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Biomedical subjects

R Fears

Publications and source records attributed to R Fears.

At least 19 recordsLinked to original sources
PubMed1992

Lack of influence of pretreatment antistreptokinase antibody on efficacy in a multicenter patency comparison of intravenous streptokinase and anistreplase in acute myocardial infarction.

Antistreptokinase antibodies present in patients as a result of previous streptococcal infections might theoretically influence the thrombolytic response to streptokinase or anistreplase. The potential influence of antibody, measured as antigen binding to immunoglobulin G, was investigated in a randomized, double-blind, multicenter patency comparison of intravenous streptokinase (1.5 million units/60 minutes) and intravenous anistreplase (30 units/2 to 5 minutes) in patients with acute myocardial infarction. Antibody results were evaluated in 333 patients (from a total study population of 370 patients) less than 76 years of age with ECG evidence of ST segment elevation who could be treated within 4 hours of the onset of symptoms. Variations in pretreatment circulating levels of antibody did not influence angiographically defined early coronary patency rates (Thrombolysis in Myocardial Infarction grade 2 or 3 perfusion, measured at a mean of 140 minutes after therapy was begun) for either streptokinase or anistreplase. Similarly the lytic response represented by systemic plasminogen activation and measured as changes in plasma plasminogen and fibrinogen levels after dosing (at mean times of 90 minutes and 24 hours) was not correlated with baseline antibody levels. Furthermore, pretreatment antibody was not a risk factor for poor outcome in response to streptokinase or anistreplase (reocclusion within 24 hours, in-hospital death, or stroke) and did not correlate with hypotension or allergic-type reactions recorded as adverse events. In conclusion, within the population limits defined by the inclusion and exclusion criteria of the study (patients were excluded if they had received streptokinase or anistreplase within the previous 6 months), pretreatment antistreptokinase immunoglobulin G is not a significant determinant of the efficacy response to streptokinase or anistreplase.

Anistreplase↗
PubMed1992

Monitoring of streptokinase resistance titre in acute myocardial infarction patients up to 30 months after giving streptokinase or anistreplase and related studies to measure specific antistreptokinase IgG.

OBJECTIVE: To examine the induction of antistreptokinase antibodies after giving streptokinase or anistreplase to patients with acute myocardial infarction. DESIGN: Patients were randomly allocated to receive either 1.5 x 10(6) IU, streptokinase or 30U anistreplase in a double blind study. Blood samples were collected immediately before treatment and subsequently at intervals up to 30 months; plasma samples were assayed for streptokinase resistance titre (functional assay) and streptokinase binding by IgG (microradioimmunoassay). SETTING: Cardiology department in a general hospital. PATIENTS: 128 consecutive eligible patients. Samples were collected for up to one year according to a prospective design: a subsection of 47 patients was selected for intensive study over the first 14 days. After one year, all available patients (67) were sampled on one further occasion. RESULTS: Antibody responses to streptokinase and anistreplase were similar. Streptokinase resistance titres exceeded pretreatment concentrations five days after dosing, and values peaked at 14 days. By 12 months after dosing, 92% of resistance titres (n = 84) had returned to within the pretreatment range. Antistreptokinase IgG concentrations also exceeded baseline concentrations within five days and peaked at 14 days. Half of the individual values had returned to within the pretreatment range by 12 months (n = 84) and 89% by 30 months (n = 18). CONCLUSION: Although we cannot be sure of the clinical significance, because of the increased likelihood of resistance due to antistreptokinase antibody, streptokinase and anistreplase may not be effective if administered more than five days after an earlier dose of streptokinase or anistreplase, particularly between five days and 12 months, and increased antistreptokinase antibody may increase the risk of allergic-type reactions.

Adult↗
PubMed1991

A comparison of the pharmacokinetic properties of streptokinase and anistreplase in acute myocardial infarction.

1. The pharmacokinetics of streptokinase (SK) and anistreplase in conventional dosage regimens of 1.5 x 10(6) i.u. of SK infused over 60 min and 30 units of anistreplase over 5 min were studied in 24 consecutive patients presenting with acute myocardial infarction, using a functional bioassay to assess concentrations. 2. The two agents were found to have similar volumes of distribution (5.68 and 5.90 l), but SK was cleared significantly more rapidly than anistreplase, resulting in a shorter terminal phase half-life (0.61 vs 1.16 h) and a shorter mean residence time (0.76 vs 1.55 h).

Aged↗
PubMed1990

Comparison of the effects of streptokinase, t-PA and APSAC on human platelet aggregation in vitro in the absence and presence of aspirin.

SK, t-PA or APSAC were incubated in human plasma (adjusted to 300,000 platelets/mm3), in vitro, for up to 90 minutes using concentrations which were equivalent to those achieved in the treatment of AMI patients. Aggregation was measured in response to ADP and collagen. SK inhibited platelet aggregation after a 60 minute incubation. t-PA was less inhibitory and significant effects were only achieved on extended incubation with a higher concentration of activator. APSAC markedly inhibited platelet aggregation in response to both ADP and collagen and the inhibition was achieved earlier than with SK. The difference in temporal response between APSAC and SK was not attributed to differences in systemic plasminogen activation. There was no influence of anti-SK antibody (IgG) on the platelet function response to APSAC or SK. Aspirin inhibited second phase aggregation induced by ADP but even in the presence of aspirin, the net inhibition of platelet aggregation was greater for APSAC than for SK. This marked effect of APSAC on platelet aggregation helps to explain the high initial patency and low re-occlusion rates seen when APSAC is administered to AMI patients.

Adenosine Diphosphate↗
PubMed1990

Effects of novel bile salts on cholesterol metabolism in rats and guinea-pigs.

Novel bile salts (quaternary ammonium conjugates) inhibited cholic acid binding and transport in everted ileal sacs in vitro. The cationic piperazine conjugate of lithocholic acid (di-iodide salt, compound 8, BRL 39924A) appeared most active, inhibiting binding by 29% and transport by 59% in guinea-pig ileum (200 microM). BRL 39924A also inhibited taurocholate uptake into guinea-pig ileal sacs and cholate uptake into rat ileal sacs and was selected for further study in vivo. In hyperlipidaemic rats, BRL 39924A significantly raised cholesterol 7 alpha-hydroxylase activity and decreased hepatic accumulation of exogenous cholic acid. HDL cholesterol concentration in the serum increased and the level of VLDL plus LDL cholesterol decreased. In hyperlipidaemic guinea-pigs. BRL 39924A lowered serum total cholesterol and triglyceride levels. Although metabolic changes were less than those achieved with the bile acid sequestrant, cholestyramine, the doses of BRL 39924A used were much lower (100-500 mg/kg body wt). Selective inhibition of receptor mediated bile acid uptake may be associated with local side-effects but these novel bile salts are useful pharmacological tools to examine the effects of receptor blockade on lipoprotein metabolism.

Animals↗
PubMed1990

Kinetic studies on novel plasminogen activators. Demonstration of fibrin enhancement for hybrid enzymes comprising the A-chain of plasmin (Lys-78) and B-chain of tissue-type plasminogen activator (Ile-276) or urokinase (Ile-159).

The activation of plasminogen by two novel hybrid enzymes, constructed from the A-chain of plasmin and the B-chains of tissue-type plasminogen activator (t-PA) or urokinase, was compared with the activation by the parent enzymes. Basal kinetic constants for 'Lys-plasminogen' (human plasminogen with N-terminal lysine) and 'Glu-plasminogen' (human plasminogen with N-terminal glutamic acid) activation were similar to those of the parent activators. The Km for plasminogen turnover for both hybrid enzymes was considerably decreased in the presence of both soluble fibrin and a mimic, a CNBr digest of fibrinogen. These enhancements and the related apparent negative co-operativity are similar to the behaviour of t-PA itself. The results are discussed with regard to the molecular features involved in the mechanism of fibrin stimulation.

Aminocaproic Acid↗
PubMed1989

Glucagon, cyclic AMP and adrenaline stimulate the degradation of low-density lipoprotein by cultured rat hepatocytes.

Rat hepatocytes were preincubated for 16 h with hormones or drugs and then for a further 8 h with 125I-human low-density lipoprotein (LDL). Glucagon (via cyclic AMP) and adrenaline (via cyclic AMP and alpha-effects) increased the binding of 125I-LDL to the LDL receptor, and the degradation of LDL to [125I]iodotyrosine. The effects on degradation were antagonized by dexamethasone, and the action of cyclic AMP on binding and degradation was inhibited by actinomycin D. The results are discussed in relation to the control of lipoprotein metabolism in diabetes.

Animals↗
PubMed1988

Kinetic studies on the effect of heparin and fibrin on plasminogen activators.

1. Possible interactions between fibrin(ogen) and heparin in the control of plasminogen activation were studied in model systems using the thrombolytic agents tissue-type plasminogen activator (t-PA), urokinase and streptokinase.plasminogen activator complex and the substrates Glu- and Lys-plasminogen. 2. Both t-PA and urokinase activities were promoted by heparin and by pentosan polysulphate, but not by chondroitin sulphate or hyaluronic acid. The effect was on Km. 3. In the presence of soluble fibrin (and its mimic, CNBr-digested fibrinogen) the effect of heparin on t-PA was attenuated, although not abolished. In studies using a monoclonal antibody and 6-aminohexanoic acid, it was found that heparin and fibrin did not seem to share a binding site on t-PA. 4. The activity of t-PA B-chain was unaffected by heparin, so the binding site is located on the A-chain of t-PA (and urokinase). 5. Fibrin potentiated the activity of heparin on urokinase. The activity of streptokinase.plasminogen was unaffected by heparin whether or not fibrin was present. 6. If these influences of heparin and fibrin also occur in vivo, then, in the presence of heparin, the relative fibrin enhancement of t-PA will be diminished and the likelihood of systemic activation by t-PA is increased.

Aminocaproic Acid↗
PubMed1988

Decrease in LDL and increase in HDL concentrations in type II hyperlipoproteinaemic patients on low-dose combination therapy of cholestyramine and Complamin.

A low-dose combination of Complamin retard (1 g t.i.d.) and cholestyramine (4 g b.i.d.) was compared with each agent alone in 2 serial open trials without dietary restriction using type IIa and IIb hyperlipoproteinaemic patients. Complamin alone produced decreases in LDL and VLDL cholesterol concentrations (up to 20%) whereas cholestyramine alone produced only a modest reduction in LDL (up to 15%). The combination produced marked, progressive reductions in total cholesterol (up to 35%) and LDL (up to 40%); reductions in VLDL (up to 45%), total triglyceride (up to 60%) and free fatty acids (up to 60%) were found only in type IIb patients. The average increase in HDL-cholesterol from the 2 studies for combination therapy was 35%. No side-effects were reported or measured and compliance was excellent. The results demonstrate the potential of a method of achieving beneficial actions on lipoprotein levels with a well-tolerated therapy.

Adult↗
PubMed1987

The interaction of streptokinase.plasminogen activator complex, tissue-type plasminogen activator, urokinase and their acylated derivatives with fibrin and cyanogen bromide digest of fibrinogen. Relationship to fibrinolytic potency in vitro.

The effects of purified soluble fibrin and of fibrinogen fragments (fibrin mimic) on the activation of Lys-plasminogen (i.e. plasminogen residues 77-790) to plasmin by streptokinase.plasminogen activator complex and by tissue-type plasminogen activator were studied. Dissociation constants of both activators were estimated to lie in the range 90-160 nM (fibrin) and 16-60 nM (CNBr-cleavage fragments of fibrinogen). The kinetic mechanism for both types of activator comprised non-essential enzyme activation via a Rapid Equilibrium Ordered Bireactant sequence. In order to relate the fibrin affinity of plasminogen activators to their fibrinolytic potency, the rate of lysis of supported human plasma clots formed in the presence of unmodified or active-centre-acylated precursors of plasminogen activators was studied as a function of the concentration of enzyme derivative. The concentrations of unmodified enzyme giving 50% lysis/h in this assay were 0.9, 2.0 and 11.0 nM for tissue-type plasminogen activator, streptokinase.plasmin(ogen) and urokinase respectively. However, the potencies of active-centre-acylated derivatives of these enzymes suggested that acylated-tissue plasminogen activator and streptokinase.plasminogen complexes of comparable hydrolytic stability were of comparable potency. Both types of acyl-enzyme were significantly more potent than acyl-urokinases.

Acylation↗
PubMed1987

Mode of action of lipid-lowering drugs.

Following the recent demonstration that both cholestyramine and nicotinic acid decrease mortality from coronary heart disease, there is a new enthusiasm for hypolipidaemic therapy. The agents in current use are, however, insufficiently active or are accompanied by unacceptable side effects. An understanding of the mode of action is necessary, both to optimize treatment guidelines (e.g. regarding combination therapy or use in specific subsets of patients) and to develop new agents with preferred actions on rate-limiting steps. A reduction in LDL cholesterol concentration remains the principal desired action, although an elevation in HDL may also be beneficial. The main categories of commercially available agent comprise the anion exchange resins (inhibitors of bile acid absorption); cholesterol absorption inhibitors; fibrates (probably acting by enhancing lipoprotein lipase); and probucol (affecting LDL clearance). The most interesting of the new agents in clinical trials are the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitors, but other types of agent are at an earlier stage of evaluation, e.g. acyl-CoA: cholesterol acyltransferase inhibitors and peptide cofactors. It is not yet certain whether all the approaches to cholesterol lowering have equal validity, although an effect on biological endpoints is obtained for a variety of agents. Future evaluation will be aided by the implementation of noninvasive methods to quantify atherosclerosis and by the use of simple, 'dry-chemistry', cholesterol assays to screen populations.

Adrenergic beta-Antagonists↗