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PubMedDate not supplied

Study on interaction of gastrointestinal agents in the presence of cytoprotective drugs. Part III. In vitro study on the adsorption of selected prokinetic drugs on sucralfate.

Adsorbance of certain prokinetic drugs, regulating the motility of the digestive tract, on a cytoprotective drug--sucralfate was investigated. The evaluation of adsorbance capability was carried out by means of a statistical method in in vitro conditions, taking into account environmental pH, concentration of the investigated drugs as well as the form of sucralfate. Obtained results prove that the analyzed active agents are adsorbed on sucralfate at all the investigated pH ranges and the capability of sucralfate binding depends on its form and environmental pH. The highest binding capability was revealed by samples with pH = 3.6 in the presence of sucralfate in the form of suspension, while the lowest binding capability was observed at pH = 1.5 in the presence of sucralfate in the form of paste. The adsorbance capacity of sucralfate (k) at pH = 3.6 is the highest for cisaprid (k = 8.5) and it is significantly lower for metoclopramide (k = 1.5)

Adsorption↗
PubMed2005

Use of amifostine, a novel cytoprotective, in alpha-amanitin poisoning.

BACKGROUND: Mortality from ingestions of the mushroom Amanita phalloides remains as high as 20-40% with many surviving patients requiring liver transplantation. A variety of treatments for Amanita ingestion have been evaluated, yet other than supportive measures, no effective therapy has been identified. In addition, an antidote for Amanita toxicity may not be practical due to delayed patient presentation. The drug amifostine was proposed to potentially improve survival from alpha-amanitin toxicity by conferring cytoprotective effects on hepatocytes at risk for cell death. Amifostine is used as a radio--and chemo-protective agent. It protects against lipoperoxidation, interferes with the cross-linking of DNA, and may act by other mechanisms yet to be identified, making it attractive for potentially attenuating ongoing hepatic necrosis. It has not previously been studied in a toxicologic model. STUDY OBJECTIVE: To determine whether amifostine is an effective postexposure therapy for alpha-amanitin, the primary lethal toxin in Amanita phalloides. METHODS: Swiss mice (n = 30 in all groups) were given an approximate LD75 dose of intraperitoneal (i.p.) alpha-amanitin. Amifostine was administered i.p. 6 h after poisoning in three cumulative dosing groups: 250 mg/kg; 500 mg/kg; and 1600 mg/kg. Controls received equal volumes of i.p. sterile 0.9% saline. Mice were monitored and time of death recorded. At day 7, survival was assumed and the remaining mice were euthanized. Qualitative histologic comparisons of hepatic and renal toxicity were performed. RESULTS: At day 7, only 10% of the control mice survived. Survival in the amifostine 250, 500, and 1600 mg/kg groups was 20%, 20%, and 3%, respectively. No statistically significant differences were detected in Kaplan-Meier survival between the control group and those receiving 250 or 500 mg/kg; however, there was a statistically significant decrease in survival for the group receiving 1600 mg/kg (p = 0.0002). CONCLUSION: No survival benefit was seen with cumulative doses between 250 and 500 mg/kg; however, higher doses may result in subsequent toxicity and decreased survival.

Amanitins↗
PubMedDate not supplied

Mass spectrometric identification of urinary and plasma metabolites of 6-(6'-carboxyhexyl)-7-n-hexyl-1,3-diazaspiro-[4-4]-nonan-2,4-dione, a new cytoprotective agent.

The compound IBI-P-01028, or R,S-cis-6-(6'-carboxyhexyl)-7-trans-n-hexyl-1,3-diazaspiro-[4-4]-nona n-2,4- dione, is a new cytoprotective agent under development. To study the metabolites of this compound in laboratory animals, we administered it to dogs and rats, and analyzed extracts from dog and rat urine, and from dog plasma, by GC-MS. The metabolic profiles were different in the rat and dog. In the dog (plasma and urine), one metabolite was found, and in the rat urine two other metabolites were found. The unmetabolized drug was found only in the dog plasma and urine.

Animals↗
PubMed2006

Sequence analysis shows that Lifeguard belongs to a new evolutionarily conserved cytoprotective family.

Cellular sensitivity to apoptotic stimuli is determined by several regulatory proteins. The biological and biomedical impact of these regulatory proteins is of fundamental importance for understanding and controlling apoptotic processes. We used a bioinformatic approach to characterise the antiapoptotic protein Lifeguard (LFG). LFG is an evolutionarily well-conserved protein with homologues in many species. Due to its hydrophobic nature it is predicted to reside in cellular membranes, namely the endoplasmatic reticulum and the plasma membrane, with seven transmembrane spanners and a small cytoplasmic domain. The consensus motif of a protein family with unknown function UPF0005 was found in the C-terminus. The structure of Lifeguard resembles the antiapoptotic protein Bax Inhibitor-1 (BI-1). Concordantly, it was shown that Bax co-immunoprecipitates with LFG. Our results indicate that LFG belongs to a new cytoprotective family with evolutionarily conserved functions in the prevention of programmed cell death.

Amino Acid Sequence↗
PubMed1991

Double blind, placebo controlled trial on the cytoprotective effect of misoprostol in subjects with rheumatoid arthritis, osteoarthritis and seronegative spondarthropathy on NSAIDs.

Ninety arthritic patients were randomly allotted to receive misoprostol 200 micrograms thrice daily or placebo, for 4 weeks, while they were started on various NSAIDs. While upper gastrointestinal symptoms occurred equally in both groups, patients on placebo had significantly more post-therapy abnormal endoscopy findings. Misoprostol was well tolerated without any adverse side effects; it did not interfere with the therapeutic efficacy of the NSAIDs. Arthritic patients requiring long term NSAID therapy appear to benefit from misoprostol because of its cytoprotective effect on the gastrointestinal mucosa.

Adult↗
PubMed1991

Colloidal bismuth subcitrate evokes adaptive cytoprotection in rat gastric mucosa.

The 6-keto-prostaglandin-F1 alpha content (as the stable break-down product of prostacyclin) of rat antral and fundic gastric, as well as of duodenal mucosa, significantly increases after 1, 5 and 10 mg/kg orally administered colloidal bismuth subcitrate treatment. The results indicate that (i) colloidal bismuth subcitrate-induced stimulation of endogenous prostacyclin content ("adaptive cytoprotection") of rat gastroduodenal mucosa may contribute to its therapeutic effect; (ii) the effect of colloidal bismuth subcitrate is not due exclusively to the bismuth content of the molecule, but seems to be connected with the structure of colloidal bismuth subcitrate itself; (iii) the effect seems to be dose-dependent, showing a dose-response relationship.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Myocardial cytoprotective efficacy of azapropazone in a swine model of regional myocardial ischemia/reperfusion injury.

The purpose of the present study is to determine the myocardial cytoprotective efficacy of azapropazone (AZA) on regional myocardial function in anesthetized swine model of regional myocardial ischemia/reperfusion injury. AZA was administered (100 mg/kg, i.v.) 15 minutes prior to reflow. The left anterior descending (LAD) coronary artery occlusion was maintained for a total of 30 minutes and then reperfused for 120 minutes. The effects of AZA on regional segmental shortening (% SS) as well as on neutrophil migration were examined in the (proximal) central and border (distal) zones within the area at risk (AAR). AZA reduced the incidence of myocardial fibrillation which occurred in some animals during the LAD occlusion/reperfusion periods. AZA produced a significant recovery of left ventricular segmental shortening (% SS) in the border, but not in the central zones within the AAR. No significant differences in the hemodynamic parameters were observed between the AZA (n = 14) and the saline-treated (n = 17) groups. AZA produced a significant inhibition of neutrophil migration (as evident from the decrease in myeloperoxidase activity) into epi- and endocardium central and border zones within the AAR. It is concluded that AZA may elicit its cardioprotection in moderately but not in severely injured myocardium by inhibiting the neutrophil migration.

Animals↗
PubMed1990

Site-and cytoprotective drugs in the short-term treatment of peptic ulcer. What is their current role?

Many endoscopically controlled comparisons with H2-blockers have widely documented that site- and cytoprotective drugs constitute effective and safe agents for the short-term treatment of gastric and duodenal ulcer. Their efficacy however, is counter-acted by the need for multiple daily administration which requires greater patient compliance. Due to its ability to eradicate Helicobacter pylori (HP) from the gastric antrum and retard relapses, colloidal bismuth may be the first choice anti-ulcer drug for those HP positive patients who do not accept continuous maintenance treatment after healing. A specific subgroup of duodenal ulcer patients who may particularly benefit from a short-term treatment with such agents (namely colloidal bismuth) are the non-responders to an 8-week course of H2-antagonists; conversely, actual evidence does not support the hypothetical superiority of such agents over H2-blockers in the treatment of cigarette smokers or chronic consumers of NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Cytoprotection by histamine in rat gastric mucosa.

The effects of histamine on endogenous prostaglandins and on the damage caused by 0.6 N HCl were tested in rat gastric mucosa. The damage was assessed both macroscopically and microscopically. Histamine increased the prostaglandin E2 level in vivo and stimulated the synthesis of prostaglandin E2 and 6-keto-prostaglandin F1 alpha in vitro. These effects of histamine were inhibited by treatment with cimetidine beforehand. Histamine inhibited both the gross visible mucosal damage and deep necrosis caused by the intragastric instillation of 0.6 N HCl. This effect was overcome by cimetidine or indomethacin, but not by diphenhydramine. These results suggest that histamine stimulates prostaglandin synthesis and induces cytoprotection in rat gastric mucosa, perhaps with the involvement of the H2 receptor.

Animals↗
PubMed1990

Vascular mediation of gastric mucosal damage and cytoprotection.

This review addresses questions surrounding the role of the mucosal circulation in damage and protection against chemical injury to the stomach. The modern history of the topic is briefly summarized, and widely used methods are appraised critically. The role of the circulation is examined in mucosal injury and in cytoprotection, and a new conceptual model is described which involves the vasculature and inflammatory mediators.

Animals↗
PubMed1990

[Role of protons and bicarbonate in adaptative gastric cytoprotection].

The unknown mechanism of adaptative gastric cytoprotection (AGC) induced by 20% ethanol and subsequent injury with 70% ethanol was studied in wistar rats. Pretreatment with indomethacin or HgII2 did not prevent the AGC, there suggesting that neither endogenous PGS nor gastric mucus take part in its mechanism. On the other hand, ranitidine pretreatment blocked and even aggravated the damage induced by ethanol-ethanol. In contrast, the latter phenomenon was reverted by 20% acidified ethanol. It is concluded that a back diffusion of H+ and bicarbonate play important roles in the AGC mechanism.

Animals↗
PubMed1986

Cytoprotective effect of the prostacyclin derivative iloprost against liver cell death induced by the hepatotoxins carbon tetrachloride and bromobenzene.

It was investigated whether the prostacyclin derivative Iloprost (Schering, Berlin) protects rat hepatocytes against lethal damage induced by carbon tetrachloride (CCl4) and bromobenzene (BB). Iloprost was tested in whole animal experiments (intoxication with 2 ml CCl4/kg) and with primary hepatocyte cultures (intoxication with 1.6 mM BB). Cell damage was estimated by light microscopic examination of hepatocellular morphology and by the release of hepatocellular enzymes (glutamic-pyruvic transaminase, GPT; glutamic-oxalacetic transaminase, GOT; lactic dehydrogenase, LDH) into the blood or culture medium. In both experimental set-ups, Iloprost (0.1 micrograms/kg/min in whole animal experiments and 10(-9)-10(-12) M in primary hepatocyte cultures) largely preserved normal hepatocellular morphology after intoxication. Furthermore, the toxin-induced release of hepatocellular enzymes into the blood (GOT, GPT) or into the culture medium (LDH) was reduced by 50%-70% in the presence of Iloprost. It is concluded that the prostacyclin derivative Iloprost possesses cytoprotective activity on rat hepatocytes against lethal injury by CCl4 or BB.

Alanine Transaminase↗
PubMed1989

On the 7-oxo-PGI2 induced late appearing long-lasting cytoprotective effect.

Our results indicate that 7-oxo-PgI2 pretreatment may induce a long lasting cytoprotective effect by preventing ischemia induced intracellular potassium loss and sodium accumulation in myocardial cells of guinea pigs furthermore by protecting from ischemic ultrastructural changes as sarcomere shortening, mitochondrial swelling and irregularity of I, A and Z bands in the rabbit myocardium.

Animals↗
PubMed1989

Microscopic correlates of adaptive cytoprotection in an ethanol injury model.

The present study histologically investigated the efficacy of pretreating rat gastric mucosa with the mild irritants, 10% and 25% ethanol (EtOH), against the known damaging effects of 100% EtOH. Fasted rats received 1 ml of either water, 10% EtOH, or 25% EtOH by orogastric intubation. Fifteen minutes later, a portion of these animals was sacrificed and tissue samples of the oxyntic region of the stomach were excised and processed for quantitative histologic analysis. Remaining animals received a 1 ml oral bolus of the necrotizing agent, 100% EtOH. Five minutes later, these animals were sacrificed and tissues were prepared in a like manner. In a separate series of experiments, the aforementioned protocols were repeated, except that all animals received the prostaglandin synthetase inhibitor, indomethacin (5.0 mg/kg intraperitoneally), 30 min before administration of the mild irritant. Microscopically, the administration of water or 10% EtOH alone caused a small and comparable amount of superficial injury to the gastric mucosa. Moreover, both substances failed to induce protection in stomachs subsequently exposed to 100% EtOH. Indomethacin pretreatment did not significantly alter any of these findings. In marked contrast, 25% EtOH alone elicited a substantial degree of superficial damage to the gastric mucosa. Nevertheless it significantly reduced the depth of injury in animals subsequently challenged by 100% EtOH. Indomethacin failed to aggravate the effects of 25% EtOH alone, but partially inhibited the protective effect of this mild irritant against 100% EtOH induced damage. Our findings indicate that adaptive cytoprotection is a real phenomenon that can be demonstrated microscopically. Such protection is limited primarily to the deep mucosal layers (i.e. gastric glands), appears in part to be prostaglandin mediated and seems to require the generation of moderate surface cell damage (as occurred with 25% EtOH, but not 10% EtOH) to induce its initiation.

Animals↗
PubMedDate not supplied

[Cytoprotective effect of rosaprostol during treatment with non-steroidal anti-inflammatory agents in arthrorheumatic pathologies].

A clinico-endoscopic study has been carried out in a group of 22 patients treated with 1 g of naproxene + 2 g of rosaprostol compared in a blind situation with another group of 19 patients treated with a similar dose of naproxene + placebo in order to evaluate the cytoprotective action of rosaprostol. Analysis of the results showed a high correlation between intake of rosaprostol and low onset of algico-dyspeptic disturbances and mucosal lesions of some gravity, although the problem of the monitoring of patients undergoing long-term treatment with NSAID remains unsolved.

Adult↗
PubMed1989

[The adaptive cytoprotection of exocrine pancreas in rats].

A model of acute necroto-hemorrhagic pancreatitis was prepared by injecting 5% sodium taurocholate-trypsin solution directly into the pancreatic duct of the rat. Fourty eight hours before the preparation of acute pancreatitis, intraductal injection of 0.1%, 0.2% or 0.4% sodium taurocholate-trypsin solution as mild irritant was able to decrease the mortality to 27%, 17% and 17% respectively. The maximal elevation of the serum amylase concentration in acute pancreatitis was decreased to 43%, 47% and 54%, respectively. Microscopic examination of the pancreatic tissue of the rats which were alive after pretreatment of mild irritants showed that the acute pancreatitis was milder and there was a tendency to change to chronic pancreatitis. Thus, we conclude that there is a phenomenon of adaptive cytoprotection on the exocrine pancreas in rats. The mechanisms of the phenomenon remain to be explored.

Acute Disease↗
PubMed1986

Anti-ulcer drugs in antisecretory doses for "cytoprotection" in arthritic patients?

Gastric injury and dyspepsia are major side-effects of acetylsalicylic acid (ASA) or most non-steroidal anti-inflammatory drugs (NSADs) which cause either gastric ulcerations or gastroduodenal erosions. There is only a limited number of trials in which the possibility of preventing or treating gastric lesions due to those drugs have been studied in man. This paper reviews trials in which H2-receptor antagonists, pirenzepine and prostaglandins have been investigated. - Pirenzepine given in antisecretory doses seems to improve gastrointestinal symptoms induced by ASA or NSADs. Cimetidine and misoprostol might prevent fecal blood loss. Gastroduodenal lesions might be prevented by pirenzepine, misoprostol and enprostil. It might be possible that cimetidine or ranitidine heal NSAD-induced peptic ulcers better than placebo in arthritic patients who stop the ingestion of NSADs. - All over the results of the cited trials are inconclusive, since the number of patients studied were too small and the design of almost all trials was incomparable. Furthermore, all cited studies do not correspond to Robert's concept of "cytoprotection", since H2-blockers, pirenzepine and prostaglandins have been applied in antisecretory doses in man.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1985

[Dalargin--a peptide preparation with cytoprotective action].

The role and possible clinical use of regulatory peptides, a new type of regulatory substances, is discussed. Special attention is paid to the opioid peptides and their analogues. The new drug dalargin has been developed on the basis of the endogenous opioid peptide leucine-encephalin. Its action has been studied using experimental models. It has been established that the optimal dose (10 micrograms/kg) of dalargin is effective in preventing ulceration in the cystamine duodenal ulcer rat model and the development of stomach erosive lesions in immobilization stress, reducing the degree of liver degeneration in CCl4 poisoning, etc. With an increase of the dose of dalargin the effect "escapes". Dalargin is primarily bound by delta-receptors, it produces no analgetic effect and does not enter the brain. Dalargin exhibits a pronounced cytoprotective and regeneratory action and may take an important place in treating the internal organ diseases.

Animals↗