Suppression of type I collagen gene expression by prostaglandins in fibroblasts is mediated at the transcriptional level.
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BACKGROUND: Tissues undergoing a chronic inflammatory process, such as the synovium in rheumatoid arthritis, are characterized by the infiltration of lymphocytes of different subsets and activation of monocyte/macrophages. Interleukin-1 (IL-1), a monocyte/ macrophage product that stimulates synovial fibroblasts to produce matrix metalloproteinases (MMPs), prostaglandins, and other cytokines, also has profound effects on the synthesis of extracellular matrix components such as type I collagen. In previous studies, we have shown that synovial fibroblasts and chondrocytes isolated from human joint tissues are particularly sensitive to prostaglandins, which modulate the effects of IL-1 on collagen gene expression in an autocrine manner. MATERIALS AND METHODS: BALBc/3T3 fibroblasts were treated with IL-1 and prostaglandins in the absence and presence of indomethacin to inhibit endogenous prostaglandin biosynthesis. Collagen synthesis was analyzed by SDS-PAGE as [3H]proline-labeled, secreted proteins, and prostaglandin production and cyclic adenosine 3',5'-cyclic monophosphate (camp) content were assayed. The expression of type I collagen gene (Col1a1) promoter-reporter gene constructs was examined in transient transfection experiments, and the binding of nuclear factors to the Col1a1 promoter region spanning -222 bp/+ 116 bp was analyzed by DNase I footprinting and electrophoretic mobility shift (EMSA) assays. RESULTS: IL-1 increased the synthesis of type I and type III collagens in BALBc/3T3 fibroblasts; greater increases were observed when IL-1-stimulated synthesis of PGE2 was blocked by indomethacin. Transient transfection experiments demonstrated dose-dependent inhibition of the-222 bp Col1a1 promoter by exogenously added prostaglandins with the order of potency of PGF2alpha > PGE2 > PGE1 DNase I footprinting showed increased protection, which extended from the region immediately upstream of the TATA box, owing to the binding of nuclear factors from PGE2- or PGE1-treated BALBc/3T3 cells. EMSA analysis showed zinc-dependent differences in the binding of nuclear factors from untreated and prostaglandin-treated cells to the -84 bp/-29 bp region of the Col1a1 promoter. CONCLUSIONS: These results show that the inhibition of Col1a1 expression by IL-1 in fibroblasts is mediated by prostaglandins at the transcriptional level and suggest that PGE-responsive factors may interact directly or indirectly with basal regulatory elements in the proximal promoter region of the Col1a1 gene. (+info)
Randomized trial of low-dose misoprostol and naproxen vs. nabumetone to prevent recurrent upper gastrointestinal haemorrhage in users of non-steroidal anti-inflammatory drugs.
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BACKGROUND: Prophylactic misoprostol or non-steroidal anti-inflammatory drugs (NSAIDs) with low gastric toxicity (nabumetone) has been shown to reduce mucosal injury. AIM: To compare nabumetone vs. co-therapy of naproxen with low-dose misoprostol for secondary prevention of upper gastrointestinal bleeding in NSAID users. METHODS: NSAID users presenting with upper gastrointestinal bleeding were enrolled if they required long-term NSAIDs. After ulcer healing, they were randomized to receive: naproxen (500-1000 mg/day) and misoprostol (200 microg b.d.), or nabumetone (1000-1500 mg/day) and placebo misoprostol for 24 weeks. The primary end-point was recurrent upper gastrointestinal bleeding. The secondary end-point was the proportion of patients suffering from major gastrointestinal events including ulcer bleeding, symptomatic ulcers and severe dyspepsia. RESULTS: A total of 90 patients were included in the intention-to-treat analysis (misoprostol/naproxen 45, nabumetone 45). Recurrent bleeding occurred in 10 patients (22.2%) receiving misoprostol/naproxen compared with three (6.7%) receiving nabumetone (relative risk 3.33, 95% CI: 0.98-11.32, P=0.069). The proportion of patients suffering from major gastrointestinal events at 24 weeks was 31.1% in the misoprostol/naproxen group and 28.9% in the nabumetone group. CONCLUSIONS: Misoprostol/naproxen is not superior to nabumetone for secondary prevention of upper gastrointestinal bleeding. Neither low-dose misoprostol nor nabumetone is adequate for high-risk NSAID users. (+info)
A multicentre randomized controlled trial of oral misoprostol and i.m. syntometrine in the management of the third stage of labour.
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Postpartum haemorrhage accounts for nearly 28% of maternal mortality in developing countries. Syntometrine is an effective and commonly used oxytocic in preventing postpartum haemorrhage, but it requires a controlled storage environment and i.m. administration. Misoprostol is an orally active uterotonic agent. A total of 2058 patients having a singleton pregnancy, low risk for postpartum haemorrhage and vaginal delivery were randomized to receive either 1 ml syntometrine or 600 microgram misoprostol for the management of the third stage of labour. There were no significant differences between the two groups in the mean blood loss, the incidence of postpartum haemorrhage and the fall in haemoglobin concentration. The need for additional oxytocic injection was significantly higher in the misoprostol group [relative risk (RR) 1.62, 95% confidence interval (CI) 1.34-1.96], but that of manual removal of placenta was reduced (RR 0.29, 95% CI 0.09-0.87). Shivering and transient pyrexia were more common in the misoprostol group. Oral misoprostol might be used in the management of the third stage, especially in situations where the use of syntometrine is contraindicated and facilities for storage and parenteral administration of oxytocics are limited. (+info)
A comparative study of surgical and medical procedures: 932 pregnancy terminations up to 63 days gestation.
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The aim of this retrospective study was to compare the efficacy and complications associated with early medical and surgical pregnancy termination. The study population comprised 932 consecutive women undergoing pregnancy termination at gestations of 63 days or less. There were no age or parity differences between the study groups. Medical termination was performed with mifepristone 200 mg orally and misoprostol 800 microgram vaginally; surgical aspiration termination was performed under general anaesthesia. Outcome measures were: surgical curettage for presumed retained products of conception; ongoing pregnancy; and planned and emergency review in the unit. Early medical and surgical termination were associated with a 90.2 and 94.5% complete abortion rate respectively (P = 0.025). The complete abortion rate with medical termination decreased significantly with increasing parity; no such relationship with surgical abortion was found. Women of parity three or more were less likely to have a complete abortion following a medical (83.3%) compared to surgical procedure (97.7%) (P = 0.028). The ongoing pregnancy rate was 0.9% with medical and 0.5% with surgical termination (P = NS). Medical termination was associated with a lower complete abortion rate than surgical termination, particularly for women of higher parity. However, early medical termination allows over 90% of women to avoid the risks of surgical instrumentation of the uterus and anaesthesia. (+info)
This study examined whether the prostaglandin E(1) analogue misoprostol (400 microgram), when placed vaginally at the time of intrauterine insemination (IUI) improves pregnancy rates. A prospective, placebo-controlled, randomized and double-blind study involving 274 women in 494 IUI cycles resulted in a total of 64 pregnancies (13% per cycle). Misoprostol cycles totalled 253, with 43 pregnancies (17% per cycle), whereas placebo cycles totalled 241, with 21 pregnancies (9% per cycle). The cumulative pregnancy rate with misoprostol treatment was significantly greater than with placebo (P = 0.004, Cox proportional hazards regression). The benefit of misoprostol was seen in clomiphene cycles (14 versus 4%, P = 0.006), and was indicated in FSH cycles (33 versus 15%, borderline significance) and natural cycles (15.6 versus 7.7%, not significant), but was not seen in clomiphene/FSH cycles (18.2 versus 23.5%, not significant). Misoprostol treatment did not increase pain score on the day of IUI (1.1 versus 1.4) and at 1 day post IUI (0.6 versus 0.8). Complications were rare in both groups [six (2%) subject cycles in the misoprostol cycles compared with two (1%) in the placebo group]. It is concluded that the use of vaginal misoprostol may improve the chance for pregnancy in women having IUI in a wide variety of cycle types. (+info)
A prospective randomized control trial comparing medical and surgical treatment for early pregnancy failure.
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A prospective randomized control trial was designed to assess the effectiveness of single dose, 800 microg misoprostol administered p.v. compared with surgical evacuation for the treatment of early pregnancy failure. A total of 80 women with a diagnosis of early pregnancy failure were randomized to study (vaginal misoprostol) and control (surgical curettage) groups. Success of treatment, side-effects as assessed during, immediately after and 10 days after treatment, and patient satisfaction were compared. Intravaginal misoprostol was successful in 82.5% (33 out of 40) of the patients. None of the control group patients required a repeat evacuation. The number of patients who experienced significant abdominal pain following treatment did not differ between the groups. The duration of pain was shorter in the control group; however, they required more analgesics during this short period. The number of patients with significant vaginal bleeding, the duration or severity of bleeding did not show any significant difference between the groups. All 33 patients in the study group who had successful treatment expressed satisfaction, whereas only 58% of the control group did so. In conclusion this randomized control study demonstrated the efficacy and safety of the administration of 800 microg of misoprostol p.v. for the management of early pregnancy failure. (+info)
The impact of nonsteroidal anti-inflammatory drug-induced gastropathy.
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Gastric and duodenal injury related to nonsteroidal anti-inflammatory drug (NSAID) use is extremely common, and a variety of strategies can be employed to reduce this frequent side effect of an otherwise useful category of medications. Although the best approach may be to discontinue NSAID treatment, this is not always possible for patients with arthritis pain or for those who require low-dose aspirin therapy for underlying cardiovascular disease. In arthritis cases, one of the new cyclooxygenase-2 specific inhibitors can be used to replace a traditional NSAID, but the addition of another drug to treat and heal ulcers is normally still needed. Patients taking aspirin are also candidates for additional treatment. (+info)
The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection.
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Protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryptase, modulates smooth muscle tone and exocrine secretion in the salivary glands and pancreas. Given that PAR-2 is expressed throughout the gastrointestinal tract, we investigated effects of PAR-2 agonists on mucus secretion and gastric mucosal injury in the rat. PAR-2-activating peptides triggered secretion of mucus in the stomach, but not in the duodenum. This mucus secretion was abolished by pretreatment with capsaicin, which stimulates and ablates specific sensory neurons, but it was resistant to cyclo-oxygenase inhibition. In contrast, capsaicin treatment failed to block PAR-2-mediated secretion from the salivary glands. Intravenous calcitonin gene-related peptide (CGRP) and neurokinin A markedly elicited gastric mucus secretion, as did substance P to a lesser extent. Specific antagonists of the CGRP1 and NK2, but not the NK1, receptors inhibited PAR-2-mediated mucus secretion. Pretreatment with the PAR-2 agonist strongly prevented gastric injury caused by HCl-ethanol or indomethacin. Thus, PAR-2 activation triggers the cytoprotective secretion of gastric mucus by stimulating the release of CGRP and tachykinins from sensory neurons. In contrast, the PAR-2-mediated salivary exocrine secretion appears to be independent of capsaicin-sensitive sensory neurons. (+info)