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PubMed1983

Review of the comparative analgesic efficacy of salicylates, acetaminophen, and pyrazolones.

Use of salicylates, acetaminophen, and pyrazolones has become increasingly complex, extending from the treatment of acute, mild pain to chronic, moderately severe pain. The intensity, rather than the nature, of the pain determines the efficacy of aspirin. A clinical dose-response relationship has been established, and time-effect curves indicate that the total threshold-raising effect depends on dosage frequency. Contrary to popular belief, aspirin and acetaminophen appear to be equipotent and equianalgesic for the relief of most pain. The combination of aspirin (650 mg) plus codeine (30 mg) is only slightly more effective than aspirin alone. The same holds true for acetaminophen (600 mg) plus codeine (60 mg); the efficacy of the combination is only slightly better than that of acetaminophen alone.

Acetaminophen↗
PubMed1989

High-performance liquid chromatography of reducing carbohydrates as strongly ultraviolet-absorbing and electrochemically sensitive 1-phenyl-3-methyl-5-pyrazolone derivatives.

We found that 1-phenyl-3-methyl-5-pyrazolone reacts with reducing carbohydrates almost quantitatively to yield 2:1 compounds having no stereoisomers, which strongly absorb the uv light at 245 nm and are easily oxidizable on a glassy carbon electrode. Reverse-phase partition chromatography on a column of Capcell Pak C18 with uv or electrochemical detection allowed rapid analysis of aldoses and N-acetylhexosamines with the detection limit of 1 pmol or 100 fmol, respectively. This method proved especially useful for analysis of component monosaccharides of glycorproteins. It was also shown to be valid for separation of reducing oligosaccharides; maltodextrins with a degree of polymerization up to 19 were similarly derivatized and separated on this stationary phase.

Animals↗
PubMed1992

High-performance capillary electrophoresis of unsaturated oligosaccharides derived from glycosaminoglycans by digestion with chondroitinase ABC as 1-phenyl-3-methyl-5-pyrazolone derivatives.

This paper proposes a new method for simultaneous analysis of unsaturated disaccharides derived from glycosaminoglycans by enzymatic digestion with chondroitinase ABC, based on high-performance capillary electrophoresis (HPCE) of their 1-phenyl-3-methyl-5-pyrazolone derivatives. The O-sulphate group is stable in this derivatization, and this method allows reproducible microdetermination of glycosaminoglycans. This paper also demonstrates the applicability of this method to estimation of urinary chondroitin sulphates. Urinary creatinine as an inherent internal standard could also be estimated by HPCE, though in another mode of separation, i.e. ion-exchange electrokinetic chromatography.

Antipyrine↗
PubMed1978

Differential mutagenicity of reaction products of various pyrazolones with nitrite.

Four pyrazolones in frequent use, i.e. antipyrine (AP), aminopyrine (AMP), sulpyrine (SP) and isopropylantipyrine (IPA), were compared for their reactivity with nitrite and for the in vitro mutagenicity of their reaction products by Ames' reversion tests. In various acidic solutions at 37 degrees C, AP, AMP and SP were found to react easily with nitrite and yield various products including dimethylnitrosamine (DMNA) and 4-nitrosoantipyrine (4-NAP) in the cases of AMP and AP, respectively. When tested with Salmonella typhimurium TA100 and TA98 after lyophilization, the reaction products of AP (AP-N) were found to be mutagenic in both strains, while products of AMP and SP (AMP-N and SP-N) were mutagenic only in TA100. The presence of unknown ultimate mutagens, other than DMNA and 4-NAP, were evidenced in AP-N, AMP-N and SP-N. Incubation with S-9 mixture did not affect the mutagenicity of SP-N and decreased that of AP-N and AMP-N. In clear contrast to AP, AMP and SP, it was found that IPA remained essentially intact upon reaction with nitrite. No mutagenicity was detected with the reaction mixture (IPA-N) in either strain.

Aminopyrine↗
PubMed2001

Analysis of sialo-N-glycans in glycoproteins as 1-phenyl-3-methyl-5-pyrazolone derivatives by capillary electrophoresis.

A method for the analysis of the sialo-N-glycans in glycoproteins was established by the electrokinetic chromatography mode of capillary electrophoresis (CE) in sodium dodecyl sulfate (SDS) micelles as 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatives, using sialo-N-glycans in fetuin as a model. Six major and some minor peaks were observed for the N-glycans in fetuin, which were well separated from each other using 50 mM phosphate buffer, pH 6.0, containing SDS to a concentration of 30 mM in an uncoated fused-silica capillary, and these peaks were assigned to sialo-N-glycans having either of the biantennary or beta1-3/beta1-4 linked galactose-containing complex type triantennary N-glycans as the basic structures, by an indirect method based on the assignment of the peaks in high-performance liquid chromatography separated in parallel with CE and peak collation between these two separation methods. The attaching position of the sialic acid residue was determined using the linkage preference of neuraminidase isozymes. The established system is considered to be useful for routine analysis of microheterogeneity of the carbohydrate moiety of this model glycoprotein from the following reasons: (1) the derivatization with PMP proceeds quantitatively under mild conditions without causing release of the sialic acid residue, (2) the derivatives can be sensitively detected by UV absorption, (3) the procedure is simple, rapid and reproducible. Preliminary results of N-glycan analysis for several other glycoproteins under these conditions are also presented.

Antipyrine↗
PubMed2001

Capillary electrophoretic analysis of carbohydrates derivatized by in-capillary condensation with 1-phenyl-3-methyl-5-pyrazolone.

Our previous papers on capillary electrophoresis (CE) have shown that samples can be derivatized in a capillary and the derivatives can be analyzed immediately after derivatization, provided that the derivatization reaction is so rapid as to complete in seconds. The present paper presents extended application of in-capillary derivatization to a much slower reaction such as the condensation of reducing carbohydrates with 1-phenyl-3-methyl-5-pyrazolone (PMP) which requires 30 min at 70 degrees C in pre-column derivatization by manual operation. It was necessary to first drive the introduced plugs of sample and reagent solutions to put them together at the entrance of the heated portion of a capillary, then to allow the superimposed plugs to react for a relevant period. We showed how to determine the introduction times of the sample and the reagent solutions as well as intermediate running buffer, the voltages to be applied for plug driving and product analysis, and the duration of voltage application, all of which are important for effective in-capillary derivatization. An example of the analysis of maltooligosaccharides by this technique is presented. It was shown that maltooligosaccharides were quantitatively derivatized with PMP in 35 min at 57 degrees C, and the derivatives could be analyzed in ca. 15 min by CE immediately after derivatization. Separation was satisfactory in 200 mM borate buffer, pH 8.2 containing sodium dodecyl sulfate to a concentration of 200 mM. Although the theoretical plate number, and accordingly the resolution, were significantly lower than the corresponding values in pre-capillary derivatization, reasonable reproducibility was ensured for both migration time (RSD 3.5% on average) and peak area (RSD less than 3%) under the optimized conditions. It is notable that sample amount could be lowered to the 10 fmol level, in contrast to the 10 pmol level in pre-capillary derivatization. In addition, since the technique employed here (the modified at-inlet technique of in-capillary derivatization) is easily automated, the established system will be highly beneficial for routine analysis of carbohydrates. Analysis by this technique was also shown to be useful for kinetic study of the derivatization reaction.

Antipyrine↗
PubMed1999

3-Pyrazolone analogues of the 3-isoxazolol metabotropic excitatory amino acid receptor agonist homo-AMPA. Synthesis and pharmacological testing.

We have previously shown that the higher homologue of (S)-glutamic acid [(S)-Glu], (S)-alpha-aminoadipic acid [(S)-alpha-AA] is selectively recognized by the mGlu(2) and mGlu(6) subtypes of the family of metabotropic glutamic acid (mGlu) receptors. Furthermore, a number of analogues of (S)-alpha-AA, in which the terminal carboxyl group has been replaced by various bioisosteric groups, such as phosphonic acid or 3-isoxazolol groups, have been shown to interact selectively with different subtypes of mGlu receptors. In this paper we report the synthesis of the 3-pyrazolone bioisosteres of alpha-AA, compounds (RS)-2-amino-4-(1,2-dihydro-5-methyl-3-oxo-3H-pyrazol-4-yl)butyric acid (1) and (RS)-2-amino-4-(1,2-dihydro-1,5-dimethyl-3-oxo-3H-pyrazol-4-yl)butyric acid (2). At a number of steps in the reaction sequences used, the reactions took unexpected courses and provided products which could not be transformed into the target compounds, and attempts to synthesize the 2,5-dimethyl isomer of 2, compound 3, failed. An X-ray crystallographic analysis of the intermediate 1,2-dihydro-4-(2-hydroxyethyl)-2,5-dimethyl-3H-pyrazol-3-one (5b) confirmed the expected regioselectivity of the reaction between methylhydrazine and alpha-acetylbutyrolactone (4). Neither 1 nor 2 showed significant effects at the different types of ionotropic glutamic acid receptors or at mGlu(1a) (group I), mGlu(2) (group II), and mGlu(4a) and mGlu(6) (group III) receptors, representing the three indicated groups of mGlu receptors.

Journal Article↗
PubMed1996

New potent antihyperglycemic agents in db/db mice: synthesis and structure-activity relationship studies of (4-substituted benzyl) (trifluoromethyl)pyrazoles and -pyrazolones.

The synthesis, structure-activity relationship (SAR) studies, and antidiabetic characterization of 1,2-dihydro-4-[[4-(methylthio)phenyl]methyl]-5-(trifluoromethyl)-3H- pyrazol-3-one (as the hydroxy tautomer; WAY-123783, 4) are described. Substitution of 4-methylthio, methylsulfinyl, or ethyl to a benzyl group at C4, in combination with trifluoromethyl at C5 of pyrazol-3-one, generated potent antihyperglycemic agents in obese, diabetic db/db mice (16-30% reduction in plasma glucose at 2 mg/kg). The antihyperglycemic effect was associated with a robust glucosuria (> 8 g/dL) observed in nondiabetic mice. Chemical trapping of four of the seven possible tautomeric forms of the heterocycle by mono- and dialkylation at the acidic hydrogens provided several additional potent analogs (39-43% reduction at 5 mg/kg) of the lead 4 as well as a dialkylated pair of regioisomers that showed separation of the associated glucosuric effect produced by all of the active analogs in normal mice. Further pharmacological characterization of the lead WAY-123783 (ED50 = 9.85 mg/kg, po in db/db mice), in oral and subcutaneous glucose tolerance tests, indicated that unlike the renal and intestinal glucose absorption inhibitor phlorizin, pyrazolone 4 does not effectively block intestinal glucose absorption. SAR and additional pharmacological data reported herein suggest that WAY-123783 represents a new class of potent antihyperglycemic agents which correct hyperglycemia by selective inhibition of renal tubular glucose reabsorption.

Absorption↗
PubMed1980

Chronic toxicity of pyrazolones: the problem of nitrosation.

1 During 6-month oral toxicity studies of dipyrone in rats and dogs, there was an increase in the number of reticulocytes and Heinz bodies at the highest dose, and a slight haemosiderosis was induced. 2 Similar results were obtained after parenteral administration (intravenously and subcutaneously). 3 These studies fail to contribute to the knowledge of the mechanism of allergic reactions in man. 4 In vitro studies in conditions imitating the physiological environment, show to what extent nitrosation of dipyrone takes place. 5 Subsequent toxicological investigations with the two reaction compounds, or the nitrosation product itself, are powerful instruments to show whether the nitrosamine or nitrosamide formed is dangerous. 6 In the case of pyrazolones, only aminopyrine forms a carcinogenic nitrosamine.

Animals↗
PubMed1984

Acute hemolytic anemia induced by a pyrazolonic drug in a child with glucose-6-phosphate dehydrogenase deficiency.

In a 36-month-old child a severe hemolytic anemia occurred after the administration of a pyrazolonic drug. Erythrocyte glucose-6-phosphate dehydrogenase activity was absent in the patient. Intermediate enzymatic levels were demonstrated in the mother and in the maternal grand-mother with a corresponding erythrocyte mosaicism at the methemoglobin elution test. Some cells showed Heinz bodies and peculiar changes in the morphology in the initial phase of the crisis. There is no mention in the literature of a hemolytic action of this drug.

Aminopyrine↗
PubMed1980

Receptor-directed inhibition of chemotactic factor-induced neutrophil hyperactivity by pyrazolon derivatives. Definition of a chemotactic peptide antagonist.

The two pyrazolon derivatives, phenylbutazone and sulfinpyrazone, selectively inhibit chemotactic peptide-induced effects on neutrophils. As they antagonize the induction of acute neutropenia in vivo and of cellular hyperadhesiveness, lysosomal enzyme release, hexose monophosphate shunt activity, and superoxide production in vitro, these effects occur with a specificity not shared with other prostaglandin biosynthesis inhibition by these drugs resembles the competitive type of antagonism and occurs at concentrations attainable in vivo under clinical conditions. The locomotory machinery, the direction-finding mechanisms, and the basic metabolic machinery of the cell are unaffected. These drugs interfere with specific binding of the formylpeptide to its receptor on neutrophils.

Agranulocytosis↗
PubMed1988

[UV-spectrophotometry in drug control. 41. Drug substances with chromophores and auxochromes in monocyclic compounds (pyrazolone, pyrazolidine, pyridazine, pyrimidine and pyrazine) and bicyclic compounds (benzoxazole, imidazole, benzthiazole and indene)].

The results of a systematic examination of the spectra of 15 drug substances with chromophores and auxochromes in monocyclic (pyrazolone, pyrazolidin, pyridazine, pyrimidine and pyrazine) and bicyclic compounds (benzoxazol, imidazole, benzthiazole and indene) in the UV and visible range were evaluated. Influences of substituents and solvents on shifts of the E, K, B and R bands were discussed.

Benzothiazoles↗
PubMed1986

Pyrazolone drugs in outpatient pain treatment.

Even today, pyrazolone drugs still play an essential role in outpatient pain treatment. Their applications and limitations are discussed from the point of view of the general practitioner treating outpatients.

Acetaminophen↗
PubMed1985

Biphasic effect of pyrazolone derivatives on drug-metabolizing enzyme in rat liver.

The pyrazolone derivatives aminophenazone, phenazone, and propyphenazone known as inducers are capable of inhibiting initially monooxygenase-dependent biotransformation steps. In the dose of 1.5 mmol X kg-1 they prolong the hexobarbital narcosis (max. 1 h after administration) due to a reduced hexobarbital metabolism in the liver. An influence on the N-demethylation (aminophenazone as substrate) ist not substantial. The catalytic binding site of cytochrome P-450 is not influenced. In aminophenazone- and phenazone-treated animals the inhibitory phase is followed by a stimulatory one. After the repeated administration the inhibitory phase continues up to the third measured 1 h after administration. The initially inhibitory effect of inducers seems to be caused by a mutual interference of a complete or partial binding to various forms of cytochrome P-450. However, effects on the CNS cannot be excluded.

Aminopyrine↗
PubMed1978

[Biochemical study of nucleic acids of placenta and fetal liver and caryometric of trophoblastic giant cells and fetal hepatocytes of Rattus norvegicus albinus, during action of sodium 1-phenyl-2, 3-dimethyl-5-pyrazolon-methane sulfonate (Dipyrone) (author's transl)].

Female pregnant rats of 2BAW strain were divided in 2 groups: the 1st, received 50 mg/kg corporal weight of sodium 1-phenyl-2,3-dimethyl-5-pyrazolon-4-methylamino-methane sulfonate (Dipyrone), single dose daily, by i.p. injections, from 16th to 20th day of pregnancy; the 2nd, received 0,5 ml of distilled water, single dose daily, by i.p. injections, during the same period. All the animals were sacrificed 2 hours after the last injection. The biochemical results of nucleic acids in the placentas and fetal livers, and the caryometric data of trophoblastic giant cells and fetal hepatocytes, demonstrated that: 1. When compared the 2 groups, as much the nucleic acids levels (RNA and DNA) of placentas as the nuclear size of trophoblastic giant cells, do not presented statistical differences; 2. The biochemical levels of nucleic acids (RNA and DNA) of fetal livers decreased, while the nuclear size of hepatocytes increased in the experimental group, with reference to control group.

Aminopyrine↗