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Synthesis of 1,3,4-oxadiazole derivatives of diclofenac and mefenamic acid are described. The target compounds 5-[2-(2,6-dichloroanilino)benzyl]-2-aryl-1,3,4-oxadiazole (3a-3e) and 5-[2-(2,3-dimethylanilino)phenyl]-2-(aryl)-1,3,4-oxadiazole (6a-6e) were obtained by treating 2 and 5 with various aromatic acids using POCl(3) as dehydrating agent. They were purified and characterized by IR, (1)H-NMR and elemental analysis. These compounds were further subjected to antiinflammatory, analgesic and acute ulcerogenic activity. Compound 3c and 6d exhibited good antiinflammatory activity and compounds 3c, 3e, 6c, 6d, 6e were found to be non ulcerogenic.
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A method for assessing inflammatory pain response was developed by modification of the formalin test. Formalin (0.5%, 25 microliters) was injected into the hindpaw of the mouse, and the durations spent in licking or biting response were measured as an indicator of pain response. The response curve was biphasic, having two peaks, from 0 to 5 min (first phase) and from 15 to 20 min (second phase). Morphine, ethylketocyclazocine, ketocyclazocine and pentazocine inhibited the response dose-dependently at the first and the second phases. Aspirin, oxyphenbutazone and dexamethasone inhibited only the second phase. Aminopyrine and mefenamic acid which acted at both central and peripheral sites inhibited both phases; however, the inhibition of the second phase was stronger than that of the first phase. Substance P (SP) antagonist inhibited only the first phase. Bradykinin (BK) inhibitor caused a inhibition of both first and second phases, and pretreatment of compound 48/80 and indomethacin inhibited only the second phase. From these facts, it was suggested that SP and BK played a role in the pain response at the first phase, and histamine, BK and PG were involved at the second phase. Naloxone produced hyperalgesia and bestatin produced analgesia at the second phase; then, it seems that the endogenous opioid system is activated by formalin stimulation and modulates the pain perception. Based on these findings, it is presumed that the pain of the first phase is evoked by the direct stimulation of the nerve fibers, and that of the second phase is due to the inflammatory reaction.
76 women with dysfunctional uterine bleeding.
A new and simple high-performance liquid chromatography assay was developed and validated for the simultaneous determination of the above-mentioned drugs in small samples of human plasma (0.25 mL). After protein precipitation with acetonitrile, satisfactory separation was achieved on a Hypersil BDS C18 column (250 × 4.6 mm, 5 m) using a mobile phase comprising 20 mmol/L ammonium phosphate buffer (pH = 3) and acetonitrile at a ratio of 35:65, vol/vol; the elution was isocratic at ambient temperature with a flow rate of 1 mL/min. The UV detector was set at 265 nm.
Primary dysmenorrhoea is characterised by painful menstrual cramps which appear to have no macroscopically identifiable pelvic pathology. 50% of postpubescent females suffer from dysmenorrhoea, and 10% are incapacitated for 1 to 3 days each month. Many of these patients have an increased synthesis of prostaglandins in their endometrial tissue with increased prostaglandin release in the menstrual fluid. The increased amount of prostaglandins induces incoordinate hyperactivity of the uterine muscle resulting in uterine ischaemia and pain. Recent clinical and laboratory studies have shown that many of the non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, flufenamic acid, mefenamic acid and indomethacin are capable of relieving primary dysmenorrhoea. These drugs are inhibitors of the prostaglandin synthetase enzymes which are necessary for prostaglandin biosynthesis. Thus, with ibuprofen it has been shown that clinical relief of the dysmenorrhoeic symptoms accompanies the reduction of menstrual fluid prostaglandins. With the oral contraceptive pill there is good relief of primary dysmenorrhoea, significant decrease in menstrual fluid prostaglandins, but no reduction in menstrual fluid volume; this suggests that the reduction in prostaglandins is secondary to the inhibition of endometrial growth and development. In some forms of secondary dysmenorrhoea elevated prostaglandin levels have been implicated. However, the evidence is less conclusive for dysmenorrhoea secondary to endometriosis and uterine myomas than for dysmenorrhoea associated with intrauterine devices. With the intrauterine device, prostaglandin synthetase inhibitors such as flufenamic acid, ibuprofen and naproxen are able not only to relieve dysmenorrhoea but also to reduce menstrual blood loss to normal levels. Thus, the use of appropriately selected prostaglandin synthetase inhibitors can offer effective relief from the miseries of some types of dysmenorrhoea with subsequent restoration of normal daily activities.
The pharmacokinetics of mefenamic acid (MA), 2 mg/kg, were studied in 17 preterm infants with symptomatic patent ductus arteriosus. They were given this dosage orally at 24 h intervals. There were marked inter-individual differences in some of the pharmacokinetic parameters after the first dose; peak plasma concentration (Cmax) varied from 1.2 to 6.1 micrograms/mL with a mean of 3.8 micrograms/mL, time to reach Cmax (tmax) varied from 2 to 18 h with a mean of 7.7 h and plasma half-life (t1/2) varied from 3.8 to 43.6 h with a mean of 18.7 h. The group of infants (10/17) who had ductus closure after the first dose had significantly lower clearance (P < 0.01), longer t1/2 (P < 0.01) and higher 24 h plasma concentration (P < 0.001) compared to the group of infants (7/17) who had no ductus closure after the first dose. It appeared that the plasma concentration of MA had to be above 2.0 micrograms/mL and maintained at this concentration for at least 12 h for MA associated with ductus closure in preterm infants to take effect. In view of the inter-individual variation of plasma MA concentration and the effective plasma concentration, we suggest that measurement of the plasma concentration should be done 24 h after the first dose. This might be useful for safe and effective therapy for infants with ductus closure failure after the first dose.
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This paper investigates the removal of a broad range of pharmaceuticals during nanofiltration (NF) and reverse osmosis (RO) applied in a full-scale drinking water treatment plant (DWTP) using groundwater. Pharmaceutical residues detected in groundwater used as feed water in all five sampling campaigns were analgesics and anti-inflammatory drugs such as ketoprofen, diclofenac, acetaminophen and propyphenazone, beta-blockers sotalol and metoprolol, an antiepileptic drug carbamazepine, the antibiotic sulfamethoxazole, a lipid regulator gemfibrozil and a diuretic hydrochlorothiazide. The highest concentrations in groundwater were recorded for hydrochlorothiazide (58.6-2548ngL(-1)), ketoprofen (85%). Deteriorations in retentions on NF and RO membranes were observed for acetaminophen (44.8-73 %), gemfibrozil (50-70 %) and mefenamic acid (30-50%). Furthermore, since several pharmaceutical residues were detected in the brine stream of NF and RO processes at concentrations of several hundreds nanogram per litre, its disposal to a near-by river can represent a possible risk implication of this type of treatment.
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We studied binding of T4 to the lipid-complexed apolipoproteins (apo) of high density lipoproteins (HDL), the major lipoprotein carrier of thyroid hormones in human plasma, and to lipid-free apoA-I. HDL isolated from fresh normal plasma by ultracentrifugation (density, 1.063-1.210 g/mL) was photoaffinity labeled with [3,5-(125)I]T4 and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two bands corresponding to apoA-I (28.3K) and apoC-II or apoC-III (8.6-9.2K) were seen, and their radioactivity decreased by 50-60% when labeled in the presence of 1 mumol/L T4. Photoaffinity labeling of isolated apoA-I also was demonstrated and was decreased 74% by 1 mumol/L T4, suggesting a higher affinity of the lipid-free protein for T4. T4 binding of isolated apoA-I was optimal at pH 7-8, reached a maximum after 1 h at 23 C, and decreased after incubation at 37 C. Scatchard analysis revealed a single T4-binding site with a Ka of 7.5 x 10(7) L/mol at 23 C, pH 8.2. The potency of T4 analogs as inhibitors of T4 binding to isolated apoA-I was L-T4 = D-T4 = triiodothyroacetic acid = L-rT3 much greater than L-T3 much greater than L-thyronine. The binding of T4 to apoA-I was reduced by known inhibitors of T4 binding to serum proteins (diclofenac = mefenamic acid = furosemide = 8-anilinonaphthalene sulfonic acid much greater than dilantin greater than heparin greater than barbital) and by lipids (unsaturated fatty acids greater than cholesterol = cholesterol esters = phospholipids greater than saturated fatty acids = diglycerides = triglycerides). We conclude that the binding of T4 to HDL is mediated by a specific interaction of the hormone with apoA-I and with apoC-II and/or apoC-III. Since the lipid constituents of HDL inhibit T4 binding to apoA-I, the HDL subfraction in plasma that carries most of the HDL-bound T4 should be one with a low lipid content.
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Bovine corneal endothelial cells (BCECs) were treated for 48 hours with 640 compounds from a Food and Drug Administration (FDA)-approved drug library and then challenged with thapsigargin or H2O2 to induce UPR or oxidative stress, respectively. Cell viability was measured using the CellTiter-Glo survival assay. Selected "hits" were subjected to further dose-response testing, and their ability to modulate expression of UPR and oxidative stress markers was assessed by RT-PCR, Western blot, and measurement of protein carbonyl and 8-hydroxydeoxyguanosine (8-OHdG) adducts in immortalized human corneal endothelial cells (iHCECs).
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Menorrhagia affects the lives of many women. The assessment of menstrual flow is highly subjective and gauging the severity of the condition by objective assessment of menstrual blood loss is impractical. In treating menorrhagia, the primary aim should be to improve quality of life. Women are willing to undergo quite invasive treatment in order to achieve this. Drug therapy is the initial treatment of choice and the only option for those who wish to preserve their reproductive function. Despite the availability of a number of drugs, there is a general lack of an evidence-based approach, marked variation in practice and continuing uncertainty regarding the most appropriate therapy. Adverse effects and problems with compliance also undermine the success of medical treatment. This article reviews the available literature to compare the efficacy and tolerability of different medical treatments for menorrhagia. Tranexamic acid and mefenamic acid are among the most effective first-line drugs used to treat menorrhagia. Despite being used extensively in the past, oral luteal phase norethisterone is probably one of the least effective agents. Women requiring contraception have a choice of the combined oral contraceptive pill, levonorgestrel-releasing intrauterine system (LNG-IUS) or long-acting progestogens. Danazol, gestrinone and gonadotropin-releasing hormone analogues are all effective in terms of reducing menstrual blood loss but adverse effects and costs limit their long-term use. They have a role as second-line drugs for a short period of time in women awaiting surgery. While current evidence suggests that the LNG-IUS is an effective treatment, further evaluation, including long-term follow up, is awaited. Meanwhile, the quest continues for the ideal form of medical treatment for menorrhagia--one that is effective, affordable and acceptable.
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Single-channel currents were recorded from the plasma membrane of white adipocytes of 6-8-week-old male Sprague-Dawley rats. In outside-out patches (high K(+), no Ca(2+) in pipette), a voltage-dependent K-channel (delayed rectifier) with a single-channel conductance (gamma) of 16 pS (24 degrees C) in modified Ringer's was active at a density of 0.5/microm(2). It was blocked by TEA (IC(50)=1.5 mM). A Ca(2+)-activated non-selective cation channel (NSC-channel) appeared at a mean density of 1/microm(2) in inside-out patches ([Ca(2+)](i)=1.2 mM). gamma was 28 pS (24 degrees C). The NSC showed weak voltage dependence and was blocked by mefenamic acid and by internal ATP. In the cell-attached mode spontaneous activity could be blocked reversibly by 100 nM insulin. Noradrenaline (NA, 100 nM) induced a flickering activity of the NSC-channels. Isoproterenol (100 nM) caused activity of the NSC-channel as well. After 1 microM propranolol even 1 microM NA did not induce any activity. The alpha-antagonist phentolamine had no effect on isoproterenol- or on NA-induced currents. The beta(3)-agonists BRL 37344 and BRL 35135A induced activity of the NSC-channel at 100 nM as well. We conclude that white adipocytes express ion channels which are comparable to those in brown adipocytes and that beta-receptor activation opens NSC-channels thus allowing for Na(+) entry into white adipocytes.
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A comparison was made between the relative effects of aspirin, mefenamic acid, dihydrocodeine , dextropropoxyphene and paracetamol on visceral pain (chemically-inducing writhing), respiratory rate and prostaglandin (PG) biosynthesis (cyclo-oxygenase activity). A close correlation was found to exist between inhibition of PG biosynthesis and inhibition of visceral pain for mefenamic acid, aspirin and paracetamol. Analysis of the complete activity profiles derived from evaluation of the test parameters yielded the following rank order of overall ratios of their beneficial anti-writhing/anti-cyclo-oxygenase to respiratory depressive activities: (1) mefenamic acid, (2) aspirin, (3) dihydrocodeine , (4) dextropropoxyphene and paracetamol.
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Television microscopy was used to observe the responses of in vivo arterioles and venules of the rat cremaster muscle to the topical application of angiotensin II (10(-8) and 10(-6) M). Neither the first- (A1) or second-order arterioles (A2) nor the first- (V1) or second-order venules (V2) constricted significantly to angiotensin II. However, after the inhibition of local prostaglandin synthesis with either mefenamic acid or indomethacin, both A1 and A2, but not the venules, gave a significant constrictor response to angiotensin II (10(-6) M). Arterioles and venules, which were preconstricted with norepinephrine, dilated to their initial baseline diameters after angiotensin II (10(-6) M), a response not observed when the microvessels were pretreated with either an angiotensin antagonist or a prostaglandin synthesis inhibitor. These observations indicate that endogenous prostaglandins exert a significant dilator influence on the larger arterioles, that this dilator influence appears to oppose the constrictor effect of angiotensin II, and that angiotensin II acts on specific receptors to induce synthesis and/or release of dilator prostaglandins in large arterioles. However, prostaglandins cannot account for the absence of a venular constriction to angiotensin.
Clonidine is an imidazoline derivative antihypertensive medication that is also used as adjunctive therapy for neuropathic pain disorders via topical administration. Clonidine overdose can manifest both central and peripheral alpha-adrenergic agonist effects.
We report on three cases of fixed drug eruption, including a non-pigmenting generalized bullous fixed drug eruption, caused by mefenamic acid in its pure form.
1. Sodium transport across isolated frog skin, as measured by the short-circuit current, was decreased by acetylsalicylic acid, mefenamic acid, paracetamol and phenylbutazone. Indomethacin (6 X 10(-6) M) had a biphasic effect on the short-circuit current: a transient increase followed by a sustained decrease. 2. The release of prostaglandin-like material from the skin was reduced by acetylsalicylic acid and indomethacin. Paracetamol caused a significant reduction in the short-circuit current response of the skin to low doses of arachidonic acid, but the response to the highest dose tested was not significantly altered. 3. Indomethacin (6 X 10(-6) M) increased the sensitivity of the skin to applied prostaglandin E1. The other prostaglandin synthetase inhibitors did not have this effect. Indomethacin (6 X 10(-6) M) also enhanced the effect of antidiuretic hormone on the short-circuit current. 4. Indomethacin (30 X 10(-6) M) increased the short-circuit current and diminished the response to applied prostaglandin E1. 5. In sulphate Ringer, theophylline increased the short-circuit current and diminished the response to prostaglandin E1. 6. Prostaglandin E1 increased the levels of cyclic AMP in frog skin and these increases preceded the increases in short-circuit current. There was a seasonal variation in the level of cyclic AMP in the skin: the levels in winter exceeded those in summer. There was also a seasonal variation in the cyclic AMP response to prostaglandin E1: the winter response was greater than that in summer. 7. Indomethacin (6 X 10(-6) M) had a biphasic effect on cyclic AMP levels in the skin, an initial increase followed by a decrease. Indomethacin also potentiated prostaglandin E1 stimulated cyclic AMP accumulation. 8. Theophylline increased cyclic AMP levels in the skin and potentiated prostaglandin E1 stimulated cyclic AMP accumulation. 9. Pre-treatment of the skin with theophylline reversed the effects of cyclic AMP on the short-circuit current and open-circuit potential. 10. It is concluded that endogenous prostaglandins help to maintain sodium transport across isolated frog skin and that the effects of E-type prostaglandins on the short-circuit current are mediated by increased cyclic AMP levels. The transient increase in short-circuit current and the increased skin sensitivity caused by indomethacin (6 X 10(-6) M) are attributed to inhibition of phosphodiesterase activity. The failure of theophylline to potentiate the short-circuit current response of the skin to prostaglandin E1 is attributed to alteration of cyclic AMP action on the skin by theophylline.
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Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil) or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day). Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN) and creatinine activities were measured.
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The aim of the present study was to establish whether, in terminal arterioles from the rat cremaster, acetylcholine (ACh) elicits nitric oxide (NO)-independent dilation corresponding to the transient ACh-induced endothelium-dependent hyperpolarization described in arteries. For this purpose, the responses of terminal arterioles [mean diam 15.0 +/- 0.4 (SE) microns] were studied by intravital microscopy in rat cremaster muscle. During 15 min of superfusion by 10(-5) M ACh, the response was characterized by an initial maximal dilation (peak time < 3 min) followed by a more sustained dilation that slightly decreased with time. Inhibition of NO synthesis by 2 x 10(-4) M N omega-nitro-L-arginine (L-NNA) significantly reduced, but did not eliminate, both the peak and sustained responses. Simultaneous administration of 2 x 10(-4) M L-NNA and 2 x 10(-5) M mefenamic acid, an inhibitor of prostaglandin synthesis, did not induce a significantly different response from that observed with L-NNA alone. Procaine (10(-3) M), which is known to inhibit completely ACh-induced hyperpolarization in carotid artery, drastically reduced the initial part of the ACh-induced dilation but not the sustained response. Simultaneous administration of procaine and L-NNA almost completely inhibited the peak response to ACh. Similar results were obtained when L-NNA was combined with a superfusion bath containing 20 mM KCl, a concentration known to reduce hyperpolarization in arteries.(ABSTRACT TRUNCATED AT 250 WORDS)
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A 48-year-old woman was hospitalized with the diagnosis of hepatitis. She presented with symptoms of jaundice, headache, elevated bilirubin, and elevated hepatic enzymes. She related a recent episode of a bronchial infection that was treated during the previous eight days with paracetamol (500mg, 2 doses only), chlorpheniramine, betamethasone and clindamycin. After an initial clinical and laboratorial improvement, she began to complain of pruritus of the palms and soles. Thereafter, vesicles evolving to blisters developed and a deterioration of her general health ensued. Serologies for hepatitis A, B, and C viruses were negative. Intrahepatic cholestasis and Stevens Johnson Syndrome (SJS) were the final diagnosis. The association of the Stevens Johnson Syndrome and intrahepatic cholestasis simultaneously, related to adverse drug reactions, is very rare. The drugs reportedly involved are mainly antibiotics, such as ampicillin, vancomycin, amoxicillin/clavulinic acid and erythromycin. Other drugs involved are non-steroidal anti-inflamatory drugs, such as mefenamic acid, ibuprofen, and sulindac. The reactions can be minor or severe and can even cause death, an outcome that has been reported in patients of all races and ethnic groups, but appears to be more rare in patients of Latin origin. We present a discussion of this case and review the main characteristics of the Stevens Johnson Syndrome.
Desmopressin may be a useful therapeutic tool for many women with IUD-related menorrhagia. Its mechanism of action lies in an ability to enhance local haemostasis, without affecting uterine blood flow.
Mefenamic acid is a common widely prescribed drug with analgesic activity. Authors report two cases of multifocal fixed drug eruption induced by mefenamic acid. Cases were diagnosed on basis of clinical examination and histopathology of skin lesion. Only a few cases have been reported in the literature and these are the first two described in Greece.
The MMAS total scores improved significantly in both groups at all time points, but were significantly greater for the LNG-IUS than for usual treatment [mean difference over 2 years was 13.4 points, 95% confidence interval (CI) 9.9 to 16.9 points; p < 0.001]. However, this difference between groups was reduced and no longer significant by 5 years (mean difference in scores 3.9 points, 95% CI -0.6 to 8.3 points; p = 0.09). By 5 years, only 47% of women had a LNG-IUS in place and 15% were still taking usual medical treatment. Five-year surgery rates were low, at 20%, and were similar, irrespective of initial treatments. There were no significant differences in serious adverse events between groups. Using the EQ-5D, at 2 years, the relative cost-effectiveness of the LNG-IUS compared with usual medical treatment was £1600 per QALY, which by 5 years was reduced to £114 per QALY. Using the SF-6D, usual medical treatment dominates the LNG-IUS. The qualitative findings show that women's experiences and expectations of medical treatments for HMB vary considerably and change over time. Women had high expectations of a prompt effect from medical treatments.
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.
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Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics.
The ester prodrug (MA-NH) was prepared by condensing mefenamic acid with N-hydroxymethylsuccinimide in the presence of Phosphorus oxychloride. The pharmacokinetic profile, including stability and release of mefenamic acid and N-hydroxymethylsuccinimide from the ester prodrug (MA-NH) was studied by RP- HPLC in acidic medium (pH 1.2), basic medium (pH 7.4), 80 % v/v human plasma, 10 % w/v rat intestinal homogenate and 10 % w/v rat liver homogenate (pH 7.4).