Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins.

There is concern that cyclooxygenase (COX)-2 inhibitors may promote atherothrombosis by inhibiting vascular formation of prostacyclin (PGI2) and an increased thrombotic risk of COX-2 inhibitors has been reported. It is widely accepted that the prothrombotic effects of COX-2 inhibitors can be explained by the removal of platelet-inhibitory PGI2. Using microarray chip technology, we have previously demonstrated that thrombomodulin (TM) mRNA is upregulated in cultured human coronary artery smooth muscle cells by the stable prostacyclin mimetic iloprost. This study is the first to demonstrate a stimulation of the expression of functionally active thrombomodulin in human smooth muscle cells by prostaglandins, endogenously formed via the COX-2 pathway. Because TM is an important inhibitor of blood coagulation, these findings provide a novel platelet-independent mechanism to explain the prothrombotic effects of COX-2 inhibitors. The full text of this article is available online at http://circres.ahajournals.org.

[Non-steroidal anti-inflammatory drugs and intestinal side effects]. / Niesteroidowe leki przeciwzapalne a powiklania jelitowe.

Non-steroidal anti-inflammatory drugs (NSAID), including acetylsalicylic acid, are the most commonly applied in the world, however at the same time they constitute a risk factor for gastrointestinal complications. The main mechanism of action of NSAID is based on reducing the synthesis of prostaglandins by means of inhibiting the activity of cyclooxygenase (COX), namely, of COX-1, which generates gut protective prostaglandins, and COX-2, induced at the sites of inflammation, tissue lesions and certain neoplasm. Complications caused by NSAID within the upper gut are subject to numerous studies; however those affecting the intestines are considerably less known. The complications accompanying the use of NSAID may include intestinal strictures, enteropathy with anemia and the loss of protein, macroscopically inflammatory changes as erosions and ulceration, aggravated diverticulosis, and recurrences of ulcerative colitis. During treatment with NSAID the incidence of changes within the intestine is comparable to that within the upper gut. The incidence and character of complications concerning the small and large intestines are still under investigation. Frequently, post-NSAID intestinal changes may not present any clinical signs; it is only a serious complication (haemorrhage, perforation) that becomes the first symptom. Introducing selective COX-2 inhibitors into the treatment has significantly reduced the complications within both upper and lower digestive tract; however, the knowledge of the security profile for these preparations is not yet complete.

Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.

BACKGROUND: Most epidemiological studies evaluating the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and acute renal failure (ARF) found an increased risk for developing ARF while taking NSAIDs. Despite these studies, little is known about the effect of dose and duration of therapy, risk of individual NSAIDs, comorbidity, or concomitant use of other nephrotoxic drugs. METHODS: This is a nested case-control study using the General Practice Research Database from the United Kingdom. Participants were 386,916 patients aged 50 to 84 years on January 1, 1997, and free of known cancer, renal disorder, cirrhosis, or systemic connective tissue disease. After validation of cases identified from this cohort, 103 patients were confirmed as idiopathic cases of ARF and compared with 5,000 controls frequency matched by age and sex. RESULTS: Current users of NSAIDs had a relative risk (RR) for ARF of 3.2 (95% confidence interval [CI], 1.8 to 5.8), and the risk declined after treatment was discontinued. Increased risk was present with both short- and long-term therapy and was slightly greater among users of high doses. History of heart failure (HF), hypertension, diabetes, and hospitalizations and consultant visits in the previous year were all associated with a greater risk for ARF. There was a suggestion of a modification of the effect of NSAIDs in patients with hypertension and those with HF. Use of selected cardiovascular drugs was associated with a 5-fold increase in risk for ARF. Diuretics presented the greatest risk. Risk increased with concomitant use of NSAIDs and diuretics (RR, 11.6; 95% CI, 4.2 to 32.2) and NSAIDs and calcium channel blockers (RR, 7.8; 95% CI, 3.0 to 20.5). CONCLUSION: NSAID users had a 3-fold greater risk for developing a first-ever diagnosis of clinical ARF compared with non-NSAID users in the general population. NSAIDs should be used with special caution in patients with hypertension and/or HF.

Antisecretory and mucosal protective actions of misoprostol. Potential role in the treatment of peptic ulcer disease.

Misoprostol, a synthetic methyl ester analogue of prostaglandin E1, inhibits basal, nocturnal, and stimulated gastric acid secretion. In doses of 400 to 1,200 micrograms daily, misoprostol accelerates the healing of duodenal and gastric ulcers in humans. In addition to its antisecretory actions, misoprostol has gastroduodenal mucosal protective (cytoprotective) effects in animals and in humans. In humans, these cytoprotective actions have been demonstrated in acid-dependent studies using non-antisecretory doses and in acid-independent studies using antisecretory doses. Patients with peptic ulcer disease may have a relative deficiency of mucosal prostaglandin synthesis as compared with nonulcer control subjects. In addition, patients who consume nonsteroidal anti-inflammatory drugs and those who are cigarette smokers may also have depressed gastric mucosal prostaglandin synthesis. There is some evidence that misoprostol reverses the deleterious effect of smoking on duodenal ulcer healing and that it is effective in treating and preventing mucosal damage induced by nonsteroidal anti-inflammatory drugs and alcohol.

The effects of deprivation of prostaglandin precursors on vascular sensitivity to angiotensin II and on the kidney in the pregnant rabbit.

1 Pregnant rabbits were deprived of essential fatty acids from day ten of pregnancy, and results compared with a control group on a normal diet. 2 At term, cannulation of jugular and carotid vessels was performed under anaesthesia, to study the vascular sensitivity to angiotensin II and basal blood pressure. 3 Plasma renin levels, urinary electrolytes and protein were measured. 4 Placental and renal tissue was examined histologically. 5 Though no changes were found in tissues, blood or urine, a markedly significant increase in response to angiotensin II was found in the group deprived of essential fatty acids. This parallels the findings in vascular response in human pre-eclampsia.

Prostaglandins in peptic ulcer disease. An overview of current status and future directions.

Naturally occurring prostaglandins almost certainly play an important role in maintaining the integrity of the gastrointestinal mucosa. Clinical evidence available to date indicates that synthetic analogues of prostaglandins heal gastroduodenal ulcer only in doses that suppress gastric acid. However, non-antisecretory doses of prostaglandins may eventually have a role in the treatment of ulcer disease by maintaining ulcer healing and preventing recurrence. This possibility along with the potential of prostaglandins to prevent gastroduodenal mucosal injury caused by NSAIDs, alcohol, aspirin and stress, if supported by the results of ongoing clinical trials, may prove to be a major therapeutic advance for the treatment of acid peptic disease.

Some recent biochemical findings with possible therapeutic implications for schizophrenia.

Hemodialysis resulted in remission of psychopathological symptoms in eight of ten chronic schizophrenics and successful hemodialysis was associated with a decrease of leucine endorphin levels in the blood. Three endorphins (endogenous peptides) have been isolated from the brain, and among them beta-endorphin was found to be the most potent in inducing behavioral changes in the rat. Nevertheless, neither a positive, nor an inverse relationship between the severity of schizophrenic psychopathology and CSF endorphin concentrations could be borne out by clinical experiments. Most recently, on the basis of an entirely different line of research, the possibility that schizophrenia is a prostaglandin deficiency disease has been raised.

Immature rats show ovulatory defects similar to those in adult rats lacking prostaglandin and progesterone actions.

Gonadotropin-primed immature rats (GPIR) constitute a widely used model for the study of ovulation. Although the equivalence between the ovulatory process in immature and adult rats is generally assumed, the morphological and functional characteristics of ovulation in immature rats have been scarcely considered. We describe herein the morphological aspects of the ovulatory process in GPIR and their response to classical ovulation inhibitors, such as the inhibitor of prostaglandin (PG) synthesis indomethacin (INDO) and a progesterone (P) receptor (PR) antagonist (RU486). Immature Wistar rats were primed with equine chorionic gonadotropin (eCG) at 21, 23 or 25 days of age, injected with human chorionic gonadotropin (hCG) 48 h later, and sacrificed 16 h after hCG treatment, to assess follicle rupture and ovulation. Surprisingly, GPIR showed age-related ovulatory defects close similar to those in adult rats lacking P and PG actions. Rats primed with eCG at 21 or 23 days of age showed abnormally ruptured corpora lutea in which the cumulus-oocyte complex (COC) was trapped or had been released to the ovarian interstitum, invading the ovarian stroma and blood and lymphatic vessels. Supplementation of immature rats with exogenous P and/or PG of the E series did not significantly inhibit abnormal follicle rupture. Otherwise, ovulatory defects were practically absent in rats primed with eCG at 25 days of age. GPIR treated with INDO showed the same ovulatory alterations than vehicle-treated ones, although affecting to a higher proportion of follicles. Blocking P actions with RU486 increased the number of COC trapped inside corpora lutea and decreased ovulation. The presence of ovulatory defects in GPIR, suggests that the capacity of the immature ovary to undergo the coordinate changes leading to effective ovulation is not fully established in Wistar rats primed with eCG before 25 days of age.

Prostaglandin deficiency.

Healthy cells from virtually all tissues synthesize a variety of prostaglandins, autacoids which can significantly alter cellular functions. An absolute or relative deficiency of prostaglandins has now been demonstrated in many diseases or clinical conditions. These include 'natural' disorders such as peptic ulcer disease and diabetes mellitus. These also include 'acquired' or iatrogenic conditions such as cyclosporine nephrotoxicity and the gastropathy induced by nonsteroidal anti-inflammatory drugs. We believe that the diversity of the disorders associated with prostaglandin deficiency may be wider and of greater pathogenetic importance than is currently recognized. We propose: 1) that prostaglandin deficiency will be demonstrated in many abnormalities which are now described as of uncertain etiology; and 2) that adverse effects from many commonly prescribed drugs may also be related to an unrecognized and unfavorable alteration in prostaglandin synthesis, disposal, or activity.

Successful treatment by defibrination with ancrod in a patient with hyperacute renal allograft failure and a deficiency of plasma prostacyclin stimulating factor.

Hyperacute and renal allograft failure, whether due to rejection or other mechanisms, such as perfusion injury, is usually associated with extensive intraglomerular fibrin deposition and allograft loss. Defibrination with ancrod was used to treat a patient with hyperacute renal allograft failure and extensive glomerular fibrin deposition and necrosis. The patient's plasma had normal fibrinolytic activity but a complete absence of the ability to generate prostacyclin-like activity from rat aortic endothelium "in vitro". Treatment was associated with complete recovery of renal function, disappearance of glomerular fibrin, and restoration toward normal of glomerular structure.

[Oculo-cutaneous tyrosinase-positive albinism]. / Albinisme oculo-cutané tyrosinase-postif.

In the present work, the authors discuss the participation of prostaglandins in inflammatory reaction due to U. V. light and the consequences of prostaglandins deficiency. A patient of algerian origin was observed: this 60 year old woman, exhibited an albinism thyrosinase positive and tolerated fairly well an exposure to the U. V. light despite her disease. For ten years she has presented face, neck and arms hyperkeratosis, for five years, arm actinic porokeratosis, and for two years back and face carcinomas. M. E. D. is higher than the standard value. The discussion is open on the fact that this M. E. D. rise might result from prostaglandins deficiency (PE E2 F2). Moreover prostaglandins deficiency increases epidermal multiplication and could account for hyperkeratosis and malignant change, especially so as the patient suffers from albinism and lives in a sunny country. The authors, besides, attempts to relate the other symptoms of this patient to the hypothetical deficiency of prostaglandins; absence of the melanosome maturation, delays in cicatrisation and perhaps immunity perturbations.

Gastroduodenal ulcers: causes, diagnosis, prevention and treatment.

During the past decade, new acid antisecretory drugs have been developed, and our understanding of the mechanisms of mucosal ulceration has been broadened. However, the major change has been an appreciation of the role of Helicobacter pylori in peptic ulcer disease.

Gastroprotective role of glucocorticoids during NSAID-induced gastropathy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) make significant contributions to gastric ulcer disease which remains widespread. Although several factors have been postulated as pathogenic elements of the gastric injury induced by NSAIDs, it is, however believed that prostaglandin deficiency plays a critical role in the pathogenesis of this injury. During prostaglandin deficiency, other defensive mechanisms might operate to attenuate NSAID-induced gastropathy. According to our results, NSAIDs, similar to stress, induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist the harmful actions of these drugs. In this article, we review our experimental data suggesting that glucocorticoids may play a role as natural defensive factors in maintaining the integrity of the gastric mucosa during NSAID therapy and might operate to attenuate NSAID-induced gastropathy.

[Contribution of glucocorticoid hormones to gastroprotective effect of ischemic preconditioning in rats with normal and deficient prostaglandin production].

The study was designed to investigate whether glucocorticoid hormones participate in gastroprotective effects of ischemic preconditioning in rats with normal and deficient prostaglandin production. To estimate the role of glucocorticoids adrenalectomy followed by appropriate corticosterone replacement and inhibition of corticosterone synthesis by metyrapone were used. Prostaglandin synthesis was inhibited by indomethacin. In control rats gastric ischemic preconditioning (a 0.5 h ischemia-reperfusion) induced plasma corticosterone rise and attenuated gastric injury caused by 3.5 h ischemia-reperfusion. The gastroprotective effect of ischemic preconditioning was prevented by adrenalectomy as well as metyrapone pretreatment in both groups, in the rats with normal and deficient prostaglandin production. Acute corticosterone replacement to adrenalectomized rats during ischemic preconditioning restored the protective effect of ischemic preconditioning on the gastric mucosa even in the rats with inhibited prostaglandin synthesis. Thus, the glucocorticoid hormones were shown to contribute to gastroprotective effect of ischemic preconditioning in the rats with normal and deficient prostaglandin production.

Hormonal influences of early postnatal indomethacin and ibuprofen in neonatal rats.

OBJECTIVE: Indomethacin and ibuprofen are administered to preterm neonates for symptomatic patent ductus arteriosus. The drugs suppress prostaglandins (PGs) which modulate growth and secretion of various hormones. We examined the hypothesis that early postnatal indomethacin and ibuprofen influence growth and GH-IGF-I-insulin and HPA axes in neonatal rats. DESIGN: Rat pups received IP injections of saline (Sal) on P1, P2, and P3; 10mg/kg ibuprofen on P1 followed by 5mg/kg on P2 and P3; or 0.2mg/kg indomethacin on P1 followed by 0.1mg/kg on P2 and P3. Serum and hepatic GH, GHBP and IGF-I; and serum corticosterone and insulin levels were determined. RESULTS: Ibuprofen suppressed somatic growth in the sucking rats, but the effect was transient, resolving by P14. Indomethacin had an opposite, latent effect on body weight and liver to body weight ratios in weanling rats. Both indomethacin and ibuprofen had profound hormonal effects that differed in magnitude and timing. Indomethacin resulted in a sustained elevation in corticosterone levels at P21, while ibuprofen increased serum and hepatic GH levels. Both drugs suppressed GHBP in serum at P7 and P14; and liver at P4 and P7, but a rebound increase in serum GHBP was noted at P21 with Ibuprofen only. Both drugs increased serum IGF-I at P7. The effect remained sustained with indomethacin. CONCLUSIONS: These results provide evidence for an involvement of PGs in the regulation of growth as well as the GH-IGF and HPA axes. Therefore, early postnatal exposure to PG inhibitors may further exacerbate postnatal growth restriction and ability to cope with stress.