RESUMEN
Supplementing the food of Heidenhain pouch gastric fistula dogs with a KC1 product greatly extends the survivability of these dogs. Since there is a continuous discharge of gastric juice from the pouch to the exterior each time a meal is consumed, clinical signs such as dehydration, anorexia, rough hair coat and lethargy usually occur within a few months after gastric pouch surgery and, unless extensive supportive measures are taken, most dogs will die shortly thereafter. The five dogs which did not receive KC1 supplementation died within 6 months after surgery with a mean survival time of 2.4 +/- 0.9 months. Seven dogs that received a daily oral supplement of 1.5 g KC1 (20 mEq) in their food have, on average, survived more than ten times longer than dogs which received no KC1 supplementation, with a mean survival time of 25.1 +/- 4.4 months. All KC1 supplemented dogs survived for more than 15 months with three dogs currently surviving for 36-40 months. When two dogs experienced decreased serum potassium, sodium and/or chloride levels and showed clinical signs of electrolyte imbalance despite receiving daily oral KC1 supplementation, intervention with intravenous (i.v.) lactated Ringer's solution and increased amounts of oral KC1 supplement reversed these symptoms within 1-2 weeks. Dogs that received only i.v. Ringer's therapy died with 1 week of the onset of clinical signs. Daily oral KC1 supplementation, careful observation of behavior and eating patterns, and routine physical examinations and serum electrolyte measurements can greatly extend the life expectancy of dogs with Heidenhain pouch gastric fistulas.
Asunto(s)
Perros/fisiología , Jugo Gástrico/metabolismo , Cloruro de Potasio/administración & dosificación , Estómago/fisiología , Administración Oral , Alimentación Animal , Animales , Perros/cirugía , Femenino , Fístula Gástrica , Cloruro de Potasio/uso terapéutico , Estómago/cirugía , Factores de TiempoRESUMEN
Rioprostil (3-100 micrograms/kg/day p.o.), but not cimetidine (30 mg/kg/day p.o.), healed pre-existing aspirin (1950 mg)-induced gastric lesions in dogs despite daily aspirin (975 mg) administration. Gastric antisecretory doses of rioprostil (10 and 100 micrograms/kg/day) decreased lesion scores by 71 to 77 and 90 to 93% after 7 and 11 days, respectively. A nonantisecretory dose of rioprostil (3 micrograms/kg/day) decreased lesion scores by 80% after 14 days. In contrast, lesion scores in dogs receiving either vehicle or a maximal gastric antisecretory dose of cimetidine (30 mg/kg/day) remained unchanged during the 28-day course of treatment. In addition, rioprostil prevented the weight loss which accompanied daily administration of aspirin (975 mg) in vehicle- or cimetidine-treated dogs. When cimetidine-treated dogs were switched to daily rioprostil (100 micrograms/kg/day) and aspirin (975 mg/day) therapy, lesions healed within 6 days. In separate studies, rioprostil had no effect on the sensitivity of the gastric mucosa to subsequent aspirin administration. In addition, discontinuation of maintenance therapy during rioprostil treatment was of no increased benefit (i.e., lesions did not heal faster). Finally, in a model of urate-induced knee-joint synovitis, rioprostil treatment did not inhibit the anti-inflammatory or analgesic efficacy of aspirin, or have any proinflammatory effect of its own.
Asunto(s)
Antiulcerosos/farmacología , Aspirina/toxicidad , Mucosa Gástrica/efectos de los fármacos , Prostaglandinas E/farmacología , Analgesia , Animales , Aspirina/farmacología , Peso Corporal/efectos de los fármacos , Dinoprostona/metabolismo , Perros , Femenino , Masculino , Rioprostilo , Sinovitis/tratamiento farmacológicoRESUMEN
Rioprostil, a primary alcohol prostaglandin E1 analog, inhibits gastric acid secretion and prevents gastric lesions induced by a variety of irritants in experimental animals. Because rioprostil is relatively short-acting, it would be of significant benefit clinically if its duration of action could be extended to allow once daily dosing. This investigation demonstrates that when administered via an osmotically driven pump (Osmet, Alza Corp.), rioprostil prevents the acute effects of aspirin on the gastric mucosa of dogs, accelerates the healing of aspirin-induced gastric lesions, and heals preexisting aspirin-induced gastric lesions during chronic administration of aspiring. The potency of rioprostil against acute gastric lesion formation was greatest when delivered from a 24-hr release pump (ED50 = 0.77 micrograms/kg/24 hr) and was 37 times greater than when administered as a single oral bolus. In addition, this activity occurred at doses which had little or no gastric antisecretory activity in betazole-stimulated Heidenhain pouch dogs. When delivered from a 24-hr pump, rioprostil (100 micrograms/kg/24 hr) healed preexisting aspirin-induced gastric lesions within 8 days after removal of aspirin, or after 15 days during continued daily aspirin administration. Additional studies determined that administration of rioprostil at doses of 720, 1440, or 2160 micrograms/kg/24 hr (935-2805 times the gastroprotective ED50 in 24 hr pumps) was well tolerated, with only slight, transient increases in body temperature, softening of the stools, and mild sedation at the highest dose. Administration of rioprostil daily for 5 days at 960 micrograms/kg/24 hr from 24-hr release pumps was also well tolerated by all dogs with no evidence of any accumulation of effect of rioprostil. In summary, administration of rioprostil via an osmotic pump increases its potency and duration of action against the gastric lesion-inducing effect of aspirin, and maintains a wide ratio of safety.
Asunto(s)
Antiulcerosos/administración & dosificación , Aspirina/antagonistas & inhibidores , Prostaglandinas E/administración & dosificación , Úlcera Gástrica/tratamiento farmacológico , Enfermedad Aguda , Administración Oral , Animales , Antiulcerosos/efectos adversos , Enfermedad Crónica , Perros , Femenino , Jugo Gástrico/efectos de los fármacos , Jugo Gástrico/metabolismo , Bombas de Infusión , Masculino , Prostaglandinas E/efectos adversos , Rioprostilo , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/prevención & controlRESUMEN
Rioprostil, a primary alcohol prostaglandin E1 analog, prevents gastric lesion formation induced by a variety of irritants, including aspirin, in rats and dogs. In the present study, rioprostil reduced both gastric lesion formation and fecal blood loss in dogs caused by daily aspirin administration (1,950 mg/day) for 3 consecutive days. A gastric antisecretory dose of 100 micrograms/kg p.o. t.i.d. of rioprostil reduced fecal blood loss by 96% to a level (0.76 +/- 0.10 mg Hb/g stool) similar to basal blood loss in non-aspirin-treated vehicle dogs (0.61 +/- 0.08 mg Hb/g stool) as determined by HemoQuant assay. A nonantisecretory dose of rioprostil (1 microgram/kg p.o. t.i.d.) reduced fecal blood loss by 70% compared to vehicle-treated dogs. Gastric lesion severity scores in dogs treated with 100 or 1 micrograms/kg p.o. t.i.d. of rioprostil were 61 and 52% lower, respectively, than the mean severity score in the vehicle-treated group. There was a highly significant (p less than 0.001) correlation between gastric lesion score and fecal blood loss independent of the treatment each dog received. The efficacy of a nonantisecretory dose suggests that the gastric lesion effect of rioprostil may be independent of gastric antisecretory effects. The correlation of fecal blood loss with gastric lesion score suggests the possibility that either measurement may be used as an indication of gastric lesion occurrence or severity.
Asunto(s)
Antiulcerosos/uso terapéutico , Aspirina/efectos adversos , Mucosa Gástrica/efectos de los fármacos , Hemorragia Gastrointestinal/inducido químicamente , Prostaglandinas E/uso terapéutico , Gastropatías/inducido químicamente , Animales , Perros , Femenino , Mucosa Gástrica/patología , Hemorragia Gastrointestinal/prevención & control , Gastroscopía , Masculino , Sangre Oculta , Rioprostilo , Gastropatías/prevención & controlRESUMEN
Rioprostil, a primary alcohol prostaglandin E1 analogue, inhibits gastric acid secretion, both in vivo and in vitro, and prevents the formation of experimentally-induced gastric lesions in rats and dogs. In vitro experimental evidence suggests that the mechanism of the gastric antisecretory activity of rioprostil involves inhibition of the membrane bound histamine-stimulated adenylate cyclase. In vivo, rioprostil inhibits gastric acid secretion in 4-h pylorus-ligated rats, in gastric fistula dogs stimulated by betazole, tetragastrin, bethanechol, or 2-deoxy-D-glucose, and in Heidenhain pouch dogs stimulated by food. Rioprostil can completely prevent macroscopically visible gastric lesions induced by a variety of noxious agents in rats, including 50% ethanol, aspirin, indomethacin, strong acid, strong base and hypertonic saline. In dogs, rioprostil, but not the H2-blockers cimetidine or ranitidine, totally prevents endoscopically visible gastric lesions induced by aspirin tablets or 60% ethanol, and accelerates the healing of established aspirin-induced gastric lesions from 20 days (vehicle control) to 6 days (33 micrograms/kg p.o., t.i.d.) or 11 days (3 micrograms/kg p.o., t.i.d.). The precise mechanism for the antigastrolesive activity of rioprostil is not known, but may involve increased mucus and bicarbonate secretion, maintaining or increasing gastric mucosal blood flow, increasing the rate of cellular restitution, or possibly antigastrin activity that has been demonstrated in dogs. In rats, rioprostil also prevents duodenal lesions induced by cysteamine, small intestinal lesions induced by indomethacin, and colonic lesions induced by ethanol. The antisecretory and antigastrolesive potency of rioprostil given transdermally to rats is similar to its potency when given systemically, although its diarrhoeagenic potential is lower when given topically compared to oral administration. When used in combination with several non-steroidal anti-inflammatory drugs (NSAIDs) in a model of arthritis in rats, rioprostil inhibits gastric lesion formation without interfering with the anti-inflammatory or analgesic potency of the NSAIDs. In addition, concomitant use of either antacid or cimetidine with rioprostil does not inhibit either the antisecretory or antigastrolesive potency of rioprostil, with the effect of the combination being additive. The doses required to inhibit formation of experimentally-induced gastric lesions in both rat and dog are lower than those required to inhibit gastric acid secretion. This separation of antigastrolesive from antisecretory activity distinguishes rioprostil from other non-prostanoid antisecretory agents, such as histamine H2- receptor antagonists, and establishes rioprostil as a 'selective antigastrolesive agent' (SAGA).(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Antiulcerosos/farmacología , Prostaglandinas E/farmacología , Animales , Antiácidos/farmacología , Antiinflamatorios no Esteroideos/efectos adversos , Perros , Ácido Gástrico/metabolismo , Humanos , Prostaglandinas Sintéticas/farmacología , Ratas , RioprostiloRESUMEN
A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32, and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Aminas/síntesis química , Ácido Gástrico/metabolismo , Aminas/farmacología , Aminopirina/metabolismo , Animales , Benzotiazoles , Benzoxazoles/síntesis química , Benzoxazoles/farmacología , Bucladesina/farmacología , Fenómenos Químicos , Química , Cimetidina/farmacología , Mucosa Gástrica/efectos de los fármacos , ATPasa Intercambiadora de Hidrógeno-Potásio , Histamina/farmacología , Ligadura , Masculino , Omeprazol/farmacología , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/metabolismo , Antro Pilórico/fisiología , Ranitidina/farmacología , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacologíaRESUMEN
It has been hypothesized that prolonged achlorhydria causes compensatory elevation of serum gastrin, and that there is an association in rats between sustained hypergastrinemia, hyperplasia of gastric enterochromaffin-like cells, and subsequent formation of gastric carcinoids in 2-year carcinogenicity studies. The present study examined whether daily administration of gastric antisecretory drugs in rats for 4 days could cause hypergastrinemia associated with inhibition of acid output. Rats were dosed orally for 4 days with the histamine H2-receptor antagonist ranitidine or the H+,K+-sensitive ATPase inhibitor omeprazole, and examined on day 5 for effects on gastric acid secretion and serum gastrin. Omeprazole (138 mg/kg/day significantly inhibited gastric acid secretion and increased serum gastrin levels. Large, single daily doses of ranitidine (1000-2000 mg/kg/day) had no effect on 24-hr acid or gastrin secretion; however, ranitidine did inhibit next-day acid secretion with associated increases in serum gastrin when administered in three divided doses. These results with ranitidine support the hypothesis that a sustained gastric antisecretory action will cause a compensatory hypergastrinemia, regardless of the antisecretory agent used. The ability to detect increased serum gastrin levels associated with inhibition of acid secretion, after administration of antisecretory agents for only 4 days, suggest that this short 5-day test may be useful for determining the potential of antisecretory agents to cause hypergastrinemia due to 24-hr inhibition of acid secretion and may be predictive of long-term hyperplastic changes.
Asunto(s)
Antiulcerosos/farmacología , Gastrinas/sangre , Animales , Femenino , Ácido Gástrico/metabolismo , Masculino , Omeprazol/farmacología , Ranitidina/farmacología , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
This investigation examined the effect of rioprostil, a primary alcohol prostaglandin E1 analog, on betazole-stimulated gastric acid secretion and on basal and food-stimulated (postprandial) serum gastrin levels in gastric fistula dogs. Rioprostil inhibited betazole-stimulated gastric acid secretion with an ED50 of 16 (10-24) micrograms/kg, intragastrically. A near-maximal gastric antisecretory dose (100 micrograms/kg, intragastrically) had no effect on basal serum gastrin levels but significantly attenuated the rapid rise in serum gastrin which follows feeding, a result different from that reported for other prostaglandin E1 analogs. A nonantisecretory dose of rioprostil (1.0 micrograms/kg, intragastrically) also attenuated the rise in postprandial serum gastrin. An antigastrin effect using a nonantisecretory dose of an antiulcer agent has not been reported previously and may indicate that rioprostil has a direct inhibitory effect on secretion of gastrin. The ability of rioprostil to inhibit gastric acid secretion and decrease postprandial peak serum gastrin levels, coupled with previously established cytoprotective efficacy, makes it an attractive clinical candidate for the treatment and prevention of peptic ulcer disease.
Asunto(s)
Antiulcerosos/farmacología , Ácido Gástrico/metabolismo , Gastrinas/antagonistas & inhibidores , Prostaglandinas E/farmacología , Animales , Depresión Química , Perros , Femenino , Fístula Gástrica , Gastrinas/sangre , Contenido Digestivo/análisis , Úlcera Péptica/tratamiento farmacológico , Radioinmunoensayo , RioprostiloRESUMEN
It is well known that nonsteroidal antiinflammatory agents produce gastric mucosal lesions in both laboratory animals and man. However, the effect of an arthritic condition on their susceptibility to ulcerogenic agents and on the efficacy of antiulcer agents is less definitive. As a model to explore these questions, the effect of oral administration of aspirin or ethanol on gastric lesion formation was examined in rats with or without established adjuvant-induced polyarthritis. In addition, the antilesion efficacy of rioprostil, a primary alcohol prostaglandin E1 analog, was evaluated in both groups of rats. The results demonstrated that arthritic rats were more sensitive to the lesion-inducing effect of aspirin, but were more resistant to the lesion-inducing effect of ethanol when compared to normal rats. An increase in endogenous gastric prostaglandin production in arthritic rats may account for their relative resistance to ethanol. Aspirin inhibited the prostaglandin synthetic capacity of the stomach in both normal and arthritic rats, which may be responsible for eliminating the relative resistance of arthritic rats to gastric irritation. Rioprostil effectively prevented aspirin or ethanol-induced lesion formation in both arthritic and nonarthritic rats, but its potency against either irritant was decreased in arthritic rats.
Asunto(s)
Antiulcerosos/farmacología , Artritis Experimental/complicaciones , Artritis/complicaciones , Prostaglandinas E/farmacología , Úlcera Gástrica/inducido químicamente , Animales , Aspirina/toxicidad , Etanol/toxicidad , Masculino , Prostaglandinas/biosíntesis , Ratas , Ratas Endogámicas , Rioprostilo , Úlcera Gástrica/complicacionesRESUMEN
This paper characterizes the ability of rioprostil, a synthetic primary alcohol prostaglandin E1 analog, to inhibit gastric acid secretion and prevent experimentally induced gastric lesions in rats and dogs, and determines the selectivity (the separation in potency) for these effects. In 4-hr pylorus ligated rats, rioprostil inhibited gastric acid output when administered i.v., s.c., p.o. or intraduodenally, with ED50 values of 0.9, 1.8, 2.9 and 3.7 mg/kg, respectively. Rioprostil suppressed meal-stimulated acid output in Heidenhain pouch dogs and inhibited gastric acid output stimulated by tetragastrin, 2-deoxy-D-glucose, betazole or bethanechol in gastric fistula dogs with ED50 values of 7, 10, 16 and 17 micrograms/kg p.o., respectively. These values in dogs were not significantly different from each other, suggesting that the mechanism of the antisecretory effect of rioprostil is similar regardless of the secretagogue used. Rioprostil prevented ethanol induced gastric lesions in rats (ED50 = 1.5 micrograms/kg p.o.; 12.0 micrograms/kg s.c.) after a 30-min pretreatment. The 8-fold difference in potency between the p.o. and s.c. routes may reflect a local component in the antilesion mechanism of rioprostil. In dogs, rioprostil inhibited aspirin-induced gastric lesions with a p.o. ED50 of 1.6 micrograms/kg. Maximum antilesion activity in dogs for cimetidine or ranitidine was less than 50%, whereas rioprostil inhibited lesion formation by 100% without the appearance of side effects. Oral antilesion selectivity of rioprostil in rats (antisecretory ED50/antilesion ED50) was nearly 2000-fold using the optimum pretreatment time (30 min), and was 12-fold when the pretreatment time (4 hr) was the same as the duration of the antisecretory assay.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antiulcerosos/farmacología , Mucosa Gástrica/efectos de los fármacos , Prostaglandinas E Sintéticas/farmacología , Prostaglandinas E/farmacología , Animales , Aspirina/toxicidad , Cimetidina/farmacología , Perros , Relación Dosis-Respuesta a Droga , Etanol/toxicidad , Femenino , Ácido Gástrico/metabolismo , Masculino , Ranitidina/farmacología , Ratas , Ratas Endogámicas , RioprostiloRESUMEN
Prostaglandins may have many biological actions including hypotensive and antipeptic ulcer activity. The purpose of this investigation was to determine if the primary alcohol prostaglandin E1 analog rioprostil1 prevents ethanol-induced gastric lesions (antigastrolesive activity), inhibits gastric acid secretion (antisecretory activity), or causes diarrhea in rats when administered topically, and to compare these responses to the effect of rioprostil following enteral (oral or intraduodenal) administration. Rioprostil exhibited antigastrolesive activity in rats when administered either orally or when applied topically. The topical antigastrolesive potency of rioprostil against ethanol-induced lesions [ED50 = 3.7 (0.5-12) micrograms/kg] was similar to its oral potency [ED50 = 1.9 (1.7-2.2) micrograms/kg]. In 4 hr pylorus-ligated rats, topically administered rioprostil inhibited total gastric acid output with a potency [ED50 = 5.1 (2.6-24) mg/kg] similar to intraduodenal administration [ED50 = 3.7 (2.8-5.3) mg/kg]. In addition, in these rats rioprostil increased mucin levels and did not cause dermal irritation. Finally, the incidence of diarrhea was lower when rioprostil was applied topically than when given orally with a 16-fold difference in potency between these two routes of administration. These data show that when rioprostil is applied via the skin it has antigastrolesive, gastric antisecretory and mucus stimulatory effects in rats equal to enteral administration, and a diarrheagenic potency lower than following oral administration. This profile suggests that topical administration of rioprostil may be a useful means of delivery for clinical treatment of peptic ulcer disease.
Asunto(s)
Diarrea/inducido químicamente , Ácido Gástrico/metabolismo , Mucinas/biosíntesis , Prostaglandinas E/farmacología , Gastropatías/prevención & control , Administración Tópica , Animales , Antiulcerosos , Etanol , Ácido Gástrico/efectos de los fármacos , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Masculino , Prostaglandinas E/uso terapéutico , Prostaglandinas E/toxicidad , Prostaglandinas Sintéticas , Ratas , Ratas Endogámicas , Rioprostilo , Gastropatías/inducido químicamenteRESUMEN
ORF 17583, a histamine H2-receptor antagonist, inhibited gastric acid secretion in pylorus-ligated rats (ED50 = 4.9 mg/kg intraduodenal; 3.4 mg/kg p.o.; and 0.21 mg/kg i.p.) and in total gastric fistula or Heidenhain pouch dogs stimulated by betazole (ED50 = 0.12 mg/kg p.o. and 0.08 mg/kg i.v.), histamine, tetragastrin, bethanechol, 2-deoxy-D-glucose or a meal (ED50 values ranged from 0.11-0.26 mg/kg p.o.). The nonspecific inhibition of gastric acid by ORF 17583 supports the existence of interdependence between histamine and the gastrin and cholinergic receptors on the parietal cell surface. Antisecretory potency of ORF 17583 after intraduodenal administration in pylorus-ligated rats was 6.4 times greater than cimetidine, 1.8 times greater than ranitidine, equal to that of omeprazole and 8 times less than that of famotidine. Oral antisecretory potency of ORF 17583 in gastric fistula dogs was 31 times greater than cimetidine, 3.7 times greater than ranitidine and equal to that of omeprazole and famotidine. Studies using equieffective antisecretory doses of ORF 17583 and ranitidine in dogs suggested that ORF 17583 has a short duration of antisecretory activity similar to that of ranitidine.
Asunto(s)
Ácido Gástrico/metabolismo , Antagonistas de los Receptores H2 de la Histamina/farmacología , Omeprazol/farmacología , Ranitidina/análogos & derivados , Animales , Perros , Femenino , Ligadura , Masculino , Píloro , Ranitidina/farmacología , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
This study was undertaken to investigate the ability of a cytoprotective synthetic primary alcohol PGE1 analog, rioprostil, to protect the rat gastric mucosa against topically applied 40% (v/v) ethanol. Use of an ex vivo gastric chamber model facilitated correlation of changes in dynamic physiological parameters (PD and net cation fluxes) with changes in mucosal structure. We were particularly interested in defining changes in mucosal structure which accompanied topical application of rioprostil and which might explain subsequent resistance to the effects of ethanol. Topical application of rioprostil for 10 min provided concentration-dependent protection against ethanol-induced hemorrhagic erosions. The most effective dose and concentration tested (25 micrograms rioprostil at a concentration of 10 micrograms/ml) completely prevented ethanol-induced lesion formation. Protection was not accompanied by significant preservation of the interfoveolar epithelium against ethanol, but did involve prevention of vasocongestion and limitation of damage to the superficial epithelium. Complete recovery of physiological parameters indicative of gastric mucosal barrier integrity occurred within 20 min. The most effective concentrations of rioprostil produced extensive subepithelial edema and, concurrently, significant increases in net efflux of sodium ions, decreases in mucosal PD, and loss of mucosal folding.
Asunto(s)
Antiulcerosos/farmacología , Mucosa Gástrica/efectos de los fármacos , Prostaglandinas E/farmacología , Prostaglandinas/farmacología , Administración Tópica , Animales , Antiulcerosos/administración & dosificación , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Etanol/efectos adversos , Etanol/antagonistas & inhibidores , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/ultraestructura , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/prevención & control , Potenciales de la Membrana/efectos de los fármacos , Microscopía Electrónica de Rastreo , Potasio/metabolismo , Prostaglandinas/clasificación , Prostaglandinas E/administración & dosificación , Ratas , Ratas Endogámicas , Rioprostilo , Sodio/metabolismoRESUMEN
Gastrointestinal irritation is the most significant side effect in patients chronically taking nonsteroidal antiinflammatory drugs (NSAID) for treatment of arthritic conditions. Rioprostil, a primary alcohol prostaglandin E1 analog, prevents gastric bleeding induced by several NSAID in a rat model of arthritis that is similar in many aspects to human rheumatoid arthritis. Daily oral dosing of rioprostil (50 micrograms/kg BID for 15 days) did not influence the course of the adjuvant disease in rats or alter the antiinflammatory or analgesic effect of the NSAID. In a 13 week efficacy study in dogs, rioprostil (40-60 micrograms/kg, PO) completely prevented gastric hemorrhagic lesions induced by daily administration of aspirin.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Antiulcerosos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Artritis/tratamiento farmacológico , Úlcera Péptica Hemorrágica/prevención & control , Prostaglandinas E/uso terapéutico , Úlcera Gástrica/complicaciones , Animales , Artritis Experimental/patología , Modelos Animales de Enfermedad , Perros , Mucosa Gástrica/patología , Masculino , Úlcera Péptica Hemorrágica/etiología , Píloro/patología , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas , Rioprostilo , Úlcera Gástrica/inducido químicamenteRESUMEN
Rioprostil, a primary alcohol prostaglandin E1 analog, is currently undergoing clinical evaluation for use in the treatment of peptic ulcer disease. Since antacids are often used in conjunction with other antiulcer agents, studies were conducted to determine if concomitantly administered antacid modifies the antiulcer activity of rioprostil. This investigation showed that concomitant administration of antacid (0.25-1.0 ml Maalox) does not inhibit the ability of rioprostil (0.125-4.0 micrograms/kg, p.o.) to prevent ethanol-induced gastric lesions in rats. The antiulcer effect of the drug combination was additive, suggesting that each compound acts independently to prevent gastric bleeding. These results in animals suggest that clinically the use of antacid will not compromise the efficacy of rioprostil and that the combination may be a useful mode of therapy for the treatment of peptic ulcer disease.
Asunto(s)
Antiácidos/administración & dosificación , Antiulcerosos , Prostaglandinas E/administración & dosificación , Úlcera Gástrica/prevención & control , Alprostadil/análogos & derivados , Animales , Mucosa Gástrica/patología , Masculino , Ratas , Rioprostilo , Úlcera Gástrica/patologíaRESUMEN
This paper describes the pharmacology of ORF 17910, a specific, long-acting histamine H2-receptor antagonist. ORF 17910 (ED50 = 0.26 mg/kg) is 26 and 2.7 times more potent p.o. than cimetidine and ranitidine, respectively, at inhibiting acid output in betazole-stimulated total gastric fistula dogs. When given i.v., ORF 17910 (ED50 = 0.06 mg/kg) is 3.6 times more potent than ranitidine. Qualitatively similar antisecretory potency differences are seen in rats (ED50 = 3.7 mg/kg intraduodenal). ORF 17910 retains 43 and 37% of its antisecretory potency 16 hr after dosing in dogs and rats, respectively, suggesting a long duration of action, whereas ranitidine is either inactive (rats) or loses 97% of its potency (dogs) at this time. When the parenteral and enteral (p.o. or intraduodenal) potencies of ORF 17910 and ranitidine are compared, ORF 17910 appears less bioavailable than ranitidine, although this difference is greater in the rat than in the dog and diminishes with time. In rabbit isolated parietal cell (pA2 = 7.96) and guinea pig isolated atria preparations (pA2 = 7.51), ORF 17910 is more potent than both cimetidine and ranitidine at inhibiting the effects of histamine. At high concentrations, the inhibitory effect of ORF 17910 in atria can not be overcome completely, a property which may contribute to its long duration of action in vivo. In several additional test systems, ORF 17910 does not exhibit any biologically significant pharmacology and appears to be specific for the histamine H2-receptor.
Asunto(s)
Cimetidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Ranitidina/farmacología , Tiadiazoles/farmacología , Antagonistas de Andrógenos , Animales , Perros , Femenino , Ácido Gástrico/metabolismo , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Células Parietales Gástricas/efectos de los fármacos , Pepsina A/metabolismo , Conejos , Ratas , Ratas EndogámicasRESUMEN
Etintidine is a potent competitive antagonist of histamine H2-receptors. It is 4.6 and 2.2 times more potent than cimetidine in the isolated guinea pig atrium (pA2 = 7.18) and the isolated rabbit parietal cell (pA2 = 6.51), respectively. Etintidine is 2.0 (ED50 = 1.8 mg/kg, i.g.) times more potent than cimetidine at inhibiting betazole-stimulated total acid output in the chronic gastric fistula dog. In the 4 hr pylorus-ligated rat etintidine is a potent inhibitor of total acid output (ED50 = 22 mg/kg, i.d.), total pepsin output, and is well absorbed from the gastrointestinal tract. Additional pharmacological and biochemical studies indicate that etintidine displays minimal competition with appropriate ligands for the alpha 1, alpha 2, cholinergic and neuroleptic receptors in vitro, and has minimal effects on the immunological, autonomic and central nervous systems at doses much higher than antisecretory doses. While high doses of both cimetidine and etintidine increase serum prolactin levels in rats, the effect of etintidine is less than that of cimetidine. Similarly, the prolongation of hexobarbital-induced sleep time in rats is less than with cimetidine. These data indicate that etintidine may be potentially useful and safe in the treatment of peptic ulcer disease and may offer some advantages over cimetidine in terms of less potential for side effects.
Asunto(s)
Antagonistas de los Receptores H2 de la Histamina/farmacología , Imidazoles/farmacología , Animales , Cimetidina/farmacología , Constricción , Perros , Femenino , Jugo Gástrico/efectos de los fármacos , Jugo Gástrico/metabolismo , Cobayas , Atrios Cardíacos/efectos de los fármacos , Pruebas de Hemaglutinación , Hexobarbital/farmacología , Histamina/farmacología , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/metabolismo , Pepsina A/metabolismo , Prolactina/metabolismo , Píloro , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Sueño/efectos de los fármacosRESUMEN
This paper describes the pharmacology of ORF 17578, a new histamine H2-receptor antagonist, in comparison to the standard H2-blockers cimetidine and ranitidine. ORF 17578 inhibited betazole-stimulated gastric acid output in gastric fistula dogs and gastric acid secretion in pylorus-ligated rats. When administered enterally (p.o. or i.d.) ORF 17578 (ED50 = 0.21 mg/kg in dogs and 2.5 mg/kg in rats) was 10 to 11 times more potent than cimetidine and 1.8 to 2.1 time more potent than ranitidine in dogs and rats. In both species, duration of p.o. antisecretory activity was longer than with ranitidine. When administered parenterally ORF 17578 (ED50 = 0.15 mg/kg i.v. in dogs and 1.1 mg/kg i.p. in rats) was more potent than cimetidine and ranitidine in rats and similar in potency to ranitidine in dogs. Comparison of parenteral to enteral potencies suggests that ORF 17578 was well absorbed from the gastrointestinal tract of both species with a bioavailability profile similar to that of ranitidine. In rabbit isolated parietal cells (pA2 = 7.53) and guinea-pig isolated atria (pA2 = 7.26), ORF 17578 competitively antagonized the effects of histamine with a potency greater than cimetidine and similar to ranitidine. Results from several additional test systems indicated that ORF 17578 was specific for the histamine H2-receptor and did not exhibit the additional pharmacology often associated with cimetidine.
Asunto(s)
Cimetidina/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Ranitidina/análogos & derivados , Ranitidina/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Perros , Femenino , Ácido Gástrico/metabolismo , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Inmunidad/efectos de los fármacos , Técnicas In Vitro , Masculino , Ratones , Células Parietales Gástricas/efectos de los fármacos , Pepsina A/metabolismo , Preparaciones Farmacéuticas/metabolismo , Conejos , Ratas , Ratas Endogámicas , Receptores Androgénicos/efectos de los fármacosRESUMEN
Rioprostil (2-decarboxy-2-hydroxymethyl-15-deoxy-16RS-hydroxy-16-methyl prostaglandin (PG)E1) is a potent orally active inhibitor of gastric acid secretion in both rats and dogs. It prevents gastric lesions in rats induced by ethanol, acetylsalicylic acid, strong acid, strong base, hypertonic saline and thermal injury at doses 100 times less than its antisecretory dose. The cytoprotective effect of rioprostil can be observed when given 4 min before challenge with ethanol and measured 60 min later. The peak antiulcer effect is observed when rioprostil is given 30 min before ethanol challenge and the oral ED50 is 1.93 (1.74-2.15) micrograms/kg. Rioprostil possesses weak PGE-like activity in an isolated tissue cascade, no contragestational activity in rats, hamsters or rabbits, and no remarkable cardiovascular or pulmonary activity in dogs. The animal pharmacology of this compound suggests that it should be useful in the treatment or prophylaxis of peptic ulcer disease and gastric lesions associated with noxious irritants such as ethanol and nonsteroidal antiinflammatory drugs.