RESUMEN
Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEXinduced antinociception.
Asunto(s)
Cetoprofeno/análogos & derivados , Receptores Opioides/genética , Receptores de Serotonina/genética , Trometamina/farmacología , Dolor Visceral/tratamiento farmacológico , Ácido Acético/farmacología , Analgesia/métodos , Analgésicos/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Cetoprofeno/farmacología , Ratones , Antagonistas de Narcóticos/farmacología , Óxido Nítrico/genética , Serotonina/genética , Antagonistas de la Serotonina/farmacología , Dolor Visceral/genética , Dolor Visceral/patologíaRESUMEN
Neuropathic pain is a complication of cancer and diabetes mellitus and the most commonly used drugs in the treatment of the diabetic neuropathic pain have only limited efficacy. The aim of this study was to evaluate the role of the biomarker interleukin-1beta (IL-1ß) in the pharmacological interaction of gabapentin with tramadol in a model of diabetic neuropathic pain. CF-1 male mice, pretreated with 200 mg/kg i.p. of streptozocin (STZ), were used and at day 3 and 7 were evaluated by the hot plate test and the spinal cord level of IL-1ß was determined. Antinociceptive interaction of the coadministration i.p. of gabapentin with tramadol, in basic of the fixed the ratio 1:1 of their ED50 values alone, was ascertained by isobolographic analysis. Tramadol was 1.13 times more potent than gabapentin in saline control mice, 1.40 times in STZ mice at 3 days and 1.28 times in STZ at 7 days. The interaction between gabapentin and tramadol was synergic, with an interaction index of 0.30 and 0.22 for mice pretreated with STZ at 3 and 7 days. The combination of gabapentin with tramadol reversed the increased concentration of IL-1ß induced by STZ in diabetic neuropathic mice. These findings could help clarify the mechanism of diabetic neuropathy.
Asunto(s)
Neuropatías Diabéticas/complicaciones , Gabapentina/farmacología , Interleucina-1beta/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/genética , Tramadol/farmacología , Analgésicos/farmacología , Animales , Neuropatías Diabéticas/metabolismo , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Masculino , Ratones , Neuralgia/metabolismo , Dimensión del Dolor/métodos , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Estreptozocina/farmacologíaRESUMEN
OBJECTIVE: Diabetic neuropathy (DN) is the most common complication of diabetes and pain is one of the main symptoms of diabetic neuropathy, however, currently available drugs are often ineffective and complicated by adverse events. The purpose of this research was to evaluate the antinociceptive interaction between gabapentin and minocycline in a mice experimental model of DN by streptozocin (STZ). METHODS: The interaction of gabapentin with minocycline was evaluated by the writhing and hot plate tests at 3 and 7 days after STZ injection or vehicle in male CF1 mice. RESULTS: STZ (150 mg/kg, i.p.) produced a marked increase in plasma glucose levels on day 7 (397.46 ± 29.65 mg/dL) than on day 3 (341.12 ± 35.50 mg/dL) and also developed neuropathic pain measured by algesiometric assays. Gabapentin produced similar antinociceptive activity in both writhing and hot plate tests in mice pretreated with STZ. However, minocycline was more potent in the writhing than in the hot plate test in the same type of mice. The combination of gabapentin with minocycline produced synergistic interaction in both test. CONCLUSION: The combination of gabapentin with minocycline in a 1:1 proportion fulfills all the criteria of multimodal analgesia and this finding suggests that the combination provide a therapeutic alternative that could be used for human neuropathic pain management.
Asunto(s)
Aminas/administración & dosificación , Analgésicos/administración & dosificación , Ácidos Ciclohexanocarboxílicos/administración & dosificación , Neuropatías Diabéticas/tratamiento farmacológico , Minociclina/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Ácido gamma-Aminobutírico/administración & dosificación , Aminas/metabolismo , Analgésicos/metabolismo , Animales , Ácidos Ciclohexanocarboxílicos/metabolismo , Neuropatías Diabéticas/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Gabapentina , Masculino , Ratones , Minociclina/metabolismo , Dimensión del Dolor/métodos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Atorvastatin is a statin that inhibits the 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Several landmark clinical trials have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. It is assumed that the beneficial effects of statin therapy are entirely due to cholesterol reduction. Statins have an additional activity (pleiotropic effect) that has been associated to their anti-inflammatory effects. The aim of the present study was to assess the antinociceptive activity of atorvastatin in five animal pain models. The daily administration of 3-100mg/kg of atorvastatin by oral gavage induced a significant dose-dependent antinociception in the writhing, tail-flick, orofacial formalin and formalin hind paw tests. However, this antinociceptive activity of atorvastatin was detectable only at high concentrations in the hot plate assay. The data obtained in the present study demonstrates the effect of atorvastatin to reduce nociception and inflammation in different animal pain models.
Asunto(s)
Modelos Animales de Enfermedad , Ácidos Heptanoicos/farmacología , Ácidos Heptanoicos/uso terapéutico , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Dolor/tratamiento farmacológico , Pirroles/farmacología , Pirroles/uso terapéutico , Animales , Atorvastatina , Relación Dosis-Respuesta a Droga , Calor/efectos adversos , Masculino , Ratones , Dolor/fisiopatologíaRESUMEN
Animal models are used to research the mechanisms of pain and to mimic human pain. The purpose of this study was to determine the degree of interaction between dexketoprofen and dexibuprofen, by isobolographic analysis using the formalin orofacial assay in mice. This assay presents two-phase time course: an early short-lasting, phase I, starting immediately after the formalin injection producing a tonic acute pain, leaving a 15 min quiescent period, followed by a prolonged, phase II, after the formalin and representing inflammatory pain. Administration of dexketoprofen or dexibuprofen produced a dose-dependent antinociception, with different potency, either during phases I or II. The co-administration of dexketoprofen and dexibuprofen produced synergism in phase I and II. In conclusion, both dexketoprofen and dexibuprofen are able to induce antinociception in the orofacial formalin assay. Their co-administration produced a synergism, which could be related to the different degree of COX inhibition and other mechanisms of analgesics.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ibuprofeno/farmacología , Cetoprofeno/farmacología , Animales , Conducta Animal , Interacciones Farmacológicas , Cara , Masculino , Ratones , Boca , Dimensión del Dolor , EstereoisomerismoRESUMEN
OBJECTIVE AND DESIGN: The antinociception induced by the intraperitoneal coadministration in mice of combinations of metamizol and paracetamol was evaluated in the tail flick test and orofacial formalin test. METHODS: The antinociception of each drugs alone and the interaction of the combinations was evaluated by isobolographic analysis in the tail-flick and in the formalin orofacial assay of mice. RESULTS: Mice pretreated with the drugs demonstrated that the antinociception of metamizol and paracetamol is dose-dependent. The potency range on the antinocifensive responses for metamizol or paracetamol was as follows: orofacial (Phase II) > orofacial (Phase I) > tail flick. In addition, the coadministration of metamizol with paracetamol induced a strong synergistic antinociception in the algesiometer assays. Both drugs showed effectiveness in inflammatory pain. CONCLUSION: These actions can be related to the differential selectivity of the drugs for inhibition of COX isoforms and also to the several additional antinociception mechanisms and pathways initiated by the analgesic drugs on pain transmission. Since the efficacy of the combination of metamizol with paracetamol has been demonstrated in the present study, this association could have a potential beneficial effect on the pharmacological treatment of clinical pain.
Asunto(s)
Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Dolor/prevención & control , Prostaglandina-Endoperóxido Sintasas/metabolismo , Acetaminofén/uso terapéutico , Animales , Dipirona/uso terapéutico , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Formaldehído/farmacología , Calor , Masculino , Ratones , Ratones Endogámicos , Dolor/inducido químicamente , Dimensión del Dolor/métodosRESUMEN
To enhance analgesia, combination of analgesics drugs of proven efficacy is a strategy which is accompanied by a reduction of adverse effects. The present study was undertaken to characterize the antinociceptive interaction of morphine with different non-steroidal anti-inflammatory drugs (NSAIDs) using isobolographic analysis and the writhing test of mice. One of the possible mechanisms of action of spinally administered morphine with non-steroidal antiinflammatory drugs was investigated using the DOR antagonist naltrindole. The study demonstrated a synergistic antinociception of spinal administered combinations of morphine with the following NSAIDs agents: diclofenac, ketoprofen, meloxicam, metamizol, naproxen, nimesulide, parecoxib and piroxicam. The supraadditive effect seems to be independent of the selectivity of each NSAIDs to inhibit COX-1 or COX-2. The findings of the present work suggest that the combinations of opioids and non-steroidal anti-inflammatory drugs have a direct action on spinal processing of the nociceptive information, which may achieved by additional mechanisms independent of prostaglandin synthesis inhibition and/or activation of opioid receptors. The lack of effect of naltrindole to modify the analgesic activity of the combination of opioids and NSAIDs indicates that others pain regulatory systems are involved in this central action. Therefore, these combinations could be a viable alternative to clinical pain management, especially trough multimodal analgesia.
Asunto(s)
Analgésicos Opioides/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Morfina/farmacología , Naltrexona/análogos & derivados , Receptores Opioides delta/fisiología , Médula Espinal/efectos de los fármacos , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/uso terapéutico , Animales , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/uso terapéutico , Sinergismo Farmacológico , Inyecciones Espinales , Masculino , Ratones , Ratones Endogámicos , Morfina/administración & dosificación , Morfina/uso terapéutico , Naltrexona/administración & dosificación , Naltrexona/farmacología , Naltrexona/uso terapéutico , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Receptores Opioides delta/antagonistas & inhibidores , Médula Espinal/fisiopatologíaRESUMEN
The antinociceptive activity of dexketoprofen was studied in mice using the formalin assay for orofacial pain. The interaction between dexketoprofen and co-administered tramadol was studied using isobolographic analysis. The intraperitoneal administration of dexketoprofen or tramadol, showed dose-dependent antinociceptive activity in both phases of the assay. When administered together, the interaction was mildly synergistic during the first phase, and antagonistic in the second phase. Selective opioid receptor antagonists where used in order to measure the analgesic activity of tramadol in other regions of the CNS. The co-administration of dexketoprofen and tramadol, with previous administration of naltrexone, showed high synergistic activity during the first phase, and less but still synergistic during the second. When using naltrindole, the interaction was mildly more synergistic than the mixture dexketoprofen+tramadol during both phases. Using norbinaltorphimine, the interaction was synergistic in both phases, more marked in the second. These results suggest that the opioid activity of tramadol has an inhibiting effect in antinociceptive activity of the interaction between dexketoprofen and tramadol during the inflammatory (late) stages of pain.
Asunto(s)
Analgésicos/uso terapéutico , Cetoprofeno/uso terapéutico , Antagonistas de Narcóticos/farmacología , Dolor/tratamiento farmacológico , Tramadol/uso terapéutico , Analgésicos/farmacología , Animales , Sinergismo Farmacológico , Cetoprofeno/farmacología , Masculino , Ratones , Antagonistas de Narcóticos/administración & dosificación , Dolor/inducido químicamente , Tramadol/farmacologíaRESUMEN
The purpose of the present study was to evaluate the nature of the antinociceptive interaction among dexketoprofen (DEX), a mixed inhibitor of the cyclo-oxygenases, and tramadol (TRAM), a weak opioid with monoaminergic activity that inhibits norepinephrine and serotonin re-uptake. We assessed antinociception in the acetic acid writhing test, the tail flick and the formalin (FT) tests, and gastrointestinal transit (GIT) after the administration of a charcoal meal. The analysis of the interaction was carried out using isobolograms and interaction indexes or the fixed-dose method GIT. The administration of DEX or TRAM individually induced dose-dependent antinociception in all the algesiometric tests. In the three tests, TRAM was between 5.2 (FT, phase I) and 35 times (FT, Phase II) more potent than DEX. When testing combinations at different potency ratios (1 : 1, 1 : 3, 3 : 1), we could demonstrate synergy in all algesiometric tests, only when drugs were combined in a 1 : 1 proportion. Interestingly, the proportion of the drugs in the combination could change the type of interaction from synergy to antagonism. On the inhibition of GIT, a dose-related inhibition was established for TRAM, but not for DEX. Using a fixed-dose protocol, we could demonstrate antagonism between DEX and TRAM on the inhibition of GIT. The results of the present study suggest that a combination of DEX and TRAM in a 1 : 1 proportion could be adequate to use in future clinical trials in humans.
Asunto(s)
Tránsito Gastrointestinal/efectos de los fármacos , Cetoprofeno/análogos & derivados , Dolor/tratamiento farmacológico , Tramadol/farmacología , Trometamina/análogos & derivados , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Carbón Orgánico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Cetoprofeno/administración & dosificación , Cetoprofeno/farmacología , Masculino , Ratones , Dolor/etiología , Dimensión del Dolor , Tramadol/administración & dosificación , Trometamina/administración & dosificación , Trometamina/farmacologíaRESUMEN
Opioids and non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve acute and chronic pain. The purpose of this study was to determine the degree of interaction between dexketoprofen and NSAID examples of COXs inhibitors using the isobolographic analysis in the formalin orofacial test in mice. The drugs, i.p., induced a dose-dependent antinociception with different potencies in both test phases. Combinations of dexketoprofen with naproxen, nimesulide, ibuprofen or paracetamol on the basis of the fixed ratio (1:1) of their ED(50)'s values alone demonstrated synergism in both phases. This is important since the orofacial pain is a test not currently used in mice; the drugs are all analgesic for humans and phase II is representative of inflammatory pain. The synergism was: COX-3>COX-2>COX-1 inhibitors, this is particularly interesting since the inhibitor of COX-3, paracetamol, displayed a robust anti-inflammatory activity in an assay of acute and inflammatory pain that mimics inflammatory pain in humans. In conclusion, the synergism of the dexketoprofen/NSAID combinations may improve this type of therapeutic profile, since with low doses of the components, side effects are not likely to occur, and they may be used in long-term treatments.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Formaldehído/toxicidad , Dolor/tratamiento farmacológico , Animales , Sinergismo Farmacológico , Cara , Femenino , Masculino , Ratones , Boca , Dolor/inducido químicamenteRESUMEN
The present study was undertaken to characterize the interactions between nonsteroidal anti-inflammatory drugs and the alpha(2)-adrenoceptor agonist clonidine in an acute nociceptive test. The writhing test was selected as a model of acute visceral pain. Isobolograms were constructed to assess the interactions of clonidine and each nonsteroidal anti-inflammatory drugs, when coadministered intraperitoneally and intrathecally (i.t.). The simultaneous intraperitoneal administration of fixed ratios of ED(50) fractions of all nonsteroidal anti-inflammatory drugs (naproxen, piroxicam, paracetamol, dipyrone or metamizol and nimesulide) combined with clonidine resulted in synergistic interactions. The same combinations administered intrathecally were additive. The synergistic interactions between systemic nonsteroidal anti-inflammatory drugs and clonidine may involve supraspinal mechanisms.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Clonidina/farmacología , Dimensión del Dolor/efectos de los fármacos , Analgésicos/farmacocinética , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Clonidina/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Quimioterapia Combinada , Femenino , Inyecciones Intraperitoneales , Inyecciones Espinales , Masculino , Ratones , Dimensión del Dolor/métodosRESUMEN
The antinociceptive activity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been explained mainly on the basis of their inhibition of the enzyme cyclooxygenase (COX); however, this inhibition is not enough to completely explain the analgesic efficacy of these drugs. The modulation exerted by serotonergic systems on antinociception is well known. The purpose of the present work was to further explore the role of serotonin in the antinociceptive activity of NSAIDs using the writhing test and the tail-flick test of the mice after the inhibition of serotonin biosynthesis with intraperitoneal p-chlorophenylalanine (p-CPA). Pretreatment with p-CPA produced a significant decrease in the antinociceptive activity of NSAIDs administered either by the intraperitoneal or intrathecal routes, in both algesiometric tests. These results suggest a complementary mechanism of antinociception for NSAIDs, independent of their ability to inhibit the activity of COX, involving the activation of descending serotonergic pathways. By the pharmacological nature of the study, one limitation was the absence of biochemical measurement of the synthesis of 5-HT, since the reduction of the brain 5-HT synthesis by pretreatment with p-CPA will be expressed as a diminished antinociceptive activity of NSAIDs, which would be a new argument to consider NSAIDs acting as central analgesic agents.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Dimensión del Dolor/efectos de los fármacos , Dolor/metabolismo , Serotonina/biosíntesis , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Fenclonina/farmacología , Masculino , Ratones , Tiempo de Reacción/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Factores de TiempoRESUMEN
The nonsteroidal anti-inflammatory drugs (NSAIDs) clonixin, diclofenac, piroxicam, ketoprofen, meloxicam, and paracetamol induced antinociception after intraperitoneal or intrathecal administration in mice submitted to an acute thermal algesiometric test without inflammation (tail-flick). Antinociception was evaluated by the increase in reaction time difference (Delta latency), between readings obtained before and after the administration of drugs. The antinociception induced by doses of NSAIDs producing between 20% and 30% of the maximum possible effect (MPE) 30 min after intraperitoneal and 15 min after intrathecal injections was compared with the antinociception obtained after pretreatment with 1 mg/kg atropine ip, 30 min before. Systemic atropine (1 mg/kg) significantly antagonized NSAID-induced antinociception in all cases, both after intraperitoneal and intrathecal administration. Cholinergic depletion by intracerebroventricular hemicholinium-3 (HC-3, 5 microg) 5 h before prevented the antinociceptive effect of all NSAIDs. These observations suggest that intrinsic muscarinic cholinergic facilitatory pathways represent an important modulating system in pain perception in this animal model of acute thermal pain. The results of the present work support the increasingly accepted notion that NSAIDs are effective analgesics even when inflammation is not present, acting by mechanisms that involve actions on spinal and supraspinal nociceptive transmission. It is suggested that, similar to morphine and clonidine, the active mechanism of NSAIDs may involve the release of acetylcholine (ACh) in the spinal cord.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/antagonistas & inhibidores , Antiinflamatorios no Esteroideos/farmacología , Atropina/farmacología , Dimensión del Dolor/efectos de los fármacos , Animales , Femenino , Masculino , Ratones , Dimensión del Dolor/métodos , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiologíaRESUMEN
The inhibition of cyclooxygenase enzymes by nonsteroidal anti-inflammatory drugs (NSAIDs) does not completely explain the antinociceptive efficacy of these agents. It is known that cholinergic agonists are antinociceptive, and this study evaluates the interactions between carbachol and some NSAIDs. Antinociceptive activity was evaluated in mice by the acetic acid writhing test. Dose-response curves were constructed for NSAIDs and carbachol, administered either intraperitoneally (i.p.) or intrathecally (i.t.). The interactions of carbachol with NSAIDs were evaluated by isobolographic analysis after the simultaneous administration of fixed proportions of carbachol with each NSAID. All of the drugs were more potent after spinal than after systemic administration. The combinations of NSAIDs and carbachol administered i.p. were supra-additive; however, the i.t. combinations were only additive. Isobolographic analysis of the coadministration of NSAIDs and carbachol and the fact that atropine antagonized the synergistic effect suggest that carbachol may strongly modulate the antinociceptive activity of NSAIDs; thus, central cholinergic modulation would be an additional mechanism for the antinociceptive action of NSAIDs, unrelated to prostaglandin biosynthesis inhibition.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Carbacol/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Carbacol/farmacocinética , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Sinergismo Farmacológico , RatonesRESUMEN
UNLABELLED: We evaluated the noradrenergic modulation of the antinociceptive activity of diclofenac in mice using the acetic acid writhing test. Dose-response curves were obtained for the antinociceptive effect of diclofenac, phenylephrine, clonidine, desipramine, prazosin, and yohimbine administered both systemically and intrathecally, and ED(50)s were calculated. Noradrenergic modulation was evaluated by performing an isobolographic analysis of the systemic or intrathecal coadministration of fixed-ratio combinations of diclofenac with each adrenergic drug. The systemic, but not the intrathecal, combinations of diclofenac with phenylephrine or clonidine showed supraadditivity, suggesting that the activation of alpha(1) and alpha(2) adrenoceptors interfered with the nociceptive transmission at spinal and supraspinal levels. Supraadditive effects were not demonstrated for the intrathecal injection of diclofenac combined with phenylephrine, clonidine and a selective norepinephrine uptake inhibitor (desipramine) or adrenergic antagonists. We conclude that interaction between adrenoceptors and diclofenac can modulate antinociception by activating common or different mechanisms. Diclofenac has an antinociceptive activity that, in addition to cyclooxygenase inhibition, can be modulated by additive and supraadditive interactions with adrenergic drugs. IMPLICATIONS: Diclofenac analgesia in mice can be modulated by interaction with adrenergic drugs. The systemic but not the intrathecal administration of phenylephrine and clonidine produced supraadditive interactions. For desipramine, prazosin, and yohimbine, supraadditive interactions were not statistically demonstrated. The coadministration of drugs inducing supraadditive effects could be clinically relevant for the treatment of chronic pain because of reduction of doses and side effects.
Asunto(s)
Adrenérgicos/farmacología , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Diclofenaco/farmacología , Animales , Clonidina/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Ratones , Fenilefrina/farmacología , Prazosina/farmacología , Yohimbina/farmacologíaRESUMEN
The frequency of oestrus cycles in female mice was significantly reduced by the implantation of a pellet of subcutaneous ketoconazole (50 mg every 6 days). The effect was more pronounced after 22 days than after 13 days and it was probably related with the progressive reduction in steroid synthesis induced by the inhibition of key steroidogenic P450 cytochromes by the drug. In addition, the influence of ketoconazole on the incidence of seizures after the administration of intraperitoneal pentylenetetrazol was evaluated in female mice. Pentylenetetrazol produced a higher percentage of seizures during dioestrus than during oestrus. Pretreatment with ketoconazole significantly increased the percentage of animals with induced seizures in oestrus but not in dioestrus as compared to controls, probably through reduced progesterone levels. The reduced seizure threshold confirm the modulatory role exerted by progesterone on central nervous system excitability, and may be relevant in epileptic patients undergoing antifungal therapy.
Asunto(s)
Antifúngicos/farmacología , Ciclo Estral/efectos de los fármacos , Cetoconazol/farmacología , Convulsiones/fisiopatología , Animales , Convulsivantes/farmacología , Femenino , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos , Pentilenotetrazol/farmacología , Convulsiones/inducido químicamente , Factores de TiempoRESUMEN
The antinociceptive activity of several nonsteroidal anti-inflammatory drugs (NSAIDs) that were administered either intraperitoneally or intrathecally was assessed in mice by two algesiometric tests. The first was the writhing test, which assessed the abdominal constrictions that were induced by intraperitoneal acetic acid (a chemical test), and the second was the tail flick test, which measured pain responses to heat stimuli. The corresponding effective doses and their relative potencies were compared because these tests use different nociceptive stimuli with different transmission pathways. The intraperitoneal and intrathecal dose-response curves for the antinociception induced by every NSAID that was tested were parallel in the writhing test. In the tail flick test, however, only the intraperitoneal and intrathecal dose-response curves for ketoprofen, piroxicam, naproxen, nimesulide, paracetamol and diclofenac were parallel. The results obtained in this study confirm that NSAIDs possess different abilities to induce inhibition of cyclooxygenase, and they can be indirectly assessed by their different antinociceptive activities, depending on the algesiometric assays that are used. The antinociception of most NSAIDs might involve central mechanisms. The findings demonstrate the increasing importance of the spinal cord in processing and modulating nociceptive input, because intrathecal administration of NSAIDs is always more effective (in terms of potency) than systemic administration; thus, the antinociceptive efficacy of NSAIDs strongly depends on the algesiometric assay that is used and on the type of the nociceptive stimulus to which the test subject is exposed.