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PubMed1981

Competition between serum albumin and soluble fraction of liver for binding of warfarin and other drugs.

The binding of Warfarin by human serum albumin (HSA) and subcellular fractions from rat liver was investigated to evaluate the roles of such interactions in the pharmacokinetic properties of the anticoagulant. In vitro intracellular distribution studies showed that Warfarin was bound primarily by the soluble fraction of rat liver. Equilibrium dialysis studies were carried out to test the hypothesis that the hepatic extraction of Warfarin and drug interactions between Warfarin and other drugs involved competition between albumin and the soluble fraction of liver. A three compartment dialysis cell was designed and constructed for such studies. Three types of competitive binding interactions were identified. Iopanoic acid displaced Warfarin from HSA resulting in increased Warfarin in the protein-free compartment and in the compartment containing the soluble fraction. On the other hand, tolbutamide displaced Warfarin from HSA to the liver soluble fraction with relatively little effect on unbound anticoagulant. Sulfinpyrazone produced a third type of interaction characterized by displacement of Warfarin from HSA with an increase in the concentration of unbound drug. It was concluded that competitive binding between albumin and soluble liver proteins, is important in the hepatic uptake of Warfarin. The three compartment dialysis cells may be useful to simulate the distribution of drugs and drug combinations between non-dialyzable macromolecules.

Animals↗

PubMed1979

Management of gout.

Although the traditional oral colchicine regimen is often used for the acute attack, the intravenous route has advantages. Indomethacin, phenylbutazone, oxyphenbutazone and the newer nonsteroidal anti-inflammatory agents, such as ibuprofen, naproxen and fenoprofen, are quite successful. For chronic management of hyperuricemia, it is helpful to distinguish between overproducers of uric acid, for whom allopurinol is the rational therapy, and underexcreters of uric acid, for whom probenecid or sulfinpyrazone is indicated.

Allopurinol↗

PubMed1994

Suppression of cAMP-induced pigment granule aggregation in RPE by organic anion transport inhibitors.

PURPOSE: To investigate the mechanism(s) by which intracellular cAMP levels are elevated to induce pigment granule aggregation in teleost retinal pigment epithelium (RPE). METHODS: Pigment granule migration was studied in vitro using RPE sheets isolated from dark-adapted green sunfish, Lepomis cyanellus. After preculture to allow pigment granule dispersion, RPE sheets were incubated with various agents to test their ability to induce pigment granule aggregation. RPE sheets were then fixed, and pigment granule position was assessed microscopically. RESULTS: Pigment granule aggregation was induced by nonderivatized cAMP. At maximally effective concentration (1 mM), cAMP was as effective as its more membrane-permeant analogs dbcAMP and 8-Br-cAMP. Forskolin (1 or 10 microM), a stimulator of adenylyl cyclase, was also effective at inducing pigment aggregation. Two inhibitors of organic anion transport, probenecid and sulfinpyrazone, inhibited cAMP-induced aggregation by approximately 80% but had no effect on forskolin-induced aggregation. Several agents shown to stimulate RPE adenylyl cyclase in other species failed to induce pigment aggregation in isolated RPE sheets. CONCLUSIONS: Our observations strongly suggest that exogenously applied, nonderivatized cAMP can gain access to the cytoplasm of isolated RPE cells via organic anion transporters. Thus, if cAMP were secreted by retinal cells into the subretinal space, it could be taken up by RPE cells and subsequently act as an intracellular messenger to activate dark-adaptive physiological processes such as pigment granule aggregation.

Animals↗

PubMed1996

[Ion exchange interactions on silica gel in thin-layer chromatography. IV. Plate investigations by UV spectroscopy].

The properties of silica gel as stationary phase are determined mainly by siloxane, silanol and metal-silanate functional groups. The metals (Na, Ca etc.) getting into the product as trace elements in the course of manufacture may cause the appearance of artefacts. In our previous studies the ion exchange interactions between salt-type analytes and silanol or metal-silanate groups were investigated. It was found in the TLC test of the salts of organic acids and N-bases that the acids and bases are separated from their counter ions and accept protons from or donate to the silica gel layer. In the present paper several analytes of above type have been investigated in situ by remission spectroscopy. These are: phenobarbital, sulfinpyrazone, sulfucetamide, benzoic acid, salicylic acid, (and their Na-salts) and papaverine hydrochloride. Remission spectra were registered from the start spot directly after application and then from the spot after development with the CHCl3EtOH (9 + 1) mobile phase. Based on the difference between the remission spectra of protonated and deprotonated forms of the analytes, the deviations from the initial state could be established. On the basis of the shift of lambda max values one can conclude to the approximate ratio of the protonated (acid) and deprotonated (anion, base) form present in the examined points (middle or edge) of the chromatographic spot. Significantly different protonation states of the analytes were found in the start spots and in the developed spots. These findings are interpreted by the ion exchange interactions between the pharmacon and silica gel. The results provide a deeper insight into the mechanisms of TLC process.

Benzoates↗

PubMed1977

Platelets, thrombosis and atherosclerosis.

The interaction of platelets with the vessel wall can contribute to the early stages in the development of atherosclerosis through effects on smooth muscle cell proliferation, endothelial permeability, and possibly by causing vessel wall injury. Platelets are involved in the development of thrombi in response to vessel injury, and the repeated formation of platelet emboli and platelet-fibrin emboli from the mural thrombi may be one of the factors that cause clinical complications of atherosclerosis. Drugs which inhibit platelet function, particularly those that prolong shortened platelet survival (sulfinpyrazone and dipyridamole) may prove to be important in inhibiting the response of blood to vessel injury and thereby modifying the extent of atherosclerosis and its complications.

Arteries↗

PubMed1977

Platelet-mediated pulmonary hypertension: reduction by platelet inhibition.

Altering the platelet behavior with sulfinpyrazone or heparin--probably by inhibiting the platelet release reaction--reduces the emboli-induced pulmonary hypertension to the same extent as platelet depletion. Evaluation of platelet function in human pulmonary microembolism and consideration of substances which minimize or prevent platelet effects seems to be warranted on the basis of these experiments.

Animals↗

PubMed1979

Pyrazolidine derivatives: a comparative study of their effects on platelet aggregation.

Quantitative studies were carried out of the in vitro and ex vivo effects of phenylbutazone and 3-oxoalkyl substituted diphenyldioxopyrazolidines (kebuzone, tribuzone, benzopyrazone) on platelet aggregation. The specified pyrazolidine derivatives exhibited in vitro inhibitory effects on secondary platelet aggregation (induced by adrenaline and collagen), commensurable with the effects of sulfinpyrazone. The ex vivo efficacy was markedly influenced by the height of the drug level in blood and by differences in the elimination kinetics of the pyrazolidine derivatives in human organism. Inhibitory activities against primary aggregation (induced by ADP and thrombin) were found in vitro mainly in the phenyloxoalkyl derivative of diphenyldioxopyrazolidine (benzopyrazone) and its analogues. By substitution on the phenyl attached to its alkyl side chain (for example, by a halogen in the meta position), compounds were obtained which also possessed higher activities inhibiting secondary platelet aggregation.

Humans↗

PubMed1976

Pharmacokinetic and clinical studies of a new uricosuric agent - benzbromarone.

Benzbromarone, a potent uricosuric agent, is a benzofuran derivative with a bromine on the 3rd and 5th positions of the benzene ring. Readily absorbed after oral administration, it is promptly dehalogenated in the liver and excreted via the biliary system. Peak drug concentration usually precedes maximal uricosuria following a single dose of 40 mg of benzbromarone, since benzarone, one of the two metabolites, likewise has a uricosuric action. Longterm studies in 24 gouty patients indicate that the drug is well tolerated. It has not produced any skin rash or renal colic. Renal hemodynamics, blood picture, and liver enzymes were unchanged. Since it is eliminated by the biliary tract, it may cause diarrhoea in some patients. Being a very potent uricosuric agent, it is not advocated in patients with a history of uric acid lithiasis. The uricosuric effect is not liable to be counteracted when used in conjunction with hyperuricemic diuretics. The drug is particularly useful in patients with chronic gouty arthritis and tophi, either refractory or allergic to probenecid, sulfinpyrazone, or allopurinol.

Adult↗

PubMed1984

Use of antiplatelet agents in pediatric hypercoagulable states.

Many diseases in children are associated with thrombotic tendencies either as a complication or as part of the pathophysiologic process. Disorders in which platelet consumption and/or activation occur include myeloproliferative syndromes, sickle cell disease, cardiac prostheses, arteriovenous shunts, vasculitis, diabetes mellitus, and hemolytic-uremic syndrome and other renal diseases. Platelet involvement can be demonstrated by several indicators, including an increase in platelet release product levels in the plasma (beta-thromboglobulin, platelet factor 4, and thromboxane B2). The agents that have the greatest success in thrombotic disorders where platelet involvement is prominent include the prostaglandin pathway cyclo-oxygenase inhibitors aspirin and sulfinpyrazone, as well as dipyridamole. Although indications and dosages for the use of antiplatelet agents in children can be suggested, the treatment of each patient should be individualized in light of current knowledge.

Adolescent↗

PubMed1982

Studies of a patient with recurring thrombotic thrombocytopenic purpura.

A young woman with recurring bouts of thrombotic thrombocytopenic purpura presented an opportunity to study a single patient serially and in depth. This patient underwent 12 remissions in response to fresh frozen plasma, and as little as 250 ml of plasma or plasma from which cryoprecipitate had been extracted with efficacious. Neither the Lian factor nor alterations in either cold-insoluble globulin or protein C could be demonstrated. Evidence in support of the concept of "exhausted" platelets was generated, in that immediately before a thrombocytopenic relapse, platelet function was altered as manifested by bruising, prolongation of the bleeding time, and decreased platelet aggregation. The in vitro addition of normal plasma to such platelets did not improve aggregation. The antiplatelet agent sulfinpyrazone did not seem to add efficacy. Serial observations support the hypothesis that the progression of pathophysiologic events in this patient is: exhausted platelets, thrombocytopenia, hemolysis, renal perturbations, and central nervous system dysfunction.

Adolescent↗

PubMed2006

Micellar electrokinetic capillary chromatographic method for the quantitative analysis of uricosuric and antigout drugs in pharmaceutical preparations.

A simple MEKC method is described for the separation and quantification of seven widely used uricosuric and antigout drugs, including allopurinol (AP), benzbromarone (BZB), colchicine (COL), orotic acid (OA), oxypurinol (OP), probenecid (PB), and sulfinpyrazone (SPZ). The drugs were separated in a BGE of borate buffer (45 mM; pH 9.00) with SDS (20 mM) as the micellar source and the separated drugs were directly monitored with a UV detector (214 nm). Several parameters affecting the separation and analysis of the drugs were studied. Based on the normalized peak-area ratios of the drugs to an internal standard versus the concentration of the drugs, the method is applicable to quantify BZB, COL, and SPZ (each 5-200 microM), AP, OA, OP, and PB (each 10-200 microM) with detection limits (S/N = 3, 0.5 psi, 5 s injection) in the range of 0.6-4.0 microM. The precision (RSD; n = 5) and accuracy (relative error; n = 5) of the method for intraday and interday analyses of the analytes at three levels (30, 120, and 180 microM) are below 4% (n = 3). The method was demonstrated to be suitable for the analysis of AP and COL in commercial tablets with speed and simplicity.

Calibration↗

PubMed1997

Inhibition of coumarin 7-hydroxylase activity in human liver microsomes.

Nine organic solvents and 47 commonly used P450 substrates and inhibitors were examined for their effects on coumarin 7-hydroxylase (CYP2A6) activity in human liver microsomes. Of the nine organic solvents examined (final concentration 1%, v/v), only methanol did not inhibit the 7-hydroxylation of coumarin (0.5 to 50 microM) by human liver microsomes. Dioxane and tetra-hydrofuran, which are structurally related to coumarin, were the most inhibitory solvents examined. Although the rates of coumarin 7-hydroxylation varied enormously among nine samples of human liver microsomes and cDNA-expressed CYP2A6 (Vmax = 179 to 2470 pmol/ mg protein/min), the Km for coumarin 7-hydroxylation was fairly constant (ranging from 0.50 to 0.70 microM). The following chemicals caused little or no inhibition of CYP2A6 as defined by a Ki > 200 microM: caffeine, chlorzoxazone, cimetidine, dextromethorphan, diazepam, diclofenac, erythromycin, ethinylestradiol, ethynyltestosterone, fluconazole, furafylline, furfural, hexobarbital, itraconazole, mephenytoin, methimazole, metronidazole, naringenin, naringin, nifedipine, norfloxacin, norgestrel, orphenadrine, quinidine, papaverine, phenacetin, pyrimethamine, ranitidine, spironolactone, sulfaphenazole, sulfinpyrazone, testosterone, tolbutamide, troleandomycin, and warfarin. In other words, these chemicals, at a final concentration of 100 microM, failed to inhibit CYP2A6 when the concentration of coumarin was equal to Km (0.50 microM). The following chemicals were classified as strong inhibitors of CYP2A6 (defined by Ki < 200 microM): clotrimazole, diethyldithiocarbamate, ellipticine, ketoconazole, 8-methoxypsoralen, 4-methylpyrazole, metyrapone, miconazole, alpha-naphthoflavone, nicotine, p-nitrophenol, and tranylcypromine. The potency with which each chemical inhibited the 7-hydroxylation of coumarin was independent of which sample of human liver microsomes was studied. One of the most potent inhibitors of coumarin 7-hydroxylase was 8-methoxypsoralen (methoxsalen), which was determined to be a mechanism-based inhibitor (suicide substrate) of CYP2A6 (k(inactivation) 0.5 min-1). With the exception of 8-methoxypsoralen, preincubation of human liver microsomes and NADPH with the aforementioned inhibitors did not increase their ability to inhibit CYP2A6. The most potent competitive inhibitor of CYP2A6 was tranylcypromine (Ki = 0.04 microM). Several of the chemicals that strongly inhibited CYP2A6, such as ketoconazole and tranylcypromine, are often used with the intention of selectively inhibiting human P450 enzymes other than CYP2A6. The results of this study underscore the need for a systematic evaluation of the specificity of commonly used P450 inhibitors.

Adult↗

PubMed1987

Cardioprotection by anti-ischaemic and cytoprotective drugs.

Cardioprotective drugs are agents that prevent or moderate harmful consequences of impaired cardiac energetics, such as sudden coronary death (SCD) due to early post-occlusion ventricular fibrillation (EPVF), development of incapacitating myocardial necrosis. Cardioprotection may be due to anti-ischaemic action, correcting the imbalance between vascular supply and myocardial demand for blood, but also to cytoprotective effect, preserving cellular integrity in the presence of factors damaging structure and function of the cardiac cell membrane such as ischaemia, ionic imbalance and that of pH, etc. Neither anti-ischaemic nor cytoprotective effect alone, or in combination, are sufficient to warrant full cardioprotection, i.e. both prevention of SCD and limitation of infarct size. Thus the beta-blocker pindolol which is anti-ischaemic in its effect reducing myocardial O2 demand and protects from SCD and EVFP, failed to limit infarct size. Even interventions of a mainly cytoprotective type of action protecting from SCD and EPVF, such as the linoleic acid-rich diet, or lidocaine, were unable to limit infarct size, 7-oxoPGI2 (anti-ischaemic and cytoprotective) failed to protect from SCD, VF and did not limit infarct size. On the other hand the nonsteroidal anti-inflammatory drugs which, like salicylates or sulfinpyrazon, reduce myocardial O2 demand and protect from post-occlusion SCD and EPVF, effectively limiting infarct size.

Animals↗

PubMed1988

Which role for antiplatelet and anticoagulant drugs in unstable angina pectoris?

Two large placebo-controlled, randomized, double-blind clinical trials have demonstrated the benefit of aspirin therapy in preventing myocardial infarction and death in patients with unstable angina. The Veterans Administration Cooperative Study of 1266 men hospitalized with unstable angina showed that 324 mg of aspirin daily for 12 weeks reduced the incidence of myocardial infarction by 51% (p = 0.001), and the data suggested a similar reduction in mortality. The Canadian McMaster University multicenter trial of 555 patients showed that treatment with 1300 mg of aspirin per day for a mean of 18 months reduced the incidence of cardiac death and nonfatal myocardial infarction together by 51% (p = 0.008). The reduction in death alone was 71% (p = 0.004). In the Canadian study there was no observed benefit of sulfinpyrazone. The Canadian trial confirmed the results of the VA Cooperative Study and showed statistical significance for reduction by aspirin of death as well as of myocardial infarction. It showed similar benefits in women as in men with unstable angina. The life-table curves for aspirin-treated and control patients continued to separate throughout the 2-year study period, demonstrating the value of continued treatment. The VA study showed no evidence of gastrointestinal side effects from 324 mg of aspirin daily administered in a buffered solution. Heparin therapy for unstable angina has appeared promising, but no properly conducted randomized trial has been accomplished.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina, Unstable↗

PubMed1993

Platelet aggregation inhibitors in neurology.

This literature review reports on secondary prevention of ischaemic stroke. The aim of secondary prevention is to protect patients who belong to a risk group from the occurrence of brain infarction. Symptomatic patients with a demonstrated carotid artery stenosis of 70% and more will most probably benefit from carotid endarterectomy if performed by a skilled surgeon in the absence of contraindications. Oral anticoagulant drugs play a minor role in the medical prevention of brain infarction. Antiplatelet drugs, however, have been in use for almost two decades and (meta-)analysis of clinical trials points to acetylsalicylic acid as a drug with a modest but certain contribution of about 15% in the endpoint reduction, even at lower dosages. The addition of dipyridamole to classic acetylsalicylic acid dose appears to increase the endpoint reduction to 30%. Neither dipyridamole nor sulfinpyrazone as monotherapy have been demonstrated to be efficacious in the secondary prevention of ischaemic stroke. Ticlopidine seems a promising alternative for acetylsalicylic acid in those patients who suffer adverse effects from acetylsalicylic acid. Ticlopidine itself, however, has a number of side-effects that limit its application. New clinical trials are under way in order to improve the efficacy of drug treatment in the secondary prevention of brain infarction.

Brain Ischemia↗

PubMed1984

Agents interfering with the platelet-vessel wall interaction.

Drugs that inhibit platelet activation may prevent thrombosis and atherosclerosis. The mechanism by which coumarins, heparin, calmodulin inhibitors, calcium entry blockers, drugs that interfere with cyclic AMP function and arachidonate metabolism, and several other compounds might achieve this protection, is discussed. Only a few of these drugs (acetylsalicylic acid, dipyridamole, sulfinpyrazone) have been tested for clinical efficacy in man. So far the results of these studies have revealed modest protection from infarction and other cardiovascular diseases.

Arachidonic Acid↗

PubMed1979

The Arthus reaction in rats, a possible test for anti-inflammatory and antiheumatic drugs.

The Arthus reaction is an immunologically induced inflammatory response characterized by immune complex deposition, complement fixation, polymorphonuclear leukocyte infiltration and tissue damage. Many of these same pathological tissue alterations are found in the lesions of rheumatoid arthritis (RA). The similarities between the reversed passive Arthus reaction (RPAR) and RA led us to investigate the usefulness of the RPAR in the search for new antirheumatic agents. The RPAR was elicited in the skin of rats using chicken ovalbumin and the IgG fraction of rabbit anti-ovalbumin. Paramethasone, hydrocortisone, indomethacin, pirprofen, sulfinpyrazone, thalidomide and theophylline all gave significant inhibition of the RPAR. Ibuprofen, naproxen, cyprohepatadine and cromolyn sodium were inactive, while phenylbutazone and ASA exhibited a dose-dependent effect. The data show that the Arthus reaction, which is the result of the complex interaction of many factors, can be affected either generally or selectively at different time intervals by various therapeutic agents. The RPAR in rats may prove useful in detecting new therapeutic agents for the treatment of RA.

Animals↗

PubMed1996

The inhibitory effects of antirheumatic drugs on the activity of human leukocyte elastase and cathepsin G.

The serine proteinases elastase and cathepsin G from polymorphonuclear granulocytes play a critical role in articular cartilage degradation, not only as proteolytic enzymes able to degrade the extracellular matrix but also by additionally modulating the level of active matrix metalloproteinases, key enzymes of the proteolytic destruction of cartilage during rheumatoid arthritis. The aim of our study was to examine whether anti-inflammatory drugs and selected compounds inhibited elastase and cathepsin G, and also to determine whether it is necessary to use a highly purified elastase preparation to screen drugs for their ability to block the activity of this enzyme. Eglin C and the glycosaminoglycan-peptide complex DAK-16, at concentrations ranging from 10(-9) to 10(-4) M, dose-dependently inhibited elastase and cathepsin G while the nonsteroidal anti-inflammatory drugs oxyphenbutazone, phenylbutazone, sulfinpyrazone and diclofenac-Na required high concentrations to demonstrate some inhibitory effects on the activity of both enzymes. None of the other anti-inflammatory drugs tested at a concentration of 10(-4) M such as acetylsalicylic acid, dexamethasone, indomethacin, ketoprofen, naproxen, oxaceprol, pirprofen and tiaprofenic acid demonstrated any marked inhibitory activity on either of these proteinases. Only a few drugs, when dosed therapeutically, achieved synovial fluid concentrations sufficient to inhibit the activities of both proteinases. The antirheumatic drugs demonstrated similar inhibition profiles in purified or partially purified elastase preparations. Thus the leukocyte extract containing the partially purified elastase and cathepsin G which can be rapidly and easily prepared at low costs appears to be an efficient mean of screening potentially new therapeutic agents for their ability to inhibit leukocyte elastase and cathepsin G.

Antirheumatic Agents↗