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The work presented in this paper aims toward the synthesis of aryl thiourea derivatives 4a-l of pyrazole based nonsteroidal anti-inflammatory drug named 4-aminophenazone, as potential inhibitors of intestinal alkaline phosphatase enzyme. The screening of synthesized target compounds 4a-l for unraveling the anti-inflammatory potential against calf intestinal alkaline phosphatase gives rise to lead member 4c possessing IC 50 value 0.420 ± 0.012 µM, many folds better than reference standard used (KH 2 PO 4 IC 50  = 2.8 ± 0.06 µM and L-phenylalanine IC 50  = 100 ± 3.1 µM). SAR for unfolding the active site binding pocket interaction along with the mode of enzyme inhibition based on kinetic studies is carried out which showed non-competitive binding mode. The enzyme inhibition studies were further supplemented by molecular dynamic simulations for predicting the protein behavior against active inhibitors 4c and 4g during docking analysis. The preliminary toxicity of the synthesized compounds was determined by using brine shrimp assay. This work also includes detailed biochemical analysis along with RO5 parameters for all the newly synthesized drug derivatives 4a-l., (© 2020. Springer Nature Switzerland AG.)

Coordination-driven self-assembly of organometallic η6-arene ruthenium(ii) supramolecular architectures (MA1-MA4) was carried out by employing dinuclear ruthenium acceptors [Ru2(μ-η4-C2O4)(CH3OH)2(η6-p-cymene)2](CF3SO3)2 (Rua), [Ru2(μ-η4-C6H2O4)(CH3OH)2(η6-p-cymene)2](CF3SO3)2 (Rub), [Ru2(dhnq)(H2O)2(η6-p-cymene)2](CF3SO3)2 (Ruc) and [Ru2(dhtq)(H2O)2(η6-p-cymene)2](CF3SO3)2 (Rud) separately with a new tetratopic donor (TD) in methanol at room temperature [TD = N,N,N',N'-tetra(pyridin-4-yl)-[1,1'-biphenyl]-4,4'-diamine]. All the coordination architectures were characterized by using spectroscopic techniques. The potency of these self-assembled architectures against human cervical cancer HeLa and human lung adenocarcinoma A549 cell lines is explored in vitro using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), annexin V-FITC/PI and 2',7'-dichlorofluorescein-diacetate assays.

Background/aim: The perioperative phase is supposed to be a period with high vulnerability for cancer dissemination. Acetaminophen and metamizole are common analgesics administered during this phase. We investigated the effect of acetaminophen, metamizole and 4-methylaminoantipyrine (MAA) on proliferation and apoptosis of colon carcinoma cell lines (SW 480 and HT 29)., Materials and Methods: Proliferation was detected by cell proliferation ELISA BrdU, and apoptosis by Annexin V staining. Cytochrome c and caspase 3, 8 and 9 expression levels were detected by western blot., Results: Acetaminophen, metamizole or MAA caused slight changes in proliferation. Acetaminophen, metamizole or the combination increased apoptosis in both cell lines. All agents decreased caspase 3 and 8 expression in SW480. Acetaminophen decreased caspase 9 expression in both cell lines., Conclusion: In clinically relevant doses, acetaminophen and/or metamizole induce apoptosis in both colon cancer cell lines. Both mitochondrial and death receptor pathways might be involved in acetaminophen-induced apoptosis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Water reuse for aquifer recharge could be an important route for the introduction of emerging organic contaminants (EOCs) into the environment. The installation of a Horizontal Permeable Reactive Barrier (H-PRB) could constitute a tertiary treatment process to remove EOCs from treated domestic wastewater prior to recharge activities. The sorption-desorption behaviour of six neutral EOCs present in treated domestic wastewater (acetaminophen, caffeine, carbamazepine, cotinine, 4-acetamidoantipyrine (4-AAA) and 4-formylaminoantipyrine (4-FAA)) has been evaluated. Clinoptilolite and palygorskite have been studied as sorbents to be installed in the H-PRB. Batch tests were carried out using an EOC initial concentration ranging from 5 to 100 μg L -1 . Apart from acetaminophen and caffeine, both materials showed a limited sorption capacity of neutral EOCs (K d  = 0.63-5.42 L kg -1 ). In general, the experimental results show that EOCs exhibit a higher sorption affinity for clinoptilolite than for palygorskite. With the exception of carbamazepine, the sorption of the compounds occurs mainly by interactions with mineral surfaces as indicated by the comparison of the partition coefficients into organic matter and into mineral surfaces. According to the molecular geometry of the compounds and the sorption sequences observed, it appears that the dimensions of the organic molecules play a key role in the sorption process. All the studied EOCs exhibit irreversible sorption and sorption-desorption hysteresis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of in vitro diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the in vitro diagnosis of allergic reactions to metamizole.

In order to evaluate the pharmacokinetics of metamizol in the presence of morphine in arthritic rats, after subcutaneous administration of the drugs, an easy, rapid, sensitive and selective analytical method was proposed and validated. The four main metamizol metabolites (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) were extracted from plasma samples (50-100μl) by a single solid-phase extraction method prior to reverse-phase high performance liquid chromatography with diode-array detection. Standard calibration graphs for all metabolites were linear within a range of 1-100μg/ml (r(2)≥0.99). The intra-day coefficients of variation (CV) were in the range of 1.3-8.4% and the inter-day CV ranged from 1.5 to 8.4%. The intra-day assay accuracy was in the range of 0.6-9.6% and the inter-day assay accuracy ranged from 0.9 to 7.5% of relative error. The lower limit of quantification was 1μg/ml for all metabolites using a plasma sample of 100μl. Plasma samples were stable at least for 4 weeks at -20°C. This method was found to be suitable for studying metamizol metabolites pharmacokinetics in arthritic rats, after simultaneous administration of metamizol and morphine, in single dose., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The structurally characterized lower rim 1,3-di{4-antipyrine}amide conjugate of calix[4]arene (L) exhibits high selectivity toward Hg(2+) among other biologically important metal ions, viz., Na(+), K(+), Ca(2+), Mg(2+), Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), Pb(2+), and Ag(+) as studied by fluorescence, absorption, and ESI MS. L acts as a sensor for Hg(2+) by switch-off fluorescence and exhibits a lowest detectable concentration of 1.87 ± 0.1 ppm. The complex formed between L and Hg(2+) is found to be 1:1 on the basis of absorption and fluorescence titrations and was confirmed by ESI MS. The coordination features of the mercury complex of L were derived on the basis of DFT computations and found that the Hg(2+) is bound through an N(2)O(2) extending from both the arms to result in a distorted octahedral geometry with two vacant sites. The nanostructural features such as shape and size obtained using AFM and TEM distinguishes L from its Hg(2+) complex and were different from those of the simple mercuric perchlorate. L is also suited to sense pyrimidine bases by fluorescence quenching with a minimum detection limit of 1.15 ± 0.1 ppm in the case of cytosine. The nature of interaction of pyrimidine bases with L has been further studied by DFT computational calculations and found to have interactions through a hydrogen bonding and NH-π interaction between the host and the guest.

Background: We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass., Methods: Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined., Results: Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group., Conclusion: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

The photochemical behaviour of three relevant metabolites of the analgesic and antipyretic drug dipyrone, 4-methylaminoantipyrine (4-MAA), 4-formylaminoantipyrine (4-FAA) and 4-acetylaminoantipyrine (4-AAA), was evaluated under simulated solar irradiation (Suntest system). For 4-MAA, different aqueous solutions (synthetic seawater, freshwater and Milli-Q water) as well as different operational conditions were compared. According to the experimental results, 4-MAA resulted as being an easily degraded molecule by direct photolysis, with half-life times (t1/2) ranging from 0.12 to 0.58 h, depending on the irradiation conditions. Faster degradation was observed in synthetic waters, suggesting that the photolysis was influenced by the salt composition of the waters. However, no effect on the degradation rate was observed by the presence of natural photosensitizers (dissolved organic matter, nitrate ions). 4-FAA and 4-AAA showed slower photodegradation kinetics, with t1/2 of 24 and 28 h, respectively. A study of photoproduct identification was carried out by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-time-of-flight mass spectrometry (LC-TOF-MS) (ESI positive mode), which allowed us to propose a tentative photodegradation pathway for 4-MAA and the identification of persistent by-products in all the cases. Finally, the application of an acute toxicity test (Daphnia magna) showed an increase in toxicity during the photolytic process, a consequence of the formation of toxic photoproducts.

The synthesis of Cu(II) complexes derived from Schiff base ligands obtained by the condensation of 2-hydroxybenzaldehyde or terephtalic aldehyde with 4-amino-antipyrine (4-amino-2,3-dimethyl-1-phenyl-3-pyrazolin-5-one) is presented. The newly prepared compounds were characterized by( 1)H-NMR, UV-VIS, IR and ESR spectroscopy. The determination of the antimicrobial activity of the ligands and of the complexes was carried out on samples of Escherichia coli, Klebsiella pneumoniae, Acinetobacter boumanii, Pseudomonas aeruginosa, Staphylococcus aureus and Candida sp. The qualitative and quantitative antimicrobial activity test results proved that all the prepared complexes are very active, especially against samples of Ps. aeruginosa, A. Boumanii, E. coli and S. aureus.

A series of 13 new (S,Z)-2-aminopurine methylenecyclopropane analogues was synthesized, and their antiviral activity was investigated. The nucleophilic displacement of chlorine of 2-amino-6-chloropurine derivative 5 with allyl-, propargyl-, cyclopropylmethyl-, isopropyl-, benzyl-, cyclohexyl-, and 2-hydroxyethylamine gave N(6)-alkyl compounds 2a, 2b, 2c, 2d, 2e,2f, and 2g. A similar reaction of 5 with allyl, cyclopropylmethyl, propyl, or pentyl alcohol catalyzed by K(2)CO(3) afforded O(6)-alkyl analogues 3a, 3c, 3h and 3i. Propane- and pentanethiol furnished S(6)-alkyl compounds 4h and 4i. The N(6)-alkyl derivatives 2a, 2b, O(6) analogues 3a, 3c, 3h, 3i, and S(6) compounds 4h, 4i which were highly effective in all CMV assays and exhibited the lowest cytotoxicity in proliferating HFF cells appear to be good candidates for in vivo assays. Activity of new analogues against HSV-1 or HSV-2 was restricted to BSC-1 and Vero cultures. Compounds 2c, 2b, 3a and 3h were effective against EBV in one of two assays (Daudi or H-1). Analogues 3a and 4i were the most active anti-VZV agents whereas compounds 3h, 3i, and 4h inhibited the replication of HBV in a micromolar concentration range.

We report about a 66-year-old-male patient who was hospitalized with generalized exanthema and increase of liver enzymes after intake of metamizole because of flue-like symptoms. Despite initial high dose steroids, disease activity persisted, and therefore liver biopsy was performed. Histology revealed acute hepatitis with perivenular non-bridging confluent necrosis and granuloma formation consistent with drug-induced hepatitis. A metamizole-induced process was suspected. Lymphocyte transformation test confirmed the sensitization of the patient's lymphocytes to metamizole and three of its four metabolites (4-methylaminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine). Other drugs could be excluded with high probability. In the follow-up, the general condition of the patient improved, and liver enzymes decreased under treatment with steroids. Thus, we conclude that in this patient metamizole has induced an allergic reaction not only of the skin but also of the liver. To our knowledge, an allergic cholestatic hepatitis caused by metamizole has been reported only once in literature.

This paper describes the synthesis of new cyclic imides obtained by reaction with aminophenazone (CAS 58-15-1, 4-aminoantipyrine) and different anhydrides with further cyclization with acetic acid under reflux. Their structures were confirmed by spectral data (IR and NMR) and elemental analysis. The analgesic activity of the synthesized compounds was investigated initially with the writhing test in mice and the most promising compound, a 3,4-dichloromaleimide derivative (3), was analyzed using other models of nociception. The results indicated that compound 3 exerts potent analgesic activity in mice, being more active than some reference drugs. The analgesia caused by this compound was not reversed by naloxone in the writhing test. In the hotplate test, compound 3 did not increase the latency period of pain induced by thermal stimuli, confirming that it does not interact with opioid systems.

Objective: We previously found that, compared with healthy subjects. asymptomatic hepatitis-B virus (HBV) carriers displaying slow acetylator phenotype demonstrate a significant prolongation of the elimination half-life of 4-methylaminoantipyrine (MAA) and a decrease in the clearance of formation of 4-aminoantipyrine (AA) and 4-formylaminoantipyrine (FAA). However, the formation of 4-acetylaminoantipyrine (AAA) was unchanged. The present study was designed to examine the effect of the asymptomatic HBV carrier state on the metabolism of dipyrone. as a model drug, in rapid acetylators., Methods: The plasma and urine concentrations of the metabolites of dipyrone were measured in eight asymptomatic HBV carriers and eight healthy subjects who had normal liver function tests, all displaying the rapid acetylation phenotype and genotype, after the administration of a 1.0-g oral dose of dipyrone., Results: The following pharmacokinetic parameters were evaluated: peak plasma concentration, time to peak plasma concentration, elimination rate constant, area under the plasma concentration-time curve (0-->infinity), amount excreted (0-->infinity), renal and non-renal clearances for MAA and the clearances of formation for AA, FAA and AAA. No significant differences were found between the two subject groups., Conclusion: The effect of hepatic viral carrier state on drug metabolism may vary according to metabolic pathways and genetic polymorphism.

Objective: Dipyrone is a veteran analgesic and antipyretic drug. After oral administration it is rapidly converted by hydrolysis to 4-methylaminoantipyrine (MAA), which is further metabolized to 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-acetylaminoantipyrine (AAA). It is still debated whether the site of dipyrone action is in the central nervous system or in the periphery. The purpose of this study was to assess whether dipyrone metabolites cross the blood-brain barrier (BBB) when administered systemically., Methods: Twenty-eight patients undergoing diagnostic lumbar puncture (LP) were randomly assigned to receive two 0.5-g dipyrone tablets either 30 min, 1, 1.5, 2, 4, 6, 8 h or 12 h before the lumbar tap. A 5-ml blood sample was drawn concomitantly., Results: All four metabolites were found in the cerebrospinal fluid (CSF). Their appearance in the CSF lagged but followed that found in the plasma. Mean CSF/plasma ratios were 0.40 (for samples taken between 0.5-2 h) and 0.83 (for samples taken between 4-12 h) for MAA, 0.62 for AA, 0.55 for FAA and 0.40 for AAA (for all samples). Significant correlation was found between plasma and CSF concentrations for MAA, AA, FAA and AAA., Conclusion: The concentration-time course of dipyrone metabolite CSF concentrations are in agreement with that of their plasma concentrations and the analgesic effect of dipyrone.

A rapid solid-phase extraction (SPE) procedure was developed for the quantitative isolation of three important antipyrine (dipyrone) metabolites from human plasma: 4-formylaminoantipyrine (FAA), 4-aminoantipyrine (AA) and 4-methylaminoantipyrine (MAA). Separation and quantitation were performed using micellar liquid chromatography (MLC) with a 0.1 mol l-1 sodium dodecyl sulfate (SDS)-2.5% pentanol mobile phase and UV detection at 262 nm. The metabolites were well resolved in less than 5 min using an octadecyl silica-bonded stationary phase. The extraction procedure involved passing 0.3 ml of plasma sample through a disposable SPE cartridge packed with C18 bonded porous silica. The adsorbed metabolites were removed from the cartridge with methanol. The eluent was evaporated to dryness and the residue was reconstituted with mobile phase and injected into the chromatographic system. The cartridge blank interferent peaks, the effects on reproducibility of sample loading in the cartridge and volume needed for desorption of metabolites were evaluated. The concentration of metabolites ranged between 2.4 and 4 micrograms ml-1. The present procedure yields recoveries for the three metabolites ranging from 93 to 100%. The relative standard deviation (Sr) ranged between 1.2 and 13.6%. Limits of detection (LODs) were 10.5, 11.5 and 17.0 ng ml-1 for FAA, AA and MAA, respectively.

Plasma and saliva pharmacokinetics of dipyrone (CAS 5907-38-0) metabolites, 4-methylaminoantipyrine (MAA), 4-aminoantipyrine (AA), 4-formylaminoantipyrine (FAA) and 4-acetylaminoantipyrine (AAA), has been studied in 10 healthy volunteers, after oral administration of 1.0 g dipyrone, MAA, AA, FAA and AAA saliva concentrations correlated significantly with the respective plasma concentrations (r = 0.81, r = 0.62, r = 0.83 and r = 0.91, p < 0.001). MAA and AA concentrations in saliva were lower than in plasma while the FAA and AAA saliva concentrations were similar to the respective plasma concentrations. The saliva/plasma concentration ratios were highly dependent on sampling time. The elimination half-life of the final metabolites FAA and AAA can be equally evaluated from plasma and saliva data. For MAA, plasma and saliva t1/2 values were significantly correlated despite a substantial intra-subject difference. No correlation was found for AA plasma and saliva derived pharmacokinetic parameters. Similar to the plasma AAA/AA ratio, the saliva AAA/AA ratio in spot sample 6 h following oral dose might be proven to be a reliable discriminatory index for acetylation phenotyping.

The formation and urinary excretion of the dipyrone metabolites, methylaminoantipyrine (MAA), aminoantipyrine (AA), formylaminoantipyrine (FAA) and acetylaminoantipyrine (AAA) were determined following administration of a single oral 1.0 g dose of dipyrone to 12 healthy volunteers. The AAA/AA plasma ratio showed that 3 subjects were slow and 9 were rapid acetylators. Pharmacokinetic parameters were determined separately for each group. A good correlation was found between the plasma and urine AAA/AA ratios. The renal clearance of the four metabolites was similar for both phenotypes. A significant difference in the rate of formation of dipyrone metabolites was found for AA, 0.25 (slow) vs 0.1 ml.min-1.kg-1 (rapid), and for AAA 0.75 (slow) vs 7.53 ml.min-1.kg-1 (rapid). There were comparable differences between slow and rapid acetylators in the AUC and the urinary excretion extrapolated to infinity for AA and AAA. The present results show that the kinetics of dipyrone metabolites in plasma and urine can provide a useful measure of the activity of the enzymes involved in their production.

Peroxidatic oxidation of N-alkyl and sulfalkyl-substituted 4-aminopyrazolones (amidopyrine and metapyrine) is mediated by oxyperoxidase, whereas the oxidation of non-substituted 4-aminoantipyrine occurs via the classical peroxidase cycle, without oxyperoxidase accumulation. The free radicals formed at the first step of the oxidation cycle show a tendency for disproportionation and exchange. During catalysis in heavy water the oxidation of substituted aminopyrazolones is accelerated by plant peroxidase. This effect is due to the activation of the second oxidative state of the enzyme. Complete peroxidatic oxidation of amidopyrine results in the formation of several reaction products. The main product is not identified as dioxypyramidone formed via nonenzymatic peroxidatic oxidation. The oxidation of the indicator (azopyram) which represents an amidopyrine-aniline mixture results first in the formation of amidopyrine radicals. The reaction product (dye) is formed via the binding of these radicals to aniline radicals. The latter are predominantly formed via a nonenzymatic route during the reduction of the amidopyrine radicals by aniline. Similar to the formation of azopyram and the full oxidation of amidopyrine, this reaction is accompanied by the displacement of the substituents from the 4-amino group.

Sodium [N-(1,5-dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-N-methylamino] methanesulfonate (dipyrone) cannot be detected as such in biological fluids since absorption is preceded by hydrolysis to 4-methylaminoantipyrine, which is actually absorbed and further metabolized. In the present work standardized TLC Rf values and gas chromatographic retention indices for the four main urinary metabolites of dipyrone were determined. Inclusion of these parameters in the principal component analysis "scores plot" allows dipyrone to be included as a possible candidate in the not oriented search for unknown drug assumption in cases of overdose intoxication or poisoning.

A comparative, randomized, double-blind study of diclofenac sodium 75 mg im versus Baralgin (a combination drug composed of dipyrone and two spasmolytics) 5 mL iv was performed on 57 patients with renal colic. Both groups were comparable as to age, sex, pain evolution time before treatment, and no treatment for renal colic in the six hours preceding trial drug administration. No significant differences were found between the two groups with respect to the evolution of pain after the first dose or in the frequency of administration of a second dose. Tolerability was good in both groups, but sweating and pain throughout the vein were observed in one patient in the Baralgin group. We concluded that diclofenac sodium constitutes an excellent alternative to pyrazolone analgesics, with the advantages of being monotherapy and having good tolerability, when used as intramuscular injection in ambulatory patients.

Methadone, a potent long-acting opioid analgesic, is only seldom prescribed for postoperative pain relief in Germany. It was the aim of the present investigation to evaluate its efficacy and to establish an adequate dose range using intravenous patient-controlled analgesia (PCA), as well as to determine possible drug interactions with the antipyretic analgesic metamizol (dipyrone). 120 patients recovering from elective major abdominal, gynaecological or orthopaedic surgery under standardized balanced anaesthesia were randomly allocated to three groups to self-administer intravenous 1-methadone. Demand doses were 0.573 mg (group LD), 1.145 mg (group HD) or 0.573 mg to which 50 mg metamizol (dipyrone) were added (group LM). Infusion rate was set to 0.137 mg 1-methadone/h in every group, lockout time was 1 min. Hourly maximum dose was set to 5.95 mg 1-methadone/h. During an average PCA duration of 21 hours patients demanded mean dosages of 16.4 mg (LD), 18.7 mg (HD) or 13.4 mg (LM) 1-methadone. Although individual variation in drug consumption was high, effective pain relief was possible in all cases. Cardiovascular and respiratory status during the observation period was always normal. 88-93% of patients preferred PCA in comparison with earlier experienced conventional postoperative pain treatment. It is concluded that patients are able to control adequate drug consumption, i.e. to avoid overdosage, by adjusting demand frequency if variable demand dosages are offered. Thus 13-19 mg 1-methadone per day can be recommended as reasonable dose range for pain relief during the early postoperative period.(ABSTRACT TRUNCATED AT 250 WORDS)

High performance liquid chromatographic methods for the individual determination of khellin, phenobarbitone and dipyrone in tablets are presented. The methods specify a reverse phase column: methanol + water (68 + 32) as mobile phase at a flow rate of 0.7 ml/min with detection at 254 nm for khellin, visgnagin and dipyrone; water + ammonia + methanol (94.5 + 0.5 + 5) as a mobile phase at a flow rate of 0.7 ml/min with detection at 240 nm for phenobarbitone. At sensitivity of 0.01 AUFS, linearity ranges were found to be 0.5-4 micrograms/ml for khellin, 2.5-12.5 micrograms/ml for dipyrone and 1-7 micrograms/ml for phenobarbitone and with relative standard deviations less than 2%. The mean percentage recoveries +/- SD of khellin, dipyrone and phenobarbitone added to tablets were found to be 101.0 +/- 0.65, 100.0 +/- 0.74 and 99.9 +/- 0.74, respectively. The system can detect 2% w/w visnagin in khellin.

The efficacy of dipyrone to modulate antitumor activity of mitoxantrone (MTN) and doxorubicin (DOX) was studied in vivo in mice bearing P388 murine lymphocytic leukemia sensitive (P388/S) and resistant P388/DOX) to DOX. P388/DOX-bearing mice demonstrated marginally higher sensitivity to dipyrone at 200 mg/kg when compared to P388/S-bearing mice. However, dipyrone could significantly enhance the antitumor activity of MTN and DOX in both P388/S and P388/DOX-tumor-bearing mice. MTN was cross-resistant to P388/DOX.

The use of metamizole is controversial, as reflected in the very different national regulations affecting it. The striking disparities between policies for metamizole made us try to determine if there were reasons to ban, limit or liberalize its utilization. After reviewing the literature, it was concluded that metamizole should not be withdrawn from the countries where its use is still relatively free. However, metamizole causes life-threatening adverse events that are usually unpredictable and can only be prevented by better prescribing habits, so it is suggested that its use as a first-line agent should be restricted to the treatment of the pain of acute colic and circumstances in which parenteral administration of a non-narcotic agent is mandatory. Studies are needed to determine the role of second-line oral analgesics in terms of their overall toxicity and efficacy. In the meantime it is proposed that oral metamizole should be used only when other analgesics (e.g. paracetamol) have failed.

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC. The mean Cmax of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in mean Cmax was linear, but the increase in AUC was not. The increases in mean Cmax and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in mean Cmax and AUC for 4-AcAA were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested.

In earlier studies (Ivanov, Staneva-Stoycheva, 1984) we have found an inhibitory effect of metamyzole (Analgin-Pharmachim) on the contractile responses of electrically stimulated guinea-pig ileum and mouse vas deferens, which is antagonized by naloxone. In the present study an attempt is made to clarify whether these presynaptic effects of metamyzole are due to direct interaction with presynaptic opiate receptors. The method of radioligand binding of /3H/-naloxone to the opiate receptors in a crude membrane fraction of rat brain was used. It was found that in the wide concentration range used (10(-5)-10(-9) M), metamyzole does not compete with /3H/-naloxone for binding to the receptor sites. The biochemical study has shown that the presynaptic opiate receptors do not participate in the mechanism of the presynaptic effects of metamyzole, established in earlier studies.

The effect of oral contraceptive steroids (OCS) on the rate of hepatic demethylation of 14C-dimethylaminoantipyrine (DAP) was studied directly in healthy young volunteers using a newly developed noninvasive breath analysis technique. After oral administration of a trace dose of DAP the specific activity of 14CO2 in breath was determined during 6 h and expressed as half life. The half life of eighteen female and twelve male control subjects was 2.4 +/- 1.2 h (2 SD) and 2.2 +/- 0.6 h (2 SD), respectively. In seven women starting OCS a progressive prolongation of DAP half life during a single menstrual period was observed. In seventeen women who had taken OCS in 21 day cycles, for more than 3 months, the half life was significantly (P less than 0.001) prolonged (4.4 +/- 2.1 h) when measured after 21 consecutive days of OCS intake. On average, stopping OCS for 7 days or giving phenobarbital in addition to OCS shortened DAP half life significantly (from 4.4 +/- 2.1 h to 3.2 +/- 1.1 h, n = 17, P less than 0.005; and from 4.6 +/- 2.0 h to 3.2 +/- 1.0 h, n = 12, P less than 0.01, respectively). Eight of twelve women on OCS responded to OCS intake and to OCS cessation and phenobarbital, whereas four women did not respond to any of these measures. These data suggest that inhibition of hepatic demethylation of DAP by OCS is time dependent and reversible. The extent of inhibition appears to be an individual characteristic of a given person.

Metamizol (sodium N-(1,5-dimethyl-3-oxo-2-phenylpyrazolin-4-yl)-N-methylamino-methylsulphonate; Dipyrone) a non-narcotic analgesic was tested for hypnotic potentiating effect. Metamizol potentiated the hypnosis induced by pentobarbital, barbital and chloral hydrate. This effect was dose-dependent and was inversely proportional to the duration of the analgesic pretreatment. An augmented hypothermia and competition at drug metabolizing sites seem to be the mechanisms involved in the observed effect.

The study was carried out to provide further evidence that the two pyrazolone derivatives, metamizol and aminophenazone, produce central antinociceptive effects by stimulating inhibition descending from the periaqueductal grey (PAG) to the spinal cord. Experiments were carried out on rats in which the tail-flick response to radiant heat, nociceptive activity in ascending axons of the spinal cord, and activity of neurones in the PAG and the substantia nigra were studied. Microinjection of procaine (10 micrograms) into the PAG reduced the tail-flick latency and abolished the increase in latency caused by i.p. injection of metamizol (40 mg/kg) and aminophenazone (150 mg/kg); it did not significantly reduce the antinociceptive effect of i.p. injection of morphine (2 mg/kg). Threshold doses of morphine (1 and 2 micrograms) administered by intrathecal (i.t.) injection potentiated the effect of threshold doses of metamizol injected i.p. (10 mg/kg) or into the PAG (10 micrograms) in the tail-flick test. Morphine (2 micrograms) injected i.t. potentiated the effect of i.v. injection of metamizol (80 mg/kg) on nociceptive activity in ascending axons by eliminating the stimulant effect of metamizol on about one third of the axons. Threshold doses of morphine injected i.t. failed to potentiate the antinociceptive effect of aminophenazone (50 mg/kg) injected i.p. in the tail-flick test. The results support the view that metamizol and aminophenazone activate pathways descending from the PAG and exerting an inhibitory effect on nociceptive impulse transmission at the spinal level.

The effect of phenobarbital (PB) and 3-methylcholanthrene (3-MC) on the metabolic behavior of aminopyrine (AM) was studied using an isolated hepatocyte system prepared from male Wistar rats. The formation of 4-formylaminoantipyrine (FAA) was increased after pretreatment with PB, but not 3-MC. However, the total amounts of AM and its main metabolites recovered from hepatocyte system after the incubation for 30 min were considerably reduced both by PB and 3-MC-pretreatment. Furthermore, when using 4-monomethylaminoantipyrine (MAA), the first metabolite of AM, as a substrate, 3-MC-pretreatment resulted in a more significant decrease in the total amounts of MAA and its further metabolites recovered than did PB. Present observation suggests the participation of cytochrome P-448 as well as cytochrome P-450 in the metabolism of AM.

The risk of agranulocytosis following the use of metamizole was studied by the method of controlled cases. All cases of agranulocytosis and their control cases in Sofia for the period 1982-1986 were included in the study. The mean agranulocytosis morbidity for this period was 3.16 cases for one million population for one year. The etiologic fraction was 7.1%. The relative risk of agranulocytosis following the use of metamizole is 1.25, the maximal risk is 0.03 cases for one million persons using metamizole for one year and the maximal lethal risk is 0.007 cases for one million persons using metamizole for one year. The use of metamizole in Bulgaria for the same period was studied, too. The data presented as a number of defined daily doses used by 1000 population for one day show that the use of metamizole in this country is high. A tendency toward an increase of 7.3% per year was found during the investigation. At the same time the agranulocytosis morbidity remained constant during the period of investigation. The results of the study lead to the conclusion that the use of metamizole is not related to a higher risk of agranulocytosis.

Implantation of a stone in the ureter of the dog by ureterotomy results in focal hyperperistalsis which is accentuated by administration of norepinephrine, and reduced by administration of phenoxybenzamine or isoproterenol. Administration of dipyrone reduces the hyperperistalsis, but this action does not appear to be that of either a beta-agonist of an alpha-antagonist.

A case of acute, transient agranulocytosis and thrombocytopenia associated with ingestion of dipyrone is reported. This once widely used analgesic, which is now banned in the United States, was obtained by the patient as "aspirin" while traveling in Mexico. Studies of the effects of this patient's serum on purified CD34+ marrow cells, which were highly enriched for hematopoietic progenitors, showed not only a drug-dependent suppression of the in vitro growth of myeloid progenitors, as has been reported previously, but also a drug-dependent suppression of primitive multipotential progenitors (CFU-Mix) and erythroid progenitors (BFU-E). These findings indicate that autoimmune, antibody-hapten interactions which have been reported to occur in dipyrone- and aminopyrine-induced agranulocytosis are not restricted to the neutrophil lineage.

On the basis of experimental and clinical studies the authors recommend to use mebikar with promedol in complex with other drugs for the treatment of traumatic shock in the prehospital and hospital periods. It was found to substantially improve results of the antishock therapy.

The carcinogenicity of dipyrone (sulpyrin)--[(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4 -yl) methylamino]methanesulfonic acid sodium salt monohydrate--which is widely used as an antipyretic anodyne in Japan and in some European countries, was examined in 314 (C57BL/6 X C3H)F1 mice. Male animals were given 0.5% (group I-a) or 0.125% (group I-b) dipyrone in their drinking water for 78 weeks, and female animals were given 1.0% (group II-a) or 0.25% (group II-b) dipyrone in their drinking water for 78 weeks; both males and females were observed for 86 weeks. Twenty-seven of 48 (56%) group I-a animals and 36 of 44 (82%) group II-a animals developed hepatic tumors, and the tumors in group II-a mice developed earlier than those in the control animals. The tumor incidences were significantly higher than those of 8 of 44 (18%) and 3 of 51 (6%) in the respective control groups. The multiplicity of the hepatic tumors was also significantly increased in groups I-a, I-b, and II-a. Hepatic adenoma incidence was related to the dose of dipyrone in the males. These results show that dipyrone enhances the development of hepatic tumors in mice.

The effects of the constituents of Baralgin ( metamizole , fenpiverinium , and pitofenone ) on mechanical activity were studied in isolated human preparations of the upper urinary tract. Metamizole in concentrations up to 10(-3) mol/l did influence neither spontaneous phasic activity nor activation by high external potassium, norepinephrine, or acetylcholine. Fenpiverinium blocked the increase in frequency of phasic-rhythmic contractions and the tonic tension development induced by acetylcholine. Fenpiverinium did influence neither spontaneous phasic activity nor activation by high potassium or norepinephrine. Pitofenone (10(-3)mol/l) antagonized completely spontaneous phasic-rhythmic as well as norepinephrine- or acetylcholine-induced phasic activity. The tonic activation induced by norepinephrine and acetylcholine was nearly completely inhibited. Pitofenone (10(-6) to 10(-3) mol/l) antagonized the high potassium-induced activation in a concentration-dependent way. The EC50 of pitofenone amounted to 2 X 10(-4) mol/l. Uptake measurements of 14C- pitofenone (2 X 10(-4) mol/l) in isolated ureteral segments showed the drug to be accumulated in the ureteral tissue; a tissue/medium ratio of about 3 was found at an exposure time of 60 min. The accumulation of the drug was reversible after washing in drug-free solution, indicated by the loss of radioactivity increasing with longer washing times. The results show that pitofenone has a direct relaxant effect on smooth muscle of the upper urinary tract, whereas fenpiverinium has exclusively anticholinergic properties. Metamizole had no direct effect on smooth muscle activity, and its clinical effects may be rather due to its analgesic action.