[Pyrazolone and active phosphate].
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Analgesics↗
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AHR-5850: a potent anti-inflammatory compound.
AHR-5850 is a non-steroidal anti-inflammatory compound possessing antipyretic and analgesic properties. AHR-5850 was 16.4 and 22.8 times more potent than phenylbutazone in suppressing acute (Evans blue-carrageenan pleural effusion) and chronic (adjuvant-induced arthritis) inflammation, respectively. The analgesic activity of AHR 5850 was 43 times that of acetylsalicylic acid in the Randall-Selitto assay, and 156 and 56.3 times more potent than phenylbutazone in the acetylcholine-induced abdominal constriction in mice and in the bradykinin-induced nociceptive response in dogs, respectively. Single-dose studies showed that AHR-5850 produced less gastric irritation than acetylsalicylic acid when applied topically to the exposed gastric mucosa of cats or when administered orally to rats and dogs. Upon subchronic oral administration to rats, the therapeutic ratio of AHR-5850 was twice that of phenylbutazone. This was based on the ratio of its potency relative to phenylbutazone in producing intestinal lesions to its anti-inflammatory potency relative to phenylbutazone in the adjuvant-induced arthritis.
Acute Disease↗
Inhibitory effects of methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo[3,4-d]pyrimidine-2-carboxylate (AA-2379) on lysosomal enzyme and arachidonic acid release from rat polymorphonuclear leukocytes and its mode of action.
AA-2379 (methyl 7-butyl-4,5,6,7-tetrahydro-3-methylamino-4,6-dioxo-5-propyl- 2H-pyrazolo [3,4-d]pyrimidine-2-carboxylate) has antiinflammatory, analgesic, and antipyretic activities, and inhibits the type III allergic (Arthus) reaction. In the studies reported here, we investigated the effect of AA-2379 on rat polymorphonuclear leukocyte (PMN) functions to clarify the mechanism of the antiinflammatory and antiallergic actions of AA-2379. AA-2379 at 10(-4) M inhibited lysozomal enzyme release. AA-2379 inhibits formyl methionyl-leucyl-phenylalanine (fMLP)- and C5a-induced arachidonic acid release; their 50% inhibitory concentrations were 2.8 x 10(-5) and 3.8 x 10(-5) M, respectively. Because dibutyryl cAMP, a cAMP analogue, and 3-isobutyl-1-methylxanthine, a cAMP phosphodiesterase inhibitor, inhibited fMLP-induced arachidonic acid release, and AA-2379 inhibited cAMP phosphodiesterase and increased cAMP content in PMNs, it is likely that AA-2379 inhibited arachidonic acid release by increasing cAMP content in rat PMNs. Furthermore, from the studies of fMLP-induced arachidonic acid release in Ca free medium it is suggested that AA-2379 inhibits the process which depends on Ca concentration in the medium. These results suggest that the inhibitory effect of AA-2379 on inflammation and allergic reactions such as the Arthus reaction is partly exerted by inhibiting PMN functions such as arachidonic acid and lysozomal enzyme release.
3',5'-Cyclic-AMP Phosphodiesterases↗
The anti-inflammatory profile of dapsone in animal models of inflammation.
Dapsone has been shown to possess anti-inflammatory activity in a variety of animal models. It possesses oral anti-oedema activity especially pronounced in novel models of acute inflammation, viz. anti-IgG and reversed passive Arthus oedemas. However, it is not very active in the guinea pig u.v. erythema model. It is effective in chronic models such as adjuvant arthritis and the cotton pellet granuloma although multiple administration may also produce cyanosis. Antipyretic and analgesic effects for dapsone have been demonstrated and are similar to those produced by phenylbutazone. It inhibits zymosan-induced beta-glucuronidase release from cultured macrophages and also the activity of this enzyme. Dapsone does not appear to be ulcerogenic in the rat.
Animals↗
Attempted suicide in Hanoi, Vietnam.
BACKGROUND: Attempted suicide is a key predictor of suicide, which is among the dominant causes of young people's deaths worldwide. Very little is known about the characteristics of suicide attempters in Asia, especially in Vietnam. METHODS: Medical records of 509 patients (515 attempted-suicide events) admitted to Bach Mai General Hospital in Hanoi, Vietnam from 1 January 1999 to 30 April 2001 were analysed according to the criteria of the WHO Multicentre Study of Attempted Suicide. RESULTS: The suicide attempters' mean age was 28.3+/-12.9 years. Nearly half (48.7%) were aged 15-24. The female-to-male ratio of patients living in urban areas (2.1:1) was higher than in rural areas (1.2:1). In urban areas, students (32 %) and homeworkers (28%) and, in rural areas, farmers (56 %) and students (17%) were the salient occupational categories. Acute life stressors were the main causes (73.8%) of suicide attempts. Only in some 6% of cases had a psychiatric illness been diagnosed before the suicide attempts. As a means of attempting suicide, intoxication with analgesics and antipyretics (e. g. paracetamol) with low medical lethality scores was a frequent method among the urban patients, the majority of whom (81%) consequently stayed in hospital less than 24 h. Pesticide and rat poison, more commonly (57.2%) used by attempters in rural areas, had higher medical lethality scores and also necessitated more prolonged hospital treatment. CONCLUSIONS: Some suicide-preventive strategies used in the West for young people may be applicable in Vietnam. Reducing access to pesticides and rat poison is comparable to western efforts to make paracetamol or firearms less freely available. Skills in resolving family and other conflicts can be taught in schools according to WHO's suicide-prevention resources for teachers.
Adolescent↗
A pharmacokinetic study of paracetamol in Thai beta-thalassemia/HbE patients.
BACKGROUND: Thalassemia may alter the pharmacokinetics of several drugs in thalassemic patients. Paracetamol is a commonly used analgesic and antipyretic drug which is extensively metabolized in the liver via glucuronidation. The aim of this study was to compare the pharmacokinetics of paracetamol (PCM) and its metabolites [paracetamol glucuronide (PCM-G), paracetamol sulfate (PCM-S), and paracetamol cysteine (PCM-C)] in 16 patients with 16 normal subjects. METHOD: Following an overnight fast, a single dose of paracetamol (1,000 mg of Tylenol(R)) was given and blood samples were obtained at predose, 0.5, 1, 1.5, 2, 3, 4, 5, 7, and 9 h after dosing for determination of the plasma levels of PCM and its metabolites by high-performance liquid chromatography. RESULTS: There was no significant difference in maximum concentration of PCM between groups. However, a significantly shorter elimination half-life of PCM was observed in the thalassemic subjects (p<0.001). Total apparent clearance of PCM was significantly faster in thalassemic subjects (p<0.01) while the apparent volume of distribution of PCM did not change. The area under the concentration time curve (AUC(0->infinity)) of PCM-G and PCM-S increased in thalassemic subjects (p<0.05) whereas this parameter for PCM-C was slightly lower in the patients. The half-lives of PCM metabolites were significantly shorter (p<0.01) in thalassemic subjects. CONCLUSION: The results indicate that the elimination of PCM and its metabolites in thalassemic subjects is faster than that in normal subjects. Our pharmacokinetic data provide additional evidence that plasma PCM-G is higher in thalassemic patients with hyperbilirubinemia, which could be a casual relationship in regulating the UDP-glucuronosyltransferase expression.
Acetaminophen↗
Orally active antioxidative copper(II) aspirinate: synthesis, structure characterization, superoxide scavenging activity, and in vitro and in vivo antioxidative evaluations.
Ever since it was proposed that reactive oxygen species (ROS) are involved in the pathogeneses of various diseases, superoxide dismutase (SOD)-mimetic complexes have been intensively studied. We prepared copper(II) aspirinate [Cu2(asp)4] from Cu(II) and aspirin, which has been in use for many years as an antipyretic, an analgesic, and an anti-inflammatory agent. However, Cu2(asp)4 has been found to have additional activities, including anti-inflammatory, antiulcer, anti-ischemic/reperfusion agent, anticancer, antimutagenic, and antimicrobial activities. The activity of copper salicylate [Cu(sal)2] was also compared with that of Cu2(asp)4. The structure of the Cu2(asp)4 was determined using X-ray structure analysis. Its SOD-mimetic activity was determined using cytochrome c, electron spin resonance (ESR) spectroscopy, and ESR spin trap methods. The activity of Cu2(asp)4 was slightly greater than CuSO4 and copper acetate [Cu(ace)2] and slightly less than that of Cu(sal)2. The in vitro antioxidant activity, evaluated in human epithelial or transformed neoplastic keratinocyte cells, HaCaT, and normal dermal fibroblasts in terms of cell survival following ultraviolet B (UVB) irradiation, was significantly increased in the presence of Cu2(asp)4, Cu(sal)2, and CuSO4. Further, ROS generation following UVA irradiation in the skin of hairless mice following oral treatment with Cu2(asp)4 for three consecutive days was significantly suppressed compared to the vehicle- or Cu(ace)2-treated mice. On the basis of these results, Cu2(asp)4 was observed to be a potent antioxidative compound possessing antioxidative activity in biological systems. In conclusion, Cu2(asp)4 is a potent antioxidative agent that may be useful for future treatment of diseases resulting from ROS.
Administration, Oral↗
Adverse respiratory reactions to aspirin and nonsteroidal anti-inflammatory drugs.
Aspirin-exacerbated respiratory disease (AERD) is an adult-onset condition that manifests as asthma, rhinosinusitis/nasal polyps, and sensitivity to aspirin and other cyclooxygenase-1 (COX-1)-inhibitor nonsteroidal anti-inflammatory drugs (NSAIDs). There is no cross-sensitivity to highly selective COX-2 inhibitors. AERD is chronic and does not improve with avoidance of COX-1 inhibitors. The diagnosis of AERD is made through provocative challenge testing. Following a positive aspirin challenge, patients can be desensitized to aspirin and NSAIDs. The desensitized state can be maintained indefinitely with continued daily administration. After desensitization, there is an approximately 48-hour refractory period to adverse effects from aspirin. The pathogenesis of AERD remains unknown, but these patients have been shown to have multiple abnormalities in arachidonic acid metabolism and in cysteinyl leukotriene 1 receptors. AERD patients can take up to 650 mg of acetaminophen for analgesic or antipyretic relief. Patients can also use weak COX-1 inhibitors, such as sodium salicylate or choline magnesium trisalicylate. Treatment of AERD patients with antileukotriene medications has been helpful but not preferential when compared with non-AERD patients. An alternative treatment for many AERD patients is aspirin desensitization. This is particularly effective in reducing upper-airway mucosal congestion, nasal polyp formation, and systemic steroids.
Adult↗
Analgesics during pregnancy.
The thalidomide tragedy of the late 1950s clearly proved the need for caution, and questionable drug use should always be avoided. The teratogenic potential of a drug is related to dosage and time of administration. During blastogenesis, fetal death may occur; during embryogenesis, deformity may develop; and during the last trimester, functional anomalies or "covert embryopathy" may be seen. Finally, the benefit to risk ratio of every drug must be carefully weighed, and only those with proved safety to the feto-maternal unit should be prescribed. Aspirin may be administered to the pregnant woman as an anti-inflammatory agent but in the lowest therapeutic dosage. In the later stages of pregnancy, however, aspirin should be avoided since it may prolong labor, lead to greater blood loss during delivery, and increase the incidence of stillbirths. The pyrazolones, although not associated with teratogenic side effects, may lead to sometimes fatal agranulocytosis and, accordingly, are not recommended in pregnancy. Acetaminophen is the analgesic and antipyretic of choice during all phases of pregnancy.
Acetaminophen↗
In vitro effects of acetaminophen metabolites and analogs on the respiration of mouse liver mitochondria.
Acetaminophen, an analgesic and antipyretic, is toxic in overdose to liver and kidney. The effects on mitochondrial respiration of acetaminophen, its less toxic analog, 3-hydroxyacetanilide, and metabolites which arise from these compounds have been investigated. The parent compounds inhibited NADH-linked respiration reversibly, whereas the metabolites inhibit all mitochondrial respiration, apparently in the Complex III region of the respiratory chain. The quinone derivatives, 4-acetamido-o-benzoquinone and 2-acetamido-p-benzoquinone, are the best inhibitors, with the onset of inhibition dependent on active respiration, suggesting interaction of these compounds with oxidized components of the electron transport chain.
Acetaminophen↗
Mechanism of selective inhibition of human prostaglandin G/H synthase-1 and -2 in intact cells.
Selective inhibitors of prostaglandin synthase-2 (PGHS-2) possess potent anti-inflammatory, antipyretic, and analgesic properties but demonstrate reduced side-effects (e.g. gastrotoxicity) when compared with nonselective inhibitors of PGHS-1 and -2. We investigated the mechanism of the differential inhibition of human PGHS-1 (hPGHS-1) and -2 (hPGHS-2) in intact cells by nonsteroidal anti-inflammatory drugs (NSAIDs) and examined factors that contribute to the increased potency of PGHS inhibitors observed in intact cells versus cell-free systems. In intact Chinese hamster ovary (CHO) cell lines stably expressing the hPGHS isozymes, both PGHS isoforms exhibited the same affinity for arachidonic acid. Exogenous and endogenous arachidonic acid were used as substrates by both CHO [hPGHS-1] and CHO [hPGHS-2] cell lines. However, differences were observed in the ability of the hPGHS isoforms to utilize endogenous arachidonic acid released intracellularly following calcium ionophore stimulation or released by human cytosolic phospholipase A2 transiently expressed in the cells. Cell-based screening of PGHS inhibitors demonstrated that the selectivities and potencies of PGHS inhibitors determined using intact cells are affected by substrate concentration and differ from that determined in cell-free microsomal or purified enzyme preparations of PGHS isozymes. The mechanism of inhibition of PGHS isozymes by NSAIDs in intact cells involved difference in their time-dependent inhibition. Indomethacin displayed time-dependent inhibition of cellular hPGHS-1 and -2. In contrast, the selective PGHS-2 inhibitor NS-398 exhibited time-independent inhibition of hPGHS-1 but time-dependent inhibition of hPGHS-2 in intact cells. Reversible inhibition of cellular CHO [hPGHS-1] and CHO [hPGHS-2] was observed with the nonselective NSAIDs ibuprofen and indomethacin, whereas inhibition by the selective PGHS-2 inhibitor DuP-697 was reversible against hPGHS-1 but irreversible against hPGHS-2.
Animals↗
International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.
During the last years, several reports have indicated genotoxic effects of paracetamol, a widely used non-prescription analgesic and antipyretic drug. Thus, a careful evaluation of a possible genotoxic effect related to paracetamol use is warranted. Studies in vitro and in vivo indicate that the reactive metabolite of paracetamol can bind irreversibly to DNA and cause DNA strand breaks. Paracetamol inhibits both replicative DNA synthesis and DNA repair synthesis in vitro and in experimental animals. Paracetamol does not cause gene mutations, either in bacteria or in mammalian cells. On the other hand, a co-mutagenic effect of paracetamol has been reported. Furthermore, paracetamol increases the frequency of chromosomal damage in mammalian cell lines, isolated human lymphocytes and experimental animals. Two independent studies have shown an increase in chromosomal damage in lymphocytes of human volunteers after intake of therapeutic doses of paracetamol, whereas a third study was negative. Paracetamol-induced chromosomal damage appears to be caused by an inhibition of ribonucleotide reductase. This indicates that a threshold level for the paracetamol-induced chromosomal damage may exist. Genotoxic effects of paracetamol have, however, been demonstrated both in vitro and in vivo at or near therapeutic concentrations. The data indicate that the use of paracetamol may contribute to an increase in the total burden of genotoxic damage in man. Thus, there may be a need to evaluate the therapeutic benefit of paracetamol, taking into consideration not only its potential to induce acute and chronic organ damage, but also genotoxic effects.
Acetaminophen↗
Inhibition of lyso-PAF: acetyl-CoA acetyltransferase by salicylates and other compounds.
Diflunisal and benoxaprofen (20-100 microM) produced dose-dependent inhibitions of lyso-platelet activating factor: acetyl-CoA acetyltransferase in a lysate of rat pleural neutrophils. Salicylate and aspirin were inhibitory at concentrations of 1 mM and above. Nordihydroguaiaretic acid was a relatively potent inhibitor (I50 = 6 microM). Other compounds, including anti-inflammatory steroids, cyclooxygenase and 5-lipoxygenase inhibitors, appeared ineffective at relevant concentrations. Inhibitions by diflunisal and salicylate occurred at concentrations similar to expected plasma levels in humans at therapeutic doses. An inhibition of platelet-activating factor synthesis may contribute to the antiinflammatory, analgesic, or antipyretic actions of these compounds.
Acetyl-CoA C-Acetyltransferase↗
The mode of action of aspirin and similar compounds.
Aspirin-like drugs inhibit the biosynthesis of prostaglandins in all tissues and species so far studied. The concentrations necessary for this action are achieved after therapeutic dosage. The evidence is reviewed which establishes this biochemical action as the basic mode of therapeutic action of aspirin-like drugs as anti-inflammatory, analgesic, and antipyretic compounds. It may also account for the shared side effects, including the hypersensitivity to aspirin-like drugs shown by some allergic patients.
Anti-Inflammatory Agents↗
Immunomodulating and articular protecting activities of a new anti-rheumatic drug, TAK-603.
We investigated the pharmacological activities of a newly synthesized anti-rheumatic drug, TAK-603. (1) In vivo: In adjuvant arthritic (AA) rats, TAK-603 inhibited the hind paw swelling and the body weight loss. The minimum effective dose was 3.13 mg/kg/day (p.o.). Histological and radiographic studies showed that TAK-603 suppressed the development of synovial lesions and joint and bone destruction. TAK-603 was also effective in AA rats when administered for the first 7 days after the adjuvant injection. It suppressed type IV allergy (25 mg/kg/day, p.o.) but had no effect on type III allergy. It had little effect in acute inflammation, analgesic and antipyretic models. These data suggest that TAK-603 acts on the immune system, especially on cellular immunity. (2) In vitro: TAK-603 suppressed the mitogen-induced proliferation of mouse lymphocytes and the ConA-induced IFN-gamma and IL-2 production by rat lymphocytes at 10(-7) to 10(-5) M. It also significantly inhibited the IL-1 induced extracellular matrix reduction in rabbit chondrocytes. It had no effects on prostaglandin E2 (PGE2) production in rat peritoneal cells. These data show that TAK-603 has the ability to suppress the immune system and protect cartilage from destruction. TAK-603 is expected to be a promising drug for rheumatoid arthritis.
Adjuvants, Immunologic↗
The chronic hepatotoxic, tumor-promoting, and carcinogenic effects of acetaminophen in male B6C3F1 mice.
Acetaminophen (ACT), the most commonly used analgesic and antipyretic in the United States, was previously demonstrated to be a hepatocarcinogen in one mouse study but not in rats. In order to help elucidate the potential mechanisms of carcinogenesis by this nongenotoxic chemical and its relationship to hepatotoxicity, ACT was fed to groups of 60-120 male B6C3F1 mice at dietary concentrations of 5000 or 10,000 ppm from 6 weeks of age for periods of up to 70 weeks to study the hepatotoxic effects of ACT. To test for potential liver tumor-promoting effects of ACT, N-nitrosodiethylamine (DEN) was injected intraperitoneally at 40 mg/kg into additional groups of 30-60 male B6C3F1 mice at 4 weeks of age. Two weeks later some mice received ACT at dietary concentrations of 5000 or 10,000 ppm. Mice were sacrificed either at 24 weeks after DEN injection or after 22 or 70 weeks of ACT exposure. The livers were weighed and prepared for qualitative and quantitative histological evaluation of focal hepatocellular proliferative lesions (FHPL) including microscopic hyperplastic foci and neoplasms by automated image analysis. At 24 weeks the incidence and number of FHPL per square centimeter were significantly increased only in DEN-treated mice receiving 10,000 ppm ACT. Chronic hepatotoxicity was mild at this time. At 72 weeks ACT alone had no effect on the incidence or number of naturally occurring liver tumors despite severe chronic hepatotoxicity and suppression of body weight gain in mice receiving 10,000 ppm and only mild toxicity at 5000 ppm. There were histological findings suggesting that the chronic hepatotoxicity had, in part, a vascular pathogenesis. This study provided evidence against the hypothesis that chronic hepatotoxicity, in and of itself, results in an increased incidence of naturally occurring liver tumors in mice.
Acetaminophen↗
Enhancement effects of barbital on the teratogenicity of aminopyrine.
Aminopyrine and its compound with barbital have been used in humans as analgesics and antipyretics. A compound, pyrabital (2 molecules of aminopyrine and 1 molecule of barbital) given daily on Days 9, 10 and 11 of gestation produced significant yields of fetal deaths and malformations in ICR/Jcl mice. Most malformations induced were ruptured omphaloceles (eventration of the abdominal viscera), which were associated with malrotation of the intestine, cleft palates, and tail anomalies, finger and toe anomalies. Aminopyrine also induced significant yields of fetal deaths and malformations. However, the incidence of fetal deaths and malformations induced by a dose of pyrabital was significantly higher than that by an equivalent dose of aminopyrine which was contained in pyrabital. When aminopyrine (0.21 mg/g) and barbital (0.09 mg/g) were given in 2 separate injections to pregnant mice, teratogenicity was approximately equal to that by the equivalent dose of pyrabital (0.3 mg/g). Consequently, potent teratogenicity of pyrabital is not caused by the compound, but only by the coexistence of barbital and aminopyrine. Such enhancement effects of barbital may be due to the induction of enzymes responsible for transforming aminopyrine to teratogenic forms, because pretreatment with barbital and phenobarbital similarly enhanced embryotoxicity of aminopyrine.
Abnormalities, Drug-Induced↗
Acetaminophen stimulates the peroxidative metabolism of anthracyclines.
Acetaminophen, a common analgesic and antipyretic drug, is frequently administered to individuals undergoing anthracycline chemotherapy. Here, the effect of acetaminophen on the metabolism of daunorubicin and doxorubicin by isolated enzymes lactoperoxidase and myeloperoxidase, and by myeloperoxidase-containing human leukemia HL-60 cells was investigated using spectrophotometric and EPR techniques. We report that at pharmacological concentrations acetaminophen strongly stimulates oxidation of the anthracyclines by lactoperoxidase and myeloperoxidase systems, which results in irreversibly altered (colorless) products. The initial rate and efficacy of daunorubicin oxidation depends on pH. While at pH approximately 7 the oxidation is rapid and extensive, almost no oxidation occurs at pH approximately 5. In the absence of daunorubicin, oxidation of acetaminophen by lactoperoxidase/hydrogen peroxide is only weakly dependent on pH, however, at pH 7.4 it strongly depends on [daunorubicin]. Ascorbate and reduced glutathione strongly inhibited oxidation of anthracyclines by lactoperoxidase and HL-60 systems. Using EPR, a daunorubicin-derived radical was detected in a daunorubicin/acetaminophen/peroxidase/hydrogen peroxide system as a narrow single line (0.175 mT) with g = 2.0047. When daunorubicin was omitted, only an acetaminophen-melanin EPR signal was detected (g = 2.0043, line width approximately 0.5 mT). Similar results were obtained with doxorubicin. We suggest that the stimulation by acetaminophen is primarily due to its preferential oxidation by peroxidases to the corresponding phenoxyl radical, which subsequently reacts with daunorubicin (doxorubicin). Because biological properties of oxidatively transformed anthracyclines will certainly be different from those of their parent compounds, the possible acetaminophen-enhanced degradation of the anthracyclines in vivo is likely to interfere with anticancer and/or cardiotoxic activities of these agents.
Acetaminophen↗