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At least 19 recordsLinked to original sources
PubMed1986

Role of alpha-1 acid glycoprotein, albumin, and nonesterified fatty acids in serum binding of apazone and warfarin.

Altered concentrations of serum proteins and nonesterified fatty acids (NEFAs) often accompany malignant diseases. Free fractions (fu) of apazone and warfarin were measured by equilibrium dialysis in serum samples obtained from 31 patients with cancer and 18 control subjects. Mean fu values of both drugs were significantly higher in the patient group. Multivariate analysis showed albumin, NEFA, and AAG for apazone and albumin, NEFA, and age for warfarin accounted for 60% and 63%, respectively, of interpatient variation in bound/free drug concentration ratios in the group of patients with cancer. The interactions of apazone and warfarin with AAG were further characterized; the more avid site had association constants of 4.5 X 10(5) and 2.3 X 10(5) L/mol, respectively. Finally, it is strongly suggested that when hypoalbuminemia is present and a drug binds to AAG with an affinity constant comparable to or higher than that to albumin, then fu will become dependent on the concentration of AAG.

Adult↗
PubMedDate not supplied

A re-evaluation of the HSA-piroxicam interaction.

Piroxicam binding to HSA was studied using equilibrium dialysis and fluorescence methods. It was shown that this drug, like its analogs isoxicam and tenoxicam, binds to the apazone locus (site I area) and to a lesser extent to the diazepam site (site II). The piroxicam binding to HSA can be modulated by various specific ligands--apazone, warfarin, diazepam, ibuprofen--and these drug interactions have to be considered not only as potential displacement from the HSA binding sites but also in terms of induced allosteric effects.

Apazone↗
PubMed1989

Blood distribution of tenoxicam in humans: a particular HSA drug interaction.

Blood binding of tenoxicam was studied in vitro by equilibrium dialysis. Isolated human plasma proteins and blood cells were checked, and the distribution of the bound form was then calculated. The results showed that tenoxicam is mainly bound to HSA and that binding percentages are not different when measured in plasma (98.4%) and in an HSA solution at physiological concentration (704 microM, 98.15%). In these conditions, within the range of 1-150 microM, the tenoxicam binding percentage remained constant, evidence of a nonsaturable process. When a lower HSA concentration (10 microM) was used, the binding parameters of the tenoxicam interaction were calculated by using the same equilibrium dialysis data, by 3 methods of analysis- a stoichiometric method and site-oriented methods, fixing or not the number of HSA binding sites (n) as integer values. The best fit was observed with the first method, suggesting that two main interactions occurred. The site-oriented method gave lesser fits, the better being observed when n was not fixed. Its value, 1.77, suggest the possibility of two binding sites, one of them not preformed. The effects of known markers of site I, warfarin and apazone, of site II, diazepam and ibuprofen and of palmitic acid showed that tenoxicam is bound simultaneously to both sites I and II. The binding capacity of site I for tenoxicam is enhanced by diazepam: as this compound alone is bound to site II, this result suggests that the two HSA binding sites are not independent.

Bilirubin↗
PubMed1991

The problems and pitfalls of NSAID therapy in the elderly (Part I).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide when grouped by generic categories and account for 3 to 9% of total prescription numbers in various countries. While NSAIDs are responsible for approximately 25% of all reported adverse drug reactions, aging may substantially increase the risk of NSAID-induced reactions. Several factors may contribute to NSAID-related toxicity in the elderly. The increase in morbidity associated with aging may result in consumption of a wide range of potent drugs, while inappropriate drug therapy and aberrant compliance are also capable of contributing to adverse drug reactions in geriatric patients. Age-related alterations in pharmacokinetics may influence the handling of NSAIDs in the elderly; in particular, dosage reduction is appropriate for azapropazone (apazone), naproxen, ketoprofen and salicylates administered to healthy aged patients, whereas the presence of renal disease may also necessitate dosage reduction of diflunisal, indomethacin, sulindac and mefenamic acid. Changes in NSAID pharmacodynamics with aging, such as increased CNS sensitivity to NSAIDs and impaired homeostasis, also predispose the elderly to NSAID-related adverse effects. It is undisputed that gastrointestinal toxicity due to NSAID therapy is a class effect. A significant association has been found between aspirin and uncomplicated gastric, but not uncomplicated duodenal ulcer, while nonaspirin NSAIDs are significantly associated with both uncomplicated gastric and duodenal ulceration. The use of NSAIDs is accompanied by a 2- to 5-fold risk of serious complications of peptic ulcer disease, i.e. haemorrhage or perforation, which increases in the elderly, particularly women. A broad range of renal side effects has been ascribed to NSAIDs, of which acute renal impairment is the most common in the elderly. Although most NSAIDs have been reported to cause hepatotoxicity, serious abnormalities of liver function are rare and are largely unpredictable. Other adverse effects due to NSAIDs have also been described, some of which (e.g. cardiovascular, CNS and haematological effects) may be more common in the elderly.

Aged↗
PubMed2000

Pharmacotherapy for Behcet's syndrome.

OBJECTIVES: To determine the effects of available pharmacological interventions in treating the different clinical features of Behcet's syndrome. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register, and Medline up to January 1998. The computer search was complemented by a hand search of all bibliographic references from the reference lists of included trials. Principal investigators were contacted to seek unpublished literature. All languages were included. SELECTION CRITERIA: Studies were eligible if they fulfilled all of the four following criteria: 1. Randomized controlled trials, single or double-blind; 2. Participants were patients with Behcet's Syndrome as defined by the International Study Group, 1990 (Int Study Group, 1990); 3. Interventions included any pharmacological therapy compared to placebo or some other pharmacological intervention for the treatment of Behcet's syndrome. 4. Outcome measures included active ocular inflammatory processes, arthritis, mucocutaneous manifestations (oral ulcer, genital ulcer, erythema nodosum), laboratory changes and major events such as adverse effects and death. DATA COLLECTION AND ANALYSIS: The 32 potentially relevant references were assessed by two independent reviewers (MA, AS) according to the inclusion criteria. Ten trials fit the inclusion criteria and were included in this review. From the 10 included trials, data were independently extracted by the same two observers and crosschecked. The quality of the included trials was assessed independently by two observers (MA, AS) using a validated scale (Jadad 1996). For dichotomous measures, the treatment effect for each trial was calculated using a fixed effect model [Peto model (Petitti 1994)]. The weighted mean differences were based, if available, on end-of-trial results. The analysis was conducted separately for each different intervention. Since the trials could not be pooled it was not possible to carry out a sensitivity analysis by quality scores or a subgroup analysis by drug dosages. Because of this lack of comparability across trials and the small number of trials, we could not conduct a heterogeneity test or a funnel plot. MAIN RESULTS: Ten trials and 679 patients were included. The main results were the lack of efficacy of some of the classic treatments for Behcet's syndrome, including colchicine, cyclophosphamide and steroids for eye involvement, azapropazone and colchicine for arthritis and acyclovir, colchicine and topical interpheron for aphthas. The results confirm the protective effects of cyclosporine and azathioprine for eye involvement and benzathine-penicillin for arthritis. REVIEWER'S CONCLUSIONS: We conclude that further randomized, placebo-controlled, double-blind trials should be carried out to compare cyclosporine, azathioprine and benzathine-penicillin versus placebo in order to make the results generalizable and comparable.

Acyclovir↗
PubMed1990

Excretion of azapropazone in human breast milk.

The excretion of azapropazone in breast milk was studied in four lactating women over one dosing interval following repeated doses of 600 mg b.d. for at least three days. Plasma and milk samples were collected up to 12 hours after drug intake. An average of 0.8 mg azapropazone was calculated as being excreted in breast milk in the 12 hour period. The breast fed neonate would ingest 0.2 mg/kg during this period.

Administration, Oral↗
PubMed1980

Azapropazone binding to human serum albumin.

Azapropazone, a new non-steroidal antiinflammatory drug, is strongly bound to human serum albumin. As revealed by Scatchard analysis, one high-affinity binding site with an association constant of about 1.2 x 10(6)M-1 and two low-affinity binding sites with association constants of about 0.05 x 10(6)M-1 were found. While the high-affinity binding site of azapropazone is clearly not identical with the diazepam or digitoxin binding sites of human serum albumin, contradictory evidence was found by optical measurements and displacement studies for the similarity of the azapropazone and the warfarin binding site of human serum albumin. At present, it is suggested that both drugs bind to different areas of the same binding site. Therefore, the pronounced effects of various disease states on the plasma protein binding of azapropazone can not be explained by a binding to an unusual binding site, but seem to be due to an extreme sensitivity of the azapropazone binding area to the putative endogenous binding inhibitors, present in the blood during those disease states.

Apazone↗
PubMed1987

Concentration of azapropazone in synovial tissues and fluid.

The concentration-time curves of azapropazone in synovial fluid and tissues have been studied in arthritic patients after an i.v. bolus (600 mg) and under steady-state conditions. Synovial fluid and tissue samples were taken intraoperatively 0.45-60 h after administration. The azapropazone concentrations in synovial fluid, synovial tissue and plasma were correlated. The levels in synovial fluid were usually lower than corresponding plasma levels. Under steady-state conditions azapropazone did not accumulate in synovial tissues.

Adolescent↗
PubMed1993

Effects of chronic NSAIDs on gastric mucosal injury related to mucosal prostanoids, and plasma drug concentrations in human volunteers.

The relationship between endoscopically observed gastric mucosal damage, elicited following repeated oral intake for 7 d of four NSAIDs, to their effects on antral and fundic production of PGE2, 6-keto-PGF1 alpha and TxB2 (assayed by GC-MS), mucosal histology and plasma concentration profiles was studied in 40 normal males. Subjects received azapropazone (APZ) 600 mg b.i.d., indomethacin (IND) 50 mg t.i.d., naproxen (NAP) 500 mg b.i.d., piroxicam (PIR) 20 mg qq.d., or one placebo capsule t.i.d. (N = 8/group). Plasma NSAIDs (HPLC) levelled at 7 d. Mucosal damage occurred in the antrum region with IND and NAP. APZ and PIR exhibited no differences compared to placebo. NAP and IND reduced all three prostanoids in the antrum while APZ and PIR were ineffective. Fundic PGE2 was reduced by IND, NAP and PIR; APZ had no effects. Thus, mucosal damage relates to effects on prostanoid production in the antrum but not in the fundus.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

The amphiprotic character of azapropazone and its relevance to the gastric mucosa.

Since most non-steroidal anti-inflammatory drugs (NSAIDs) contain only one obvious ionisable group at physiological pH levels then they may be easily identified as having either acidic or basic character. Basic NSAIDs are simply non-acidic NSAIDs capable of accepting a proton within the physiological pH range. Within this range, however, a few NSAIDs contain two obvious ionisable groups, one acidic and the other basic. Such compounds should be described as amphiprotic, and include NSAIDs such as 4- and 5-amino substituted salicylic acids, niflumic acid, amfenac, WY 18251, and azapropazone. The aqueous ionisation equilibrium of such compounds is complex and is described by two macroscopic ionisation constants. Evidence has accumulated during the last decade to support the view that the pharmacokinetic behaviour of NSAIDs contributes not only decisively to their therapeutic effects but also to the type and incidence of their side-effects. A priori, using a physicochemical argument, certain amphiprotic NSAIDs should be better tolerated by the gastric mucosa than the classical acidic compound. Of those NSAIDs commercially available in the United Kingdom azapropazone remains the only one for which amphiprotic behaviour has been described. Following our examination of available data for azapropazone we conclude that the use of amphiprotic compounds represents a logical approach towards solving the problem of NSAID-induced gastric mucosal damage.

Animals↗
PubMed1978

Interaction between azapropazone and warfarin.

In vitro studies, using 2 separate techniques, have shown that the anti-inflammatory agent azapropazone caused displacement of warfarin from its plasma albumin binding and it is therfore suggested that such a displacement mechanism may be involved in the reported clinical interaction between these 2 drugs.

Apazone↗
PubMed1986

Inhibition of rat neutrophil functional responses by azapropazone, an anti-gout drug.

Azapropazone at concentrations of 0.1 to 1 mM inhibited by 30-70% rat neutrophil migration, aggregation, and degranulation in response to the synthetic chemotactic peptide fMet-Leu-Phe. Binding studies using fNle-Leu-[3H]Phe, a radiolabeled analog of fMet-Leu-Phe, showed that azapropazone did not inhibit these responses by interfering with fMet-Leu-Phe binding. Azapropazone also decreased both the apparent rate of production and maximal levels of superoxide anion (O2-) generated by cells stimulated with 100 ng/ml phorbol-12-myristate-13-acetate (PMA). The concentrations of azapropazone that inhibit these neutrophil responses in vitro approximate those previously found in vivo after administration of therapeutic doses of drug to rats or humans. Taken together, the data suggest that the efficacy of azapropazone in gouty arthritis may be partly due to its ability to inhibit key neutrophil functional responses in vivo.

Animals↗
PubMed1987

The interpretation of ligand displacement experiments: calculations for multisite acceptors.

A method is described for calculating the degree of competition for binding between two ligands which are bound at any number of site classes on a binding protein from a generalization of the equilibrium competitive binding equations, the protein's binding parameters for each of the ligands, and the total protein and ligand concentrations. Theoretical displacement curves thus obtained for each of the possible competitive binding models with a multisite protein can then be compared with experimentally determined ligand displacements in order to find which model is most realistic or if measured displacements are due rather to negative cooperativity effects. The binding parameters used for the calculations have a statistical error attached to them, since they have been obtained experimentally, so here we also propose a method for calculating the standard deviations of the theoretical displacement curves deriving from these errors. This permits the use of statistical hypothesis testing in the comparison of theoretical and experimental results. An example is shown in which this method permits the verification that two drugs (phenylbutazone and azapropazone) are both bound by the same high- and low-affinity sites of a protein (alpha-fetoprotein).

Apazone↗