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In order to determine the role of peripheral prostanoids in a newly developed mechanical visceral pain model, several NSAIDs were studied. Systemic acetylsalicylic acid and mefenamic acid, in doses known to produce cyclooxygenase inhibition, produced limited or no analgesia using a duodenal distension model and a behavioral scale for assessment. In contrast, indomethacin at 1 mg/kg, a dose 1/100th of the highest dose of the above compounds, had a marked analgesic effect in the visceral pain model (32% of control response). These data suggest that a duodenal distension stimulus does not have a peripheral prostaglandin E2-mediated nociceptive mechanism. Furthermore, the results obtained with indomethacin support an alternate, possibly central nonprostanoid visceral antinociceptive action.
The analgesic mechanism of Y-23023, a new non-steroidal anti-inflammatory drug, was investigated in the writhing response induced by intraperitoneal injection of kaolin and captopril in mice. Y-23023 (0.1-1 mg/kg, p.o.) suppressed the writhing frequency in a dose-dependent manner. Y-23023 also significantly reduced the increased levels of prostaglandin (PG) and bradykinin (BK) in the peritoneal cavity. In contrast, indomethacin, diclofenac sodium, loxoprofen sodium and mefenamic acid inhibited the writhing response, but their efficacies were lower than that of Y-23023. The peritoneal PG levels were dose-dependently reduced to the same extent as Y-23023, whereas the BK levels were not. M1, an active metabolite of Y-23023, inhibited the cyclooxygenase from sheep vesicular gland in a concentration-dependent manner, and its potency was similar to that of indomethacin. These results suggest that in addition to the suppressive effect on PG production via inhibition of cyclooxygenase, the inhibitory effect on BK production is involved in the analgesic action of Y-23023, unlike indomethacin and diclofenac sodium.
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We found no statistically significant difference in the effectiveness of ibuprofen compared to indomethacin in closing the PDA. Ibuprofen reduces the risk of oliguria. However, ibuprofen may increase the risk for chronic lung disease, and pulmonary hypertension has been observed in three infants after prophylactic use of ibuprofen. Based on currently available information ibuprofen does not appear to confer a net benefit over indomethacin for the treatment of a PDA. We conclude that indomethacin should remain the drug of choice for the treatment of a PDA. Future research may include a four arm trial where infants are randomized at birth, either to a prophylaxis arm starting at birth or to an arm in which treatment starts after a PDA is diagnosed by echocardiography within the first seven days of life. Within the prophylaxis and treatment arms, the infants would be randomized to either ibuprofen or indomethacin. The primary outcome should be intact survival (survival without handicap) at 18 months corrected age.
Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine.
Analgesic poisoning is a common medical emergency, and these drugs account for about 30% of self-poisoning in adults. Aspirin and paracetamol are taken most often, and can cause significant morbidity and mortality. However, problems with the hepatotoxicity of paracetamol have been greatly reduced by the introduction of effective treatment with agents such as N-acetylcysteine. The non-steroidal anti-inflammatory analgesics are not commonly taken in overdosage but the incidence of self-poisoning with mefenamic acid is increasing at an alarming rate. With the exception of phenylbutazone and mefenamic acid these drugs rarely seem to cause serious toxicity. The narcotic analgesics can cause profound respiratory depression and are the most dangerous drugs in overdosage.
The fenugreek seed and dry cupping are effificacious, safe, cost effective, and well tolerated.
Cotrimoxazole was the most common cause of FDE, whereas FDE with diclofenac sodium, pyrantel pamoate, clindamycin, and albendazole were reported for the first time. FDE may have multiform presentations.
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The occurrence of 15 pharmaceuticals and personal care products in the influent and effluent from the wastewater treatment plant (WWTP) and its receiving water in Beijing, China were determined. Results from the present study confirmed that caffeine, N,N-diethyl-m-toluamide and chloramphenicol were removed at a high rate (>70 % efficiency). In contrast, removal efficiency of the other 12 compounds was quite poor (ranged from -40 % to 58 %). Some compounds in the receiving river were present at higher concentrations compared to those in the WWTP effluent, indicating that sources other than treated effluents are present. The risk to the aquatic environment was estimated by a ratio of measured environmental concentration and predicted no-effect concentration. For those compounds found in the effluent and surface water, mefenamic acid, trimethoprim and gemfibrozil may pose a medium risk to aquatic environment.
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There is no benefit in using mefenamic acid and hyoscine in the prevention of pain occurring from SIS.
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Four hundred ninety three female nurses in the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Recent studies showed that the metal-coordinated non-steroidal anti-inflammatory drug (NSAID), copper indomethacin, reduced aberrant crypt formation in the rodent colon cancer model, while also exhibiting gastrointestinal sparing properties. In the present study, the stability and biological activity of three BiNSAIDs of the general formula [Bi(L)3]n, where L=diflunisal (difl), mefenamate (mef) or tolfenamate (tolf) were examined. NMR spectroscopy of high concentrations of BiNSAIDs (24h in cell medium, 37°C) indicated that their structural stability and interactions with cell medium components were NSAID specific. Assessment of cell viability using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium]bromide (MTT) assay showed that the toxicity ranking of the BiNSAIDs paralleled those of the respective free NSAIDs: diflH
A controlled trial was undertaken to compare the efficacy of transcutaneous electrical nerve stimulation (TENS) with standard intramuscular opiate analgesia in the management of postoperative pain following appendicectomy. Consecutive patients undergoing emergency appendicectomy were randomised into control, sham TENS and active TENS groups. There was a significant decrease in pain severity and analgesic intake in both active and sham TENS groups when compared with the control group (P less than 0.01). No difference was demonstrated in pain severity between active and sham TENS groups but the active TENS group required slightly less analgesia. These results suggest that the major benefit of TENS in the postappendicectomy patient is due to its 'placebo effect' and its use in this situation cannot be recommended.
Forty patients with medication-resistant menorrhagia.
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Based on the Naranjo score, this case of prolonged intrahepatic cholestasis in a young woman was likely associated with loxoprofen use.
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A number of drugs are available that act fairly specifically as "mild" analgesics, although this description by no means implies that their clinical effectiveness is limited to the relief of slight pain and trivial disability. They are effective by mouth and their action is mediated peripherally. Among the possible mechanisms of action, the inhibition of prostaglandin synthesis is currently regarded as most likely to be relevant. Some centrally acting drugs of the narcotic analgesic type, such as codeine and dextropropoxyphene are effective orally; they are usable in the same way as other mild analgesics and may be preferable for some types of pain. Many problems arise in the assessment and comparison of mild analgesics, both experimentally and clinically. Subjective assessments may be made on a pain scale by the patient himself, or by a trained observer. Individual variations are all-important, and the limitations of controlled trials need to be remembered. Alternative drugs and mixtures have little advantage over aspirin, but specific drug tolerance, in the long term, varies from patient to patient. Gastric irritation is most likely to occur with aspirin in the presence of chronic dyspepsia or acute precipitating causes such as alchoholic gastritis. Allergy also occurs in some susceptible individuals. The risk of renal damage with phenacetin is increasingly appreciated, and the possibility of hepatic damage from paracetamol is now recognised. Other side-effects and interactions are summarized in the review, and some notes are given on therapeutic and non-therapeutic use.
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Human TRPM2 channels in tetracycline-regulated pcDNA4/TO vectors were transfected into HEK293 T-REx cells and the expression was induced by tetracycline. Whole cell currents were recorded by patch-clamp techniques. Ca(2+) influx or release was monitored by fluorometry.
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Myeloperoxidase (MPO) has recently been shown in an in vitro, cell-free system to catalyze the peroxidative degradation of vincristine (VCR). Oxidation of VCR involves a ring fission between positions 20' and 21', and is thought to be facilitated by the presence of an hydroxyl (-OH) group at position 20'. We report here two different approaches, both with potential clinical application, to decrease MPO-catalyzed vinca degradation. Firstly, we tested the hypothesis that -OH substitution at position 20' increases vinca susceptibility to peroxidation by comparing the relative extent of degradation of vinorelbine (Navelbine or NVB), which lacks a 20' hydroxyl substitution, with that of VCR. As anticipated, NVB was significantly less susceptible to MPO-catalyzed peroxidation than was VCR (p < 0.01). Secondly, we screened an array of compounds that are in current clinical use for their ability to inhibit MPO. Acetaminophen, N-acetylcysteine, propylthiouracil, D-penicillamine, mefenamic acid, dapsone, and methimazole all inhibited MPO at clinically achievable concentrations. Insofar as increased MPO activity has been observed in patients with acute myeloid leukemia, these findings suggest potential strategies for improving the activity of vinca alkaloids in this disease.
Heavy menstrual bleeding (HMB) is a common, chronic problem affecting women and health services. However, long-term evidence on treatment in primary care is lacking.
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The human liver and kidney are important sites of MPA glucuronidation. MPA glucuronidation was inhibited to various extents by different NSAIDs and the four most effective inhibitors were niflumic acid, flufenamic acid, mefenamic acid and diflunisal. These drugs have similar molecular structures consisting of two aromatic rings bearing a carboxylic group.
885 women consulting their general practitioner with menorrhagia over four years.
The result of competition assay and Scatchard analysis revealed that tamoxifen does not bind to TBG at the T4 binding site, thus it is not a thyroxine competitor. Computational results also indicated that structural characteristics of tamoxifen are significantly different from those of T4 and its well-known competitors.
It is well accepted that bacterial and virus infections elevate the levels of cytokines in serum and cerebrospinal fluids. Such high levels of cytokines might alter the integrity of the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB), subsequently affecting brain penetration of drugs. However, few reports have addressed this issue. Thus, we investigated brain penetration of cyclooxygenase (COX) inhibitors, commonly used as antipyretics, in mice treated with Shiga-like toxin II (SLT-II) derived from E. coli O157:H7, which significantly elevates cytokine levels. As antipyretics, we used diclofenac, mefenamic acid, and acetaminophen. We found that SLT-II significantly increased the brain-to-plasma concentration ratio (Kp) of diclofenac and mefenamic acid, but not of acetaminophen. Moreover, the Kp of diclofenac and mefenamic acid was increased by probenecid, an anionic compound. These results suggest that efflux anion transporters might be involved in the transport of diclofenac and mefenamic acid. Western blot analysis revealed that SLT-II decreased the expression of organic anion transporter-3, an efflux transporter located on the BBB and/or BCSFB. Taken together, these results suggest that SLT-II and/or SLT-II-stimulated cytokines might change brain penetration of drugs and could possibly increase the risk of their side-effects by altering the expression of transporters.
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Case reports and small case series suggest increased central nervous system (CNS) toxicity, especially convulsions, after overdose of mefenamic acid, compared with other nonsteroidal anti-inflammatory drugs (NSAIDs), although comparative epidemiological studies have not been conducted. The current study compared rates of CNS toxicity after overdose between mefenamic acid, ibuprofen, diclofenac and naproxen, as reported in telephone enquiries to the UK National Poisons Information Service (NPIS).
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Various acyloxyethyl mefanamates were synthesized and evaluated for potential application as prodrugs. Their kinetics of hydrolysis were examined in aqueous solutions of pH 1.0 and 7.4 and in human plasma at 37 degrees C. Among the synthesized compounds, the beta-carboxypropionylethyl mefenamate and the pivaloyloxyethyl mefenamate show high stability against enzymatic and non enzymatic hydrolysis. On the other hand the acetyloxyethyl mefenamate shows t1/2s of 1.4 h, 1.41 h and 3.61 h in human plasma, solutions of pH 7.4 and pH 1.0 respectively; However, its hydrolysis to mefenamic acid in plasma was not quantitative. Preliminary in vivo study shows that acetyloxyethyl mefenamate gave plasma concentration of mefenamic acid lower than that of control after oral administration. The calculated AUC0-inf for the acetyloxyethyl and control were 45 and 85 micrograms.h/ml respectively.
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Dynamics of repolarization, quantified as restitution and electrical memory, impact conduction stability. Relatively less is known about role of slow delayed rectifying potassium current, I(Ks), in dynamics of repolarization and memory compared to the rapidly activating current I(Kr). Trans-membrane potentials were recorded from right ventricular tissues from pigs during reduction (chromanol 293B) and increases in I(Ks) (mefenamic acid). A novel pacing protocol was used to explicitly control diastolic intervals to quantify memory. Restitution hysteresis, a consequence of memory, increased after chromanol 293B (loop thickness and area increased 27 and 38 %) and decreased after mefenamic acid (52 and 53 %). Standard and dynamic restitutions showed an increase in average slope after chromanol 293B and a decrease after mefenamic acid. Increase in slope and memory are hypothesized to have opposite effects on electrical stability; therefore, these results suggest that reduction and enhancement of I(Ks) likely also have offsetting components that affect stability.