ADMINISTRATION OF H2 BLOCKERS IN NSAID INDUCED GASTROPATHY IN RATS: effect on histopathological changes in gastric, hepatic and renal tissues

ABSTRACT Background Nonsteroidal anti-inflammatory drugs induces gastric mucosal lesions because of its acidic properties. Ranitidine, an H2 receptor antagonist, has proved beneficial in patients with gastric ulcers. Objective The present study was performed to assess the effect of administering ranitidine in Nonsteroidal anti-inflammatory drugs (diclofenac, nimesulide) induced gastropathy, and their effect on the histopathology of stomach, kidney and liver. Methods Diclofenac, nimesulide, and ranitidine were administered in doses of 2, 4, and 6 mg/kg, p.o. once daily for 14 days, and their effect on gastric volume, acidity, mean ulcer number, and gastric pH. In addition, histopathological examination was also performed on sections of stomach, kidney and liver. Results Following the administration of diclofenac or nimesulide, all the gastric parameters were significantly altered as well as the histopathology of stomach, liver and kidney. In the control group, the renal sections showed normal glomeruli with no thickening of glomerular basement membrane, while in diclofenac alone, nimesulide alone, and ranitidine with nimesulide groups, the thickening of glomerular basement membrane was observed. These alterations were observed to be reversed in the ranitidine with diclofenac group. In the sections from the liver, the control group showed anastomosing plates and cords of cuboidal hepatocytes with round well stained nuclei and abundant cytoplasm. In the ranitidine with diclofenac, and ranitidine with nimesulide groups, mild dilatation of sinusoids is seen coupled with prominence of central vein. In the diclofenac alone and nimesulide alone groups, the proximal and distal convoluted tubules show mild focal tubular necrosis. In the gastric sections, the control group showed several folds forming villi, and the epithelial lining surface of the mucosa. In the ranitidine with diclofenac, and ranitidine with nimesulide groups, the duodenum showed scattered inflammatory cells composed predominantly of lymphocytes. In diclofenac alone and nimesulide alone group, the sections from the gastric areas showed partial necrosis and mild chronic inflammation respectively. Conclusion The study, therefore, has provided therapeutic rationale towards simultaneous administration of H2 receptor blocker ranitidine with diclofenac to be more beneficial as compared to ranitidine with nimesulide, to minimise the gastric intolerance of diclofenac in long term treatment of inflammatory conditions.

RESUMO Contexto Anti-inflamatórios não esteroidais induzem lesões da mucosa gástrica devido às suas propriedades ácidas. Ranitidina, um antagonista dos receptores H2, revelou-se benéfico em pacientes com úlceras gástricas. Objetivo - O presente estudo foi realizado para avaliar o efeito da administração de ranitidina em gastropatia induzida por anti-inflamatórios não esteroidais (diclofenaco, nimesulida) e seu efeito sobre a histopatologia do estômago, dos rins e fígado. Métodos Diclofenaco, nimesulida e ranitidina foram administradas em doses de 2, 4 e 6 mg/kg, p.o. uma vez diariamente por 14 dias e seu efeito sobre o volume gástrico, acidez, significam o número de úlcera e o pH gástrico. Além disso, o exame histopatológico também foi realizado em seções do estômago, dos rins e fígado. Resultados Após a administração de diclofenaco ou nimesulida, todos os parâmetros gástricos foram significativamente alterados assim como a histopatologia do estômago, fígado e rim. No grupo controle, as seções renais mostraram glomérulos normais sem espessamento da membrana basal glomerular, enquanto em diclofenaco isolado, nimesulida isolado e grupos com ranitidina e nimesulida, foi observado espessamento da membrana basal glomerular. Estas alterações observou-se serem revertidas no grupo ranitidina com diclofenaco. As seções do fígado, o grupo controle mostrou placas e cordões de hepatócitos cuboidais anastomosados com núcleos bem demarcados e citoplasma abundante. Nos grupos ranitidina com diclofenaco e ranitidina com nimesulida, leve dilatação dos sinusoides é vista acoplados com proeminência de veia central. Nos grupos diclofenaco e nimesulida sozinhos, túbulos proximais e distais contorcidos mostram necrose tubular focal leve. Nas secções gástricas, o grupo controle mostrou várias dobras formando vilosidades e a superfície do revestimento epitelial da mucosa. Nos grupos ranitidina com diclofenaco e ranitidina com nimesulida, o duodeno mostrou dispersas células inflamatórias predominantemente compostas por linfócitos. Nos grupos diclofenaco e nimesulida sozinhos, as secções de áreas gástricas mostraram necrose parcial e inflamação crônica moderada respectivamente. Conclusão - O estudo, portanto, forneceu o fundamento terapêutico para administração simultânea de bloqueador de receptor H2 (ranitidina) com diclofenaco, sendo mais benéfica em comparação com ranitidina com nimesulida para minimizar a intolerância gástrica de diclofenaco no tratamento a longo prazo de condições inflamatórias.

Effect of cimetidine on hepatotoxicity induced by isoniazid-rifampicin combination in rabbits.

OBJECTIVE: To evaluate the hepatoprotective potential of cimetidine in hepatotoxicity induced by isoniazid-rifampicin combination in albino rabbits. METHODS: Six groups of six rabbits each were studied. Three groups received saline (control), isoniazid (50 mg/Kg/d) alone or isoniazid with rifampicin (100 mg/Kg/d) daily orally for 7 days. Other groups received intraperitoneal cimetidine (50 mg/Kg/d) alone or cimetidine (50 or 120 mg/Kg/d) along with isoniazid-rifampicin combination. Serum levels of liver enzymes were measured at baseline and on day 8 and liver histology was studied on day 8. RESULTS: Rabbits receiving isoniazid alone for 7 days showed no increase in serum ALT and AST levels, whereas those receiving isoniazid-rifampicin combination had a 3-4-fold increase in these levels (p=0.02). Animals receiving cimetidine pre-treatment did not show a significant increase in ALT and AST levels. Histological changes in the liver were more common with isoniazid-rifampicin combination than with isoniazid only. These changes were reduced in animals receiving low-dose cimetidine and prevented in those receiving high-dose cimetidine. CONCLUSION: Cimetidine in high dose can prevent hepatotoxicity induced by isoniazid-rifampicin combination.

Serum concentration of testosterone, epididymal mast cell population and histamine content in relation to sperm count and their motility in albino rats following H2 receptor blocker treatment.

H2 receptor blocker treatment over a period of 2 weeks had been found to cause significant reduction in epididymal tissue mast cell population and tissue histamine content in caput, corpus and cauda regions in albino rats. There was also a highly significant fall of serum testosterone level and sperm count in these segmental fluids collected by micropuncture. The motility of sperms was also greatly reduced and the number of abnormal spermatozoa was found to be increased, the increase being highly significant in the caudal segment. In view of histamine being involved in steroidogenic activity, it appears that reduction in epididymal tissue histamine content following H2 receptor blocker treatment had caused low availability of testosterone to the tissues and thereby the reduction in sperm count and their motility. Increase in number of abnormal sperms particularly in the caudal epididymis is likely to be due to malformation and increased destruction of sperms, because of alteration in epididymal environment due to fall in serum testosterone concentration.

Biochemical and histological studies on H2-receptor antagonist ranitidine-induced hepatotoxicity in rats.

This study was designed to investigate the hepatotoxicity of ranitidine treatment in dose levels of 10, 30, and 50 mg/kg b.wt. for 3 weeks period in male rats. The results showed some adverse changes in rats treated with either 10 or 30 mg/kg. Treatment with dose of 50 mg/kg produced marked increase in the activity of both acid phosphatase in liver and aspartate aminotransferase in serum and liver, with a tendency for increase in serum alanine aminotransferase activity. Also, a significant decrease in the serum activity of both amylase and alkaline phosphatase was noted. Microscopic examination of livers of the same animals revealed absence of some hepatic cells, pyknotic nuclei, dilatation of blood sinusoids, binucleated cells, and infiltration of lymphocytes. These biochemical and histological changes indicate that ranitidine when given chronically in high dose could produce hepatotoxicity in rats.

Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists.

The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).

Effects of anti-allergic drugs on intestinal mastocytosis and worm expulsion of rats infected with Neodiplostomum seoulense

The effects of anti-allergic drugs on intestinal mastocytosis and the expulsion of Neodiplostomum seoulense were observed in Sprague-Dawley rats, after oral infection with 500 metacercariae. The drugs used were hydroxyzine (a histamine receptor H1 blocker), cimetidine (a H2 blocker), cyclosporin-A (a helper T-cell suppressant), and prednisolone (a T- and B-cell suppressant). Infected, but untreated controls, and uninfected controls, were prepared. Worm recovery rate and intestinal mastocytosis were measured on weeks 1, 2, 3, 5, and 7 post-infection. Compared with the infected controls, worm expulsion was significantly (P < 0.05) delayed in hydroxyzine- and cimetidine-treated rats, despite mastocytosis being equally marked in the duodenum of all three groups. In the cyclosporin-A- and prednisolone-treated groups, mastocytosis was suppressed, but worm expulsion was only slightly delayed, without statistical significance. Our results suggest that binding of histamine to its receptors on intestinal smooth muscles is more important in terms of the expulsion of N. seoulense from rats than the levels of histamine alone, or mastocytosis.

Histamine induced decrease of lecithin levels in broncho-alveolar lavage fluid of rats is mediated by H2 receptor.

Lecithin, a major surface active substance of the surfactant system of the lung, was estimated in broncho-alveolar lavage (BAL) fluid in four groups of healthy adult male albino rats. Rats from group I were not administered any drug and acted as controls. Group II were administered histamine diphosphate. Group III were given H1 blocker (pyrilamine maleate) followed by histamine diphosphate. Group IV received H2 blocker (ranitidine hydrochloride) followed by histamine diphosphate. Lecithin content of BAL fluid in the control group was compared with that in the other three groups. A significant decrease in lecithin content was observed in the rats that received either histamine diphosphate or H1 blocker followed by histamine diphosphate. However, compared to control rats no significant difference in lecithin content was seen in rats that received H2 blocker followed by histamine diphosphate. The results clearly indicate that the decrease in surface active lecithin content in BAL fluid following administration of histamine diphosphate was unaffected by prior administration of H1 blocker, but was blocked by prior administration of H2 blocker. It was concluded that histamine induced decrease in lecithin content of BAL fluid is mediated through H2 receptors. Since the predominant source of intra-alveolar lecithin are Type II cells of the alveolar epithelium, It is possible that Type II cells have H2 receptors, stimulation of which resulted in decreased intraalveolar lecithin.

Farmacología clínica de los antihistamínicos en medicina veterinaria / Clinical pharmacology of antihistaminic agents in veterinary medicine

A pesar de que los antihistamínicos se utilizan rutinariamente en mayor o menor medida en medicina veterinaria, poco se ha escrito sobre ellos y, por ende, existen pocos estudios formales que permiten juzgar su eficacia clínica. Aunque su advenimiento es posterior, existen más informes sobre los antihistamínicos de receptores H2 que de los H1 y son pocos los datos que ofrece la literatura acerca del uso de los inhibidores de la liberación de histamina. En parte, esta escases de informes especializados en la literatura científica, se debe a que es difícil cuantificar el alivio o bienestar que inducen los antihistamínicos. Sin embargo, es claro que por su antagonismo con histamina, pueden ayudar a la resolución de variadas enfermedades en las especies domésticas. En este sentido se presenta una revisión de la literatura, encaminada a ofrecer al lector los datos clínicos disponibles, así como las enfermedades en las que estos agentes podrían ser de utilidad. En virtud de que existen pocos datos de la farmacocinética de estos compuestos en medicina veterinaria, en particular de los antiH1, se presentan los correspondientes en humanos, pero sólo como referencia ya que es sabido que la extrapolación conduce a graves errores. Son necesarios estudios en cada especie doméstica. Asimismo se tienen disponibles las dosis de todos los antihistamínicos en las diversas especies domésticas ni para todas la indicaciones; por ello se hace referencia a las dosis empíricas usadas en veterinaria y lo establecido en humanos. Cuando es pertinente, se comenta el uso de los antihistamínicos en humanos, a fin de estimular a los investigadores a extrapolar de datos en ensayos clínicos

Estado actual de antihistamínicos / Current state of antihistamine drugs

El aumento de la prevalencia mundial de las patologías respiratorias alérgicas conlleva un aumento simultáneo en la prescripción de antihistamínicos orales. Los efectos adversos que dichos medicamentos provocan en el sistema nervioso central son muy frecuentes(1), por lo que se presenta una revisión actualizada de los antihistamínicos sistémicos bajo el clásico adagio de la Medicina: "Primum non nocere" ("antes que nada no dañar"). En esta revisión se describe las generalidades de la acción de la histamina en el organismo. Los efectos terapéuticos y secundarios de los antihistamínicos de primera y segunda generación y finalmente se presenta una descripción acabada del nuevo antialérgico epinastina

study of the effect of H1-and H2-receptor blocking drugs on the normal healing process of excised skin wounds in the rat

In this study, 240 adult healthy albino rats of both sexes were used. They were classified into control and drug-treated groups. Full thickness excised skin wounds were inflicted on the shaved dorsal aspect of the thoracic wall. The mean healing time, rate of wound contraction, the total and the saline soluble collagen concentrations in the healing wound area were measured. Loratadine did not significantly alter any of the wound healing parameters studied. Cimetidine has caused a statistically significant shortening of the mean healing time, acceleration of wound contraction rate, reduction of the total and increase in the saline soluble collagen concentration in the healing wound area 2 and 3 weeks post-wounding

Eliminacion de Helicobater Pylory en pacientes con dolor abdominal recurrente con la administracion simultanea de ranitina, subsalicilato de bismuto y claritromicina / Elimination of Helicobacter pylori in patients with recurrent abdominal pain simultaneous administration of ranitidine, bismuth subsalicylate and claritromycin

Objetivo: Evaluar la eliminación de Helicobacter pylori, así como la mejoría clínica en niños con gastritis asociada; cuando se les administró en forma simult nea claritromicina, ranitidina y subsalicilato de bismuto. Antecedentes: Diversos esquemas de tratamiento se han utilizado para la eliminación de Helicobacter pylori en niños con gastritis, con diferentes resultados. Método: Se estudiaron 22 pacientes que acudieron al servicio de Gastroenterología, del Instituto Nacional de Pediatría, durante el período comprendido entre enero de 1992 y junio de 1993. Se incluyeron todos los niños con dolor abdominal recurrente en quienes se identificó Helicobacter pylori en las biopsias de antro g strico. El tratamiento consistió en la administración simult nea de claritromicina durante 15 días y ranitidina y subsalicilato de bismuto durante un mes. Resultados: en 14 de 22 niños se logró mejoría clínica, así como la eliminación de Helicobacter pylori. Conclusiones: La eliminación de Helicobacter pylori y la mejoría clínica se obtuvieron en el 63.7 por ciento de los niños, con buena tolerancia al tratamiento.

potential effects of ranitidine [H2 receptor antagonist] on female fertility in rats

The present study dealt with the possible effects of chronic administration of histaminergic H2 receptor antagonist [ranitidine] on female fertility, as indicated by the variations in the number of Graffian follicles, corpora lutea and the serum concentration levels of estradiol [E2] and progesterone [P]. Ranitidine was daily administered [either 75 mg/kg i.v. or 150 mg/kg p.o.] to adult female albino rats for 8 weeks. Blood samples for hormonal radioimmunoassay [RIA] were collected from the retro-orbital venous plexus. The animals were then sacrificed for the histopathological study of their ovaries. Chronic administration of ranitidine either orally or intravenously could exhibit a significant inhibition effect on female fertility with subsequent inhibition of ovulation as well as significant drop in the serum concentration levels of both estradiol and progesterone. The inhibitory effect of ranitidine could be reversed completely after injection of pregnant mare serum [PMS] gonadotrophin in a dose of 10 IU for 7 days and after stopping the administration of the drug for 8 weeks [after 8 weeks of daily intravenous or oral administration]

Effect of cimetidine on weight gain in rats.

Effect on food intake and body weight was studied in rats after oral administration of cimetidine. Rats in experimental (E) group exhibited less increase in food intake (20%) compared to control (C) rats (43.8%). Mean body weight showed first reduction (-9.56%) and then very small increment in experimental animals compared to gradual gain in body weight in control animals. At the end of 6 weeks, total gain in body weight was 22.5 gm in rats of E group against 53.8 gm in rats of C group. Food efficiency ratio (FER) showed much reduction (1.13) in E group against 2.07 in C group. These results demonstrate that cimetidine (H2-receptor blocker) may have ability to reduce food intake and body weight in rats.

Efeitos cardiovasculares dos bloqueadores H2 em uma populaçäo de risco: um ensaio clínico randomizado / Cardiovascular effects of H2-antagonists in a risk population: a randomized study

Com o objetivo de avaliar os efeitos cardiovasculares dos bloqueadores H2, realizamos um ensaio clínico randonizado. Foram estudados 39 pacientes internados na sala de observaçäo de nosso serviço, que apresentavam dois ou mais fatores de risco, tais como: idade acima de 60 anos, insuficiência cardíaca, arritmias cardíacas, bloqueios de conduçäo cardíaca, uso de drogas bradicardizantes, insuficiência renal, falência hepatica, hipoxemia, hipotensäo arterial ou sepse. Os pacientes foram randomizados a receber cimetidina (300mg) ou ranitidina (50mg) via venosa. Pressäo arterial(PA), frequência cardíaca (FC) e eletrocardiograma (ECG) foram aferidos antes e após a administraçäo do medicamento. Houve reduçäo significativa da PA e da FC. O ECG näo se alterou significativamente. Concluímos que o uso de cimetidina ou de ranitidina provoca alteraçäo de PA e FC em uma populaçäo de rico

Central histaminergic involvement during stress in rats.

Effects of some drugs modulating central histaminergic (HA) transmission were evaluated on restraint stress (RS)-induced gastric ulcerogenesis, plasma corticosterone and immune responses in rats. RS for (i) 6 hr or (ii) 24 hr at room temperature, and (iii) 3 hr at 4 degrees C (CRS) all induced gastric mucosal erosions and elevated plasma corticosterone levels, the effects with the latter two RS procedures being most consistent. Pretreatment of rats with neuronal HA depletor, alpha-FMH (100 mg/kg, ip) attenuated both ulcer severity and corticosterone response, during both 24 hr RS and CRS. Similar effects were also seen with the mast cell degranulator, C-48/80 (10 micrograms/kg, i.c.v.) treatment. Further, the H1-blocker, pheniramine (25 mg/kg, ip) but not the centrally acting H2-blocker, zolantidine (5 mg/kg, ip) produced clearcut attenuations in both stress markers, during the experimental stressors. In rats immunized in SRBC, 24 hr RS (and not CRS) significantly prevented the humoral immune responses to the antigen. alpha-FMH, C 48/80 and pheniramine but not zolantidine, reversed this response during 24 hr RS. The results indicate a central HA ergic involvement in the visceral, endocrinal and immune responses during RS and suggest the probable role of both neuronal as well as extraneuronal (mast cell) HA and activation of H1-receptors in the mediation of these effects.

Actualización de la terapía antihistamínica / An up date on antihistamine therapy

Los antihistamínicos son un arma terapéutica importante en el tratamiento de múltiples cuadros alérgicos cutáneos. Los antihistamínicos H1 tradicionales han sido la base del manejo de diversas condiciones dermatológicas que cursan con prurito; sin embargo sus efectos adversos limitan su uso. Esta revisión analiza en forma suscinta los antihistamínicos tradicionales y los de baja sedación disponibles a la fecha en nuestro país

Efeitos dos bloqueadores H2 sobre o espraiamento de macrófagos in vitro / Effects of H2 blockers on the spreading of macrophages in vitro

Verificar se a cimetifdina, ranitidina e a famotidina, quando injetadas por via ip em camundongo, promovem ativaçäo macrofágica e se esta é alterada com o uso prévio de tioglicolato sódico. Tipo de estudo - Experimental. Animais - Camundongos isogênicos, Balb/c, 19-21g. Intervençiao - Utilizados oito grupos com 10 animais cada. Os animais foram tratados, por via ip, com cimetidina (100mg/Kg), ranitidina (62,5mg/Kg) e famotidina (50mg/Kg), sendo comparados com um grupo controle (salina). Vinte e quatro horas após a inoculaçäo, foi aplicada a técnica do espraiamento de macrófagos. Em etapa posterior, o mesmo procedimento foi realizado, porém em grupos tratados previamente com tioglicolato sódico (15mg/Kg). Análise estatística - Através dos testes de KrusKal-Wallis e Mann-Whitney. Resultados e conclusäo - A inoculaçäo dos anti-H2 em cavidade peritoneal de camundongos aumenta significantemente o espraiamento macrofágico, independentemente do uso prévio de um irritante peritoneal

Influência de um novo antagonista H2 sobre a disposiçäo cinética e efeitos hemodinâmicos da Nifedipina / Influence of a new H2 antagonist on cinetic disposition and hemodynamic effects of nifedipine

Num estudo placebo randomizado, 12 voluntários sadios foram tratados durante uma semana com nifedipina, 10mg 4 vezes ao dia, ou nifedipina, na mesma dose, associada à famotidina, 40mg o.i.d. O estudo farmacocinético demonstrou que as fases de distribuiçäo e eliminaçäo näo säo significativamente alteradas pela co-administraçäo deste antagonista H. Entretanto a fase absorçäo da nifedipina mostrou-se alterada se encontrando a mesma diminuida pela co-administraçäo da famotidina. Apesar das diferenças, os níveis plasmáticos da nifedipina näo mostraram alteraçöes significativas entre os dois grupos (placebo x famotidina). O intervalo de tempo sistólico mostrou que o período pré-ejeçäo (PEPc) e a razäo PEP/LVET foram significativamente reduzidos pela administraçäo da nifedipina + placebo. A associaçäo da famotidina à nifedipina entretanto demonstrou um aumento de PEPc e PEP/LVET. Após administraçäo oral isolada de famotodina constatou-se também um aumento de PEPc e da razäo PEP/LVET. Na cardiografía de impedância o volume ejetado e o débito cardíaco foram reduzidos pela famotidina, mas a freqüência cardíaca näo foi alterada. Portanto verificou-se que a famotidina exerce um efeito inotrópico negativo que poderá ser de relevância clínica, nos pacientes idosos ou com falha cardíaca. A sua associaçäo à nifedipina mostrou que näo há acúmulo digno de nota deste fármaco em pacientes sem comprometimento hepático ou hepato-renal