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PubMed2005

Case-control study of regular analgesic and nonsteroidal anti-inflammatory use and end-stage renal disease.

BACKGROUND: Studies on the association between the long-term use of aspirin and other analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) and end-stage renal disease (ESRD) have given conflicting results. In order to examine this association, a case-control study with incident cases of ESRD was carried out. METHODS: The cases were all patients entering the local dialysis program because of ESRD in the study area between June 1, 1995 and November 30, 1997. They were classified according to the underlying disease, which had presumably led them to ESRD. Controls were patients admitted to the same hospitals from where the cases arose, also matched by age and sex. Odds ratios were calculated using a conditional logistic model, including potential confounding factors, both for the whole study population and for the various underlying diseases. RESULTS: Five hundred and eighty-three cases and 1190 controls were included in the analysis. Long-term use of any analgesic was associated with an overall odds ratio of 1.22 (95% CI, 0.89-1.66). For specific groups of drugs, the risks were 1.56 (1.05-2.30) for aspirin, 1.03 (0.60-1.76) for pyrazolones, 0.80 (0.39-1.63) for paracetamol, and 0.94 (0.57-1.56) for nonaspirin NSAIDs. The risk of ESRD associated with aspirin was related to the cumulated dose and duration of use, and it was particularly high among the subset of patients with vascular nephropathy as underlying disease [2.35 (1.17-4.72)]. CONCLUSION: Our data indicate that long-term use of nonaspirin analgesic drugs and NSAIDs is not associated with an increased risk of ESRD. However, the chronic use of aspirin may increase the risk of ESRD.

Adult↗
PubMed2004

A newly synthesized poly(ADP-ribose) polymerase inhibitor, DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]-pyrimidine-4-one]: pharmacological profiles, neuroprotective effects, and therapeutic time window in cerebral ischemia in rats.

We investigated the pharmacological profiles of DR2313 [2-methyl-3,5,7,8-tetrahydrothiopyrano[4,3-d]pyrimidine-4-one], a newly synthesized poly(ADP-ribose) polymerase (PARP) inhibitor, and its neuroprotective effects on ischemic injuries in vitro and in vivo. DR2313 competitively inhibited poly(ADP-ribosyl)ation in nuclear extracts of rat brain in vitro (K(i) = 0.23 microM). Among several NAD(+)-utilizing enzymes, DR2313 was specific for PARP but not selective between PARP-1 and PARP-2. DR2313 also showed excellent profiles in water solubility and rat brain penetrability. In in vitro models of cerebral ischemia, exposure to hydrogen peroxide or glutamate induced cell death with overactivation of PARP, and treatment with DR2313 reduced excessive formation of poly(ADP-ribose) and cell death. In both permanent and transient focal ischemia models in rats, pretreatment with DR2313 (10 mg/kg i.v. bolus and 10 mg/kg/h i.v. infusion for 6 h) significantly reduced the cortical infarct volume. To determine the therapeutic time window of neuroprotection by DR2313, the effect of post-treatment was examined in transient focal ischemia model and compared with that of a free radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolone-5-one). Pretreatment with MCI-186 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. infusion for 6 h) significantly reduced the infarct volume, whereas the post-treatment failed to show any effects. In contrast, post-treatment with DR2313 (same regimen) delaying for 2 h after ischemia still prevented the progression of infarction. These results indicate that DR2313 exerts neuroprotective effects via its potent PARP inhibition, even when the treatment is initiated after ischemia. Thus, a PARP inhibitor like DR2313 may be more useful in treating acute stroke than a free radical scavenger.

Animals↗
PubMed1981

Mutagenicity testing of some commonly used dyes.

Seventeen commonly used dyes and 16 of their metabolites or derivatives were tested in the Salmonella-mammalian microsome mutagenicity test. Mutagens active with and without added Aroclor-induced rat liver microsome preparations (S9) were 3-aminopyrene, lithol red, methylene blue (USP), methyl yellow, neutral red, and phenol red. Those mutagenic only with S9 activation were 4-aminopyrazolone, 2,4-dimethylaniline, N,N-dimethyl-p-phenylenediamine, methyl red, and 4-phenyl-azo-1-naphthylamine. Orange II was mutagenic only without added S9. Nonmutagenic azo dyes were allura red, amaranth, ponceau R, ponceau SX, sunset yellow, and tartrazine. Miscellaneous dyes not mutagenic were methyl green, methyl violet 2B, and nigrosin. Metabolites of the azo dyes that were not mutagenic were 1-amino-2-naphthol hydrochloride, aniline, anthranilic acid, cresidine salt, pyrazolone T,R-amino salt (1-amino-2-naphthol-3,6-disulfonic disodium salt), R-salt, Schaeffer's salt (2-naphthol-6-sulfonic acid, sodium salt), sodium naphthionate, sulfanilamide, and sulfanilic acid. 4-Amino-1-naphthalenesulfonic acid sodium salt was also not mutagenic. Fusobacterium sp. 2 could reductively cleave methyl yellow to N,N-dimethyl-p-phenylenediamine which was then activated to a mutagen.

Coloring Agents↗
PubMed1993

WW-781, a potent reversible inhibitor of red cell Cl- flux, binds to band 3 by a two-step mechanism.

WW-781 ([3-methyl-1-p-sulfophenyl-5-pyrazolone-(4)]-[1,3-dibutylbarbit uric acid]-pentamethine oxonol), a fluorescent dye that has been used for measuring membrane potentials by optical methods, inhibits human red blood cell Cl- exchange, which is mediated by the membrane protein known as band 3 or capnophorin. The inhibition is slowly reversible upon removal of WW-781 from the medium, with a half time of approximately 4.7 min in 150 mM Cl- medium at 0 degrees C. The mechanism of inhibition by WW-781 involves a two-step binding reaction. WW-781 binds rapidly to band 3 to form an initial complex, which can also rapidly dissociate. Formation of this initial complex is followed by the much slower formation of a second complex (with a rate constant of approximately 1.1 min-1), probably involving a protein conformational change, through which WW-781 is more tightly bound to band 3. At low concentrations, WW-781 inhibits Cl- exchange with a stoichiometry of 1 WW-781 molecule per band 3 monomer, suggesting that under these conditions the binding of WW-781 is highly selective for the band 3 protein.

Anion Exchange Protein 1, Erythrocyte↗
PubMed2007

Etoricoxib tolerability in patients with hypersensitivity to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly observed, particularly among patients with chronic urticaria or asthma. The identification of a safe and reliable alternative is a frequent problem in clinical practice. Our aim was to investigate the clinical tolerability of etoricoxib, a new selective cyclooxygenase-2 inhibitor, in a group of patients with well-established NSAID hypersensitivity. METHODS: We assessed 31 adults (21 women and 10 men) who reported one or more adverse reactions to NSAIDs, manifested as cutaneous, respiratory or anaphylactic symptoms. Sixteen of them reported reactions to a single NSAID (single reactors) and 15 to more than one NSAID (multiple reactors); the most frequently involved drug was acetylsalicylic acid. First, each patient underwent allergologic tests (skin and/or oral challenge tests) with culprit NSAIDs and then tolerability tests with increasing doses of etoricoxib up to 120 mg. All challenges were performed under single-blind, placebo-controlled conditions. RESULTS: NSAID hypersensitivity was diagnosed in all 31 patients: 3 displayed positive results to pyrazolone skin tests and the other 28 to challenges with culprit NSAIDs. None reacted to either placebos or etoricoxib. CONCLUSIONS: Etoricoxib seems to be a safe alternative for patients with well-demonstrated NSAID hypersensitivity.

Adult↗
PubMed2003

Mechanisms of action of paracetamol and related analgesics.

Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1 (COX-1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in intact cells if low concentrations of arachidonic acid are available. The effects of both drugs are overcome by increased levels of hydroperoxides. At low concentrations of arachidonic acid, COX-2 is the major isoenzyme involved in PG synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol and salicylate may selectively inhibit PG synthesis involving COX-2 because the lower flux through this pathway produces lesser levels of the hydroperoxide, PGG(2), than the pathway involving COX-1. Apart from the lack of anti-inflammatory effect of paracetamol in rheumatoid arthritis, the clinical effects of paracetamol and salicylate are very similar and resemble those of the selective COX-2 inhibitors. A splice variant of COX-1, termed COX-3, may be a site of action of these drugs but, further work, particularly at low concentrations of arachidonic acid is required. We suggest that paracetamol, salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a distinct class of atypical NSAIDs which could be termed peroxide sensitive analgesic and antipyretic drugs (PSAADs).

Journal Article↗
PubMed1994

Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078.

We evaluated the effect of ONO-1078, a selective leukotriene-C4, -D4, and -E4-receptor antagonist, on bronchoconstriction intensity during inhalation challenge with dipyrone (a pyrazolone derivative) in six aspirin-sensitive asthmatics. A double-blind, randomized, crossover design was used. After ingestion of 225 mg ONO-1078 or matching placebo, subjects underwent bronchial provocation with dipyrone on two occasions, separated by 4 wk. Aerosol inhalation of dipyrone was performed increasing the concentration stepwise from 0.08 to 10% (wt/vol). FEV1 was measured every 10 min up to 30 min after inhalation of each concentration. Threshold concentrations causing a fall in FEV1 > or = 20% of baseline value were 0.4% in four subjects and 2% in the other two on the placebo day. After pretreatment with ONO-1078, threshold concentration was 10% in two subjects, and no fall in FEV1 was observed in the other four, even after inhalation of 10% dipyrone. Values of PD20 were 21.9 +/- 8.2 units (mean +/- SEM) after placebo and 311.6 +/- 40.3 units after ONO-1078, respectively, and a statistically significant difference occurred (p < 0.001). Provocation of bronchoconstriction was completely inhibited in subjects whose plasma ONO-1078 levels were more than 0.5 microgram/ml. These results support the hypothesis that sulfidopeptide leukotriene-induced bronchoconstriction is one important component in the pathophysiology of aspirin-induced asthma.

Adult↗
PubMed1986

Renal toxicity of non-steroidal anti-inflammatory drugs.

Non-steroidal anti-inflammatory drugs represent the most heavily prescribed and used class of drugs in human medicine. Most are derivatives of either salicylates, propionic acid, indoleacetic acid, anthranilic acid, pyrazolone, or oxicams. They depress the synthesis of prostaglandins from arachidonic acid by reversible inhibition of the enzyme cyclooxygenase. In the kidney, prostaglandins PGE2 and PGI2 modulate the vasoconstrictor effects of angiotensin II, norepinephrine, and vasopressin. In the presence of volume contraction, anesthesia, or disease states associated with high levels of these hormones, prostaglandins regulate glomerular filtration, vascular resistance, and renin secretion. They additionally influence urine volume and sodium content. In man, a syndrome of analgesic abuse that has been identified worldwide occurs more frequently in females than males and can result in severe renal damage, most notably renal papillary necrosis. Most common laboratory animals are relatively resistant to developing the renal lesion associated with NSAIDs unless high doses are given over long periods of time and some withholding of water is introduced into the protocol. Diuresis with 5% dextrose and water is protective. Studies of paracetamol and salicylate have demonstrated that these compounds concentrate in the papillary tip of the kidney at concentrations of 4 to 13 times the plasma levels in dogs and rabbits, respectively. Renal papillary necrosis has been described in horses on maintenance doses of phenylbutazone where dehydration or reduced water consumption has occurred. The lesion can be reproduced experimentally if water is withheld during a portion of the dosing interval. An increased incidence of uroepithelial tumors have been reported in patients with a history of analgesic abuse.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Update on ibuprofen: review article.

Non-steroidal anti-inflammatory drugs (NSAIDs) have become the principal mode of therapy for rheumatic diseases and their use has continued to increase despite concern expressed recently regarding potential hazards (Figure 1). Prior to 1969, a limited number of NSAID drugs were available. Aspirin and indomethacin became the mainstay of treatment but tolerability, particularly gastric irritation, at doses necessary to control rheumatic symptoms limited the usefulness of these valuable agents. The pyrazolone, phenylbutazone, showed slightly better gastro-intestinal (GIT) tolerability but has since been associated with an increased risk of blood dyscrasiae and is now only available for restricted use in most countries. Ibuprofen was the first of a new breed of NSAIDs originally introduced into the United Kingdom in 1969. Chemically quite distinct from its forerunners it was the first of the propionic acid derivatives to be used in rheumatic practice. The propionics have since become the largest, single and most important group of NSAIDs accounting for 50% of NSAID prescriptions in the United Kingdom. It is estimated that over 100 million patients worldwide have received ibuprofen which is now available in over 100 countries throughout the world including all the major markets. Ibuprofen was developed directly as a result of the problems associated with the use of corticosteroids in the treatment of rheumatoid arthritis and also because of the gastro-intestinal irritation and general intolerability of the established NSAIDs, at that time. Ibuprofen was readily accepted because, unlike the previous drugs, its therapeutic efficacy was easily seen to outweigh the severity of its side-effects. Ibuprofen was the first new drug with the potency of aspirin but without its major disadvantages.

Analgesia↗
PubMedDate not supplied

Developmental toxicity of orange B when given to rats by gavage.

The pyrazolone dye Orange B was given by gavage to pregnant Osborne-Mendel rats throughout gestation. Dose levels of 0, 15, 30, 100, 200, 400, or 700 mg/kg body weight were given daily. On gestation day 20, the females were killed and cesarean sections were performed. Feed consumption and maternal weight gain were not affected. No dose-related changes were seen in maternal clinical findings, implantations, fetal viability, or fetal size (weight and length). No compound-related effects were seen in sternebral development. No dose-related effect was seen in the incidence of skeletal variations in fetuses or in the number of litters containing fetuses with skeletal variations. Skeletal development, as measured by the average number of ossified vertebrae, was similar in all groups. No compound-related effects were seen in soft-tissue development.

Administration, Oral↗
PubMed1990

Intramuscular diclofenac sodium versus intravenous Baralgin in the treatment of renal colic.

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.

Adult↗
PubMed2006

Dipyrone and aminopyrine are effective scavengers of reactive nitrogen species.

Reactive nitrogen species (RNS), namely nitric oxide (NO*) and peroxynitrite (ONOO-) are produced in the inflammatory sites and may contribute to the deleterious effects of inflammation. The aim of the present study was to evaluate the putative scavenging effect of a particular group of non-steroidal anti-inflammatory drugs (NSAIDs), the pyrazolone derivatives dipyrone, aminopyrine, isopropylantipyrine, and antipyrine against RNS, using in vitro non-cellular screening systems. The results obtained showed that dipyrone and aminopyrine were highly potent scavengers of NO* and ONOO- while antipyrine exerted little effect and isopropylantipyrine no effect whatsoever against these two RNS and that, in the presence of bicarbonate, the scavenging potencies of both dipyrone and aminopyrine were slightly decreased. It could thus be inferred that the observed scavenging effects may be of therapeutic benefit for patients under anti-inflammatory treatment with dipyrone and aminopyrine in the case of overproduction of RNS. On the other hand, the possible depletion of physiological NO* concentrations, namely at the gastrointestinal tract as well as the formation of reactive derivatives of aminopyrine and/or dipyrone, resulting from their reaction with RNS, may otherwise be harmful for these patients.

Aminopyrine↗
PubMed1989

Different modes of inhibition of rat gastric mucosal 6-keto-PGF1 alpha production by indomethacin, aspirin and aminopyrine.

The actions of aminopyrine on rat gastric mucosal cyclooxygenase activity in vitro were investigated and compared with those of the cyclooxygenase inhibitors indomethacin and aspirin. Aminopyrine is a phenyl-pyrazolone derivative with potent analgesic and antipyretic properties, but is weakly ulcerogenic, while indomethacin and aspirin are known to cause considerable ulcerogenesis. Aminopyrine was less potent in its ability to inhibit cyclooxygenase activity. The inhibition by all three drugs decreased with an increase in the substrate concentration. Pre-incubation with the enzymes greatly increased the inhibitory action of indomethacin and aspirin, but only slightly increased that of aminopyrine. The inhibitory action of aminopyrine was reversible, whereas those of indomethacin and aspirin were irreversible. These findings are discussed in relation to the low incidence of gastrointestinal irritation caused by aminopyrine.

6-Ketoprostaglandin F1 alpha↗
PubMed2004

Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry. A comparison of fragmentation patterns of linear dextran obtained by in-source decay, post-source decay and collision-induced dissociation and the stability of linear and cyclic glucans studied by in-source decay.

In the first part of this study fragmentation patterns from a range of dextran oligomers (containing 4-20 anhydroglucose units) were compared in three different methods of analysis coupled with matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry. Collision-induced-dissociation (CID), prompt in-source decay (ISD) and post-source decay (PSD) all caused cleavage of the glycosidic bonds. Both CID and to a lesser extent ISD caused further cleavage of pyranose rings of the individual sugar residues. There was very little cleavage of pyranose rings detected in the PSD spectrum. Derivatisation of the reducing end-groups of the oligodextrans with 1-phenyl-3-methyl-5-pyrazolone (PMP) restricted cleavage in the MALDI mass spectrometer to the non-reducing end, and further it enabled the saccharides to be separated by HPLC so that a single chain length could be examined as a standard. Maltoheptaose was also used as a standard. In the second part of the study prompt ISD-MALDI mass spectrometry was used to compare the fragmentation of three oligoglucans, dextran, maltodextrin and gamma cyclodextrin, that have different linkages and different secondary structure. The results showed that the degree of fragmentation correlated with the degree of freedom in the saccharide chains in solution determined by NMR. Dextran the most random conformation was fragmented most whereas there was little evidence of any fragments, not even glycosidic bond breakage from cyclodextrin, even when the laser power was increased considerably. The fragmentation pattern of maltodextrin was intermediate. The patterns of fragmentation produced by MALDI mass spectrometry, particularly where standards are available to calibrate the spectrum and the energy of the laser is controlled, can be used to predict the type of linkage present.

Dextrans↗
PubMed1977

Influence of drugs on clinical chemical data for serum glucose, investigated with the automated glucose oxidase-perid method.

Fifty drugs, applied in the therapy of internal diseases, were investigated for their effect on the clinical chemical determination of serum glucose by the automated GOD-Perid method. The results showed a statistically significant depression of the reported glucose value, by 7 drugs containing the pyrazolone group and its derivatives (Baralgin, Butazolidine, Analgin, Novalgetol, Analgocain, Irgapyrin, Aminopyrin) P less than 0.001; P less than 0.01. The influence depends on the quantity of drug and on the time interval between loading and glucose analysis.

Autoanalysis↗
PubMed2005

Analysis of the monosaccharide components in Angelica polysaccharides by high performance liquid chromatography.

An analytical method of on-line high performance liquid chromatography (HLPC) was developed to simultaneously separate and identify the monosaccharide composition of three Angelica polysaccharide fractions (APF), named APF1, APF2 and APF3. In this method, APF were hydrolyzed into component monosaccharides and subsequently labeled with 1-phenyl-3-methyl-5-pyrazolone (PMP), and then the labeled monosaccharide derivatives were separated by a reverse-phase C18 column and monitored by UV absorbance at 250 nm. The results showed that nine monosaccharide derivatives have been well separated by HPLC under optimized conditions and the composition analysis of monosaccharides from APF samples could be achieved using acid hydrolysis and a set of monosaccharide standards. With this method, the within-day and day to day precisions of the composition determinations were 3.41-4.87% and 3.12-4.93% (RSD), respectively. The method was successfully applied to the determination of the component monosaccharides of Angelica polysaccharides.

Angelica sinensis↗
PubMed1995

Drug-induced severe skin reactions. Incidence, management and prevention.

Severe skin adverse drug reactions can result in death, but the rate of such events is fortunately low. The incidences of Stevens-Johnson syndrome and toxic epidermal necrolysis range from 1.2 to 6 per million per year and 0.4 to 1.2 per million per year, respectively. Stevens-Johnson syndrome is fatal in about 5% and toxic epidermal necrolysis in 30% of cases. Drugs implicated in these diseases are the sulphonamides, anticonvulsants, allopurinol, pyrazolone derivatives, oxicams and chlormezanone. The principles of symptomatic treatment are the same as for burns, and patients with extensive skin detachment should be transferred to an intensive care unit or a burn centre. Hypersensitivity syndrome is characterised by mucocutaneous eruption and fever with frequent lymphadenopathy, hepatitis and eosinophilia. Drugs implicated are mainly anticonvulsants and sulphonamides. The mortality rate of such a reaction has been estimated to be about 8%. Corticosteroid therapy has been widely used in hypersensitivity syndrome, despite the lack of controlled studies. Drug-induced vasculitis and serum sickness may also be life-threatening when the kidney, liver, gastrointestinal tract or nervous system are involved. In angioedema, congestion may involve mucous membranes and therefore impair swallowing and ventilation. Drugs associated with angioedema include penicillins, radiographic contrast agents and ACE inhibitors. Severe forms of angioedema necessitate epinephrine (adrenaline) subcutaneous injection and possibly resuscitative efforts. Corticosteroids and/or antihistamines are used to block or reduce prolonged or late phase reactions. Prompt recognition and withdrawal of the suspected drug is essential in severe drug-induced skin reactions.

Angioedema↗
PubMed1998

Analgesic abuse in the elderly. Renal sequelae and management.

Nephropathy caused by the use of 'classical' analgesics [paracetamol (acetaminophen), salicylates and pyrazolone derivatives] and renal impairment associated with nonsteroidal anti-inflammatory drugs (NSAIDs) are important health problems in the elderly. Classical analgesic nephropathy is a chronic renal disease characterised by renal papillary necrosis and chronic interstitial nephritis. The nephropathy is caused by the excessive consumption of analgesic mixtures containing at least 2 antipyretic analgesics combined with caffeine and/or codeine. The use of NSAIDs is associated with a wide range of tubular, interstitial, glomerular and vascular renal lesions. Despite the well-characterised acute biological effects of NSAIDs on the kidney, there is only limited evidence that they are associated with an increased risk of chronic renal failure. Classical analgesic toxicity can be effectively prevented by limiting the availability of over-the-counter analgesic mixtures containing 2 analgesic compounds in combination with potentially addictive substances (e.g. caffeine and/or codeine). In the elderly in particular, the prolonged, regular use of NSAIDs should be discouraged. Patients starting NSAID therapy should be monitored regularly and drug interactions should be avoided.

Aged↗