Competitive binding of bilirubin and drugs to human serum albumin studied by enzymatic oxidation.
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The mechanism of drug-induced displacement of bilirubin from the blood into tissues was studied. A model of simple, competitive binding of bilirubin and drug to one site on serum albumin was established. Variations of the free bilirubin concentration after addition of drugs were studied in vitro by measuring velocities of oxidation with hydrogen peroxide and horseradish peroxidase. In all cases, the results were in agreement with the model. The competitive effects of 20 drugs were measured and expressed quantitatively as binding constants to the bilirubin site on human serum albumin. Several drugs caused changes of the bilirubin-albumin light absorption spectrum, indicating simultaneous binding of both ligands, without an effect on the free bilirubin concentration. Noncompetitive site-to-site effects on bilirubin binding could not be demonstrated. An equation is proposed for calculation of the maximal displacing effect of a drug from knowledge of its plasma concentration, the above-determined binding constant, and the degree of protein binding of the drug. Comparison of these results with previous observations of bilirubin displacement in newborn humans and in experimental animals indicates a general agreement with a simple competitive mechanism of binding of bilirubin and drug to one site on the albumin molecule. Binding of drugs to other, noncompetitive sites is common. (+info)
Inhibitory effect of a pyrrolizidine alkaloid, crotalaburnine, on rat paw oedema and cotton pellet granuloma.
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1 The anti-inflammatory activity of crotalaburnine (=anacrotine) was investigated against increased vascular permeability and oedema produced by formalin, carrageenin, hyaluronidase, 5-hydroxytryptamine, dextran, bradykinin and prostaglandin, and against formation of granulation tissues by cotton-pellet in rats. The effect was compared with the activity of hydrocortisone, phenylbutazone, sodium salicylate and cyproheptadine against different types of inflammation.2 Crotalaburnine (40 mg/kg s.c. x 5 alternate days) had no significant inhibitory effect against formalin-induced arthritis, while hydrocortisone (40 mg/kg s.c. x 10 days) was effective from the fifth day onwards.3 Against carrageenin-induced oedema both crotalaburnine (10 mg/kg s.c.) and phenylbutazone (100 mg/kg oral) produced a similar degree of inhibition. Hydrocortisone (10 mg/kg s.c.) produced slightly greater inhibition.4 In normal rats crotalaburnine (10 mg/kg s.c.), phenylbutazone (100 mg/kg oral) and sodium salicylate (500 mg/kg i.p.) inhibited hyaluronidase-induced oedema. However, in adrenalectomized rats, there was a reduction of the inhibitory effect of sodium salicylate but not of phenylbutazone or crotalaburnine.5 Crotalaburnine (40 mg/kg s.c. and 30 mg/kg i.p., respectively) was ineffective against 5-hydroxytryptamine- and dextran-induced oedema but against bradykinin- and prostaglandin-induced oedema (in a dose of 20 mg/kg i.p.) it was quite effective. In a parallel series cyproheptadine (10 mg/kg oral and i.p., respectively) produced significant inhibition of 5-hydroxytryptamine- and dextran-induced oedema, while phenylbutazone (100 mg/kg i.p.) failed to produce any significant inhibition of prostaglandin-induced oedema.6 Against cotton-pellet granuloma crotalaburnine, in half the dose of hydrocortisone, produced similar inhibition while phenylbutazone produced much greater inhibition in five times the dose of crotalaburnine given orally.7 The possible mode of action of crotalaburnine as an anti-oedema agent is discussed. (+info)
Effect of D-glucaric acid derivatives on stability of rat liver lysosomes and erythrocytes.
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For studies on the lysosome-stabilizing effect of D-glucaric acid derivatives which have been found to have anti-inflammatory effect, the available and soluble enzyme activities of acid phosphatase of rat liver lysosomes were determined. Saliployed as standards. Lysosomes were incubated with drugs under specific conditions which allowed the data on the stabilizing activity of the drugs to be reproducible. The inhibitory effect of D-glucaro-1, 4-lactone, salicylic acid and phenylbutazone onover a wide range of concentrations. D-glucaro-1, 4-lactone as well as salicylic acid exhibited concentration-dependent lysosome-stabilizing effect whereas phenlybutazone had an optimum concentration for its lysosome-stabilizing effect. In addition, D-glucaro-1, 4-lactone,saliclicacid and phenylubtazone were also examined for their effects on heat-induced and saponin-induced hemolysis of rat erythrocyres. Both salicylic acid and phenylbutazone exhibited potent stabilziing and labilizing effects on heat-induced and saponin-induced hemolysis of eryhthrocytes, respectively. D-glucaro-1, 4-lactone, however, was incabale of affecting the hemolysis of erythrocytes. There appears to be a difference in the mechanism of the lysosome-stabilizing effects between D-glucaric acid derivatives and other anti-inflammatory drugs. (+info)
Observations on drug prescribing in rheumatoid arthritis.
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A total of 125 patients with rheumatoid arthritis were investigated about their drug therapy before referral to a specialist centre. Most referrals were from general practitioners. Only 47 of the patients had received salicylates as the first drug and 18 had never had them at all. Soluble aspirin was the preparation of salicylates most frequently prescribed (for 63 patients). Only 60 patients had been given an adequate dose and only 62 an adequate course of treatment with salicylates. In 28 patients salicylates had been stopped on account of side effects. About one-third of the patients had been prescribed oral corticosteroids.The referral letters were poor in giving details of past and present drug therapy, and there were serious omissions in reporting of previous side effects.Seventy-five general practitioners were asked to rate several currently marketed antirheumatic drugs in terms of effectiveness. Though prednisolone 15 mg daily ranked higher than aspirin 4 g daily the difference was not significant. The study shows the inadequacies of drug prescribing for rheumatoid arthritis in the Glasgow area. (+info)
Fenoprofen in treatment of osteoarthrosis of hip and knee.
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Two studies on 41 patients with osteoarthrosis of the hip or knee have shown fenoprofen-a compound with analgesic and anti-inflammatory properties-to be an effective addition to the drug treatment of these conditions. It was found to be superior to paracetamol but no statistically significant difference was shown in a comparison with phenylbutazone. (+info)
Double-bind cross-over tiral of flurbiprofen and phenylbutazone in ankylosing spondylitis.
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A double-blind cross-over study in 35 patients with ankylosing spondylitis was carried out comparing flurbiprofen (150 mg daily)-a new non-steroidal anti-inflammatory agent-with phenylbutazone (300 mg daily) over a four-week period. Flurbiprofen was well tolerated and shown to have therapeutic efficacy approaching that of phenylbutazone. The results suggest that flurbiprofen may prove a valuable alternative in the treatment of ankylosing spondylitis, and longterm efficacy and tolerance studies are clearly indicated. (+info)
Changes in human drug metabolism after long-term exposure to hypnotics.
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The influence of the newer, non-barbiturate hypnotics Mandrax (diphenhydramine-methaqualone) and nitrazepam on drug-metabolizing capacity was assessed and compared with the effect of amylobarbitone, a known inducer of drug-metabolizing enzymes. Plasma antipyrine and phenylbutazone half-lives and urinary output of 6beta-hydroxycortisol were used as indices. Volunteer subjects were exposed to therapeutic amounts of these agents and, in the case of Mandrax and barbiturates, further studies were carried out in dependent patients.Mandrax but not nitrazepam increased the rate of drug metabolism, presumably by enzyme induction. The degree of induction was comparable with that produced by hypnotic doses of amylobarbitone. The Mandrax-dependent and barbiturate-dependent patients were the fastest metabolizers studied. It is concluded that drug interactions resulting from interference with drug metabolism are as likely to occur with Mandrax as with barbiturates. On the other hand, it is unlikely that such drug interactions would occur with nitrazepam. (+info)
Delayed manifestation of ultraviolet reaction in the guinea-pig caused by anti-inflammatory drugs.
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1. Exposure of depilated skin of guinea-pig to ultraviolet (u.v.) light for 20 s produces a prolonged inflammatory response.2. The erythaema becomes evident within 15-30 min after the exposure and progressively increases in intensity reaching its maximum by 4-6 hours. The erythaema persists over 24 hours.3. Increase in vascular permeability is biphasic with an early short-lived rise peaking at 0.5 h and a prolonged secondary response peaking at 9-12 h and lasting over 48 hours.4. In presence of aspirin, phenylbutazone and indomethacin, administered prior to u.v. exposure, the inflammatory reaction is partially suppressed, depending upon the dose. The drugs are ineffective in aborting or minimizing the response when given after the inflammation is established. Corticosteroids fail to influence the u.v. inflammation in this test. The significance of these findings is discussed. (+info)