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Biomedical subjects

J Fareed

Publications and source records attributed to J Fareed.

At least 235 records · Page 13Linked to original sources
PubMed1991

Influence of hypersulfated lactobionic acid amides on tissue plasminogen activator release.

Under our experimental conditions, the sulfated bis-lactobionic acid amide, LW 10079, showed the strongest t-PA-releasing effect in the isolated perfused pig ear. In rats the sulfated bis-lactobionic acid amide LW 10121 was the most potent compound in acute t-PA release. In both experiments the bis-lactobionic acid amide LW 10082 did not work as a releaser of t-PA. Therefore in the case of LW 10082, the activation of the fibrinolytic pathway as a possible mechanism of its antithrombotic effect can be excluded.

Amides↗
PubMed1991

Use of recombinant hirudin to increase the patency rate of microanastomosis in a rabbit model.

Microvascular surgical techniques now play an extremely important role in reconstructive surgery. Failures still persist and are most commonly due to thrombotic occlusion of the microvascular anastomosis. Five to 20% of all free tissue transfers and replants are affected. A logical step in the effort to resolve this problem would be the infusion of the newly available recombinant hirudin (r-hirudin). The value of r-hirudin in microvascular surgery has not been investigated. An animal model mimicking the thrombotic mechanisms similar to those in the clinical situation has been described in which a length of rabbit femoral artery is excised, turned inside out and reinserted into the vessel with two standard microvascular anastomoses. The major factors in clinical anastomosis failure are represented in this animal model by medial disruption, imperfect vessel wall alignment, needle holes, trauma, foreign suture material and changes in flow. The type III adventitial collagen turned inward reproduces the clinical problem of adventitial strands becoming caught in the anastomosis. A predictable rate of thrombosis results depending on inversion graft length: a 2 mm segment has an occlusion rate at one week of about 30%. Using this model heparin infusions significantly decrease thrombosis rates compared to saline. Using an almost identical model we have begun a study the effect of r-hirudin on microvascular patency. New Zealand White male rabbits were anaesthetized with ketamine and xylazine. Through a groin incision the femoral vein was catheterized and tubing connected to an infusion pump. The femoral artery was exposed, and the adventitia aggressively removed since it is difficult to minimally debride adventitia in a reproducible fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗
PubMed1991

Comparison of recombinant hirudin and heparin as an anticoagulant in a cardiopulmonary bypass model.

Recombinant (r) hirudin is a potent thrombin-specific inhibitor originally derived from the natural hirudin of the leech (Hirudo medicinalis). We have studied the efficacy of r-hirudin compared to heparin in a dog model of cardiopulmonary bypass (CPB) surgery. Two administration regimens were used for r-hirudin: Group I received 1.0 mg/kg intracardiac (i.c.) bolus then intravenous (i.v.) bolus at 30 min (n = 10); Group II received 1.0 mg/kg (i.c.) bolus with 1.25 +/- 0.04 mg/kg/h (i.v.) infusion (n = 8). Group III was given heparin 1.66 mg/kg (i.c.) bolus (n = 9). Aspiration of blood from the chest cavity revealed no significant difference between the three groups. Measurement of fibrin deposits in the pump line filter revealed higher amounts in the r-hirudin groups (P = 0.02). Decreases in platelets, fibrinogen and haematocrit due primarily to haemodilution were the same in each group. The bleeding time was less prolonged for r-hirudin than for heparin (p less than 0.001). No antagonist for r-hirudin was used; however, due to its short half-life, all coagulation parameters returned to baseline within 30 min after CPB. Since r-hirudin has no effect on platelets, is a poor immunogen, does not require a plasma cofactor, and may not require an antagonist, it may provide an alternative anticoagulant to heparin in CPB. Additional studies are, however, needed to optimize the dose and to evaluate other clinical aspects of r-hirudin.

Animals↗
PubMed1991

An objective perspective on recombinant hirudin: a new anticoagulant and antithrombotic agent.

Leeches have been in medical use for many years. Hirudin, the anticoagulant obtained from the medicinal leech has been purified, characterized and can now be produced by recombinant (r) technology. R-hirudin is a potent inhibitor of thrombin and is therefore a potentially valuable anticoagulant and antithrombotic drug. This article reviews the current status of r-hirudin in this role and compares the pharmacokinetics, mechanism of action and clinical efficacy of this agent with heparin. The methods available for laboratory assessment and clinical monitoring of r-hirudin and the possible ways of antagonizing its effects are also discussed. Finally, the potential clinical applications of r-hirudin are outlined, although further laboratory and clinical studies, together with a fall in the cost of this compound are required before r-hirudin can be more widely accepted as an anticoagulant and antithrombotic agent.

Amino Acid Sequence↗
PubMed1991

Biochemical evidence for a relative lack of inhibition of thrombin formation by nonionic contrast media.

An in vitro study was done to investigate the thrombogenic potential of nonionic contrast media. Whole blood from 18 healthy volunteers was mixed with ionic contrast medium (diatrizoate, ioxaglate), a non-ionic contrast medium (iohexol), or saline (the control) and incubated in glass and plastic test tubes. Levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III complex (TAT), and antithrombin III (AT III) were measured. Evidence showed increased thrombin formation in glass tubes compared with that in plastic tubes, a finding in concordance with the known association between contact with glass and increased activation of coagulation. F1 + 2 and TAT levels were significantly increased in the nonionic mixtures compared with such levels in ionic mixtures (P less than or equal to .05). Control mixtures showed little or no overall increased thrombin formation by F1 + 2 and TAT levels compared with nonionic mixtures. These findings suggest an inhibition of thrombin generation by ionic contrast media in vitro and a relative lack of such inhibition by iohexol.

Antithrombin III↗
PubMed1991

Laboratory assays for the evaluation of recombinant hirudin.

Several laboratory methods are available to measure the anticoagulant activity of recombinant hirudin (r-hirudin), a potent thrombin inhibitor. These assays include clot-based, amidolytic, immunologic and physicochemical techniques. Although r-hirudin, like heparin, is an effective anticoagulant, the mechanism of action of the two agents is different. Thus it is not surprising that the global tests, such as the prothrombin time (PT), partial thromboplastin time (APTT) and the Heptest (Haemachem, Inc., St. Louis, Mo., USA), do not show adequate responses to r-hirudin. In the range of 0.5-10.0 microgram/ml, where full anticoagulation is achieved, as determined by animal models of thrombosis, these assays show little to no prolongation of the time to clot. In order to find a more suitable assay system, modifications of the above assays were evaluated. The diluted APTT and diluted Heptest showed linear concentration-dependent responses to lower levels of r-hirudin with an enhanced sensitivity than that of the classical assays. On the other hand, the diluted thrombin time was too sensitive. Whole-blood clotting assays, ACT and thrombelastograph, effectively measured r-hirudin levels up to 25 micrograms/ml. The amidolytic anti-factor IIa assay, specific for evaluating direct thrombin inhibition, was very effective particularly when modified to decrease the sample:thrombin ratio. This assay may be useful in quality control since it is biochemically defined, and reagents are easily standardized. The relevance of the results of the anti-IIa assay to clinical conditions, however, remains to be determined. Thrombin generation assays have limited value in monitoring the anticoagulant effect of r-hirudin since the effect of thrombin inhibition by r-hirudin on coagulation feedback mechanisms, and thus the effect on thrombin generation, appears to be minimal. Immunologic methods such as ELISA and RIA are under development, but they may only be useful for the direct quantitation of absolute levels of r-hirudin and not for monitoring the clinical anticoagulant action. Furthermore, these assays are only sensitive to sub-microgram/ml levels. Therefore, thrombin-based clotting and amidolytic assays may at present be the best choice for evaluating the functional, clinical antithrombotic effects of r-hirudin.

Blood Coagulation↗
PubMed1991

Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin.

Recombinant hirudin (r-hirudin) is currently under development as an anticoagulant for use in surgery, therapeutic anticoagulation, disseminated intravascular coagulation and other pathologic states involving the generation of thrombin. Circulating levels of r-hirudin as an antithrombotic agent range from 2 to 20 micrograms/ml (0.1-1.0 mg/kg) as determined in an animal model of stasis thrombosis. In order to establish a relationship between the r-hirudin circulating level and bleeding, we utilized a rabbit ear blood loss model. r-Hirudin did not produce any loss of blood at dosages up to 20 micrograms/ml i.v. (1.0 mg/kg). When the circulating levels were maintained at 20 micrograms/ml for periods of up to 3 h, no increase in blood loss was observed. At 50 and 100 micrograms/ml initial circulating levels (2.5 and 5.0 mg/kg) a dose-dependent increase in the blood loss was observed which was equivalent to that observed with 1.25 and 2.5 mg/kg i.v. heparin. Such levels of r-hirudin are not expected in clinical usage. In contrast to heparin, the anticoagulant actions of r-hirudin were not neutralized by protamine sulfate, platelet factor 4, other polycationic agents and heparinase. In our studies, the blood loss induced by greater than 2.0 mg/kg i.v. dosages of r-hirudin in an animal model was neutralized by the administration of an activated prothrombin complex concentrate at 25 U/kg. In a similar experimental setting, r-factor VIIa was also partially effective. These studies suggest that r-hirudin anticoagulation may not require neutralization, since bleeding effects are not observed at effective antithrombotic dosages in individuals with normal hemostatic status.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Comparative study of three recombinant hirudins with heparin in an experimental venous thrombosis model.

Three recombinant hirudins (r-hirudins) produced by genetic processes from Escherichia coli and yeast were studied. r-Hirudins could be an alternative treatment to heparin; so, the antithrombotic activity of these drugs should be compared to heparin, the reference substance, in an experimental venous thrombosis model. In this model, the effect of these r-hirudins on thrombus weight reduction were not identical. They varied depending on the original product (E. coli or yeast). The growth-inhibiting activity of r-hirudins on existing thrombi is not dose dependent, whereas that of heparin is. Moreover, in the conditions of this study, higher doses of heparin, but not of hirudins, increased the bleeding time. Although hirudin has limited applications for the time being, it seems an interesting anticoagulant drug, and the availability of r-hirudin opens new therapeutic anticoagulation perspectives.

Animals↗
PubMed1991

Recombinant hirudin--initial observations in reconstructive microsurgery.

Recent advances in microvascular techniques have significantly enhanced the success rate of these procedures. Microvascular free tissue transfers at present have a 85-90% success rate. This, however, still leaves a 10-15% failure rate due primarily to thrombosis of the blood vessels at the anastomotic site. Previous work in the field has shown that anticoagulants such as heparin can reduce the rate of thrombosis. However, heparin can also cause on-site bleeding. Hirudin, a potent thrombin inhibitor of 65 amino acids, is available through recombinant technology. Our current experimental work utilized 75 male Sprague-Dawley rats for assessing the efficacy of hirudinized saline versus saline alone and heparinized saline as an irrigant in a microsurgery model of anastomosis. After exposing the right femoral artery in a standard fashion, the artery was clamped and a standard transverse division of the vessel was made. The vessel ends were irrigated with one of the three solutions then anastomosed. Vessels were observed for patency over a 3-day period. Initial results showed comparable performance of hirudinized saline and heparized saline, both of which were better than saline, for preventing thrombosis. From these initial data, and the reduced bleeding risk associated with hirudin, this agent appears to be a useful anticoagulant in microsurgery.

Anastomosis, Surgical↗
PubMed1991

Effect of fast vs slow intralipid infusion on gas exchange, pulmonary hemodynamics, and prostaglandin metabolism.

Intralipid (20 percent, 500 ml) was infused fast (5 h) or slow (10 h) randomly in patients with lung injury to relate changes in plasma prostaglandin (PG) concentrations to gas exchange and pulmonary hemodynamics. Data were collected at baseline, midpoint of infusion, and 2 h following infusion. Vasodilator and vasoconstrictor PG metabolites, 6-keto-PGF1 alpha, and thromboxane B2, respectively, were measured in radial arterial blood samples. Slow Intralipid infusion increased shunt fraction (QS/QT) without changing mean pulmonary artery pressure (MPAP), whereas fast Intralipid infusion increased MPAP without changing QS/QT. Prostaglandin levels did not change significantly during either infusion. However, in both groups when the PG substrate was removed, hemodynamic and metabolite values decreased in parallel. In conclusion, we were unable to demonstrate a cause and effect relationship between plasma levels of 6-keto-PGF1 alpha and thromboxane B2 and the observed pulmonary hemodynamic response to slow or fast Intralipid infusion.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Experimental and clinical validation of the prophylactic antithrombotic effects of a low molecular weight heparin (enoxaparin).

Several LMWHs are currently available for commercial use. The development status of each of these products in the area of prophylaxis, therapeutics, and other indications is given in Table 4. Enoxaparin and Fraxiparin appear to be the most developed LMWHs in both the surgical and medical areas. Many well-designed clinical trials have been carried out for different clinical indications with both of these products. As demonstrated in both experimental and clinical settings, the prophylactic antithrombotic efficacy of Enoxaparin is distinct from other LMWHs. This agent has provided consistently impressive clinical results. However, at comparable dosages, other products have exhibited safety or efficacy profiles different from those of Enoxaparin. It is therefore justified to comment that the clinical performance of each LMWH is characteristic of only that particular agent. It can be stated that, provided proper developmental approaches, these agents will more than likely be the drugs of choice for the prophylaxis and therapy of thrombotic disorders. On the other hand, inadequate basic knowledge may result in the development of products with unknown safety or efficacy profiles whose introduction in clinical medicine may become related to problematic situations.

Hemorrhage↗
PubMed1991

Interaction of heparinoids with platelets: comparison with heparin and low molecular weight heparins.

Heparin interacts with platelets to impair collagen-induced aggregation and adhesion to collagen. Low molecular weight heparin and heparinoids have little or no inhibitory activity in these platelet-collagen interactions. Thrombin-induced aggregation of platelets is inhibited by any of the glycosaminoglycans that will block the action of thrombin on fibrinogen. However, heparin is a much more potent inhibitor than low molecular weight heparins or heparinoids at equigravimetric concentrations in these reactions. The inhibition of ristocetin or asialo-von Willebrand factor aggregation of platelets is partially blocked by high dose heparin but not by low molecular weight heparin or heparinoids. The heparin-induced IgG antibody, produced to a heparin-platelet complex, aggregates platelets strongly in the presence of heparin, less strongly in the presence of low molecular weight heparins and pentosan polysulfate and not at all with dermatan sulfate or the pentasaccharide. Heparan sulfate does interact with platelets and this antibody, which is of interest because of the heparan sulfate on endothelial cells. Clinical information to date suggests a low incidence of heparin antibodies in patients receiving only low molecular weight heparin of the depolymerized type. Whether long-term clinical use of low molecular weight heparins, heparan sulfate, and dermatan sulfate will give rise to specific antibodies that would cause a similar problem as heparin remains to be seen.

Autoantibodies↗
PubMed1991

Behavioral, endocrine, and neurochemical effects of sulfomucopolysaccharide treatment in the aged Fischer 344 male rat.

1. Daily treatment of male 19- to 22-month-old Fischer 344 male rats with Ateroid (20 mg/kg/day, p.o.), beginning one month before and continuing throughout testing, resulted in a significant partial reversal of age-related deficits in: a) Conditioned one-way (spatial, unsignaled) avoidance acquisition and retention b) Conditioned two-way (nonspatial, signaled) avoidance acquisition. 2. Ateroid reversed the age-related reductions in nucleus accumbens DOPAC and HVA levels, but not the age-related decrease in neostriatal HVA content or concomitant increase in 5-HIAA levels. Reduced dopamine turnover in the nucleus accumbens may underlie, at least in part, age-related deficits in conditioned avoidance learning and retention. Thus, the behavioral effects of Ateroid observed in the present study may be due to its normalizing influence on dopamine neurotransmission in the nucleus accumbens. 3. Stress-induced corticosterone secretion was greater in the old than in the young vehicle-treated rats. Ateroid treatment normalized this exacerbated corticosterone response to stress. 4. Daily Ateroid treatment did not affect any of the parameters measured in the young (5-8 months) F344 male rats. 5. Ateroid treatment did not affect the age-related reductions in exploratory behavior. The aged and young animals did not differ in their swimming ability. Thus, the effect of Ateroid on learning and memory processes does not appear to be due to an effect on locomotor or performance skills. 6. The age-related deficits in conditioned avoidance learning were not associated with abnormal basal (morning trough) plasma corticosterone levels, and Ateroid did not affect basal plasma corticosterone concentrations.

Aging↗
PubMed1991

Non-heparin glycosaminoglycan-derived drugs: a biochemical and pharmacologic perspective.

The developments in the area of glycosaminoglycan derived drugs can be summarized in the following: 1. Currently available glycosaminoglycan-derived drugs represent a first generation of clinically useful agents. At present these agents are not optimized and their basic and clinical pharmacology is poorly understood. 2. Most of these agents represent mixtures of different types of glycosaminoglycans. They can be purified to isolate their active components and perhaps many new drugs may be developed from the existing products. 3. Chemical derivatization and fractionation methods can be used to obtain more defined products. These products will be developed for specific clinical indications. 4. Each glycosaminoglycan derived product should be considered as an individual drug and should be developed separately. 5. Many semisynthetic and synthetic analogs of glycosaminoglycans will be introduced for various clinical indications.

Animals↗