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At least 685 records · Page 38Linked to original sources
PubMed2002

Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs.

It has been recently described that some non-steroidal anti-inflammatory drugs (NSAIDs) are able to induce the shedding of L-selectin in neutrophils, an adhesion molecule that plays an essential role in the inflammatory response. We have found that, according to this capability, NSAIDs could be grouped into three categories. A high releaser group (flufenamic, meclofenamic, and mefenamic acids, diclofenac and aceclofenac), a group of moderate releasers (aspirin, indomethacin, nimesulide, flurbiprofen, and ketoprofen), and a non-releaser group (phenylbutazone and the oxicams, piroxicam and meloxicam). Only NSAIDs from the high releaser group shared diphenylamine in their chemical structure. The amine group of this chemical agent proved to be essential for the anti-L-selectin activity of diphenylamine-based NSAIDs. The presence of a carboxylic acid group in the diphenylamine (N-phenylanthranilic acid) highly increased its ability to reduce the L-selectin surface expression in neutrophils. Diphenylamine and N-phenylanthranilic acid neither affected COX activity in platelets nor modified the activation state of neutrophils. Diphenylamine-related compounds, which include the diphenylamine-based NSAIDs caused a variable reduction in the neutrophil intracellular ATP concentration, which correlated with the differential ability of such compounds to trigger L-selectin shedding (r = 0.97, p < 0.01). Diphenylamine-related compounds failed to down-regulate L-selectin in a tumor necrosis factor-alpha-converting enzyme (TACE)-deficient murine monocytic cell line. Our data indicate that diphenylamine seems to be the structural core of NSAIDs accounting for their down-regulatory activity of L-selectin leukocyte expression. Diphenylamine and its related compounds exert this action on L-selectin through a prostaglandin-independent, TACE-dependent mechanism that seems to be linked to the capability of these agents to uncouple the mitochondrial oxidative phosphorylation.

ADAM Proteins↗
PubMed1993

Abnormal uterine bleeding. Finding and treating the cause.

Abnormal vaginal bleeding is a common presenting symptom with an extensive list of potential causes. In evaluating abnormal bleeding, nonuterine causes and pregnancy should first be excluded; after that, it is important to differentiate between ovulatory and anovulatory bleeding (dysfunctional uterine bleeding). Initial laboratory tests, in addition to a sensitive pregnancy test, include hemoglobin and hematocrit determinations, platelet count, and occasionally coagulation studies. An endometrial biopsy or dilation and curettage may be necessary to rule out endometrial hyperplasia or other pathology associated with the long-term unopposed estrogen stimulation experienced by anovulatory patients. In evaluating abnormal ovulatory bleeding, hysteroscopy with selected biopsy or curettage is superior to routine dilation and curettage. Anovulatory patients should be treated with an oral progestin, an oral contraceptive, or, if pregnancy is desired, an ovulation stimulant. Treatment options for patients having ovulatory cycles include an oral contraceptive, an oral progestin, danazol (Danocrine), a gonadotropin-releasing hormone agonist, mefenamic acid (Ponstel), and surgery.

Diagnosis, Differential↗
PubMed2003

Characterization of bropirimine O-glucuronidation in human liver microsomes.

1. The antitumour agent bropirimine undergoes significant Phase II conjugation in vivo. Incubation of [14C]bropirimine with human liver microsomes resulted in the formation of a single product peak (M1) using high-performance liquid chromatography with radiochemical detection and was tentatively assigned as bropirimine glucuronide based on sensitivity to beta-glucuronidase and by obtaining the expected mass of 442/444 amu with liquid chromatography/mass spectrometry. Following metabolite isolation, the structure of M1 was established as bropirimine O-glucuronide by 1H-nuclear magnetic spectroscopy. 2. Studies aimed at identifying the human liver UDP-glucuronosyltransferase (UGT) enzyme(s) involved in the glucuronidation of bropirimine were carried out using recombinant human UGTs and it was determined that glucuronidation of bropirimine was catalysed by UGT1A1, UGT1A3 and UGT1A9. Bropirimine O-glucuronidation followed Michaelis-Menten kinetics and the Km and Vmax (mean +/- SD; n = 3) were 1217 +/- 205 microM and 667 +/- 188 pmol min(-1) mg(-1), respectively. 3. The activity of bropirimine O-glucuronidation by human liver microsomes was inhibited by bilirubin (40%) and with mefenamic acid (80%). Although buprenorphine extensively inhibited the activity of bropirimine O-glucuronidation by UGT1A3, the inhibition profile did not parallel that observed in HLMs. 4. The results demonstrate that UGT1A9 and to a lesser extent UGT1A1 are responsible for the majority of bropirimine O-glucuronidation in man.

Antineoplastic Agents↗
PubMedDate not supplied

Renal papillary necrosis.

Renal papillary necrosis (RPN) is a significant problem in human beings, especially in England and in Australia where it has been reported to account for 15% to 20% of patients needing renal transplants. Many compounds, including aspirin, phenacetin, phenylbutazone, indomethacin, mefenamic acid, flufenamic acid, fenoprofin, naproxen, and ibuprofen have been linked to renal papillary necrosis in human beings. Although the exact mechanism of RPN is unknown, there are several theories that have good scientific evidence behind them. Study of RPN in animals as models for the disease in human beings is limited by several factors, including anatomical differences between human beings and most animal species as well as technical difficulties in studying the renal papilla.

Animals↗
PubMed2005

Oxidative stress mediated idiosyncratic drug toxicity.

The following describes a novel screening method for "new chemical entities" (NCEs), suitable for ADMET studies, that measures ability to form prooxidant radicals on metabolism and their ability to induce oxidative stress in intact cells. The accelerated molecular cytotoxic mechanism screening (ACMS) techniques used with isolated rat hepatocytes showed that cytotoxicity is usually initiated as a result of macromolecular covalent binding or macromolecular oxidative stress. While P450 is likely responsible for drug metabolic activation in the liver, intestine, lung, and in other nonhepatic tissues, where P450 levels are low, peroxidases including prostaglandin synthetase peroxidase can catalyze xenobiotic one-electron oxidation to form prooxidant free radicals that may cause toxicity or carcinogenesis. Inflammation markedly activates H2O2, generating NADPH oxidase and peroxidase of certain immune cells when they infiltrate tissues including the liver. Myeloperoxidase and NADPH oxidase in the Kupffer cells (resident macrophages of the liver) also become activated during inflammation. The addition of noncytotoxic concentrations of peroxidase/H2O2 to the hepatocyte incubate markedly increased drug cytotoxicity and prooxidant radical formation as shown by glutathione or lipid oxidation. Many drugs that have hepato- or gastrointestinal (GI) toxicity problems or were withdrawn from the market for safety problems, e.g., troglitazone, tolcapone, mefenamic acid, diclofenac, and phenylbutazone, were markedly more toxic and prooxidant in this inflammation model system, whereas other drugs, e.g., entacapone, were not toxic in this inflammation model. Some of the idiosyncratic hepatotoxicity responsible for recent drug withdrawals may therefore result from commonplace sporadic inflammatory episodes during drug therapy.

Animals↗
PubMed1994

Prevention and treatment of ocular inflammation with a new class of non-steroidal anti-inflammatory agents.

New non-steroidal anti-inflammatory agents (NSAIAs) were tested on lens protein-, endotoxin- and interleukin-1-induced ocular inflammation. It was found that most NSAIAs, including REV 5901, mefenamic acid, indomethacin, CK-17 and CK-102, inhibited lens protein-induced inflammation. Endotoxin induced inflammation indirectly through the release of IL-1 which was inhibited by fewer agents, including CK-17, CK-102 and prednisolone. However, the direct effect of IL-1 can only be suppressed by CK-17 and prednisolone. Therefore, CK-17 could become an important NSAIA which acts similarly to corticosteroids yet produces no steroidal side effects. CK-17 was different from most NSAIAs as it affected little, if any, arachidonate metabolism. Most importantly, CK-17 was found to be 2-fold more potent than prednisolone in inhibiting IL-1-induced uveitis, while no side effects were noted at doses tested to date.

Animals↗
PubMed1998

Effects of etomidate, propofol and thiopental anaesthesia on arteriolar tone in the rat diaphragm.

We have assessed, by intravital microscopy in rats, the effects of different anaesthetics on diaphragmatic arteriolar diameter. Rats were anaesthetized with etomidate, propofol or thiopental (groups E, P and T, respectively) and the diameters of the arterioles were measured sequentially at baseline and after topical application of either mefenamic acid (MA, 20 mumol litre-1) or N omega-nitro-L-arginine (NNA, 300 mumol litre-1), inhibitors of prostaglandins and nitric oxide, respectively. In group E, baseline arteriolar diameters were significantly higher than those in the two other groups (P < 0.01). MA and NNA induced significant constriction in the three groups (P < 0.001). However, whereas constriction induced by NNA was similar in the three groups, constriction induced by MA was significantly higher in group E compared with groups P and T (P < 0.05). We conclude that diaphragmatic arteriolar diameters in rats were greater during etomidate than during thiopental or propofol anaesthesia. This phenomenon may be mediated by prostaglandins.

Anesthetics, Intravenous↗
PubMed1986

Inhibition of trans-dihydrodiol oxidation by the non-steroidal anti-inflammatory drugs.

The homogeneous dihydrodiol dehydrogenase of rat liver cytosol (EC 1.3.1.20) reduces the mutagenicity of benzo[a]pyrene in the Ames test, suggesting that the enzyme may detoxify the trans-dihydrodiol proximate carcinogens formed from this compound. This report directly demonstrates for the first time that the purified dehydrogenase catalyzes the NADP-dependent oxidation of the potent proximate carcinogen [1,3-3H](+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene at physiological pH. An initial velocity of 1.8 nmol [3H]trans-dihydrodiol oxidized/min/mg protein was observed at a substrate concentration of 20 microM. This potential detoxification reaction was potently inhibited by the nonsteroidal anti-inflammatory drug indomethacin, yielding an IC50 value of 10 microM. At higher drug concentrations (30 microM), the inhibition persisted for many hours. In an extension of this work, benzenedihydrodiol (trans-1,2-dihydroxy-3,5-cyclohexadiene) and naphthalenedihydrodiol (trans-1,2-dihydroxy-1,2-dihydronaphthalene) were synthesized as models of the scarce proximate carcinogen trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and examined as substrates. The Km for benzenedihydrodiol was 1.74 mM and the Vmax was 530 nmol substrate oxidized/min/mg protein, while the Km for naphthalenedihydrodiol was 10.71 mM and the Vmax was 268 nmol oxidized/min/mg protein; the former compound was oxidized to catechol. Eight different non-steroidal anti-inflammatory drugs were found to inhibit the oxidation of these model trans-dihydrodiols, yielding IC50 values comparable to or lower than peak plasma concentrations observed in man. These results suggest that therapeutically relevant concentrations of the non-steroidal anti-inflammatory drugs may inhibit the oxidation of trans-dihydrodiol proximate carcinogens by this route.

3-Hydroxysteroid Dehydrogenases↗
PubMed2006

High-performance liquid chromatographic assay of indomethacin in porcine plasma with applicability to human levels.

A high-performance liquid chromatography (HPLC) assay is described for the determination of indomethacin in porcine plasma using acetonitrile to precipitate plasma proteins and for the one-step extraction. Calibration curves (using the internal standard method) are linear (r2 > 0.98) over the concentration range of 50.0 to 3000 ng/mL in both mobile phase and plasma. Precision, expressed as the inter- and intraday coefficient of variation (n = 5), is < 7% on the same day and < 5% between days at each plasma control sample of 300, 1000, and 3000 ng/mL, respectively. System precision, calculated as the coefficient of variation (n = 5), is < 7% at 3000 ng/mL of indomethacin, and the limit of quantitation in plasma is 50 ng/mL. The absolute recovery for both indomethacin and the internal standard (mefenamic acid) from plasma is over 97% (n = 3), and the concentrations do not deviate more than -2.9% to 2.4% from their actual values. The specificity of the method is confirmed. This technique is thus reported to be both rapid and specific. The real advantage is the small sample volume required (500 microL), which allows it to be considered for the quantitation of indomethacin in plasma from paediatric patients.

Animals↗
PubMed1997

The effect of tourniquet release time on the analgesic efficacy of intraarticular morphine after arthroscopic knee surgery.

A randomized, controlled study was conducted in patients undergoing elective arthroscopic knee surgery to assess the effects of tourniquet release time on analgesia after intraarticular (I.A.) injection of morphine. Standardized general anesthetic and surgical techniques were used for all patients, including a thigh tourniquet inflated at pressures between 300 and 350 mm Hg. At the conclusion of the arthroscopic procedure, 5 mg morphine in 25 mL saline was administered I.A. Patients were then randomized to one of two treatment groups. In Group 1 (n = 20), the tourniquet was kept inflated for 10 min after I.A. injection, whereas in Group 2 (n = 20), the tourniquet was deflated immediately after I.A. injection. Postoperative pain was assessed using a visual analog scale in the recovery room when the patients were awake and at 2, 4, 6, 8, and 24 h after I.A. injection. Patients who complained of pain in the recovery room received increments of intravenous meperidine 25-50 mg. On discharge from the recovery room, patients received oral mefenamic acid 250-500 mg for pain relief. The time and quantity of analgesics required were recorded. Patients in Group 1 had significantly (P < 0.05) lower pain scores than those in Group 2 at 2, 4, 6, and 8 h postoperatively. These low pain scores were associated with lower requirements of supplementary analgesics. We conclude that, as compared with releasing the tourniquet immediately after I.A. injection of morphine, maintaining the tourniquet inflated for 10 min provides superior analgesia and decreases the need for supplemental analgesics.

Adult↗
PubMed1988

Hyperkalemia induced by indomethacin and naproxen and reversed by fludrocortisone.

We have described a patient with severe rheumatoid arthritis and a history of mefenamic acid nephropathy in whom hyperkalemia and inappropriate hypoaldosteronism were caused by both indomethacin and naproxen, without major decline in renal function. It is likely that preexisting renal disease predisposed this patient to type IV renal tubular acidosis with prostaglandin synthetase inhibitors. Because he was unable to discontinue nonsteroidal anti-inflammatory drug therapy, fludrocortisone was added, correcting the hyperkalemia and allowing indomethacin therapy to be continued safely.

Fludrocortisone↗
PubMed1994

Development and use of a gastropathy index for ranking the safety of non-steroidal anti-inflammatory drugs in the elderly.

This study, conducted at the Royal Devon & Exeter Hospital, Department of Geriatric Medicine, was carried out using 2987 sets of admission data. The number of patients taking non-steroidal anti-inflammatory drugs was identified together with a suite of clinical factors used to indicate the presence of gastrointestinal pathology. From this a gastropathy index was developed to establish a rank order for the individual drugs. Ketoprofen, piroxicam and fenbufen were all significantly associated with factors suggestive of gastropathy, whereas indomethacin, diclofenac and ibuprofen appeared relatively free of such association. Naproxen, azapropazone and mefenamic acid ranked in an intermediate category. This noninvasive analysis of routinely acquired data provides a potentially useful discriminator between individual non-steroidal anti-inflammatory drugs for this age group.

Aged↗
PubMed1993

Reinduction of the hypnotic effects of thiopental with NSAIDs by decreasing thiopental plasma protein binding in humans.

The effects of 14 non-steroidal anti-inflammatory drugs (NSAIDs)--naproxen, ibuprofen, mefenamic acid, ketoprofen, indomethacin, fenoprofen, diclofenac sodium, aspirin, salicylic acid, piroxicam, sulindac, fenbufen, flurbiprofen and benzydamine, on the plasma protein binding of thiopental and the clinical consequences of such interactions were studied. Four of them, naproxen, ibuprofen, salicylic acid and aspirin, very significantly decreased the protein binding of thiopental in vitro in human plasma (P < 0.005). Structurally, they were salicylates and propionic acid derivatives among the six classes of NSAIDs studied. The aspirin study demonstrated that the protein-displacing phenomenon was temperature-dependent, and concentration-dependent. Clinically, aspirin administered intravenously resulted in a significant increase in the percentage of plasma free thiopental from 16.01 +/- 3.59% to 22.27 +/- 3.96% (P < 0.001, n = 10) in patients undergoing surgery, and resulted in three of seven patients sleeping again during recovery from thiopental-induced anesthesia. Although the effect of chronic use of NSAIDs before anesthesia is uncertain, studies should be carried out to find out if naproxen, ibuprofen, and aspirin influence the depth of anesthesia, time of recovery and duration of action of thiopental.

Adult↗
PubMed1995

Activation of rabbit platelets by Ca2+ influx and thromboxane A2 release in an external Ca(2+)-dependent manner by zooxanthellatoxin-A, a novel polyol.

1. Zooxanthellatoxin-A (ZT-A), a novel polyhydroxylated long chain compound, isolated from a symbiotic marine alga Simbiodinium sp., caused aggregation in rabbit washed platelets in a concentration-dependent manner (1-4 microM), accompanied by an increase in cytosolic Ca2+ concentration ([Ca2+]i). 2. ZT-A did not cause platelet aggregation or increase [Ca2+]i in a Ca(2+)-free solution, and Cd2+ (0.1-1 mM), Co2+ (1-10 mM) and Mn2+ (1-10 mM) inhibited ZT-A-induced aggregation. SK&F96365 (1-100 microM), a receptor operated Ca2+ channel antagonist, and mefenamic acid (0.1-10 microM), a non-specific divalent cation channel antagonist, inhibited platelet aggregation and the increase in [Ca2+]i induced by ZT-A. 3. Indomethacin (0.1-10 microM), a cyclo-oxygenase inhibitor, and SQ-29548 (0.1-10 microM), a thromboxane A2 (TXA2) receptor antagonist, inhibited platelet aggregation and the increase in [Ca2+]i induced by ZT-A. 4. Methysergide (0.01-1 microM), a 5-HT2 receptor antagonist, inhibited ZT-A-induced platelet aggregation but did not affect the increase in [Ca2+]i induced by ZT-A. 5. Tetrodotoxin (1 microM), a Na+ channel blocker and chlorpheniramine (1 microM), a H1-histamine receptor antagonist, neither affected ZT-A-induced platelet aggregation nor the increase in [Ca2+]i induced by ZT-A. 6. Genistein (1-100 microM), a protein tyrosine kinase inhibitor, and staurosporine (0.01-1 microM), a protein kinase C inhibitor, also inhibited ZT-A-induced platelet aggregation. 7. The present results suggest that ZT-A elicits Ca(2+)-influx from platelet plasma membranes. The resulting increase in [Ca2+]i subsequently stimulates the secondary release of TXA2 from platelets. Furthermore, the response to ZT-A may be associated with tyrosine phosphorylation.

Alkaloids↗
PubMed1993

Analgesic use and chronic renal disease in patients with headache.

The pattern of analgesic use, abuse and incidence of analgesic-associated nephropathy in 79 patients with chronic headache was studied. Sixty-eight of these patients had migraine. Most patients had consumed a combination of analgesics (81%) while 19% had taken single analgesics for their headache. Nonsteroidal anti-inflammatory drugs were the most commonly used analgesics (96.2%) followed by paracetamol (70.9%) and aspirin, phenacetin and caffeine compounds (5.1%). Mefenamic acid was the commonest nonsteroidal anti-inflammatory drug consumed (97.4%). Analgesic abuse which was defined as a minimum total of 1 kg of analgesics such as paracetamol or aspirin, phenacetin and caffeine compounds or 400 capsules/tablets of nonsteroidal anti-inflammatory drugs was noted in 65 patients. Nonsteroidal anti-inflammatory drugs were the most commonly abused analgesics (89.2%) followed by paracetamol (38.5%). Forty-five of the 65 analgesic abusers had an intravenous urogram or ultrasound performed and renal papillary necrosis was documented in one patient. Three (4.6%) of the analgesic abusers had mildly raised serum creatinine levels. Mild proteinuria of less than 1 gm/litre was present in 27.7% of abusers. In conclusion, although analgesic use and abuse is common in patients with chronic headache, the short term incidence of analgesic-associated nephropathy (2.2%) and renal impairment (4.6%) was low. Prolonged observations will be necessary to ascertain the safety of these drugs for long term use.

Analgesics↗
PubMed1984

Modifications in prolactin binding capacity in the rat liver induced by non-steroidal anti-inflammatory drugs.

Modifications in prolactin specific binding in the rat liver induced by different non-steroidal anti-inflammatory drugs (indomethacin, piroxicam, ketoprofen, phenylbutazone, mefenamic acid and acetylsalicylic acid) have been studied. All caused a dose-dependent inhibition of prolactin binding capacity whereas no change was found in dissociation constant values. The inhibitory effect is reversible and highly specific, since insulin binding to the same membrane preparation is not affected. The degree of inhibitory activity on prolactin binding is related to the anti-inflammatory activity of each drug, which supports the hypothesis of an involvement of prostaglandin synthesis.

Animals↗
PubMed1992

Interaction between cicletanine and the eicosanoid system in human subcutaneous resistance arteries.

In human subcutaneous resistance arteries in-vitro, the relaxation produced by the novel furopyridine compound cicletanine (30 microMs) was inhibited by 51% (P less than 0.0001) in the presence of 20 microMs of the cyclo-oxygenase inhibitor indomethacin. Maximal cicletanine-induced relaxation was reduced by both the cyclo-oxygenase inhibitor mefenamic acid and the relatively specific blocker of prostacyclin synthetase, tranylcypromine by 55% (P less than 0.0005) and 43% (P less than 0.01), respectively. The potassium channel blocker, glibenclamide (100 microMs), did not affect the relaxation produced by cicletanine but did inhibit the relaxation produced by the potassium channel blocker cromakalim (P less than 0.0001). Cromakalim-induced relaxation was inhibited in the presence of indomethacin; relaxation induced by cromakalim (30 microMs) was reduced by 22% (P less than 0.02). The relaxation produced by the hypotensive agonists sodium nitroprusside, hydrochlorothiazide, bumetanide and nicardipine was unaffected by incubation with indomethacin. The results suggest that the vascular eicosanoid system, specifically prostacyclin, may be involved in the mechanism of the acute vasodilator action of cicletanine. Although at high doses, cicletanine is a diuretic, in this model it did not act like either a thiazide or a loop diuretic. The acute vasodilator action of the thiazide diuretic, hydrochlorothiazide was a novel finding of this study. Cromakalim showed a reduced response in the presence of indomethacin suggesting an involvement of the eicosanoid system in its mechanism of action.

Antihypertensive Agents↗