RESUMO
The influence of cyclooxygenase (COX) and NO synthase inhibitors on antinociceptive action of acetaminophen (ACETA) was studied in rats. ACETA increased the nociceptive threshold for both mechanical (Randall-Selitto test) and chemical stimuli (writhing test). In both models the existence of ceiling dose of ACETA was observed. Indomethacin (IND), an inhibitor preferentially acting on COX-1, as well as nimesulide (NIM) and celecoxib (CECOX), i.e. respectively preferential and selective inhibitors of COX-2, markedly decreased the antinociceptive activity of ACETA in Randall-Selitto test. In contrast, IND increased, whereas both NIM and CECOX did not have any effect on ACETA action in writhing test. Pretreatment with LG-nitro-L-arginine (L-NO-ARG), an unspecific inhibitor of NO synthase, 7-nitroindazole (7-NI), relatively specific inhibitor of neuronal NO synthase, and L-N6(1-iminoethyl)lysine (L-NIL), relatively selective inhibitor of inducible NO synthase, significantly increased the action of the lower doses of ACETA (50 and 100 mg/kg) in writhing test, whereas it did not modify the effects of the higher doses. Similar effect of L-NO-ARG and 7-NI was observed in Randall-Selitto test, whereas L-NIL did not influence the action of ACETA. The possible involvement of COX and NO synthase systems in antinociceptive activity of ACETA is discussed.
Assuntos
Acetaminofen/farmacologia , Analgésicos não Narcóticos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoenzimas/antagonistas & inibidores , Lisina/análogos & derivados , Óxido Nítrico Sintase/antagonistas & inibidores , Acetaminofen/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Animais , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Indazóis/farmacologia , Lisina/farmacologia , Masculino , Proteínas de Membrana , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo II , Nitroarginina/farmacologia , Limiar da Dor/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Estimulação Química , Estresse Mecânico , Especificidade por SubstratoRESUMO
The present study was undertaken to investigate the role of inducible nitric oxide synthase in a rat model of persistent pain. The effects of L-N6 (1-iminoethyl) lysine (L-NIL), a relatively potent and relatively selective inhibitor of inducible nitric oxide synthase, were investigated in carrageenan induced hyperalgesia L-NIL (0.1 microMole) injected intraplantar or intrathecal markedly enhanced carrageenan induced hyperalgesia. These effects were reversed during the third hour by co-administration of L-arginine (900 mg/kg i.p.) but not D-arginine. Methylene blue (MB), a soluble guanylate cyclase inhibitor, administered intrathecally (0.1 microg) had no effect on L-NIL potentiation of carrageenan hyperalgesia but abolished antinociception induced by L-arginine. Obtained results suggest that nitric oxide derived from inducible nitric oxide synthase play an inhibitory role in carrageenan produced hyperalgesia in rat.
Assuntos
Inibidores Enzimáticos/farmacologia , Lisina/análogos & derivados , Óxido Nítrico Sintase/antagonistas & inibidores , Dor/etiologia , Animais , Arginina/farmacologia , Carragenina/farmacologia , Doença Crônica , Lisina/farmacologia , Masculino , Azul de Metileno/farmacologia , Óxido Nítrico Sintase Tipo II , Dor/enzimologia , Ratos , Ratos WistarRESUMO
Amorphos injectable form of aztreonam (BIOKTAM) was prepared. It was shown that after intramuscular or intravenous administration there are not any considerable differences in the bioavailability of aztreonam from BIOKTAM and of the drug from AZACTAM.
Assuntos
Aztreonam/farmacocinética , Monobactamas/farmacocinética , Adulto , Área Sob a Curva , Aztreonam/química , Disponibilidade Biológica , Química Farmacêutica , Feminino , Humanos , Injeções Intramusculares , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Monobactamas/químicaRESUMO
Concentrations of cefuroxime [II] in blood of rats were measured 30 and 60 min. after administration of amorphous form possessing various particles size (ranging from 0.09 to 0.4 nm) and crystal form of 1-acethoxyethyl ester of cefuroxime [I]. In vitro the concentrations of [II] were measured 15 and 45 min. after application of [I]. HPLC method was used for cefuroxime estimation. Close correlation between the particles size of the amorphous [I] and the concentrations of [II] in vivo as well as in vitro was found, the particles with lover size possessed higher bioavailability. The cefuroxime front the crystal form of ester is poorly absorbed and the concentrations of [II] after its application were similar to those observed after of the bigest particles of amorphous form both in vivo and in vitro.
Assuntos
Cefuroxima/análogos & derivados , Cefalosporinas/sangue , Mucosa Gástrica/metabolismo , Pró-Fármacos/metabolismo , Animais , Disponibilidade Biológica , Cefuroxima/administração & dosagem , Cefuroxima/sangue , Cefuroxima/química , Cefalosporinas/administração & dosagem , Cefalosporinas/química , Masculino , Permeabilidade , Ratos , Ratos WistarAssuntos
Farmacocinética , Farmacologia , Estereoisomerismo , Animais , Fenômenos Químicos , Química , HumanosAssuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Catarata/prevenção & controle , Cristalino/efeitos dos fármacos , Fatores Etários , Idoso , Catarata/etiologia , Diabetes Mellitus Tipo 2/complicações , Humanos , Hiperglicemia/complicações , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The effect of long-term administration of propranolol (0.2 and 0.4 mg/kg-1 p.o.) and that of labetalol (2.0, 4.0 and 8.0 mg/kg-1 p.o. and 1 mg/kg-1 i.p.) on the development of hypertension was studied in female rats of SHR/N/Ibn strain. The experiment was started on 6-week-old animals. Rats received the tested drugs once daily between 11 and 12 o'clock. From the 29th day on (i.e. after the age of 10 weeks) the arterial blood pressure was measured bloodlessly twice weekly 2 hours before the daily dose of the drug. Labetalol given p.o. in a dose of 2 mg/kg-1 had no effect on the development of hypertension, while the doses 4.0 and 8.0 mg/kg-1 decreased the arterial pressure by about 4 kPa (30 mm Hg). After drug withdrawal a rapid rise was observed in the arterial pressure to values approaching the values recorded in control animals. In the animals receiving labetalol parenterally (1 mg/kg-1 i.p.) the blood pressure was significantly lower than in control rats. After drug withdrawal the blood pressure increased gradually, however, even on the 54th day of the experiment it was slightly below that in controls. Propranolol given orally in doses of 0.2 mg/kg-1 delayed the development of hypertension, while in the dose of 0.4 mg/kg-1 it prevented its development. After withdrawal of the lower drug dose the blood pressure remained for about 2 weeks at a level similar to the previous one, later on it increased steeply to the values observed in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Etanolaminas/uso terapêutico , Hipertensão/prevenção & controle , Labetalol/uso terapêutico , Propranolol/uso terapêutico , Animais , Feminino , Labetalol/administração & dosagem , Propranolol/administração & dosagem , Ratos , Ratos Endogâmicos SHRRESUMO
Analogs of substance P in which the N-terminal part of native peptide was replaced by an enkephalin active fragment have been synthesized. We found this peptide to be as active as substance P on the GPI test. The analogs were completely inactive on GPI opiate test; the opiate activity was observed on MVD and RVD tests. Surprisingly, we found that SP-activity was reduced by naloxone.
Assuntos
Substância P/análogos & derivados , Substância P/farmacologia , Animais , Bioensaio , Encefalinas , Cobaias , Íleo/efeitos dos fármacos , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade , Substância P/síntese química , Ducto Deferente/efeitos dos fármacosRESUMO
Seven pentapeptides, chemically related both to C-terminal fragment of substance P and Met-enkephalin were synthetized and their pharmacological properties were investigated. Peptides I-VI (L-amino acid residue in position 2) antagonized the inhibitory action of D-Ala2-Met-EK-NH2 on isolated vas deferens in vitro but were devoid of opiate-receptor binding activity in radioreceptor studies. Peptide VII (D-Phe2-Met-EK-NH2) exerted a weak inhibitory effect on contractions of transmurally stimulated vas deferens of rat which was abolished by naloxone (10(-8) M) and showed relatively strong but short-lasting analgesic activity in vivo. This peptide at concentration above 10(-5) M partially displaced the 3H-naloxone from its binding sites in striatal membranes. The possible existence of the neuronal substance P-enkephalin self-regulatory mechanism is discussed.
Assuntos
Encefalinas/farmacologia , Substância P/farmacologia , Sequência de Aminoácidos , Analgésicos , Animais , Encefalinas/síntese química , Técnicas In Vitro , Masculino , Neurotransmissores/fisiologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos , Substância P/análogos & derivados , Substância P/síntese químicaRESUMO
The effect of opiate drugs on the caudate spindle (CS) in the cat was observed following both systemic and intracaudal administration. Systemic administration of morphine, pentazocine and pethidine inhibited the CS. The inhibitory effects of opiates were antagonized by lysergide and methysergide but not by naloxone, chlorpromazine, dehydrobenzperidol, amphetamine and atropine. Contrary to their systemic administration, the investigated opiates morphine, pentazocine, pethidine and Met5-Enkephaline enhanced the CS, when injected into the caudate nucleus close to the site of stimulation. Those facilitating effects of opiates on the CS were completely blocked by naloxone. The results suggest that serotoninergic mechanisms might be involved in the action of opiates on the neuronal activity of the caudate nucleus.
Assuntos
Núcleo Caudado/efeitos dos fármacos , Entorpecentes/farmacologia , Animais , Gatos , Núcleo Caudado/fisiologia , Sincronização Cortical , Masculino , Naloxona/farmacologia , Receptores Opioides/efeitos dos fármacosRESUMO
The three newly synthesized derivatives of N-butylpiperidine 1-butyl-4-phenyl-4-isonicotinoylaminoethylpiperidine (BG 25), 1-buty-isonicotinoylpiperidine (BG 26) and N-(1-butyl-4-phenyl-4-piperidinoyl) tetrahydropapaverine (BG 9) were evaluated for analgesic activity and opiate receptor affinity. All the three compounds showed analgesic activity both in hot-plate and flinch-squeak-jump test in mice, BG 9 being the most potent. The affinity of the compounds to opiate receptor was moderate (in comparison with pentazocine): the affinity of BG 9 was much greater than that of BG 25 and BG 26. The compounds showed a pronounced inhibitory action in stimulated guinea-pig ileum preparation; this was reversible by naloxone. As evaluated on pA basis, all three investigated compounds showed moderate antagonistic activity. Also in this respect BG 9 was more active than the other two compounds. Cholinolytic and strong spasmolytic properties were observed in isolated rat ileum preparation for BG 9 only.
Assuntos
Analgésicos/farmacologia , Ácidos Isonicotínicos/farmacologia , Papaverina/análogos & derivados , Piperidinas/farmacologia , Receptores Opioides/metabolismo , Tetra-Hidropapaverolina/análogos & derivados , Analgésicos/metabolismo , Animais , Sítios de Ligação , Cobaias , Técnicas In Vitro , Dose Letal Mediana , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Ratos , Tetra-Hidropapaverolina/farmacologiaAssuntos
Hipotálamo/metabolismo , Neurotensina/fisiologia , Neurotransmissores/fisiologia , Somatostatina/fisiologia , Hormônio Liberador de Tireotropina/fisiologia , Depressão/tratamento farmacológico , Hormônios/uso terapêutico , Humanos , Somatostatina/uso terapêutico , Hormônio Liberador de Tireotropina/uso terapêuticoRESUMO
Pain evoked potentials (EPs) were recorded in nucleus caudatus (NC) of rabbits after electric stimulation of the dental pulp. After 50--60 noxious stimuli the decrease in amplitude of evoked potentials occured. Naloxone, 1 mg/kg, temporarily abolished this effect and even after 350 noxious stimuli the habituation was not observed. On the other hand, naloxone did not affect the diminution of monosynaptic transcallosal potentials (TC--EP) evoked by repeated stimulation. It may be suggested that the habituation of EPs elicited by pain stimulation is due to endorphin release.
Assuntos
Habituação Psicofisiológica/efeitos dos fármacos , Naloxona/farmacologia , Dor/fisiopatologia , Animais , Polpa Dentária/fisiologia , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , CoelhosRESUMO
Analgesic activity of pethidine and pentazocine in the locus coeruleus lesioned rats was evaluated. Bilateral destruction of locus coeruleus resulted in a marked decrease in noradrenaline content in forebrain but did not change significantly the levels of dopamine. Lesioned animals showed a marked decrease of predrug pain threshold. However, pethidine increased more effectively the nociceptive threshold in lesioned rats. The effect observed after pentazocine was generally similar but the maximal increase in pain threshold in lesioned animals did not differ significantly from the values observed in sham lesioned rats. The action of both analgesics was markedly prolonged after the lesion of the locus coeruleus.