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Following the administration of habutobin, the fibrinogen level in the circulating blood of the rabbits decreased. These results showed that the activity of habutobin was retained in vivo. The plasma level of habutobin was determined by a ELISA-double sandwich method. The pharmacokinetics of habutobin from Trimeresurus flavoviridis venom was studied in rabbits following i.v. administration of 50 micrograms kg-1 of habutobin. The time course of the plasma concentration of habutobin fitted a two-compartment open model. The half-life of the distribution phase was 4.43 +/- 1.28 min and that of the elimination phase was 50.42 +/- 7.89 min. The area under the plasma concentration-time curve (AUC) was 38.69 +/- 6.68 micrograms min ml-1. The total body clearance was 3.82 +/- 1.08 ml min-1. When the steady state was reached, the concentration ratio of habutobin in the tissue (Ct) to that in the plasma (Cc), Ct:Cc was 0.47:1. These findings suggest that relatively little habutobin tended to remain in the tissue.

Effects of alpha-chymotrypsin and deoxyribonuclease I (DNase I) on the early phase of blood-borne lung metastasis in rats were studied using confocal laser scanning microscopy and AH-109A cells labeled either with carboxyfluorescein diacetate succinimyl ester or with 51Cr. Intravenous administration of alpha-chymotrypsin or DNase I appeared to enhance or inhibit, respectively, the tumor cell arrest in lung microvasculature as a reflection of reduction or promotion of the tumor cell clearance in the microvasculature. These results suggest that the effects of alpha-chymotrypsin and DNase I are related to induction of tumor cell aggregation and disaggregation in the blood stream, respectively.

Esperase is a proteolytic enzyme preparation that can be used as a processing aid in the food industry. The following studies were performed to establish safety for the consumer: oral toxicity study (13 wk) in the rat; teratogenicity study in the rat; gene mutation assays in Salmonella typhimurium and mammalian cells in vitro, and chromosome aberration assay in vitro. General toxicity was low; the effects seen were attributed to proteolytic activity and the loading with sodium chloride. Neither of these factors will be relevant to consumers of the processed food. There was no evidence of effects on pregnancy outcome or mutagenic potential. When these results are considered together with existing knowledge of the production organism and the chemical and microbiological characterization of the enzyme preparation, they indicate that Esperase will be safe for its intended application in food processing.

Protegentin is a formulation in the form of an ointment for local application. Its high efficacy was demonstrated in the treatment of wounds in the 1st phase of the process, extended decubitus, trophic ulcers, wounds of various genesis not healing for prolonged periods, urogenital infections, abscesses, maxillofacial phlegmon and abscessing parodontosis. The ointment showed good draining, proteolytic and bactericidal effects. The tolerance was good. The positive results were observed in 97 per cent of the cases.

The existence of a potent fibrinolytic enzyme (nattokinase, NK) in the traditional fermented food called 'natto', was reported by us previously. It was confirmed that oral administration of NK (or natto) produced a mild and frequent enhancement of the fibrinolytic activity in the plasma, as indicated by the fibrinolytic parameters, and the production of tissue plasminogen activator. NK capsules were also administered orally to dogs with experimentally induced thrombosis, and lysis of the thrombi was observed by angiography. The results obtained suggest that NK represents a possible drug for use not only in the treatment of embolism but also in the prevention of the disease, since NK has a proven safety and can be massproduced.

The effects of hemocoagulase in injectable form (hemocoagulating enzymatic fraction of South American snake Bothrops jararaca venom provided by Ravizza) on the control of intraocular bleeding during vitreous surgery were evaluated in rabbit eyes. Intraocular infusion solution with hemocoagulase (1 NIH thrombin unit/100 ml of BSS plus) significantly reduced the bleeding time. Electroretinogram b-wave and electroretinogram c-wave showed no abnormality. Infusate with hemocoagulase (1 NIH thrombin unit/100 ml of BSS plus) is not toxic to retinal tissue and appeared to be a useful agent for the control of intraocular bleeding during vitreous surgery.

The bleeding disorder of hemophilia A currently treated by replacement therapy of the missing coagulation factor, factor VIII, is frequently complicated by the development of neutralizing antibodies. The therapeutic potential of attenuated forms of the lipid-associated glycoprotein tissue factor, a known initiator of coagulation, was investigated as a factor VIII-by-passing activity. The protein moiety of tissue factor (Apo-TF) was partially purified and exhibited minimal procoagulant activity before relipidation in vitro. In pilot studies, Apo-TF injection into rabbits previously anticoagulated with an antibody to factor VIII was found to have a procoagulant effect. The efficacy of the material was further demonstrated when injection of Apo-TF in hemophilic dogs resulted in a normalization of the cuticle bleeding time. Little or no change in the blood parameters associated with disseminated intravascular coagulation was observed at lower doses, although mild to moderate effects were seen at higher doses. These data suggest a novel role for Apo-TF preparations as a potential therapeutic agent for hemophiliacs with antibodies to factor VIII once the potential thrombogenicity of such materials is evaluated.

The case is reported of a high responder haemophiliac A, aged 37 yr, who had a severe bleeding episode after surgical treatment of a renal stone. Preoperative anti-factor VIII antibody concentration was 2 UB. Although the surgery was carried out with no real problem (partial nephrotomy), on the 5th postoperative day, there was a sudden increase in the concentration of anti-factor VIII antibodies (21 UB) with a concomitant drastic fall in Factor VIII C level, and important bleeding at the surgical site. The sequential administration of human Factor VIII, "activated prothrombin complex concentrates" (FEIBA followed by AUTOPLEX), and total nephrectomy failed to stem the haemorrhage. Despite intravenous gammaglobulins, the anti-factor VIII titre reached 1300 UB. Bleeding could only be controlled by concentrated porcine Factor VIII (HYATE-C), 100 U.kg-1.8 h-1. This treatment was continued for 50 days, with no side-effects. An average dose of 130 U.kg-1.8 h-1 maintained a residual level of Factor VIII between 1 and 23%. There was a simultaneous fall in the antibody-concentration to less than 1 UB, due to steroid treatment.