatologíaRESUMEN
Tenoxicam, a new non-steroidal anti-inflammatory drug has been compared with piroxicam and indomethacin in a range of pharmacological and biochemical inflammation test systems. In a chronic (17-day) adjuvant arthritis in the rat, tenoxicam and piroxicam were equally effective in reducing several indices of inflammation and were less ulcerogenic and better tolerated than indomethacin. The oxicams reduced the oedematous and cellular components of a carrageenan pleurisy at 4 hours while at 24 hours they increased exudate volume and selectively inhibited the accumulation of mononuclear cells. These agents also reduced the inflammatory component of a delayed hypersensitivity response to methylated bovine serum albumin in the mouse. The oxicams were about 100-fold less active than indomethacin as inhibitors of prostaglandin synthetase but all three compounds reduced about equally the release of prostaglandin E2 from phagocytosing rat PMN and interleukin 1-stimulated human rheumatoid synovial cells. The compounds had no effect on the release of superoxide anion, lysosomal enzymes or collagenase from cultured cells, neither did they inhibit isolated collagenase. Only indomethacin stabilized albumin against heat denaturation.
Asunto(s)
Antiinflamatorios/farmacología , Tiazinas/farmacología , Corticoesteroides/metabolismo , Animales , Artritis Experimental/tratamiento farmacológico , Dinoprostona , Femenino , Humanos , Masculino , Colagenasa Microbiana/metabolismo , Neutrófilos/efectos de los fármacos , Piroxicam , Pleuresia/tratamiento farmacológico , Prostaglandinas/biosíntesis , Prostaglandinas E/metabolismo , Ratas , Ratas EndogámicasRESUMEN
Using etretinate as a model compound, the bone changes characteristic of hypervitaminosis A were evaluated in the rat in terms of tibial bone-breaking strain. Dose-related effects were observed in the dose range of 5-30 mg/kg p.o. for 15 days. The model proved a simple and precise means of assessing hypervitaminosis A in this species. Isotretinoin also showed a small but significant reduction in tibial breaking strain, but with a shallow dose-response curve in the range of 50-150 mg/kg.
Asunto(s)
Huesos/fisiopatología , Etretinato/toxicidad , Tretinoina/toxicidad , Vitamina A/toxicidad , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Isotretinoína , Ratas , Resistencia a la Tracción/efectos de los fármacos , Fracturas de la Tibia/inducido químicamenteRESUMEN
Guinea-pigs were sensitized by intra-articular injection of M. tuberculosis (2.0 mg) into one knee joint and arthritis induced in the opposite knee 21 days later by intra-articular injection of antigen (0.2 mg). The time course off the arthritic changes was followed for 25 days by assessment of knee swelling and hind-limb flexion. Twenty-eight days after challenge the experiment was terminated and radiographic changes evaluated by means of a microfocal X-ray unit. The effect of treatment with the anti-rheumatic drugs, D-penicillamine (100 mg/kg by mouth), dexamethasone (0.1 mg/kg i.p.), aspirin (100 mg/kg by mouth), chloroquine phosphate (30 mg/kg by mouth) and sodium aurothiomalate (2 mg/kg i.m.) given daily from 10 days after sensitization until 28 days after challenge was assessed. Changes in joint swelling and hind-limb flexion were maximal 1-3 days after challenge. None of the drug treatments influenced these parameters. Microfocal radiography showed marked changes in arthritis animals of all X-ray parameters measured. It was possible readily to identify joint erosion, trabecular loss and associated osteoporosis, the latter occurring proximal to and relatively remote from the affected joint. None of the treatments prevented the radiographic changes but exacerbation of trabecular number in the area of the epiphysis was seen with aspirin and D-penicillamine and of trabecular density further up the shaft of the femur was seen with D-penicillamine. The changes with D-penicillamine may reflect the potentiation of cell-mediated hypersensitivity with this drug reported by other workers. It was concluded that the model is not suitable for the detection of clinically active anti-rheumatic drugs but that microfocal radiography provides a sensitive index for the assessment of joint damage in small animals.
Asunto(s)
Antiinflamatorios/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis/tratamiento farmacológico , Cloroquina/uso terapéutico , Tiomalato Sódico de Oro/uso terapéutico , Penicilamina/uso terapéutico , Animales , Artritis Experimental/diagnóstico por imagen , Modelos Animales de Enfermedad , Cobayas , Articulación de la Rodilla/diagnóstico por imagen , Masculino , Radiografía , Factores de TiempoRESUMEN
Compounds having acenaphthene and indan as their parent nuclei were synthesized for antiinflammatory testing. Compounds which showed activity were 1-phenyl-5-acenaphthenylacetic acid and its alpha-methyl derivative (carrageenan rat paw edema) and the same alpha-methylacenaphthenylacetic acid and 2-(4-chlorobenzylidene)-3-oxo-5-indanacetic acid and its alpha-methyl derivative (rat adjuvant arthritis). None of the compounds was more active than the control compounds phenylbutazone and indomethacin.
Asunto(s)
Acenaftenos/síntesis química , Antiinflamatorios/síntesis química , Indanos/síntesis química , Indenos/síntesis química , Acenaftenos/farmacología , Animales , Artritis Experimental/fisiopatología , Carragenina , Edema/inducido químicamente , Edema/fisiopatología , Indanos/farmacología , RatasRESUMEN
Benoxaprofen is a potent and long-acting anti-inflammatory and antipyretic compound. Its anti-inflammatory activity has been demonstrated in carrageenan-induced oedema, in cellulose pellet granuloma and in both developing and established adjuvant arthritis tests in rats. Its antipyretic activity is greater than either aspirin or paracetamol in tests inducing pyrexia with yeast of 'E' pyrogen in rats and rabbits. Benoxaprofen has analgesic activity in tests where pain is accompanied by inflammation but not in other experimental models of pain. The weak prostaglandin synthetase inhibiting properties of this compound differentiate it from other acid anti-inflammatory compounds. The low ulcerogenic potential of benoxaprofen seen in animal models may be related to its relative inability to inhibit PG synthetase.