RESUMO

INTRODUCTION: Neurocysticercosis (NCC) is the most frequent parasitic disease in the central nervous system of humans. OBJECTIVE: to establish the correlation between clinical and tomographic variables in patients with neurocysticercosis in the neurology consultation of Hospital San Vicente de Paul and Hospital IESS Ibarra, during the year 2020. PATIENTS AND METHODS: descriptive, correlational and cross-sectional research. POPULATION AND SAMPLE: 93 patients. The information was collected in the neurology consultation. Clinical and imaging criteria were used for diagnosis. Odds Ratio (OR; 95% CI) was calculated. For multivariate analysis, binary logistic regression models were used. Statistical significance was considered when the value of p <0.05. SYMPTOMS: headache (77.4%), epilepsy (41.9%). Tomographic findings: size < 1 cm (67.7%), single lesion (54.8%), supratentorial (93.5%). There were several clinical / tomographic correlations in the bivariate analysis, the presence of epilepsy was associated with lesions of size >1 cm (OR: 9.65; 95% CI: 3.48-26.7), the vesicular + ventricular colloidal stage + nodular (OR: 3.90; 95% CI: 1.64-9.28) and parenchymal topography (OR: 5.03; 95% CI: 2.03-12.4) (p < 0.05). In the multivariate analysis, epilepsy was not associated with tomographic aspects such as the size, stage and topography of the cysticerci (p < 0.05). Headache and reduced muscle strength were associated with parenchymal topography and stage of lesions respectively (p < 0.05). CONCLUSIONS: Despite having a wide clinical spectrum, the presence of epilepsy, headache, and reduced muscle strength seem to be the most representative manifestations, so their inclusion in the development of prognostic scores should be evaluated, which allow evaluating the approach diagnostic and evolutionary in subsequent research.

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TITLE: Correlación entre variables clínicas y tomográficas en pacientes con neurocisticercosis. Estudio en una cohorte de pacientes de la Sierra Norte ecuatoriana entre 2019 y 2020.Introducción. La neurocisticercosis es la enfermedad parasitaria más frecuente en el sistema nervioso central de los humanos. Objetivo. Establecer la correlación entre variables clínicas y tomográficas en pacientes con neurocisticercosis en la consulta de neurología del Hospital San Vicente de Paúl y el Hospital Instituto Ecuatoriano de Seguridad Social de Ibarra durante 2020. Pacientes y métodos. Investigación descriptiva, correlacional y transversal. Población y muestra: 93 pacientes. La información se recolectó en la consulta de neurología. Para el diagnóstico se utilizaron criterios clínicos e imagenológicos. Se calculó la odds ratio (OR) ­intervalo de confianza al 95% (IC 95%)­. Para el análisis multivariado, se utilizaron modelos de regresión logística binaria. Se consideró significación estadística cuando p menor de 0,05. Resultados. Síntomas: cefalea (77,4%) y crisis epilépticas (41,9%). Hallazgos tomográficos: tamaño menor de 1 cm (67,7%), lesión única (54,8%) y lesión supratentorial (93,5%). Hubo varias correlaciones clinicotomográficas en el análisis bivariado: la presencia de crisis epilépticas se asoció con lesiones de tamaño > 1 cm (OR: 9,65; IC 95%: 3,48-26,7), el estadio vesicular + ventricular coloidal + nodular (OR: 3,9; IC 95%: 1,64-9,28) y la topografía parenquimatosa (OR: 5,03; IC 95%: 2,03-12,4) (p menor de 0,05). La cefalea y la reducción de la fuerza muscular se asociaron con topografía parenquimatosa y estadio de las lesiones, respectivamente (p menor de 0,05). Conclusiones. A pesar de cursar con un amplio espectro clínico, la presencia de crisis epilépticas, cefalea y reducción de la fuerza muscular parece ser la manifestación más representativa, por lo que debería evaluarse su inclusión en el desarrollo de puntuaciones pronósticas que permitan evaluar el enfoque diagnóstico y evolutivo por estudio de imagen en investigaciones posteriores.

Assuntos

Epilepsia , Neurocisticercose , Estudos Transversais , Equador/epidemiologia , Epilepsia/diagnóstico por imagem , Epilepsia/epidemiologia , Epilepsia/etiologia , Cefaleia/complicações , Humanos , Neurocisticercose/complicações , Neurocisticercose/diagnóstico por imagem , Neurocisticercose/epidemiologia

RESUMO

Emerging evidence proposes a link between immune changes and pain, which is consistent with the inflammation theory and the increased incidence of neurodegenerative diseases. Flavonoids have long been used because of their anti-inflammatory potential activity and they are considered a promising alternative to alleviate neuropathic pain. The aim of this study was to investigate the antihyperalgesic effect of hesperidin and the presence of pro-inflammatory cytokines evaluated at peripheral and central levels in the chronic constriction injury as model of neuropathic pain in rats. Mechanical and thermal hyperalgesia were assessed in the aesthesiometer and plantar tests, respectively, as related to the presence of cytokines concentrations (TNF-α, IL-1ß and IL-6) in sciatic nerve and segments of the spinal cord after 15 days chronic constriction injury model in rats receiving vehicle or hesperidin. Antihyperalgesic response of hesperidin (100 mg/kg) was associated to the presence of cytokines mainly at several sections of the spinal cord suggesting not only peripheral but also its involvement in central sensitization in the experimental neuropathic pain.

Assuntos

Analgésicos/uso terapêutico , Citocinas/metabolismo , Hesperidina/uso terapêutico , Hiperalgesia/metabolismo , Mediadores da Inflamação/metabolismo , Neuralgia/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Modelos Animais de Doenças , Hiperalgesia/tratamento farmacológico , Masculino , Neuralgia/tratamento farmacológico , Ratos , Medula Espinal/metabolismo , Resultado do Tratamento

RESUMO

Even after the Nuremberg code was published, research on syphilis often continued to fall far short of ethical standards. We review post-World War II research on this disease, focusing on the work carried out in Guatemala and Tuskegee. Over a thousand adults were deliberately inoculated with infectious material for syphilis, chancroid, and gonorrhea between 1946 and 1948 in Guatemala, and thousands of serologies were performed in individuals belonging to indigenous populations or sheltered in orphanages. The Tuskegee syphilis study, conducted by the US Public Health Service, took place between 1932 and 1972 with the aim of following the natural history of the disease when left untreated. The subjects belonged to a rural black population and the study was not halted when effective treatment for syphilis became available in 1945.

Assuntos

Experimentação Humana/história , Sífilis/história , Academias e Institutos/história , Adulto , Alabama , População Negra , Centers for Disease Control and Prevention, U.S./história , Feminino , Guatemala , História do Século XX , História do Século XXI , Experimentação Humana/ética , Humanos , Consentimento Livre e Esclarecido , Cooperação Internacional , Masculino , Pessoas Mentalmente Doentes , Militares , Penicilina G/história , Penicilina G/uso terapêutico , Prisioneiros , Profissionais do Sexo , Sífilis/tratamento farmacológico , Sífilis/transmissão , Estados Unidos , United States Public Health Service/história , Suspensão de Tratamento/ética

RESUMO

The rationale of this investigation was to examine the antinociceptive effect of an ethanol extract of Rosmarinus officinalis (RO) aerial parts, using three different experimental models: acetic acid-induced writhing test and formalin test in mice; and a model of arthritic pain: "pain-induced functional impairment model in the rat (PIFIR model)". The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from RO extract were compared with the antinociceptive effect of either tramadol (TR: 3.16-50 mg/kg, i.p. in mice, and 1.0-31.62 mg/kg, i.p. in rats) or acetylsalicylic acid (AA: 31.62-562.32 mg/kg, p.o.). RO extract (10-300 mg/kg, p.o.) significantly (P < 0.001) reduced the number of writhing movement induced by the i.p. administration of acetic acid solution in a dose-dependent way (ED50 = 108.84 mg/kg, whereas, TR showed an ED50 = 12.38 mg/kg). In addition, RO extract (30-300 mg/kg) significantly (P < 0.001) inhibited licking and shaking behaviours in both early (neurogenic pain) and in the late (inflammatory pain) phases of the formalin test. These effects were like those produced by TR. Concerning the results using the PIFIR model, RO extract (30-3000 mg/kg, p.o.) like either TR or AA, produced a significant (P < 0.001) and dose-dependent antinociceptive response in rats (RO: ED50 = 222.78 mg/kg versus TR: ED50 = 11.06 mg/kg and AA: ED50 = 206.13 mg/kg). These results strongly suggest that aerial parts of RO possess antinociceptive and anti-inflammatory activity, and reinforce the use of this plant in folk medicine.

Assuntos

Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Dor/tratamento farmacológico , Rosmarinus , Analgésicos/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Aspirina/administração & dosagem , Aspirina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inflamação/tratamento farmacológico , Masculino , Camundongos , Dor/induzido quimicamente , Medição da Dor , Componentes Aéreos da Planta , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Plantas Medicinais , Ratos , Ratos Wistar , Tramadol/administração & dosagem , Tramadol/farmacologia

RESUMO

RATIONALE: The effect of anxiety on nociception has been evaluated but not that of nociception on anxiety. OBJECTIVE: The study was conducted to analyse the influence of nociception on basal levels of anxiety-like behaviour and on the action of anxiolytic drugs. METHODS: Nociception was induced by an intra-articular injection of uric acid at 3.75 or 7.5%. Experimental anxiety was determined in the rat burying behaviour and the elevated plus maze tests. To separate specific anxiety-related drug actions, a spontaneous ambulatory test was included. The anxiolytics, buspirone (2.5 and 5.0 mg/kg, i.p.) and diazepam (0.5, 1.0 and 2.0 mg/kg, i.p.), were used. RESULTS: In the nociception test, the pain-induced functional impairment rat model, uric acid at 3.75 and 7.5% had an effect of around 35 and 75%, respectively. Uric acid (UA) at the lower dose (3.75%) lacked an effect on burying behaviour but significantly increased the time spent and number of entries to the open arms; the higher UA dose (7.5%) produced a significant increase in the time spent and number of entries to the open arms and a statistically significant reduction in cumulative burying. Diazepam and buspirone produced a clear dose-dependent reduction in cumulative burying. In the plus maze, diazepam also induced an increase in the time spent and number of entries to the open arms. In the burying behaviour test, rats with a mild level of nociception (uric acid at 7.5%) were insensitive to the anxiolytic-like effect of these anxiolytic drugs. In the plus maze test, the anxiolytic-like effect of diazepam (1.0 mg/kg) was blocked under both levels of nociception. CONCLUSIONS: These data demonstrate that nociception modifies the response to anxiolytic drugs. The role of factors with anxiogenic properties produced during inflammation, which may modify diazepam and buspirone effects, is discussed.

Assuntos

Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Buspirona/uso terapêutico , Diazepam/uso terapêutico , Dor/fisiopatologia , Análise de Variância , Animais , Ansiolíticos/administração & dosagem , Ansiedade/fisiopatologia , Aspirina/farmacologia , Comportamento Animal/efeitos dos fármacos , Buspirona/administração & dosagem , Diazepam/administração & dosagem , Relação Dose-Resposta a Droga , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Injeções Intra-Articulares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Dor/induzido quimicamente , Ratos , Ratos Wistar , Ácido Úrico

RESUMO

BACKGROUND: To assess a possible synergistic antinociceptive interaction, the antinociceptive effects of ketoprofen (KET), and caffeine (CAF) administered either separately or in combinations were determined in a model of arthritic pain. METHODS: Antinociceptive activity was assayed using "ellipsis pain-induced functional impairment in the rat" (PIFIR model). The antinociceptive efficacies were evaluated using several dose-response curves and time courses. The antinociceptive effects from the combination that produced the greater effect were compared with the maximal antinociceptive effect of either morphine, acetylsalicylic acid (ASA), or KET alone. The animals were administered with 0.05 mL intra-articular (i.a.) of uric acid to induce nociception. Groups of six rats received orally either ASA, morphine (MOR), KET, CAF, or a combination KET + CAF (24 combinations). RESULTS: ASA (ED(50) 465.2 +/- 1.5 mg/kg), MOR (ED(50) 71.0 +/- 1.6 mg/kg), and KET (ED(50) 7.2 +/- 1.4 mg/kg) alone induced dose-dependent antinociception, whereas CAF alone showed no activity at the assayed doses. Nine combinations showed various degrees of potentiation (p <0.01), while the remainder exhibited the antinociceptive effect of KET only. Combinations of 17.8 mg/kg CAF with either 1.0, 1.8, 3.2, 5.6, or 10.0 mg/kg KET yielded the highest antinociceptive potentiations. For example, antinociceptive effect was 125.6 +/- 21.4 area units (au) with KET (3.2 mg/kg) alone, but the combination with CAF (17.8 mg/kg) showed 309.5 +/- 10.3 au. The median effective dose (ED(50)) of KET alone was 7.2 +/- 1.4 mg/kg, whereas the ED(50) of KET + CAF 17.8 mg/kg was 0.4 +/- 0.6 mg/kg: KET in the presence of CAF was approximately 18 times more potent than the analgesic drug without CAF. CONCLUSIONS: These results showed that CAF was able to potentiate the analgesia of KET, but only at selected dose combinations: CAF in the doses of 10.0 and 17.8 mg/kg was able to potentiate the analgesic effect of KET, the most efficacious drug combination being CAF 17.8 mg/kg + KET 3.2 mg/kg. The combination of analgesic drugs and CAF can produce better antinociceptive effects than the analgesic drug alone. This knowledge will permit the selection of the therapeutically most effective combination ratio of drugs, employing lower doses of each drug.

Assuntos

Anti-Inflamatórios não Esteroides/farmacologia , Cafeína/farmacologia , Cetoprofeno/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Área Sob a Curva , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Cetoprofeno/farmacocinética , Ratos , Ratos Wistar

RESUMO

The potential antinociceptive effects of the S(+)- and R(-)-enantiomers of flurbiprofen (SFB and RFB, respectively) were investigated when given intravenously to rats using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. Groups of 6 rats received either vehicle or the enantiomer in turn and antinociception was determined by evaluating the dose-response curves over time. Although SFB and RFB produced dose-dependent effects with similar efficacy (SFB: 277.4 +/- 29.9 au and RFB: 293.5 +/- 20.1 au), the R(-)-enantiomer was unable to produce any antinociceptive action when assessed at the same dose ranges as SFB. It was necessary to increase the dose of RFB by 100 times to produce similar antinociception. Accordingly, S(+)-flurbiprofen was 100-fold more potent (ED50 = 0.33 +/- 0.13 mg/kg) than its antipode R(-)-(ED50 = 30.0 +/- 1.7 mg/kg). SFB generated from metabolic inversion (> 1%) after i.v. dosage of RFB, as well as impurities of SFB present in RFB preparations, tend to confirm the hypothesis that the efficacy of RFB achieved at 100 mg/kg, similar to that observed with 1 mg/kg of SFB, is attributable to SFB.

Assuntos

Analgésicos/farmacologia , Artrite/tratamento farmacológico , Flurbiprofeno/uso terapêutico , Dor/tratamento farmacológico , Animais , Área Sob a Curva , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Flurbiprofeno/análogos & derivados , Injeções Intravenosas , Masculino , Atividade Motora/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Dor/induzido quimicamente , Dor/fisiopatologia , Medição da Dor , Ratos , Ratos Wistar , Fatores de Tempo , Ácido Úrico

RESUMO

Caffeine potentiation of ketorolac-induced antinociception in the pain-induced functional impairment model in rats was assessed. Caffeine alone was ineffective, but increased the effect of ketorolac without affecting its pharmacokinetics. Intra-articular administration of adenosine and N6-cyclohexyladenosine (CHA, an adenosine A1 receptor agonist), but not 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, an adenosine A2A receptor agonist), significantly increased ketorolac antinociception. This effect was not local, as contralateral administration was also effective. Ipsilateral and contralateral administration of adenosine and CHA also increased antinociception by ketorolac-caffeine. Intra-articular 8-Bromo-adenosine cyclic 3',5'-hydrogen phosphate sodium or 8-Bromo-guanosine-3',5'-cyclophosphate sodium (cGMP) given ipsilaterally or contralaterally did not affect ketorolac-induced antinociception. Nevertheless, ipsilateral, but not contralateral, administration of 8-Br-cGMP significantly increased antinociception by ketorolac-caffeine, suggesting a local effect. The results suggest that caffeine potentiation of ketorolac antinociception is mediated, at least partially, by a local increase in cGMP and rule out the participation of adenosine receptor blockade.

Assuntos

Analgésicos não Narcóticos/farmacologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cetorolaco/farmacologia , Dor/prevenção & controle , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Administração Tópica , Analgésicos não Narcóticos/farmacocinética , Animais , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Cicloexilaminas/farmacologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Cetorolaco/farmacocinética , Medição da Dor , Agonistas do Receptor Purinérgico P1 , Ratos , Ratos Wistar , Fatores de Tempo

Assuntos

Analgésicos não Narcóticos/farmacologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cetorolaco/farmacologia , Agonistas do Receptor Purinérgico P1 , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Área Sob a Curva , Sinergismo Farmacológico , Feminino , Medição da Dor/efeitos dos fármacos , Fenetilaminas/farmacologia , Ratos , Ratos Wistar

RESUMO

Serotonin (5-hydroxytryptamine; 5-HT) elicits external carotid vasoconstriction in vagosympathectomized dogs via 5-HT1B/1D receptors and a mechanism unrelated to the 5-HT1, 5-HT2, 5-HT3 and 5-HT4 types. In order to further explore the nature of this novel mechanism, the canine external carotid effects of 2-(2-aminoethyl)-quinoline (D-1997), a novel 5-HT1 receptor agonist, were analyzed and compared with those of 5-HT and sumatriptan. Intracarotid (i.c.) infusions of 5-HT, D-1997 and sumatriptan to vagosympathectomized dogs dose-dependently decreased external carotid conductance, the rank order of agonist potency being 5-HT > sumatriptan > D-1997. The effects to D-1997 were resistant to intravenous (i.v.) pretreatment with 5-HT2 and 5-HT3/5-HT4 receptor antagonists. Remarkably, the effects induced by lower (10-100 microg/min), but not higher (300-1000 microg/min), doses of D-1997 were blocked by high doses of methiothepin (1 and 3 mg/kg, i.v.), as previously shown with 5-HT. In addition, GR-127935 (1-10 microg/kg, i.v.), partially and dose-dependently antagonized D-1997-induced responses. However, the effects of D-1997 remained unaltered after blockade of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, or inhibition of 5-HT-uptake or cyclo-oxygenase, depletion of biogenic amines or blockade of Ca2+ channels. These results may support our previous contention that lower doses of 5-HT elicit external carotid vasoconstriction in vagosympathectomized dogs by activation of 5-HT1B/1D receptors, whilst higher doses of 5-HT stimulate a novel vasoconstrictor mechanism.

Assuntos

Artéria Carótida Externa/efeitos dos fármacos , Quinolinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Simpatectomia , Vagotomia , Animais , Artéria Carótida Externa/fisiologia , Cães , Relação Dose-Resposta a Droga , Feminino , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Masculino , Metiotepina/farmacologia , Quinolinas/administração & dosagem , Fluxo Sanguíneo Regional/efeitos dos fármacos , Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/administração & dosagem , Cloreto de Sódio/farmacologia , Sumatriptana/farmacologia , Vasoconstrição/efeitos dos fármacos

RESUMO

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2 or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50 of 9.22 micrograms/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 micrograms/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

Assuntos

Anti-Inflamatórios não Esteroides/farmacologia , Modelos Biológicos , Medição da Dor/métodos , Prostaglandinas/metabolismo , Tolmetino/farmacologia , Ácido Úrico/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/sangue , Relação Dose-Resposta a Droga , Feminino , Ratos , Ratos Wistar , Fatores de Tempo , Tolmetino/sangue

RESUMO

We investigated the antinociceptive properties of dexketoprofen trometamol [S(+)-ketoprofen tromethamine salt; SKP], a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.

Assuntos

Analgésicos não Narcóticos/farmacologia , Cetoprofeno/análogos & derivados , Dor/tratamento farmacológico , Trometamina/análogos & derivados , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/farmacocinética , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Biotransformação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Flurbiprofeno/administração & dosagem , Flurbiprofeno/farmacologia , Injeções Intraventriculares , Cetoprofeno/farmacologia , Cetoprofeno/toxicidade , Cetorolaco , Masculino , Morfina/administração & dosagem , Morfina/farmacologia , Dor/induzido quimicamente , Dor/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Tolmetino/administração & dosagem , Tolmetino/análogos & derivados , Tolmetino/farmacologia , Trometamina/farmacologia , Trometamina/toxicidade , Ácido Úrico

RESUMO

The relationship between the pharmacokinetics and the antinociceptive effect of diclofenac was evaluated using the pain-induced functional impairment model in the rat. Male Wistar rats were injected with uric acid in the knee joint of the right hind limb, which induced its dysfunction. Once the dysfunction was complete, animals received a p.o. dose of 0.56, 1, 1.8, 3.2, 5.6 or 10 mg/kg of sodium diclofenac, and the antinociceptive effect and drug blood concentration were simultaneously evaluated at selected times for a period of 6 h. Diclofenac produced a dose-dependent antinociceptive effect, measured as a recovery of the functionality of the injured limb. However, the onset of the antinociceptive effect was delayed with respect to blood concentrations. Moreover, the effect lasted longer than expected from pharmacokinetic data. Therefore, when functionality index was plotted against diclofenac blood concentration, an anticlockwise hysteresis loop was observed for all doses. Hysteresis collapse was achieved using the effect-compartment model, and the plot of functionality index against diclofenac concentration in the effect-compartment data was well fitted by the sigmoidal Emax model. Our data suggest slow equilibrium kinetics between diclofenac concentration in blood and at its site of action, which leads to a delayed onset of the antinociceptive effect as well as a longer duration of the response resulting from drug accumulation in synovial fluid.

Assuntos

Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Animais , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/farmacocinética , Área Sob a Curva , Diclofenaco/sangue , Diclofenaco/farmacocinética , Masculino , Ratos , Ratos Wistar

Assuntos

Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/farmacocinética , Indometacina/farmacologia , Indometacina/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/sangue , Artrite Experimental/sangue , Artrite Experimental/fisiopatologia , Indometacina/sangue , Masculino , Medição da Dor , Ratos , Ratos Wistar

RESUMO

The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by NG nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. L-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the L-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.

Assuntos

Analgésicos/farmacologia , Cafeína/farmacologia , Óxido Nítrico/antagonistas & inibidores , Tolmetino/análogos & derivados , Animais , Cafeína/administração & dosagem , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Cetorolaco , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar , Tolmetino/farmacologia

RESUMO

The analgesic effects of acetaminophen, p.o., (ACE) and d-propoxyphene, s.c., (PROP) administered either separately or in 24 different combinations were determined in a model of pain-induced functional impairment in the rat. This allowed us to detect the analgesic interaction profile of the combinations. Furthermore, we set out to determine the optimal degree of enhancement obtained with a specific combination of the above drugs by means of the surface of synergistic interaction (SSI) of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. The ED50s for ACE and PROP were 286.1 +/- 1.4 mg/kg and 66.3 +/- 1.2 mg/kg, respectively. Over the dose ranges used, the analgesic activities of both ACE and PROP tended to be smaller than those of their respective combinations. Furthermore, 11 combinations showed various degrees of enhancement (p<0.01), while the others (13) exhibited additive analgesic effects. The combination of ACE (562.3 mg/kg) and PROP (56.2 mg/kg) produced the maximum analgesic effect. However,5 combinations of ACE with PROP (177.8-56.2, 316.2-10.0, 316.2-17.8, 316.2-56.2 and 562.3-10.0 mg/kg) produced the highest enhancement. The SSI clearly showed which combination of these analgesic drugs produced the highest degree of enhancement in the rat. This study shows that a specific combination ratio of analgesic drugs can produce optimum enhancement of their analgesic effects.

Assuntos

Acetaminofen/farmacologia , Analgésicos não Narcóticos/farmacologia , Analgésicos Opioides/farmacologia , Dextropropoxifeno/farmacologia , Acetaminofen/administração & dosagem , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos Opioides/administração & dosagem , Análise de Variância , Animais , Dextropropoxifeno/administração & dosagem , Sinergismo Farmacológico , Feminino , Injeções Subcutâneas , Modelos Teóricos , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , Ácido Úrico/administração & dosagem , Ácido Úrico/toxicidade

RESUMO

In this work we show that the pain-induced functional impairment model (PIFIR) can be used with cannulated rats as a useful procedure for pharmacokinetic/pharmacodynamic modelling. This model evaluates analgesia by measuring motor impairment of the right limb after intra-articular administration of uric acid. Time of contact with a rotating cylinder is referred to the control limb. We studied the pharmacokinetic and pharmacodynamics of naproxen after six peroral doses to Wistar rats, and we examined the adjuvant action of caffeine with naproxen. Surgery and blood sampling did not produce any difference on functional impairment either in rats without uric acid or in the dysfunction produced by uric acid. The relation between naproxen plasma concentration and the analgesic effect was obtained with few rats. Caffeine alone did not produce any significant modification in functional impairment but the co-administration significantly increased the effect of naproxen. Plasma levels of naproxen did not change when caffeine was co-administered. The PIFIR model with blood sampling is a suitable method for pharmacokinetic/pharmacodynamic relationship studies and is specially useful to characterize drug-drug interactions.

Assuntos

Analgésicos/sangue , Transtornos dos Movimentos/tratamento farmacológico , Medição da Dor/métodos , Analgésicos/farmacologia , Animais , Cafeína/farmacologia , Interações Medicamentosas , Feminino , Naproxeno/sangue , Naproxeno/farmacologia , Ratos , Ratos Wistar , Ácido Úrico

RESUMO

The involvement of nitric oxide in the antinociception produced by ketorolac was assessed using the pain-induced functional impairment model in the rat: 800 micrograms of NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, or saline was injected intra-articularly in a hind limb joint previously injured with uric acid. Animals then received ketorolac, dipyrone or no drug. Ketorolac and dipyrone produced a significant antinociceptive effect which was reduced by pretreatment with NG-nitro-L-arginine methyl ester, but not with saline. It is concluded that the antinociceptive effect of both drugs involves the local participation of nitric oxide.

Assuntos

Analgesia , Analgésicos não Narcóticos/farmacologia , Arginina/análogos & derivados , Óxido Nítrico/antagonistas & inibidores , Tolmetino/análogos & derivados , Analgésicos não Narcóticos/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Arginina/farmacologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Dipirona/farmacologia , Feminino , Membro Posterior , Cetorolaco , NG-Nitroarginina Metil Éster , Medição da Dor , Ratos , Ratos Wistar , Tolmetino/administração & dosagem , Tolmetino/farmacologia , Ácido Úrico/toxicidade

RESUMO

In the present paper, we review the cartesian description of the neuromuscular reflex and the sensorial perception as well as the hypothetical role of the pineal gland on these functions. We analyze the historical bases which support the physiological cartesian doctrine and, from the perspective of our present knowledge, we evaluate the contributions of Descartes to the scientific progress of his time. In the elaborated psychophysiological theory of the french wise, the pineal gland plays a pivotal role, raising the theory that the human soul could be located within this organ.

Assuntos

Glândula Pineal/fisiologia , Psicofisiologia/história , História do Século XVI , História do Século XVII , Humanos , Glândula Pineal/anatomia & histologia

RESUMO

In the present paper, we review the cartesian description of the neuromuscular reflex and the sensorial perception as well as the hypothetical role of the pineal gland on these functions. We analyze the historical bases which support the physiological cartesian doctrine and, from the perspective of our present knowledge, we evaluate the contributions of Descartes to the scientific progress of his time. In the elaborated psychophysiological theory of the french wise, the pineal gland plays a pivotal role, raising the theory that the human soul could be located within this organ.