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PubMed2005

Acyl glucuronidation of fluoroquinolone antibiotics by the UDP-glucuronosyltransferase 1A subfamily in human liver microsomes.

Acyl glucuronidation is an important metabolic pathway for fluoroquinolone antibiotics. However, it is unclear which human UDP-glucuronosyltransferase (UGT) enzymes are involved in the glucuronidation of the fluoroquinolones. The in vitro formation of levofloxacin (LVFX), grepafloxacin (GPFX), moxifloxacin (MFLX), and sitafloxacin (STFX) glucuronides was investigated in human liver microsomes and cDNA-expressed recombinant human UGT enzymes. The apparent Km values for human liver microsomes ranged from 1.9 to 10.0 mM, and the intrinsic clearance values (calculated as Vmax/Km) had a rank order of MFLX > GPFX > STFX > > LVFX. In a bank of human liver microsomes (n = 14), the glucuronidation activities of LVFX, MFLX, and STFX correlated highly with UGT1A1-selective beta-estradiol 3-glucuronidation activity, whereas the glucuronidation activity of GPFX correlated highly with UGT1A9-selective propofol glucuronidation activity. Among 12 recombinant UGT enzymes, UGT1A1, 1A3, 1A7, and 1A9 catalyzed the glucuronidation of these fluoroquinolones. Results of enzyme kinetics studies using the recombinant UGT enzymes indicated that UGT1A1 most efficiently glucuronidates MFLX, and UGT1A9 most efficiently glucuronidates GPFX. In addition, the glucuronidation activities of MFLX and STFX in human liver microsomes were potently inhibited by bilirubin with IC50 values of 4.9 microM and 4.7 microM, respectively; in contrast, the glucuronidation activity of GPFX was inhibited by mefenamic acid with an IC50 value of 9.8 microM. These results demonstrate that UGT1A1, 1A3, and 1A9 enzymes are involved in the glucuronidation of LVFX, GPFX, MFLX, and STFX in human liver microsomes, and that MFLX and STFX are predominantly glucuronidated by UGT1A1, whereas GPFX is mainly glucuronidated by UGT1A9.

Animals↗

PubMed2002

Interactions of human organic anion transporters and human organic cation transporters with nonsteroidal anti-inflammatory drugs.

The purpose of this study was to elucidate the interactions of human organic anion transporters (hOATs) and human organic cation transporters (hOCTs) with nonsteroidal anti-inflammatory drugs (NSAIDs) using cells stably expressing hOATs and hOCTs. NSAIDs tested were acetaminophen, acetylsalicylate, salicylate, diclofenac, ibuprofen, indomethacin, ketoprofen, mefenamic acid, naproxen, piroxicam, phenacetin, and sulindac. These NSAIDs inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4. By comparing the IC(50) values of NSAIDs for hOATs, it was found that hOAT1 and hOAT3 exhibited higher affinity interactions with NSAIDs than did hOAT2 and hOAT4. HOAT1, hOAT2, hOAT3, and hOAT4 mediated the uptake of either ibuprofen, indomethacin, ketoprofen, or salicylate, but not acetylsalicylate. Although organic cation uptake mediated by hOCT1 and hOCT2 was also inhibited by some NSAIDs, hOCT1 and hOCT2 did not mediate the uptake of NSAIDs. In conclusion, hOATs and hOCTs interacted with various NSAIDs, whereas hOATs but not hOCTs mediated the transport of some of these NSAIDs. Considering the localization of hOATs, it was suggested that the interactions of hOATs with NSAIDs are associated with the pharmacokinetics and the induction of adverse reactions of NSAIDs.

Alprostadil↗

PubMed2003

Interaction between nitric oxide and prostanoids in arterioles of rat cremaster muscle in vivo.

We studied in vivo interactions of nitric oxide (NO), oxidative stress, and prostanoids derived from the cyclooxygenase pathway in the arterioles studied by intravital microscopy in peripheral muscle. Topical administration of NO synthase (NOS) inhibitor Nomega-nitro-l-arginine (l-NNA) or cyclooxygenase inhibitor mefenamic acid (MA) alone leads to vasoconstriction. We found that l-NNA after MA induced an additional constriction, whereas MA after l-NNA induced a relative dilation. Therefore, an additional constriction was found when MA was administered after l-NNA in the presence of the thromboxane A2 synthase-PGH2 (TP) receptor antagonist SQ-29548. We also found a relative dilation when the TP receptor antagonist was administered after NOS inhibition by l-NNA. In the presence of superoxide dismutase and catalase, l-NNA-induced vasoconstriction is reduced, and the dilation observed after addition of MA in presence of the reactive oxygen species is no longer present. Taken together, these results showed that NO inhibition induced a shift in the synthesis or in the effects of cyclooxygenase products, in favor of constrictor prostanoids. This effect of NO inhibition disappears when reactive oxygen species are scavenged by superoxide dismutase and catalase.

Animals↗

PubMed1986

Endogenous modulation of alpha-adrenergic contraction in canine tracheal muscle.

We studied the effect of passive stretch on the contraction of canine tracheal smooth muscle (TSM) to alpha-adrenergic agonists and acetylcholine (ACh) in 211 epithelium-free TSM strips from 42 dogs in vitro. Passive stretch at a resting tension of 100 g/cm2 caused a time-dependent decrease in the contractile response to alpha-adrenergic agonists after beta-adrenergic blockade with propranolol. Initial contraction elicited by 10(-3) M phenylephrine (PE) and clonidine (CLO) decreased at 2 h by 31 and 100%, respectively. Decrease in alpha-adrenergic contractility did not result from tachyphylaxis; no contraction was elicited by PE or CLO given for the first time after 4-h passive stretch at 100 g/cm2. The TSM response to ACh was unchanged over the same time in the same strips. When TSM strips were incubated at zero resting tension for 6 h, some attenuation of the alpha-adrenergic contractile still occurred but was not substantial. Similarly, when strips were incubated with 10(-6) M indomethacin (INDO) or 10(-5) M mefenamic acid (MEF) at 100 g/cm2 resting tension, time-dependent attenuation of the response to PE and CLO was reduced for at least 6 h, and initial contraction elicited by PE was augmented. Response of TSM to ACh was not affected by prostaglandin synthetase inhibition with INDO. We conclude that passive stretch of canine TSM in vitro leads to decreased responsiveness to alpha-adrenergic stimulation that can be prevented with INDO or MEF. These data are consistent with the synthesis of an inhibitory eicosanoid in epithelium-free canine TSM that may be activated by mechanical deformation of the muscle.

Adrenergic alpha-Agonists↗

PubMed1994

Nitric oxide-independent response to acetylcholine by terminal arterioles in rat cremaster muscle.

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)

Acetylcholine↗

PubMed2006

Expansion of IL-10-producing CD4+ and CD8+ T cells in fixed drug eruption.

BACKGROUND: A severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN) but, unlike TEN, resolves spontaneously upon withdrawal of the causative drug. OBJECTIVE AND METHODS: We reported a case of a severe FDE caused by mefenamic acid that spontaneously resolved without use of systemic corticosteroids. To clarify the phenotype of the T cells responsible for clinical resolution of FDE, we kinetically examined gamma-interferon (IFN-gamma), interleukin (IL)-2, IL-4 and IL-10 production by peripheral blood T cells of the patient before and after oral challenge with the causative drug using flow cytometry. RESULTS: We found that the proportions of CD4+ and CD8+ T cells capable of producing IFN-gamma and IL-4 remained unchanged after challenge, while those of CD4+ and CD8+ T cells capable of producing IL-10 dramatically increased after challenge. The frequency of CD8+ T cells capable of producing IL-2 decreased after challenge. CONCLUSION: These results suggest that expansion of IL-10-producing CD4+ and CD8+ T cells may be responsible for spontaneous resolution of a severe form of FDE.

Aged↗

PubMed1984

Effect of prostaglandin synthetase inhibitors on experimentally induced convulsions in rats.

To investigate the relationship of prostaglandins (PGs) to seizure induction, the effects of six PG synthetase inhibitors on convulsions induced by flurothyl, picrotoxin, pentetrazol (PTZ), electroshock or bicuculline were evaluated. Ibuprofen, sulindac, mefenamic acid, and low dose meclofenamic acid increased the latency-to-onset in the flurothyl and/or PTZ models; the electroshock, picrotoxin and bicuculline models were not significantly affected by any of the pretreatment agents. These results suggest that PGs are involved in the mechanism(s) underlying fluorthyl- and PTZ-induced convulsions, but not picrotoxin-, electroshock-, or bicuculline-induced convulsions.

Animals↗

PubMed1988

Colonic inflammation and nonsteroidal anti-inflammatory drug administration. An assessment of the frequency of the problem.

Over an 18-month period at a single clinic, 43 new cases of colonic inflammation have been diagnosed (19 proctitis only). Crohn's colitis has been excluded from this analysis. In all these subjects a careful drug history has been taken in a prospective manner and in 4 of these 43 patients colonic inflammation appeared to be directly related to non-steroidal anti-inflammatory drug (NSAID) administration (mefenamic acid, 2; piroxicam, 2). In all 4 patients there was a time interval (mean 3 months) between initiation of treatment with NSAID and presentation with diarrhoea and weight loss. Pathological findings were minor and biochemical changes insignificant, in contrast to the protracted troublesome symptoms. Resolution of symptoms was very rapid on discontinuation of NSAID medication but 2 patients experienced immediate return of symptoms following inadvertent rechallenge. Approximately 10% of newly diagnosed colitis may be related to NSAID administration. Subjects taking NSAID medications appear to be five times more likely to develop colonic inflammation than the general population.

Adult↗

PubMed1986

Critical aspects of urine and stone analysis. Appearance of iatrogenic urinary calculi.

In 25% of the samples the often applied qualitative chemical analysis of urinary stones leads to entirely wrong results with severe therapeutic consequences. The appropriate techniques for stone analysis are infrared spectroscopy and X-ray powder diffraction. These techniques make also possible the identification of iatrogenic urinary calculi. Four types of such stones were detected here, caused by modern medication. N4-acetylsulfamethoxazole, N4-acetylsulfadiazine, mefenamic acid and silicon dioxide. It is only the correct preanalytical treatment of urine samples that prevents considerable impairment of analytical results. Without precautions especially, the oxalate concentration in urine may be doubled or tripled during one day of storage.

False Positive Reactions↗

PubMed1999

Inhibition of prostaglandin E2 synthesis in abdominal aortic aneurysms: implications for smooth muscle cell viability, inflammatory processes, and the expansion of abdominal aortic aneurysms.

BACKGROUND: There is no treatment proven to limit the growth of abdominal aortic aneurysms, in which the histological hallmarks include inflammation and medial atrophy, with apoptosis of smooth muscle cells and destruction of elastin. METHODS AND RESULTS: Aneurysm biopsies were used for explant cultures, the preparation of smooth muscle cell cultures, and isolation of macrophages. Tissue macrophages stained strongly for cyclooxygenase 2. Prostaglandin E2 (PGE2) concentrations in aneurysm tissue homogenates, conditioned medium from explants, and isolated macrophages were 49+/-22 ng/g, 319+/-38 ng/mL, and 22+/-21 ng/mL, respectively. PGE2 inhibited DNA synthesis and proliferation in normal aortic smooth muscle cells (IC50, 23.2+/-3.8 and 23.6+/-4.5 ng/mL, respectively). In smooth muscle cells derived from aneurysmal aorta, PGE2 also caused cell death, with generation of oligonucleosomes. Conditioned medium from the mixed smooth muscle and monocyte cultures derived from explants also had potent growth-inhibitory effects, and fractionation of this medium showed that the growth-inhibitory molecule(s) coeluted with PGE2. In explants, indomethacin 10 micromol/L or mefenamic acid 10 micromol/L abolished PGE2 secretion and significantly reduced IL-1beta and IL-6 secretion. In a separate case-control study, the expansion of abdominal aortic aneurysms was compared in 15 patients taking nonsteroidal anti-inflammatory drugs and 63 control subjects; median growth rates were 1.5 and 3.2 mm/y, respectively, P=0.001. CONCLUSIONS: The adverse effects of PGE2 on aortic smooth muscle cell viability and cytokine secretion in vitro and the apparent effect of anti-inflammatory drugs to lower aneurysm growth rates suggest that selective inhibition of PGE2 synthesis could be an effective treatment to curtail aneurysm expansion.

Adolescent↗

PubMed2001

Rapid reactive oxygen species production by mitochondria in endothelial cells exposed to tumor necrosis factor-alpha is mediated by ceramide.

Tumor necrosis factor (TNF)-alpha increases mitochondrial reactive oxygen species (ROS) production in tumor cells and hepatocytes. However, whether TNF-alpha stimulates mitochondrial ROS production in endothelial cells (EC) has not yet been reported. We studied the effect of TNF-alpha on mitochondrial ROS generation in EC and the signaling pathways involved. Cultured human umbilical vein EC (HUVEC) were studied by fluorescence microscopy, using dichlorodihydrofluorescein diacetate (DCFH-DA) as a marker of ROS production and propidium iodide uptake for cell viability. TNF-alpha increased DCFH oxidation in HUVEC dose-dependently. To determine the source of ROS, the mitochondrial respiratory chain inhibitors rotenone + thenoyltrifluoroacetone (TTFA), which inhibit electron entry to ubiquinone, and antimycin A (AA), a blocker of ubisemiquinone, were used. Rotenone and TTFA inhibited (n = 7, P < 0.05), whereas AA increased (118% in 3 min; n = 4, P < 0.01) ROS generation in HUVEC. In contrast, ROS production was not abolished by the nicotinamide adenine dinucleotide phosphate-dependent oxidase inhibitor diphenylene iodonium, by the xanthine oxidase inhibitor allopurinol, nor by the nitric oxide and cyclooxygenase pathway inhibitors N(omega)-nitro-L-arginine and mefenamic acid. In addition, TNF-alpha-induced ROS production was inhibited by the acidic sphingomyelinase inhibitor desipramine (5 microM; -80%, n = 4, P < 0.01) and totally blocked by the ceramide-activated protein kinase (CAPK) inhibitor dimethylaminopurine (1 mM; n = 6, P < 0.05). Thus, TNF-alpha induces mitochondrial ROS production in HUVEC that primarily occurs at the ubisemiquinone site and is mediated by ceramide-dependent signaling pathways involving CAPK.

Ceramides↗

PubMed1991

Acute effects of tumor necrosis factor on the microcirculation in rat cremaster muscle.

The acute effects of TNF on the microcirculation were studied by in vivo microscopy in rat cremaster muscle. The changes in arteriolar diameter after topical administration of recombinant TNF (rTNF; 10(-4)-10(4) ng/ml) were studied in second-, third-, and fourth-order arterioles (A2-A4) whose mean diameters under control conditions were 64.3, 30.7, and 14.8 microns respectively. rTNF induced a concentration-dependent vasodilation whose amplitude was largest for the smallest arterioles. At the highest concentration tested, arteriolar diameter increased by 21, 29, and 41% of control diameter for the A2, A3, and A4 arterioles, respectively. Indomethacin or mefenamic acid, two structurally different prostaglandin synthesis inhibitors, markedly inhibited the degree of vasodilation induced by rTNF in the three arteriolar orders. As regards the effect of rTNF on vasoconstriction in response to norepinephrine, vasoconstriction was greatest for the smallest arterioles, and did not change 10 min after rTNF administration for any of the three arteriolar orders. We conclude that (a) rTNF has a direct vasodilatory effect which is greatest in the smallest arterioles, (b) this vasodilation is at least partly mediated by prostaglandins, and (c) administration of rTNF in itself does not acutely alter the response of the arterioles to vasopressive drugs.

Animals↗

PubMed1992

General practitioners' use of non-steroidal anti-inflammatory drugs in Tayside and Fife regions.

The objectives of this study were to assess the prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) by general practitioners and to determine their attitudes to problems caused by this class of drugs. The study consisted of two parts. The first was a questionnaire survey among general practitioners in Fife and Tayside, and the second was an analysis of NSAID prescribing over 12 months among the doctors in the Carnoustie Health Centre, using duplicate prescriptions. In the questionnaire survey 61% of the general practitioners responded. The three most preferred drugs were buprofen (56%), naproxen (20%) and mefenamic acid (7%); choice of drug was determined by efficacy and personal experience. Gastrointestinal side effects were most frequently encountered, although there was little consensus amongst respondents as to their management. The duplicate prescription study showed that 14% of patients (1607 individuals) received at least one NSAID prescription in the year of study. Ibuprofen (31%), naproxen (20%) and piroxicam (15%) were most frequently prescribed and up to 16% of the patients were co-prescribed a gastroprotective agent; ranitidine (75%) was the most commonly prescribed. Despite the introduction of newer NSAIDs, ibuprofen and naproxen are still the most commonly prescribed drugs. Furthermore, although gastrointestinal side effects are commonly encountered, there is some uncertainty about their management.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1990

Problems in the treatment of premenstrual syndrome.

Three categories of treatments for premenstrual syndrome (PMS) have been proposed: those designed to correct the cause of the disorder; those designed for symptom relief; and those aimed at eliminating the menstrual cycle. Many of these recommendations are based on poor research with loose definitions of the disorder and uncontrolled open trials. This paper reviews the literature on treatment methods with emphasis on recent random, placebo controlled, double-blind studies. The most effective current management of PMS is a conservative one including accurate diagnosis, stress control, sensible levels of diet and exercise and perhaps the use of alprazolam in the premenstrual period. Other approaches such as the use of mefenamic acid and evening oil of primrose remain unproven. Progesterone has been proven uneffective. Further research is required into the value of antidepressant medication.

Alprazolam↗

PubMedDate not supplied

Impact of a nationwide limited prescribing list: preliminary findings.

In the Republic of Ireland, the state pays the cost of medical care for around 40 percent of the population through the General Medical Services (GMS). Doctors treating GMS patients are entitled to prescribe from an approved list of drugs. In October 1982, many antacids, cough and cold preparations, antihistamines, and mild analgesics were removed from the GMS prescribing list. The visiting rate and the amount of prescribing fell in the GMS during 1982-83. Drug utilization within the GMS was measured using prescription numbers and in the total population using data obtained from pharmaceutical wholesalers expressed as defined daily doses. These results showed substantial changes in GMS prescribing in the utilization of mefenamic acid, carbocysteine, and H2-receptor antagonists associated with the introduction of the limited list, suggesting a switch to these agents from delisted preparations. The therapeutic and economic implications of this policy are discussed.

Drug Prescriptions↗

PubMed1992

Thyroxine binding to the apolipoproteins of high density lipoproteins HDL2 and HDL3.

Four preparations of high density lipoprotein HDL2, five of HDL3, and purified apolipoproteins apoA-I, apoA-IV, and apoE were photoaffinity labeled with [125I]T4 and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gels were also immunoblotted with antiserum against apoA-I, apoA-II, apoA-IV, apoE, or apo(a), and the immunostained membrane was then autoradiographed. In HDL2, the two major radioactive bands migrated near the origin of the resolving gel and at 28-31 kilodaltons (kDa). The first band, stained by anti-apo(a) and anti-apoB-100, accounted for 40-96% of the total radioactivity and was attributed to lipoprotein(a), which is isolated in the same density range as HDL2. The second band, stained by anti-apoA-I, accounted for 1-57% [41-95% after correction for contaminating lipoprotein(a)] of the [125I]T4 in the resolving gel. In HDL3, the major radioactive band was identified as apoA-I and contained 93-94% of the [125I]T4 in the resolving gel. Minor radioactive bands in both HDL2 and HDL3 were identified as apoA-II (17-18 kDa), apoA-II monomer (7-10 kDa), apoE (36-38 kDa), and apoAII-apoE heterodimer (46 kDa). In addition, HDL3 contained apoA-IV (43 kDa). Photoaffinity labeling of isolated apoA-IV and apoE showed that each protein interacted with [125I]T4. In both HDL2 and HDL3, photoaffinity labeling in the presence of unlabeled L-T4 (1-10 microM) showed inhibition, suggesting a Kd in the micromolar range. This inhibition varied among different apo bands of the same HDL2 or HDL3 preparation and among the same bands of different preparations. Labeling in the presence of heparin or other inhibitors of T4 binding to plasma proteins (furosemide, diclofenac, and mefenamic acid) showed that HDL2-associated apoA-I was more sensitive to inhibition than HDL3-associated apoA-I. In conclusion, 1) HDL2 and HDL3 carry T4 mainly through apoA-I and secondarily through apoA-II and apoE. The inter- and intrasubclass variations in T4 binding and sensitivity to inhibitors can be explained by the known heterogeneity of HDL particles and possible differences in conformation of the apo. The findings reported here, that apo other than apoA-I and apoB exhibit saturable binding of T4, suggest that thyroid hormone-lipoprotein interactions may have even wider physiological implications than previously appreciated.

Affinity Labels↗

PubMed1985

Interaction of furosemide with serum thyroxine-binding sites: in vivo and in vitro studies and comparison with other inhibitors.

The diuretic furosemide inhibits serum protein binding of T4 in equilibrium dialysis, dextran-charcoal, and competitive ligand binding separation systems and displaces [125I]T4 from isolated preparations of T4-binding globulin (TBG), prealbumin, and albumin. Equilibrium dialysis studies of undiluted normal serum showed that about 10 micrograms/ml furosemide increased the free T4 and free T3 fractions. Displacement occurred at lower drug concentrations in sera with subnormal albumin and TBG levels. Binding of [14C]furosemide to TBG was inhibited by unlabeled T4, suggesting that furosemide and T4 share a common binding site. A single oral dose of 500 mg furosemide given to five patients maintained on peritoneal dialysis increased the percentage of charcoal uptake of [125I]T4 (using serum diluted 1:10) from 4.1 +/- 1.0 (+/- SE) to 10.8 +/- 4.3 (P less than 0.01) after 2 h, while decreasing total T3 from 75 +/- 5 to 56 +/- 13 ng/dl (P less than 0.01) and total T4 from 6.7 +/- 0.9 to 4.8 +/- 0.8 micrograms/dl (P less than 0.01) after 5 h. Various ligands inhibited [125I]T4 binding to serum proteins in the following relative molar relationship: T4, 1; furosemide, 1.5 X 10(3); fenclofenac, 2 X 10(4); mefenamic acid. 2.5 X 10(4); diphenylhydantoin, 4 X 10[4); ethacrynic acid, 10(5); heparin 5 X 10(5); 2-hydroxybenzoylglycine, 10(6); and sodium salicylate, 1.5 X 10(6). These studies demonstrate that furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower total T4 and T3 levels. The drug is much more potent on a molar basis than other drug inhibitors of T4 binding, but at normal therapeutic concentrations, furosemide is unlikely to decrease serum T4 or T3. However, high doses, diminished renal clearance, hypoalbuminemia, and low TBG accentuate its T4- and T3-lowering effect. Hence, furosemide should be considered a possible cause of low thyroid hormone levels in patients with critical illness. The significance of this drug in reports of impaired hormone and drug binding in renal failure requires further assessment.

Binding, Competitive↗

PubMed1994

[Studies on pyridazinone derivatives. XVI. Analgesic-antiinflammatory activities of 3(2H)-pyridazinone derivatives].

In order to examine analgesic and antiinflammatory activities of the position isomers of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (1, emorfazone), an analgesic-antiinflammatory drug, 5-ethoxy-2-methyl-4-morpholino-3(2H)-pyridazinone (2), 6-ethoxy-2-methyl-4-morpholino-3(2H)-pyridazinone (3) and 6-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (4) were prepared. Since 4 showed the most strong activity among the compounds tested, various 6-alkoxy- or 6-allyloxy-2-alkyl- or 2-cyclohexyl- or 2-phenyl-5-substituted amino-3(2H)-pyridazinones (15, 16) were prepared and examined for their activities. As a result, 4 and 2-methyl-5-morpholino-6-n-propoxy- or 6-n-butoxy-3(2H)-pyridazinone (15b, c) and 6-ethoxy-2-ethyl-5-morpholino-3(2H)-pyridazinone (15 l) were revealed to be more potent in analgesic and antipyretic activities than commercial drugs (1, aminopyrine, mepirizole, tiaramide HCl, phenylbutazone, mefenamic acid). On the basis of the available data, the structure-activity relationship in a series of 6-alkoxy-2-alkyl-5-substituted amino-3(2H)-pyridazinones (15, 16) was also discussed.

Animals↗