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H Ferres

Publications and source records attributed to H Ferres.

17 recordsLinked to original sources
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↗
PubMed1988

Slow clearance of acylated, hybrid thrombolytic enzymes.

Two hybrid plasminogen activators, plasmin A-chain/t-PA B-chain and plasmin A-chain/u-PA B-chain have been synthesized and purified in sufficient yield to permit measurement of clearance in small laboratory animals. Each hybrid enzyme was reversibly acylated at the active centre to allow the pharmacokinetic profile to be followed using an activity-based method without interference from plasma inhibitors. The acylated plasmin/u-PA hybrid had a clearance half-life (t1/2) in guinea pigs of approximately 80 min, whereas acyl u-PA had a t1/2 of 3 min. The pharmacokinetic profile of the acylated plasmin/t-PA hybrid was measured in guinea pigs, rats and rabbits; the half-lives in all three species were 60-80 min compared to half-lives of acylated, native t-PA that were in the range 0.5-1.0 min. Thus, plasmin A-chain-containing, acylated hybrid enzymes are cleared some 30- to 100-fold more slowly than the acylated parent activators.

Acylation↗
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

Preclinical pharmacological evaluation of anisoylated plasminogen streptokinase activator complex.

An ideal thrombolytic (or fibrinolytic) agent is one which would generate the formation of plasmin only where it is required, i.e. bound to fibrin within the thrombus. However, the capacity of even the newer thrombolytic agents to achieve localised plasmin generation within the thrombus is relative and depends on the concentration of the agent administered. For all available activators, the concentration required for effective clinical thrombolysis is also capable of converting plasminogen to plasmin within the circulation (plasminaemia). Since the action of plasmin is not specific to fibrin, plasminaemia results in dissolution not only of fibrin but also of several other clotting factors. For example, plasmin can degrade fibrinogen and cause impaired haemostasis. The plasminogen activators which are available, or have been developed to date, include streptokinase, urokinase, pro-urokinase, anisoylated plasminogen-streptokinase activator complex (APSAC) and tissue plasminogen activator (t-PA). All of these agents have the same biochemical mechanism of action, cleaving an arginine-valine bond in the plasminogen molecule to form plasmin, but they differ with regard to other important properties. The first property to be considered is clot specificity; the ability to dissolve fibrin as opposed to fibrinogen, and also to dissolve the clot as opposed to a haemostatic plug. Unfortunately, fibrin specificity does not equate entirely with thrombus specificity, and all currently developed plasminogen activators, by dissolving fibrin, will induce the destruction of haemostatic extravascular plugs as well as intravascular thrombi. Thus, no agent is thrombus-specific in this respect. The degree of fibrinogenolysis does vary between plasminogen activators. Those which have the least effect on haemostasis or clotting capability would seem, at first, to be preferable. However, a short term reduction in fibrinogen could also be beneficial, since it may reduce the incidence of early reocclusion and, by reducing blood viscosity, improve microcirculation to the infarct zone. The intrinsic efficiency of the plasminogen activators is a second important property. In vitro, under conditions pertaining to the circulation, urokinase is about 10 times more efficient than t-PA at converting glu-plasminogen to plasmin (on the basis of the Vmax to Km ratio), while streptokinase-plasmin is 20 times more efficient. The efficiency of these activators is increased in the presence of fibrin and lys-plasminogen, 1800-fold for t-PA, 8-fold for urokinase and 180-fold for streptokinase-plasmin.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Clinical effects and kinetic properties of intravenous APSAC--anisoylated plasminogen-streptokinase activator complex (BRL 26921) in acute myocardial infarction.

Fifty patients with a first myocardial infarction presenting within 4 hours of the onset of symptoms were treated with intravenous anisoylated plasminogen-streptokinase activator complex (APSAC-BRL 26921). Vessel patency with good flow was documented in 88%. The left ventricular ejection fraction declined with the duration of symptoms before treatment (r = -0.53, P less than 0.001). The correlation persisted for the group with anterior infarction (r = -0.46, P less than 0.05) where the mean left ventricular ejection fraction prior to discharge from hospital was 36 +/- 9% compared to 49 +/- 7% for the group with inferior infarction. Reinfarction developed in 12% and mortality at 6 months for the whole group was 6%. A degree of systemic fibrinolysis did occur with a fall in mean plasma fibrinogen from 3.20 g/l to 1.08 g/l. A pharmacokinetic study was performed in six patients demonstrating a clearance half-life of fibrinolytic activity of 87.5 +/- 5.0 min. APSAC is an effective intravenous thrombolytic agent with a relatively long half-life of fibrinolytic activity.

Adult↗
PubMed1978

beta-lactam antibiotics. II. Structure-activity relationships of 6-[alpha-(alpha'-ureido-acylamino) acylamino] penicillanic acids.

The influence on the structure-activity relationships (S.A.R.) of the stereochemistry and various alkyl, aryl, aralkyl and heterocyclic substituents at the two chiral centres in the dipeptide side-chain of a new series of penicillins was examined. In many cases the effects of these changes had a pronounced influence on the degree of activity against Gram-positive and especially Gram-negative bacteria. Several compounds indicated that the size, shape and spatial disposition of a substituent were the parameters of importance in influencing activity, rather than it lipophilic or electronic character. The most active homologues in the series provided broad-spectrum penicillins which in terms of their in vitro antibacterial properties showed improvements over certain of the marketed penicillins. Thus 6-[D-alpha(alpha'-ureidoacyl-amino)acylamino]penicillanic acids were found which had a carbenicillin-like profile, with improvements against Pseudomonas aeruginosa, Klebsiella aerogenes, sensitive and beta-lactamase-producing Gram-positive cocci.

Bacteria↗
PubMed1976

Preparation, hydrolysis, and oral absorption of lactonyl esters of penicillins.

Lactonyl esters of ampicillin and other penicillins have been synthesized as prodrugs designed to improve the oral absorption of the parent penicillins. In general, the esters hydrolyzed rapidly in the presence of tissues including blood and certain of the esters were better absorbed than the parent penicillin. The phthalidyl ester of ampicillin [talampicillin (British Pharmacopoeia approved name), BRL 8988] was selected for extended studies. The compound was found to be well absorbed in various animal species and gave ampicillin serum concentrations in fasting human volunteers 2.5-3 times those obtained for ampicillin itself.

Administration, Oral↗