Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats.

Chronic ibuprofen (0.4 g/kg intraperitoneally, once daily for 4 weeks) evidenced a series of pathologies, not previously reported in ibuprofen-dosed rats, namely hepatic encephalopathy, gastric lesions, hepatomegaly, increased AST and ALT serum values with prolonged sedation/unconsciousness, and weight loss. In particular, ibuprofen toxicity was brain edema, particularly in the cerebellum, with the white matter being more affected than in gray matter. In addition, damaged and red neurons, in the absence of anti-inflammatory reaction was observed, particularly in the cerebral cortex and cerebellar nuclei, but was also present although to a lesser extent in the hippocampus, dentate nucleus and Purkinje cells. An anti-ulcer peptide shown to have no toxicity, the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419, 10 µg, 10 ng/kg) inhibited the pathology seen with ibuprofen (i) when given intraperitoneally, immediately after ibuprofen daily or (ii) when given in drinking water (0.16 µg, 0.16 ng/ml). Counteracted were all adverse effects, such as hepatic encephalopathy, the gastric lesions, hepatomegaly, increased liver serum values. In addition, BPC 157 treated rats showed no behavioral disturbances and maintained normal weight gain. Thus, apart from efficacy in inflammatory bowel disease and various wound treatments, BPC 157 was also effective when given after ibuprofen.

Enantioselective formation of ibuprofen-S-acyl-glutathione in vitro in incubations of ibuprofen with rat hepatocytes.

Ibuprofen is metabolized to chemically reactive ibuprofen-1- O-acyl-glucuronide (I-1- O-G) and ibuprofen- S-acyl-CoA (I-CoA) derivatives, which are proposed to mediate the formation of drug-protein adducts via the transacylation of protein nucleophiles. We examined the ability of ibuprofen to undergo enantioselective metabolism to ibuprofen- S-acyl-glutathione thioester (I-SG) in incubations with rat hepatocytes, where I-CoA formation is known to be highly enantioselective in favor of the (R)-(-)-ibuprofen isomer. We proposed that potential enantioselective transacylation of glutathione forming I-SG in favor of the (R)-(-)-isomer would reveal the importance of acyl-CoA formation, versus acyl glucuronidation, in the generation of reactive transacylating-type intermediates of the drug. Thus, when (R)-(-)- and (S)-(+)-ibuprofen (100 microM) were incubated with hepatocytes, the presence of I-CoA and I-SG was detected in incubation extracts by LC-MS/MS techniques. The formation of I-CoA and I-SG in hepatocyte incubations with (R)-(-)-ibuprofen was rapid and reached maximum concentrations of 2.6 microM and 1.3 nM, respectively, after 8-10 min of incubation. By contrast, incubations with (S)-(+)-ibuprofen resulted in 8% and 3.9% as much I-CoA and I-SG formation, respectively, compared to that in corresponding incubations with the (R)-(-)-isomer. Experiments with a pseudoracemic mixture of (R)-(-)-[3,3,3-(2)H3]- and (S)-(+)-ibuprofen showed that >99% of the I-SG detected in hepatocyte incubations contained deuterium and therefore was derived primarily from (R)-(-)-ibuprofen bioactivation. Inhibition of (R)-(-)-ibuprofen (10 microM) glucuronidation with (-)-borneol (100 microM) led to a 98% decrease in I-1-O-G formation; however, no decrease in I-SG production was observed. Coincubation with pivalic, valproic, or lauric acid (500 microM each) was shown to lead to a significant inhibition of I-CoA formation and a corresponding decrease in I-SG production. Results from these studies demonstrate that the reactive I-CoA derivative, and not the I-1-O-G metabolite, plays a central role in the transacylation of GSH in incubations with rat hepatocytes.

Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa.

It has been proposed that neutrophil and oxygen dependent microvascular injuries may be important prime events in gastrointestinal (GI) toxicity of non-steroidal antiinflammatory drugs (NSAIDs). L-arginine (L-ARG) is an essential amino acid which participates in many important biochemical reactions associated to the normal physiology of the organism. In these experimentations, we studied the role of L-ARG, aminoacid precursor of NO synthesis, on ibuprofen (IB) induced gastric lesions, and also on the inflammatory and oxidative mechanisms related to mucosal damage. Oral administration of IB (100 mg kg(-1)), produced severe damage on gastric mucosa, which was more important after 6 h test-period, and was accompanied by a significant increment in myeloperoxidase (MPO) activity, as index of neutrophil activation, as well as lipid peroxidation (LP) levels and xanthine oxidase (XO) activity. However, no changes were observed in total mucosal glutathione (tGSH), nor glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity. Simultaneous treatment with equimolar doses of L-ARG (oral and i.p.), considerably reduced the number and intensity of lesions, and at the same time (6 h) the maximum protection was also observed. In addition, L-ARG inhibited the IB-induced LP and XO enhancement, but did not produce changes in leukocyte infiltration, tGSH, GSH-Px and SOD activity. These findings suggest that (1) L-ARG protective effect on gastric mucosa against IB-induced mucosal lesions could be explained by a local effect and also might be due to the systemic action of the aminoacid; (2) the active oxygen species, derived both from XO and activated neutrophils, could play a role in the pathogenesis of gastric injury induced by IB, (3) L-ARG exhibit a protective effect against IB-induced mucosal damage, probably through the inhibition of oxidative stress derived via xanthine-XO, but it does not block the oxygen free radical production through polymorphe nuclear leukocytes.

Prostaglandin E2 promotes the survival of bone marrow-derived dendritic cells.

Since dendritic cells (DC) participate in both innate and adaptive immunity, their survival and expansion is tightly controlled. Little is known about the mechanisms of DC apoptosis. PGE(2), an arachidonic acid metabolite, plays an essential role in DC migration. We propose a novel function for PGE(2) as a DC survival factor. Our studies demonstrate that PGE(2) protects DC in vitro against apoptosis induced by withdrawal of growth factors or ceramide. DC matured in conditions that inhibit endogenous PGE(2) release are highly susceptible to apoptosis and exogenous PGE(2) re-establishes the more resistant phenotype. The antiapoptotic effect is mediated through EP-2/EP-4 receptors and involves the PI3K --> Akt pathway. PGE(2) leads to increased phosphorylation of Akt, protection against mitochondrial membrane compromise, and decreased caspase 3 activity. Macroarray data indicate that PGE(2) leads to the down-regulation of a number of proapoptotic molecules, i.e., BAD, several caspases, and granzyme B. In vivo, higher numbers of immature and Ag-loaded CFSE-labeled DC are present in the draining lymph nodes of mice inoculated with PGE(2) receptor agonists, compared with animals treated with ibuprofen or controls injected with PBS. This suggests that PGE(2) acts as an endogenous antiapoptotic factor for DC and raises the possibility of using PGE(2) agonists to increase the survival of Ag-loaded DC following in vivo administration.

[Protective effects of ranitidine in ibuprofen gastroduodenopathy. An endoscopic controlled double blind study]. / Schutzwirkung von Ranitidin bei Ibuprofen-Gastroduodenopathie. Eine endoskopisch kontrollierte Doppelblindstudie an Probanden.

Protective Effect of Ranitidine in Ibuprofen Gastroduodenopathy/An endoscopically controlled double-blind study in healthy volunteers. In a randomized parallel double-blind study the gastroduodenal effects of 600 mg ibuprofen racemate (CAS 15687-27-1) tid in the presence of 150 mg ranitidine (CAS 66357-35-5, Sostril) bid or placebo was evaluated in 32 healthy volunteers undergoing upper gastrointestinal endoscopy. Drugs were taken during a period of 7 days. Endoscopic controls were performed at entry and repeated after 7 days of treatment. A damaging score was used to asses the lesions. At entry both groups showed comparable mucosal damages. The median values under ibuprofen/placebo were 1 (range 0-1) and under ibuprofen/ranitidine 1 (range 0-2). After 7 days of treatment the median lesions score increased under ibuprofen/placebo to 8 (range 1-20) whereas corresponding values in the ibuprofen/ranitidine group were constant at 1 (range 1-9). The differences between both groups were statistically significant (p < 0.05). Our data underline the protective effect of ranitidine 150 mg bid against ibuprofen both on the stomach as well as on the duodenum.

Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol. Experimental studies in the rat.

BACKGROUND: These studies were undertaken to investigate the site and nature of the antinociceptive effect of NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) and paracetamol in the central nervous system (CNS). METHODS: Different nociceptive test models were employed: the tail-flick and hot-plate tests (thermoreceptors), the writhing test (visceral chemoreceptors) the "scratching, biting, licking" (SBL) behaviour and the colorectal distension test (mechanoreceptors). Drugs were given intraperitoneally (i.p.), intracerebroventricularly (i.c.v.), intrathecally (i.t.) or as local injection via cannulae implanted stereotactically. Nerve destruction was made by local injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Whole brain and spinal cord contents of serotonin and 5-hydroxyindole acetic acid (5-HIAA) were analysed by high pressure liquid chromatography (HPLC). RESULTS: Injections of diclofenac induced antinociception in visceral pain models (writhing test, colorectal distension test), but not in two models of somatosensory pain (tail-flick and hot-plate test). The antinociceptive effect of diclofenac (i.p., i.c.v., or i.t.) was reversed by i.p. naloxone. Naloxone also reversed the effect of diclofenac injected locally into thalamic and hypothalamic areas involved in pain transmission as well as in n. paragigantocellularis or n. raphe magnus. In addition, chemical destruction of the n. raphe region attenuated the antinociceptive effect of diclofenac. Inhibition of serotonergic transmission by pretreatment with methiothepin, ritanserin, parachlorophenylalanine (PCPA) or 5,7-DHT also reduced the antinociceptive effect of diclofenac in a visceral pain model. Pretreatment with diclofenac or ibuprofen blocked pain behaviour (SBL) after activation of excitatory amino acid receptors of the NMDA type, but not pain behaviour after activation of AMPA or substance P (SP) receptors. Paracetamol inhibited hyperalgesia after both NMDA and SP. The antinociceptive effects of diclofenac, ibuprofen and paracetamol were reversed by L-arginine, but not by D-arginine. CONCLUSIONS: The antinociceptive effect of diclofenac involves a central nervous component which may be elicited from several defined areas in the CNS. Part of the antinociceptive effect seems to be mediated by descending inhibitory opioid, serotonin and/or other neurotransmitter systems interfering with visceral pain impulse traffic at the spinal level. NSAIDs and paracetamol interfere with nociception associated with spinal NMDA receptor activation. This effect involves an inhibitory action on spinal nitric oxide (NO) mechanisms. Possibly, the supraspinal antinociceptive effect of NSAIDs may be explained by an analogous action.

[Circadian dependency of ibuprofen gastropathy and the protective effect of ranitidine. An endoscopic, controlled double-blind pilot study]. / Tageszeitliche Abhängigkeit der Ibuprofen-Gastropathie und der Schutzwirkung von Ranitidin. Eine endoskopische, kontrollierte Doppelblind-Pilotstudie.

Circadian Dependency of Ibuprofen Gastropathy and Protective Effect of Ranitidine/An endoscopic, controlled double-blind pilot study. In a randomized parallel double-blind study, the gastric and duodenal effects of 600 mg S(+)-ibuprofen (CAS 15687-27-1) daily in the presence and absence of 300 mg ranitidine (CAS 66357-35-5) was evaluated in 20 healthy volunteers undergoing upper GI-endoscopy. Drugs were taken over a period of 7 days either at 8 a.m. (n = 10) or at 8 p.m. (n = 10). Endoscopic controls were performed at entry and repeated after 7 days of treatment. A damage score according to Lanza et al. was used. At entry both groups showed comparable mucosal damages. 8 a.m.-group: ibuprofen/placebo (stomach) 0.9 +/- 0.1 and 0.0 +/- 0.0 (duodenum); ibuprofen/ranitidine 0.8 +/- 0.1 (stomach) and 0.1 +/- 0.1 (duodenum). 8 p.m.-group: ibuprofen/placebo 0.9 +/- 0.1 (stomach) and 0.2 +/- 0.1 (duodenum); ibuprofen/ranitidine 0.9 +/- 0.1 (stomach) and 0.1 +/- 0.1 (duodenum). After 7 days of treatment the lesion score increased in the ibuprofen/placebo-group in the 8 a.m.-group to 3.2 +/- 1.2 (stomach) and to 0.7 +/- 0.5 (duodenum), and in the 8 p.m.-group to 8.4 +/- 1.9 (stomach) and to 2.9 +/- 1.2 (duodenum). The corresponding values in the ibuprofen/ranitidine-group were 1.8 +/- 0.8 (stomach) and 0.1 +/- 0.1 (duodenum) (8 a.m.-group) as well as 5.1 +/- 1.4 (stomach) and 0.1 +/- 0.1 (duodenum) (8 p.m.-group). The difference between the morning and the evening dose of ibuprofen as well as ranitidine protection reached statistical significance when the corresponding data were pooled (p < 0.05). Our data suggest that the gastrolesive effects of S(+)-ibuprofen are dependent of the time of drug ingestion; protection by ranitidine, however, was time-independent.

Prevention of non-steroidal anti-inflammatory agents induced acute gastric mucosal lesions by carbonic anhydrase inhibitors. An endoscopic study.

The present paper studies the effect of acetazolamide, an inhibitor of carbonic anhydrase, on acute gastric mucosal damage induced by non-steroidal anti-inflammatory drugs. The study was performed on healthy male subjects. The drugs tested were aspirin (1.5 g/day), indomethacin (75 mg/day), phenylbutazone (600 mg/day) and ibuprofen (600 mg/day) given for 7 days in 3 divided doses. Each drug was given to 5 cases in two separate periods, during which they were given acetazolamide 20 mg/kg/day or placebo in random order. Dyspeptic symptoms were evaluated. Endoscopy was performed before, and 3 and 7 days after NOSAC administration. Gastric mucosal lesions were evaluated according to the scale proposed by Lanza (J. Clin. Pharmacol., 24: 1984, 89) and the severity of the lesions was calculated. All drugs tested produced dyspeptic symptoms and acute mucosal damage of the gastric mucosa. Inhibition of gastric mucosa carbonic anhydrase by acetazolamide cessated promptly dyspeptic symptoms and reduced significantly the number and severity of drug-associated mucosal lesions.

Low-dose dopamine preserves renal blood flow in endotoxin shocked dogs treated with ibuprofen.

Drugs that inhibit prostaglandin (PG) biosynthesis improve hemodynamics and survival in experimental endotoxic and septic shock. The therapeutic utility of these agents in the management of septic patients may be limited, however, by their tendency to decrease renal blood flow (RBF) in animals and humans stressed by experimental manipulations or disease states that promote renal vasoconstriction. In the present study, we addressed this question: can low-dose intravenous (iv) dopamine (4 micrograms/kg/min), a known renal vasodilator, improve renal perfusion in endotoxin-shocked dogs treated with the PG synthesis inhibitor, ibuprofen. RBF was measured in pentobarbital anesthetized dogs using an electromagnetic flow meter. After obtaining baseline hemodynamics, Escherichia coli endotoxin (1.5 mg/kg) was given iv. The dogs were randomized 30 min later into three groups: Group I received saline; Group II received ibuprofen (12.5 mg/kg, iv); Group III received ibuprofen plus dopamine. Comparison of Groups I and II revealed that ibuprofen increased mean arterial pressure (MAP) and systemic vascular resistance (SVR) (P less than 0.0001 and P = 0.002, respectively) and decreased RBF (P = 0.019). Adding low-dose dopamine (Group II vs Group III) did not significantly affect MAP or SVR, but did augment RBF (P less than 0.001). We conclude that low-dose dopamine improves renal hemodynamics in ibuprofen-treated endotoxemic dogs.