The KCNE proteins (KCNE1 through KCNE5) function as beta-subunits of several voltage-gated K(+) channels. Assembly of KCNQ1 K(+) channel alpha-subunits and KCNE1 underlies cardiac I(Ks), while KCNQ1 interacts with all other members of KCNE forming complexes with different properties. Here we investigated synergic actions of KCNE1 and KCNE2 on functional properties of KCNQ1 heterologously expressed in COS7 cells. Patch-clamp recordings from cells expressing KCNQ1 and KCNE1 exhibited the slowly activating current, while co-expression of KCNQ1 with KCNE2 produced a practically time-independent current. When KCNQ1 was co-expressed with both of KCNE1 and KCNE2, the membrane current exhibited a voltage- and time-dependent current whose characteristics differed substantially from those of the KCNQ1/KCNE1 current. The KCNQ1/KCNE1/KCNE2 current had a more depolarized activation voltage, a faster deactivation kinetics, and a less sensitivity to activation by mefenamic acid. These results suggest that KCNE2 can functionally couple to KCNQ1 even in the presence of KCNE1.
We could demonstrate no significant pre-emptive analgesic effect with ropivacaine in adults undergoing tonsillectomy in our study. One can, however, recommend the administration of ropivacaine post-operatively after tonsillectomy, since a reduction of pain scores can thereby be achieved. For post-operative analgesia we recommend the combination of a non-opioid analgesic with a weak opioid.
Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [(14)C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ∼ 28 and ∼ 68% of boceprevir to M28, respectively, in the presence of an NADPH-generating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M+2 metabolites (M28 and M31). The formation of M28 was inhibited by 100 μM flufenamic acid (80.3%), 200 μM mefenamic acid (83.7%), and 100 μM phenolphthalein (86.1%), known inhibitors of AKRs, suggesting its formation through carbonyl reduction pathway. Formation of M28 was also inhibited by 100 μM diazepam (75.1%), 1 mM ibuprofen (70%), and 200 μM diflunisal (89.4%). These data demonstrated that CYP3A4 and CYP3A5 are primarily responsible for the formation of oxidative metabolites and the formation of M28 and M31, the keto-reduced metabolites, are most likely mediated by AKR1C2 and AKR1C3. Because the biotransformation and clearance of boceprevir involves two different enzymatic pathways, boceprevir is less likely to be a victim of significant drug-drug interaction with concomitant medication affecting either of these pathways.
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.
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The wastewater contamination of a Swiss university hospital by active pharmaceutical ingredient (API) residues was evaluated with a three months monitoring campaign at the outlet of the main building. Flow-proportional samples were collected with an automatic refrigerated sampler and analyzed for 15 API, including antibiotics, analgesics, antiepileptic and anti-inflammatory drugs, by using a validated LC-MS/MS method. The metals Gd and Pt were also analyzed using ICP-MS. Measured concentrations were compared to the predicted ones calculated after the drug average consumption data obtained from the hospital pharmacy. The hospital contribution to the total urban load was calculated according to the consumption data obtained from city pharmacies. Lastly, the environmental hazard and risk quotients (RQ) related to the hospital fraction and the total urban consumption were calculated. Median concentrations of the 15 selected compounds were ranging from 0.04 to 675 μg/L, with a mean detection frequency of 84%. The ratio between predicted and measured environmental concentrations (PEC/MEC) has shown a good accuracy for 5 out of 15 compounds, revealing over- and under-estimations of the PEC model. Mean daily loads were ranging between 0.01 and 14.2g/d, with the exception of paracetamol (109.7 g/d). The hospital contribution to the total urban loads varied from 2.1 to 100% according to the compound. While taking into account dilution and removal efficiencies in wastewater treatment plant, only the hospital fraction of the antibiotics ciprofloxacin and sulfamethoxazole showed, respectively, a high (RQ>1) and moderate (RQ>0.1) risk for the aquatic ecosystems. Nevertheless, when considering the total urban consumption, 7 compounds showed potential deleterious effects on aquatic organisms (RQ>1): gabapentin, sulfamethoxazole, ciprofloxacin, piperacillin, ibuprofen, diclofenac and mefenamic acid. In order to reduce inputs of API residues originating from hospitals various solutions can be envisioned. With results of the present study, hospital managers can start handling this important issue.
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Non-steroidal anti-inflammatories (NSAIDs) are analgesic, antipyretic, and, as their name implies, anti-inflammatory drugs, which are widely used for the treatment of a variety of human and veterinary disease conditions in which control of pain and inflammation is desired. Acetaminophen (ACE) is a common over-the-counter analgesic. Detection of a variety of widely used NSAIDs and ACE in fluid and tissue samples is an important diagnostic tool. A sensitive and selective analytical method has been developed for simultaneous screening of 12 NSAIDs and ACE by liquid chromatography-mass spectrometry with an atmospheric pressure chemical ionization interface set to operate in the negative ion mode of MS. Following sample preparation, all analytes were separated on a C18-reversed-phase column with a gradient elution of acetonitrile and acetic acid. Full-scan mass spectral fragmentation profiles were established for each analyte and individual extracted ion chromatograms were used for quantitation. Linearity of detection was observed over the 0.05-25.0 microg/mL range of standard concentrations. The instrument limits of detection (LOD), based on an individual analyte quantitation ions, fell between 0.05 and 1.0 microg/mL for all compounds. The matrix LODs were determined to be 0.05 microg/mL for phenylbutazone (m/z 307); 0.1 microg/mL for indomethacin (m/z 312), flunixin (m/z 295), and piroxicam (m/z 330); 0.5 microg/mL for ACE (m/z 150), diclofenac (m/z 250), ketoprofen (m/z 209), and mefenamic acid (m/z 240); 1.0 microg/mL for oxyphenbutazone (m/z 323); 5.0 microg/mL for ibuprofen (m/z 205), salicylic acid (m/z 137), and tolmetin (m/z 212); and 10 microg/mL for naproxen (m/z 185).
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Prostaglandin levels in the human endometrium were determined on day 2 of the menstrual cycle in eumenorrheic subjects and in patients with menorrhagia, dysmenorrhea, or both. Menorrhagic subjects had significantly higher levels of endometrial prostaglandins of the E and F series when compared with eumenorrheics. Prostaglandin E levels were markedly higher than prostaglandin F. In 10 menorrhagic subjects who completed a double-blind clinical study on the effectiveness of mefenamic acid in lowering menstrual blood loss, 9 exhibited statistically significant reduction in endometrial prostaglandin levels. A decrease in menstrual blood loss was also noted during mefenamic acid treatment in these patients. These findings are consistent with the concept that abnormally high uterine prostaglandin levels may be an important etiologic factor in menorrhagia and support the notion that one of the mechanisms of action of nonsteroidal anti-inflammatory agents in the treatment of this menstrual disorder is inhibition of endometrial prostaglandin production.
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Day-case center in a tertiary care hospital in India.
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To determine whether an educational package could influence the management of menorrhagia, increase the appropriateness of choice of non-hormonal treatment, and reduce referral rates from primary to secondary care.
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To determine the effectiveness and safety of prophylactic ibuprofen compared to placebo/no intervention or other cyclo-oxygenase inhibitor drugs (indomethacin, mefenamic acid, etc) in the prevention of PDA in preterm infants.
To study drug-associated admission to a district hospital in the Kingdom of Saudi Arabia with regard to pattern, demographic characteristics of patients and outcome.
The solid dispersions were prepared by cryogenic grinding method. Powder X-ray diffractometry, in vitro dissolution test, in vivo oral absorption study, infrared spectroscopy, and solid- and solution-state NMR spectroscopies were used to characterize the solid dispersions.
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Sixty patients with primary dismenorrhea were treated: 20 with nimesulide, 20 with fentiazac and 20 with mefenamic acid during three consecutive cycles under double blind design. The doses used in each group were: nimesulide or fentiazac 100 mg, every 12 hrs., mefenamic acid 500 mg. every 8 hrs. in all cases during 5 days, beginning a day before the beginning, of the menstruation. The pain evolution and the symptoms were evaluated three times a day using a scale from 0 to 10, so measure its intensity. Concluding, the nimesulide is useful in the treatment of pain associated with primary dismenorrhea, answering with little statistical advantage over the fentiazac and with bigger statistical advantage over the mefenamic acid. The tolerance was excellent with the three drugs studied.
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Mefenamic acid is an analgesic, antipyretic and anti-inflammatory agent. In addition induces several hematological disturbances. Present study was conducted to determine the alterations in blood PCV of the lizard Uromastix hardwickii after the administration of 7.1 mg/ml; 10.5 mg/ml and 14.0 mg/ml mefenamic acid per individual per day for 12 days to 3 test groups. The mean values of PCV were 15.5+/-0.81%, 14.5+/-0.25% and 12.0+/-0.25% for 3 test groups respectively in comparison to 23.5+/-0.40% for control. Thus a significant dose dependant reduction in mean PCV per cent following the administration of mefenamic acid for 12 days indicates the extra vascular hemolysis due to destructive change in the red cell membrane through autoantibody mechanism.
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NSAIDs reduce heavy menstrual bleeding when compared with placebo but are less effective than either tranexamic acid or danazol. However, adverse events are more severe with danazol therapy. In the limited number of small scale studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral progestogen given in the luteal phase, ethamsylate, oral contraceptive pill and the progesterone releasing IUS.
34 women with recurrent primary dysmenorrhea were given prescriptions for mefenamic acid and told to use it as needed for pain and cramps. 85% felt the dysmenorrhea had improved and 15 of the women said it was completely controlled. Virtually all felt it more effective than aspirin and 13 of 18 who could make a comparison considered it more effective than propoxyphene. There were 3instances of nausea or vomiting and 1 of sleepiness. A double-blind study is now underway.
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Current Controlled Trials ISRCTN86566246.
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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.
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The formation and high stability of the supersaturated solution were attributable to the specifically formed intermolecular interactions between MFA and EPO.
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The effects of prostaglandins (PGs) on melatonin secretion and norepinephrine (NE) and release in rat pineal gland were examined in vitro. To study melatonin secretion, pineal explants were incubated for 6 h in tissue culture 199 medium with 1-1000 nM PGE1, PGE2, or PGF2 alpha. melatonin concentration in pineal glands and media was determined by RIA, PGE2 increased pineal and medium melatonin at all concentrations tested, with a maximum of 1 nM; PGE1 was effective only at concentrations 100-1000 times greater, whereas 100 nM PGF2 alpha gland. Exposure of pineal explants to 10 microM NE brought about a 20-fold increase in melatonin release to the medium. This effect was impaired significantly, but not blocked, by prior exposure to indomethacin, acetylsalicylic acid, or mefenamic acid at supramaximal concentrations to inhibit PG synthesis (100 microM). To examine the effects of PGs on NE release, endogenous NE stores in pineal nerve endings were labeled in vitro by incubating rat pineals with [3H]NE for 30 min. Fifty minutes later, at the time when spontaneous radioactivity efflux had leveled off, transmitter release was elicited by a 1-min exposure to 80 mM K+ (S1), and the stimulus was repeated 35 min later (S2). PGs (10-100 nM) were added to the medium 20 min before S2. Ratios between fractional release of the two consecutive stimulations (S2/S1) varied between 0.84 and 1.16 in control pineals. Only 100 nM PGE2 impaired significantly transmitter release by 40%. These results suggest that PGE2 can play a role in NE-stimulated melatonin synthesis. At greater concentrations PGE2 inhibits NE release from pineal nerve endings.
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In the carrageenin-induced edema test in rats, the anti-inflammatory activity of SL-573 was 1.6 times as potent as those of phenylbutazone (PB) and ibuprofen (IP), 3.3 times as potent as that of mefenamic acid (MF) and 6.7 times as potent as that of mepirizole (MP). In the yeast-induced edema test in rats, SL-573 showed equipotent activity with IP, the activity of which was 4 times as potent as that of MP. In the dextran-induced edema test in rats, the anti-inflammatory activity of SL-573 was significantly higher than those of IP and MP. SL-573 showed no anti-inflammatory activity in the formalin-induced edema test in rats in the same way as seen with IP and MP. SL-573 markedly inhibited the increase in capillary permeability in mice induced by intraperitoneal administration of acetic acid, and its activity was 12 times as potent as that of PB and 17 times as potent as that of MF. SL-573 showed anti-granuloma activity neither systemically nor locally. SL-573 showed equi-potent activity with PB in the adjuvant arthritis test in rats and had little effect on the healing process of the skin wound in rats. The effect of SL-573 on the carrageenin-induced edema was not diminished in the adrenalectomized rats. The gastric bleeding effect of SL-573 was significantly weaker than that usually seen in nonsteroidal anti-inflammatory drugs. SL-573 did not induce intestinal perforation even at the high dose of 800 mg/kg. Additionally, SL-573 showed a protective effect on the indomethacin-induced intestinal lesions. These pharmacological profiles of SL-573 were considered to be quite characteristic as compared with those of known nonsteroidal anti-inflammatory agents.
Mefenamic acid (MA) spherical agglomerates (SAs) were prepared with various polymethacrylates having different permeability characteristics (Eudragit RS 100, Eudragit RL 100 and Eudragit L 100) and also with combination of Eudragit RS 100 and Eudragit L 100 in different ratios. SAs were prepared by spherical crystallization method using ethanol/dichloromethane solvent (crystallization) system. The influence of various formulation factors on the encapsulation efficiency, as in vitro drug release, and micromeritic properties was investigated. Target release profile of MA was also drawn. The yields of preparation and the encapsulation efficiencies were high for all formulations. The shape and surface characteristics of SAs were observed by a scanning electron microscope. The particle sizes are in the range of 0.219 ± 0.1 to 0.482 ± 0.25 mm (mean ± confidence interval t(95%)). In addition, histological studies showed that the administration of MA in SAs containing Eudragit RS/L provided a distinct tissue protection in the stomach and duodenum. Differential scanning calorimetry and X-ray diffraction of powder studies showed that MA particles crystallized in the presence of polymethacrylates did not undergo structural modifications.
The findings of biochemical studies, carried out in 30 patients suffering from psoriatic arthropathy, are analyzed. The parameters examined are: the blood and urine glycosaminoglycans, urine hydroxyproline levels, and blood hyaluronate glycan hydrolase and N-acetyl-B-D-glucosaminidase activities, i. e. the matrix and collagen metabolites as the indicators of the connective tissue destruction and lysosomal enzymes activation responsible, among other factors, for this destruction. The studies have revealed a correlation between the enzymic activity augmentation and the levels of the connective tissue degradation products and the dissemination and severity of the skin and articular processes. The patients have been treated with mefenamic acid, an enzymic activity inhibitor. The therapy has been effective in 76% of patients; 13% of these have developed a remission shortly after therapy (in 46.7 days on an average). The therapy has alleviated both skin and articular symptoms; a tendency to normalization of the biochemical characteristics has been observed. A continuous course of therapy has not been associated with side effects. The author recommends this pathogenetically based and confirmed by laboratory investigations method to be included into a complex of therapeutic measures for patients with psoriatic arthropathy.