RESUMEN

Cholestasis is associated with analgesia. The histamine H(2) receptors control pain perception. The involvement of histamine H(2) receptors on modulation of nociception in a model of elevated endogenous opioid tone, cholestasis, was investigated in this study using zolantidine and cimetidine as two H(2) receptor antagonists and dimaprit as a selective H(2) receptor agonist. Cholestasis was induced by ligation of the main bile duct using two ligatures and transsection of the duct at the midpoint between them. A significant increase in tail-flick latencies was observed in cholestatic rats compared to non-cholestatic rats. Administration of zolantidine (10, 20 and 40 mg/kg) and cimetidine (25, 50 and 100 mg/kg) in the cholestatic group significantly increased tail-flick latencies while dimaprit (10 and 20 mg/kg) injection in the cholestatic group decreased tail-flick latencies compared to the saline treated cholestatic group. Antinociception produced by injection of zolantidine and cimetidine in cholestatic rats was attenuated by co-administration of naloxone. Drug injection in non-cholestatic rats did not alter tail-flick latencies compared to the saline treated rats at any of the doses. At the doses used here, none of the drugs impaired motor coordination as revealed by the rota rod test. These data show that the histamine H(2) receptor system may be involved in the regulation of nociception during cholestasis. According to the hypothesis that increasing the nociception threshold in cholestasis may lead to a decrease in the perception of pruritus, the provision of the drugs that increase the threshold to nociception may be a novel approach to the treatment of cholestatic pruritus.

Asunto(s)

Benzotiazoles/farmacología , Cimetidina/farmacología , Modelos Animales de Enfermedad , Antagonistas de los Receptores H2 de la Histamina/farmacología , Percepción del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Fenoxipropanolaminas/farmacología , Piperidinas/farmacología , Analgesia/psicología , Animales , Benzotiazoles/antagonistas & inhibidores , Colestasis/complicaciones , Colestasis/tratamiento farmacológico , Cimetidina/antagonistas & inhibidores , Dimaprit/farmacología , Masculino , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dolor/complicaciones , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Percepción del Dolor/fisiología , Fenoxipropanolaminas/antagonistas & inhibidores , Piperidinas/antagonistas & inhibidores , Ratas , Ratas Wistar , Receptores Histamínicos H2/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante

RESUMEN

Many analgesic drugs, including µ-opioids, cannabinoids, and the novel nonopioid analgesic improgan, produce antinociception by actions in the rostral ventromedial medulla (RVM). There they activate pain-inhibiting neurons, termed "OFF-cells," defined by a nociceptive reflex-related pause in activity. Based on recent functional evidence that neuronal P450 epoxygenases are important for the central antinociceptive actions of morphine and improgan, we explored the convergence of opioid and nonopioid analgesic drug actions in RVM by studying the effects of the P450 epoxygenase inhibitor CC12 on the analgesic drug-induced activation of these OFF-cells and on behavioral antinociception. In rats lightly anesthetized with isoflurane, we recorded the effects of intraventricular morphine and improgan, with and without CC12 pretreatment, on tail flick latency and activity of identified RVM neurons: OFF-cells, ON-cells (pronociceptive neurons), and neutral cells (unresponsive to analgesic drugs). CC12 pretreatment preserved reflex-related changes in OFF-cell firing and blocked the analgesic actions of both drugs, without interfering with the increase in spontaneous firing induced by improgan or morphine. CC12 blocked suppression of evoked ON-cell firing by improgan, but not morphine. CC12 pretreatment had no effect by itself on RVM neurons or behavior. These data show that the epoxygenase inhibitor CC12 works downstream from receptors for both µ-opioid and improgan, at the inhibitory input mediating the OFF-cell pause. This circuit-level analysis thus provides a cellular basis for the convergence of opioid and nonopioid analgesic actions in the RVM. A presynaptic P450 epoxygenase may therefore be an important target for development of clinically useful nonopioid analgesic drugs.

Asunto(s)

Analgésicos/antagonistas & inhibidores , Cimetidina/análogos & derivados , Imidazoles/farmacología , Bulbo Raquídeo/efectos de los fármacos , Morfina/antagonistas & inhibidores , Percepción del Dolor/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Sulfuros/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Cimetidina/antagonistas & inhibidores , Citocromo P-450 CYP2J2 , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450 , Masculino , Bulbo Raquídeo/citología , Bulbo Raquídeo/fisiología , Modelos Neurológicos , Percepción del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptor Cannabinoide CB1/fisiología , Receptores Opioides mu/fisiología , Receptores Presinapticos/efectos de los fármacos , Receptores Presinapticos/fisiología , Transducción de Señal/efectos de los fármacos , Ácido gamma-Aminobutírico/fisiología

RESUMEN

[(3)H]cimetidine, a radiolabeled histamine H(2) receptor antagonist, binds with high affinity to an unknown hemoprotein in the brain which is not the histamine H(2) receptor. Improgan, a close chemical congener of cimetidine, is a highly effective pain-relieving drug following CNS administration, yet its mechanism of action remains unknown. To test the hypothesis that the [(3)H]cimetidine-binding site is the improgan antinociceptive target, improgan, cimetidine, and 8 other chemical congeners were studied as potential inhibitors of [(3)H]cimetidine binding in membrane fractions from the rat brain. All compounds produced a concentration-dependent inhibition of [(3)H]cimetidine binding over a 500-fold range of potencies (K(i) values were 14.5 to >8000nM). However, antinociceptive potencies in rats did not significantly correlate with [(3)H]cimetidine-binding affinities (r=0.018, p=0.97, n=10). These results suggest that the [(3)H]cimetidine-binding site is not the analgesic target for improgan-like drugs.

Asunto(s)

Analgésicos/farmacología , Encéfalo/metabolismo , Cimetidina/análogos & derivados , Cimetidina/antagonistas & inhibidores , Analgésicos/química , Animales , Sitios de Unión , Cimetidina/química , Cimetidina/farmacología , Relación Dosis-Respuesta a Droga , Histamina/metabolismo , Antagonistas de los Receptores H2 de la Histamina/metabolismo , Masculino , Estructura Molecular , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley

RESUMEN

Improgan, a congener of the H(2) antagonist cimetidine, produces non-opioid antinociception which is blocked by the CB(1) antagonist rimonabant, implying a cannabinoid mechanism of action. Since cannabinoids produce hypothermia as well as antinociception in rodents, the present study investigated the pharmacological activity of improgan on core body temperature and nociceptive (tail flick) responses. Improgan (60, 100 and 140 microg, intraventricular [ivt]) elicited significant decreases in core temperature 3-30 min following injection with a maximal hypothermic effect of -1.3 degrees C. Pretreatment with rimonabant (50 microg, ivt) produced a statistically significant but incomplete (29-42%) antagonism of improgan hypothermia. In control experiments, the CB(1) agonist CP-55,940 (37.9 microg, ivt) induced significant decreases in core temperature (-1.8 degrees C) 3-30 min following injection. However, unlike the case with improgan, pretreatment with rimonabant completely blocked CP-55,940 hypothermia. Furthermore, CP-55,940 and improgan elicited maximal antinociception over the same time course and dose ranges, and both effects were attenuated by rimonabant. These results show that, like cannabinoid agonists in the rat, improgan produces antinociception and hypothermia which is blocked by a CB(1) antagonist. Unlike cannabinoid agonists, however, improgan does not produce locomotor inhibition at antinociceptive doses. Additional experiments were performed to determine the effect of CC12, a recently discovered improgan antagonist which lacks affinity at CB(1) receptors. Pretreatment with CC12 (183 microg, ivt) produced complete inhibition of both the antinociception and the hypothermia produced by improgan, suggesting the possible role of an unknown improgan receptor in both of these effects.

Asunto(s)

Analgésicos/farmacología , Temperatura Corporal/efectos de los fármacos , Cimetidina/análogos & derivados , Umbral del Dolor/efectos de los fármacos , Receptor Cannabinoide CB1/fisiología , Animales , Cimetidina/antagonistas & inhibidores , Cimetidina/farmacología , Imidazoles/farmacología , Masculino , Piperidinas/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Rimonabant , Sulfuros/farmacología

RESUMEN

Improgan, a chemical congener of cimetidine, is a highly effective non-opioid analgesic when injected into the CNS. Despite extensive characterization, neither the improgan receptor, nor a pharmacological antagonist of improgan has been previously described. Presently, the specific binding of [(3)H]cimetidine (3HCIM) in brain fractions was used to discover 4(5)-((4-iodobenzyl)thiomethyl)-1H-imidazole, which behaved in vivo as the first improgan antagonist. The synthesis and pharmacological properties of this drug (named CC12) are described herein. In rats, CC12 (50-500nmol, i.c.v.) produced dose-dependent inhibition of improgan (200-400nmol) antinociception on the tail flick and hot plate tests. When given alone to rats, CC12 had no effects on nociceptive latencies, or on other observable behavioral or motor functions. Maximal inhibitory effects of CC12 (500nmol) were fully surmounted with a large i.c.v. dose of improgan (800nmol), demonstrating competitive antagonism. In mice, CC12 (200-400nmol, i.c.v.) behaved as a partial agonist, producing incomplete improgan antagonism, but also limited antinociception when given alone. Radioligand binding, receptor autoradiography, and electrophysiology experiments showed that CC12's antagonist properties are not explained by activity at 25 sites relevant to analgesia, including known receptors for cannabinoids, opioids or histamine. The use of CC12 as an improgan antagonist will facilitate the characterization of improgan analgesia. Furthermore, because CC12 was also found presently to inhibit opioid and cannabinoid antinociception, it is suggested that this drug modifies a biochemical mechanism shared by several classes of analgesics. Elucidation of this mechanism will enhance understanding of the biochemistry of pain relief.

Asunto(s)

Cimetidina/análogos & derivados , Antagonistas de los Receptores H2 de la Histamina/metabolismo , Imidazoles/farmacología , Receptores Histamínicos H2/efectos de los fármacos , Sulfuros/farmacología , Analgésicos Opioides/farmacología , Animales , Autorradiografía , Benzoxazinas/farmacología , Sitios de Unión/efectos de los fármacos , Cimetidina/antagonistas & inhibidores , Cimetidina/metabolismo , Cimetidina/farmacología , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/farmacología , Histamina/farmacología , Imidazoles/síntesis química , Indicadores y Reactivos , Inyecciones Intraventriculares , Ligandos , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Ratones , Morfolinas/farmacología , Naloxona/farmacología , Naftalenos/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sulfuros/síntesis química

RESUMEN

Cryofixation is currently accepted as the best initial fixation step to preserve not only the fine structure but also the antigenicity of biological samples. To elucidate the functional transformation of gastric parietal cells, we have newly developed an in vitro experimental model, named the isolated gastric mucosa. In this study, acid secretion of the parietal cell was stimulated with histamine or inhibited with cimetidine, and the samples were cryofixed by plunge freezing for light microscopy or high-pressure freezing for electron microscopy. As a result, the organization of glandular cells was well-preserved and quite similar to freshly excised rat gastric mucosa for at least 2 h after isolation. Immunohistochemistry of H+/K+-ATPase demonstrated a translocation of H+/K+-ATPase from the cytoplasm to the apical membrane associated with histamine-stimulation. In cimetidine-treated mucosa, most of the parietal cells were morphologically in the resting state, showing numerous tubulovesicles in their cytoplasm. In contrast, histamine-stimulated parietal cells exhibited well-developed intracellular canaliculi lined with long microvilli. To the best of our knowledge, the present study is first to demonstrate an electron micrograph that strongly suggests a membrane fusion between the tubulovescile and the apical membrane. Moreover, a stimulation-associated translocation of ezrin was clearly shown from the cytoplasm to the apical region, corresponding to apical microvilli development in the isolated gastric mucosa model. We here describe the preparation of the isolated rat gastric mucosa model, which provides new insights into the functional transformation of parietal cells by the application of cryotechniques.

Asunto(s)

Criopreservación/métodos , Mucosa Gástrica/citología , Células Parietales Gástricas/metabolismo , Animales , Cimetidina/antagonistas & inhibidores , Cimetidina/farmacología , Proteínas del Citoesqueleto , Mucosa Gástrica/ultraestructura , Histamina/metabolismo , Histamina/farmacología , Inmunohistoquímica , Técnicas In Vitro , Masculino , Microscopía Electrónica , Células Parietales Gástricas/enzimología , Células Parietales Gástricas/ultraestructura , Fosfoproteínas/metabolismo , Ratas , Ratas Wistar

RESUMEN

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

Asunto(s)

Humanos , Talidomida , Talidomida/administración & dosificación , Talidomida/farmacocinética , Talidomida/historia , Talidomida/aislamiento & purificación , Talidomida/metabolismo , Talidomida/normas , Talidomida/síntesis química , Talidomida/toxicidad , Talidomida/uso terapéutico , Administración Oral , Cimetidina/antagonistas & inhibidores , Diltiazem/antagonistas & inhibidores , Eritema Nudoso/etiología , Fenobarbital/antagonistas & inhibidores , Interacciones Farmacológicas/fisiología , Rifampin/antagonistas & inhibidores , Síndrome de Inmunodeficiencia Adquirida del Felino/terapia , Warfarina/antagonistas & inhibidores

RESUMEN

Improgan, a nonopioid antinociceptive agent, activates descending, pain-relieving mechanisms in the brain stem, but the receptor for this compound has not been identified. Because cannabinoids also activate nonopioid analgesia by a brain stem action, experiments were performed to assess the significance of cannabinoid mechanisms in improgan antinociception. The cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chloro phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) induced dose-dependent inhibition of improgan antinociception on the tail-flick test after i.c.v. administration in rats. The same treatments yielded comparable inhibition of cannabinoid [R-(+)-(2,3-dihydro-5-methyl-3-[(4-mor pholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl)methanone monomethanesulfonate, WIN 55,212-2] analgesia. Inhibition of improgan and WIN 55,212-2 antinociception by SR141716A was also observed in Swiss-Webster mice. Radioligand binding studies showed no appreciable affinity of improgan on rat brain, mouse brain, and human recombinant CB(1) receptors, ruling out a direct action at these sites. To test the hypothesis that CB(1) receptors indirectly participate in improgan signaling, the effects of improgan were assessed in mice with a null mutation of the CB(1) gene with and without SR141716A pretreatment. Surprisingly, improgan induced complete antinociception in both CB(1) (-/-) and wild-type control [CB(1) (+/+)] mice. Furthermore, SR141716A inhibited improgan antinociception in CB(1) (+/+) mice, but not in CB(1) (-/-) mice. Taken together, the results show that SR141716A reduces improgan antinociception, but neither cannabinoids nor CB(1) receptors seem to play an obligatory role in improgan signaling. Present and previous studies suggest that Delta(9)-tetrahydrocannabinol may act at both CB(1) and other receptors to relieve pain, but no evidence was found indicating that improgan uses either of these mechanisms. SR141716A will facilitate the study of improgan-like analgesics.

Asunto(s)

Analgésicos/farmacología , Cannabinoides/antagonistas & inhibidores , Cimetidina/análogos & derivados , Cimetidina/farmacología , Dronabinol/farmacología , Dolor/fisiopatología , Piperidinas/farmacología , Pirazoles/farmacología , Receptores de Droga/fisiología , Analgésicos/antagonistas & inhibidores , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Moduladores de Receptores de Cannabinoides , Cannabinoides/farmacocinética , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/fisiología , Cimetidina/administración & dosificación , Cimetidina/antagonistas & inhibidores , Endocannabinoides , Calor , Inyecciones Intraventriculares , Masculino , Ratones , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/farmacocinética , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Cannabinoides , Receptores de Droga/efectos de los fármacos , Rimonabant , Factores de Tiempo

RESUMEN

BACKGROUND/AIM: Based on animal models, lafutidine, a novel histamine H(2) receptor (H(2)R) antagonist, is reported to show potent and long-lasting antagonisms of histamine H(2)R-mediated effects. However, no reports have been published concerning its direct interaction with the human H(2)R. This study aims at characterizing its interaction with human H(2)R. METHODS: Chinese hamster ovary cell lines stably expressing human H(2)Rs were obtained. The dose-dependent effects of lafutidine and famotidine on [(3)H]tiotidine binding and histamine-stimulated cAMP production were analyzed. The effects of preincubation with 2.78 x 10(-7) M of lafutidine or famotidine for 30 min on histamine-dependent cAMP production and [(3)H]tiotidine binding were also examined after 0, 1, 2, 4, and 12 h. This concentration is below the C(max) of lafutidine (10 mg p.o.) and above the C(max) of famotidine (20 mg p.o.). RESULTS: Lafutidine inhibited [(3)H]tiotidine binding and histamine-stimulated cAMP production as or more potently than famotidine. At higher concentrations lafutidine was more potent than famotidine. In addition, preincubation with 2.78 x 10(-7) M lafutidine, but not with 10(-5) M famotidine, had marked inhibitory effects which persisted as long as after extensive washing. CONCLUSION: Lafutidine shows a potent and long-lasting antagonism on the human H(2)R.

Asunto(s)

Acetamidas/farmacología , Cimetidina/análogos & derivados , Famotidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Receptores Histamínicos H2/efectos de los fármacos , Animales , Células CHO/efectos de los fármacos , Células CHO/metabolismo , Cimetidina/antagonistas & inhibidores , Cimetidina/metabolismo , Cricetinae , AMP Cíclico/biosíntesis , Relación Dosis-Respuesta a Droga , Humanos , Receptores Histamínicos H2/metabolismo , Transfección

RESUMEN

The effects of muscimol, aminooxyacetic acid (AOAA), diamino-n-butyric acid (DABA), baclofen, bicuculline, picrotoxin, strychnine, diazepam, phenobarbitone and phenytoin on cimetidine-induced seizures were studied in mice. Cimetidine (400-1000 mg/kg, i.p.) induced dose-dependent tonic convulsion. Muscimol, AOAA and DABA effectively protected mice against cimetidine-induced seizures. Bicuculline and picrotoxin significantly potentiated the seizures induced by cimetidine and effectively antagonized the protective effects of muscimol, AOAA and DABA against the seizures. Diazepam and phenobarbitone significantly protected the mice against cimetidine-induced seizures while phenytoin and strychnine did not significantly alter the seizures. These results indicate that the attenuation of central gamma-aminobutyric acid neurotransmission may underlie cimetidine-induced seizures in mice.

Asunto(s)

Cimetidina/antagonistas & inhibidores , Cimetidina/toxicidad , Receptores de GABA/efectos de los fármacos , Convulsiones/inducido químicamente , Aminobutiratos/farmacología , Ácido Aminooxiacético/farmacología , Animales , Baclofeno/farmacología , Bicuculina/farmacología , Diazepam/farmacología , Femenino , Ratones , Muscimol/farmacología , Fenobarbital/farmacología , Fenitoína/farmacología , Picrotoxina/farmacología , Convulsiones/prevención & control , Estricnina/farmacología

RESUMEN

The uptake and metabolism of 3H-noradrenaline has been examined in the FL cell-line derived originally from human amnion. Cell cultures metabolised 3H-noradrenaline (1.0 mumol/l) to 3H-normetanephrine and, to a lesser extent, to metabolites (not distinguished) of the O-methylated deaminated fraction; primary deaminated metabolites were not detected. 3H-normetanephrine formation a) was not saturable in the noradrenaline concentration range 0.2-150 mumol/l, b) was decreased to 20%-30% of control levels by uptake2 inhibitors (O-methylisoprenaline, 20 and 100 mumol/l; cimetidine, 10 mumol/l; hydrocortisone, 200 mumol/l) and c), was almost insensitive to uptake1 inhibitors (cocaine, 30 mumol/l; desipramine, 3 mumol/l). Uptake of noradrenaline was manifested after 30 minutes as a 6-fold increase in the cell content of the amine following inhibition of catechol-O-methyl transferase, either alone or in conjunction with inhibition of monoamine oxidase. Uptake was decreased maximally to 40% of control levels by O-methylisoprenaline. IC50 values for inhibition of the O-methylisoprenaline-sensitive component of uptake were (in mumol/l): corticosterone (0.3), papaverine (1.1), O-methylisoprenaline (3.0), cimetidine (6.0), (-)noradrenaline (460), and tetraethylammonium (2230). Except for the last agent, for which a comparative value is not available, the IC50's are in good agreement with those for inhibition of uptake2 in the Caki-1 cell-line reported by other investigators. The component of uptake resistant to O-methylisoprenaline was depressed by papaverine (a 50% decrease at 50 mumol/l), but was not affected by the other uptake2 inhibitors or by cocaine (30 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Amnios/metabolismo , Inhibidores de Catecol O-Metiltransferasa , Norepinefrina/metabolismo , Norepinefrina/farmacocinética , Amnios/citología , Células Cultivadas , Cimetidina/antagonistas & inhibidores , Cocaína/antagonistas & inhibidores , Desipramina/antagonistas & inhibidores , Humanos , Hidrocortisona/antagonistas & inhibidores , Isoproterenol/análogos & derivados , Isoproterenol/antagonistas & inhibidores , Metilación , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Norepinefrina/antagonistas & inhibidores , Normetanefrina/biosíntesis

RESUMEN

There is considerable interest in the role of serotonin (5-HT) in the pathophysiology of schizophrenia and in the mechanism of action of clozapine, an atypical antipsychotic agent and a potent dopamine (DA), 5-HT2/5-HT1C and histamine (H) antagonist. Cimetidine, an H2 antagonist, produces robust, transient increase in plasma prolactin (PRL) levels in man following intravenous administration. This effect has been attributed, in part, to indirect central serotonergic mechanisms involving 5-HT2 receptors in the hypothalamus, but the evidence is inconclusive. This study investigated the effects of cimetidine on plasma PRL levels in unmedicated schizophrenic patients versus normal controls and the effect of chronic treatment with clozapine on the cimetidine-induced PRL response. The PRL response to cimetidine was significantly blunted in male but not female schizophrenic patients. The PRL response in male schizophrenic patients was inversely related to psychopathology. Chronic treatment with clozapine completely suppressed the plasma PRL response following cimetidine. These data are consistent with the hypothesis of an abnormality of serotonergic activity, including downregulation of 5-HT2 receptors, in male but not female schizophrenic patients. The role of antagonism of 5-HT2 receptors in the action of clozapine is discussed.

Asunto(s)

Cimetidina/farmacología , Clozapina/farmacología , Prolactina/sangre , Esquizofrenia/sangre , Adulto , Cimetidina/antagonistas & inhibidores , Clozapina/uso terapéutico , Femenino , Humanos , Masculino , Receptores de Serotonina/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Antagonistas de la Serotonina/farmacología , Caracteres Sexuales

RESUMEN

Cimetidine, a histamine 2 (H2) antagonist, produces a decrease in arterial pressure due to vasodilatation, especially in critically ill patients. This may be because cimetidine acts as a histamine agonist. We, therefore, investigated the effects of the histamine 1(H1) receptor antagonist, diphenhydramine, on the haemodynamic changes observed after cimetidine in ICU patients. Each patient was studied on two separate days. In a random fashion, they received cimetidine 200 mg iv on one day, and on the other, a pretreatment of diphenhydramine 40 mg iv with cimetidine 200 mg iv. In the non-pretreatment group, mean arterial pressure (MAP) decreased from 107.4 +/- 8.4 mmHg to 86.7 +/- 11.4 mmHg (P less than 0.01) two minutes after cimetidine. Also, systemic vascular resistance (SVR) decreased during the eight-minute observation period (P less than 0.01). In contrast, in the pretreatment group, little haemodynamic change was seen. We conclude that an H1 antagonist may be useful in preventing hypotension caused by iv cimetidine, since the vasodilating activity of cimetidine is mediated, in part, through the H1 receptor.

Asunto(s)

Cimetidina/antagonistas & inhibidores , Cuidados Críticos , Difenhidramina/uso terapéutico , Hemodinámica/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Depresión Química , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Postadulticide pulmonary hypertension mechanisms and treatment with antihistamines and supplemental oxygen were studied in eight dogs with heartworm disease. To ensure severe postadulticide thromboembolism, additional heartworms (either 20 or 40 into 4 dogs each) were transplanted into naturally infected dogs before thiacetarsamide treatment. During pentobarbital anesthesia, 2 pulmonary hemodynamic studies were conducted on each dog with a sequence of baseline, hypoxia with FlO2 = 10%, hyperoxia with FlO2 = 100%, a second baseline, treatment with either diphenhydramine (D) or cimetidine (C), and another hypoxia. All dogs were pulmonary hypertensive, with each dog having a mean pulmonary arterial pressure (PPA) greater than 20 mm of Hg. Mean PPA increased from baseline conditions (25.0 +/- 4.5 SD for D and 24.3 +/- 4.4 for C) to hypoxia (28.5 +/- 4.7 for D and 28.4 +/- 3.7 for C), and decreased during hyperoxia (16.9 +/- 3.0 for D and 17.4 +/- 3.0 for C), respectively. Neither antihistamine reduced PPA at normoxia. The degree of pulmonary hypertension when breathing room air increased even more during hypoxia, and this increase was not attenuated by either antihistamine. Histamine did not appear to mediate pulmonary hypertension during postadulticide thromboembolism, nor to modify the hypoxia-mediated pulmonary hypertension at this disease stage. Because baseline PO2 was low (66.6 +/- 11.7 mm of Hg for D and 69.4 +/- 14.2 for C) and because PPA decreased during administration of oxygen, the pulmonary hypertension was mostly hypoxia-induced. In addition to the arterial lesions, much of the pulmonary hypertensive mechanism was an active and reversible vasoconstriction in response to hypoxia caused by the secondary lung disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Asunto(s)

Arsenamida/uso terapéutico , Cimetidina/farmacología , Difenhidramina/farmacología , Dirofilariasis/veterinaria , Enfermedades de los Perros/etiología , Hipertensión Pulmonar/veterinaria , Oxígeno/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Cimetidina/antagonistas & inhibidores , Difenhidramina/antagonistas & inhibidores , Dirofilariasis/complicaciones , Dirofilariasis/tratamiento farmacológico , Enfermedades de los Perros/terapia , Perros , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Hipoxia/tratamiento farmacológico , Hipoxia/veterinaria

RESUMEN

Experiments were conducted to study the transport of the histamine H2-receptor antagonist, cimetidine, in luminal membrane vesicles prepared from rabbit renal cortex. Cimetidine accumulated in the vesicles with time. Cimetidine uptake was sensitive to changes in vesicle size, suggesting that the compound is transported into an osmotically reactive intravesicular space. Its rate of uptake could be described by both a saturable and a nonsaturable process. The Km was 4.6 +/- 4.0 microM and the Vmax was 6.8 +/- 2.3 pmol X s-1 X mg protein-1 (mean +/- SD, n = 4). N1-methylnicotinamide (NMN), cimetidine, cimetidine sulfoxide, and ranitidine inhibited the uptake of cimetidine. Cimetidine uptake in the presence of an outwardly directed proton gradient was enhanced in vesicles preloaded with a higher concentration of unlabeled cimetidine (2.4 X 10(-4) M). An outwardly directed proton gradient enhanced the uptake of cimetidine to values exceeding its equilibrium accumulation. Uptake stimulated in this way could be inhibited by the cation, NMN, the bases, ranitidine, and cimetidine sulfoxide, and interestingly, by the anion, probenecid. The effect of probenecid did not appear to be due to nonspecific effects on membrane binding, membrane potential, or vesicle size. These data are consistent with data obtained in isolated perfused proximal tubules, demonstrating that probenecid inhibits cimetidine transport. The data in this study suggest that the effect of probenecid on cimetidine transport specifically involves the transporter in the luminal membrane.

Asunto(s)

Cimetidina/metabolismo , Corteza Renal/metabolismo , Animales , Transporte Biológico , Cimetidina/antagonistas & inhibidores , Concentración de Iones de Hidrógeno , Masculino , Membranas/metabolismo , Concentración Osmolar , Conejos

RESUMEN

Los autores destacan como uno de los avances más importantes en el tratamiento de los padecimientos del tracto digestivo la incorporación de los antagonistas de los receptores H2 de la histamina. Se realiza una amplia revisión bibliográfica, en la cual se expone el efecto inhibidor de la cimetidina en la secreción del ácido gástrico y la pepsina y en la secreción nocturna. Se destaca la efectividad del producto en la profilaxis y tratamiento de las homorragias digestivas altas. Se comunica sobre el esquema terapéutico y los efectos secundarios de la cimetidina. Se proporciona información breve sobre otro antagonista de los receptores H2 de la histamina la ranitidina

Asunto(s)

Cimetidina/uso terapéutico , Hemorragia Gastrointestinal/prevención & control , Hemorragia Gastrointestinal/tratamiento farmacológico , Cimetidina/antagonistas & inhibidores

RESUMEN

The prolactin lowering activity of dihydroergokryptine was investigated both in rats and in humans. The drug was administered orally at the doses of 0.2, 1 and 5 mg/Kg to intact or reserpinized male rats. Nine male adult volunteers were given 300 mg cimetidine iv 90 min after receiving 2, 3 or 4.5 mg of dihydroergokryptine and 3, 4.5 and 6.75 mg of dihydroergocristine or placebo per os in a randomized, cross-over design. Eight young adult males were injected im with 10 mg sulpiride 120 min after randomly receiving dihydroergokryptine 2.5 and 5 mg or placebo in a cross-over manner. Finally, five healthy young women were given dihydroergokryptine 2.5 and 5 mg, bromocriptine 2.5 mg and placebo in a cross-over design. Dihydroergokryptine caused a strong, long-lasting, dose-dependent fall of plasma prolactin concentrations in both rats and humans. Moreover, it inhibited the reserpine-induced rise of plasma prolactin in rats, as well as the cimetidine-or sulpiride-induced hyperprolactinemia in humans. Dihydroergokryptine proved twice as potent as dihydroergocristine and about half as potent as bromocriptine. Effective doses of both dihydrogenated ergot alkaloids were much better tolerated than bromocriptine.

Asunto(s)

Dihidroergotoxina/farmacología , Prolactina/sangre , Adulto , Animales , Bromocriptina/farmacología , Cimetidina/antagonistas & inhibidores , Femenino , Humanos , Masculino , Distribución Aleatoria , Ratas , Ratas Endogámicas , Reserpina/antagonistas & inhibidores , Sulpirida/antagonistas & inhibidores

RESUMEN

The effect of nitrosocimetidine (NC) on the frequency of sister-chromatid exchanges (SCEs) in human lymphocytes has been studied. The frequency of SCEs induced by a 1-h exposure to 2.6 X 10(-4) M NC was 4-fold greater than that in the solvent control. A 72-h exposure to NC had a similar dose-related effect. We also examined the effect of the sulfhydryl compounds cysteine, cysteamine, cystamine and glutathione, the reducing agent dithionite, and vitamins C and E on the NC-induced SCEs. None of these compounds induced SCEs. Cysteine, cysteamine, and cystamine significantly reduced the number of NC-induced SCEs, and the others did not.

Asunto(s)

Cimetidina/análogos & derivados , Cimetidina/toxicidad , Linfocitos/efectos de los fármacos , Compuestos Nitrosos/toxicidad , Intercambio de Cromátides Hermanas/efectos de los fármacos , Ácido Ascórbico/farmacología , Células Cultivadas , Cimetidina/antagonistas & inhibidores , Cistamina/farmacología , Cisteamina/farmacología , Cisteína/farmacología , Ditionita/farmacología , Glutatión/farmacología , Humanos , Metilnitronitrosoguanidina/toxicidad , Compuestos Nitrosos/antagonistas & inhibidores , Vitamina E/farmacología

RESUMEN

Cimetidine, an H2 receptor antagonist, administered into a lateral ventricle of the rat brain caused a significant increase in tail flick latency. Dimaprit, a specific H2 agonist, failed to counteract the analgesic effect of cimetidine. In contrast, it enhanced the effect of cimetidine and per se had marked analgesic activity. The specific opioid antagonist naloxone was without effect. Pretreatment with CaCl2 completely prevented the action of cimetidine. These findings suggest that the analgesic action of cimetidine and dimaprit is not due to specific effects on H2 receptors.

Asunto(s)

Analgesia , Cimetidina/antagonistas & inhibidores , Nociceptores/efectos de los fármacos , Receptores Histamínicos H2/efectos de los fármacos , Receptores Histamínicos/efectos de los fármacos , Tiourea/farmacología , Animales , Cloruro de Calcio/farmacología , Cimetidina/farmacología , Dimaprit , Inyecciones Intraventriculares , Masculino , Naloxona/farmacología , Consumo de Oxígeno , Ratas , Ratas Endogámicas

RESUMEN

The effects of cimetidine and gefarnate on endogenous prostacyclin, prostaglandin E2 and thromboxane were studied in vivo in rat gastric mucosa. The animals received cimetidine (20 mg/kg, i.p.) and/or gefarnate (100 mg/kg, s.c.) twice a day for 7 days. Gastric mucosal 6-keto-prostaglandin F1 alpha (as prostacyclin), prostaglandin E2 and thromboxane B2 (as thromboxane A2) were determined by radioimmunoassay. Cimetidine reduced prostacyclin, prostaglandin E2, but not thromboxane A2. Gefarnate inhibited the cimetidine-induced reduction of prostacyclin and prostaglandin E2; in cimetidine-untreated controls, it did not produce an increase in those prostaglandins and thromboxane A2 above the normal levels.

Asunto(s)

Cimetidina/farmacología , Epoprostenol/metabolismo , Mucosa Gástrica/metabolismo , Gefarnato/farmacología , Prostaglandinas E/metabolismo , Terpenos/farmacología , Tromboxanos/metabolismo , Animales , Cimetidina/antagonistas & inhibidores , Depresión Química , Dinoprostona , Mucosa Gástrica/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas