[Sustained dynamic release characteristics of fibrin glue enwrapping cisplatin].

OBJECTIVE: To summarize the sustained dynamic release characteristics of fibrin glue enwrapping cisplatin. METHODS: In this in vivo study, 20 patients received fibrin glue enwrapping cisplatin placed into the abdominal cavity while another 20 patients received cisplatin as the control group. Their peripheral blood and urine samples were collected at a regular interval to determine the concentrations and the pharmacokinetic parameters of cisplatin. RESULTS: The peak peripheral blood concentration of cisplatin in the study group was significantly lower than that in the control group [(192.2 ± 33.5) vs (1077.6 ± 176.6) µg/L, P < 0.01]. And the peak urine concentration of cisplatin was significantly lower in the study group than that in the control group [(18.6 ± 8.7) vs (55.8 ± 12.7) µg/L, P < 0.01]. The elimination half-life of cisplatin was 23.32 h and 13.93 h respectively in the study and control groups. The elimination half-life and the area under the curve in peripheral blood and urine samples of the study group were significantly longer than those of the control group (P < 0.01). CONCLUSION: The fibrin glue enwrapping cisplatin has the excellent in vivo characteristics of sustained dynamic release. Thus it may prolong the retention of cisplatin in abdominal cavity and lower its concentration in peripheral blood.

Advantages and safety of local treatment with MMC/Beriplast P for cancer tumors.

To target the treatment of small points of cancer, Beriplast P, already used clinically as a physiological tissue adherent drug carrier, was mixed with the anticancer drug, mitomycin C (MMC). In this in vitro study, MMC did not release quickly from the clot of MMC/Beriplast P. The antitumor effect of this mixture was examined for its effect on cancer growth. In one series of experiments, tumor tissues were inoculated with MMC/100 microliters Beriplast P and in another series, MMC/100 microliters Beriplast P was injected into tumors at a weight of 300 mg. In the first series of experiments, tumor tissue treated with 0.3 mg MMC/100 microliters Beriplast P was replaced with plasma cells and lymphocytes, and no viable cancer cells could be found. In the second series, MMC/100 microliters Beriplast P delayed tumor growth, and the survival of Balb/c mice injected with 0.08 mg MMC/100 microliters Beriplast P was significantly longer than that of mice injected with 0.08 mg MMC/100 microliters saline solution (P = 0.026). In addition, the abdominal aorta, vena cava, and intestine around the area of treatment with 1.6 mg MMC/100 microliters Beriplast P were not damaged. These results indicate that the mixture of Beriplast P and MMC is more effective than MMC solution alone in the local treatment of residual cancer.

A comparison of fibrin sealants in relation to their in vitro and in vivo properties.

INTRODUCTION: Fibrin sealants (FS) have been used for many years to facilitate hemostasis and to provide suture support and sealing/adhesion of tissues after surgery. While their composition is similar, different formulations, application devices, and varying concentrations of key components mean that the properties of clots formed by individual FS can be diverse. MATERIALS AND METHODS: We performed several studies, including animal models, to compare the properties of 12 different commercially available FS/application device combinations using partial liver and kidney resection models to assess hemostatic efficacy and a novel pig skin model to measure adhesive clot strength. The quality of mixing was determined using colored spray images. RESULTS: Although the FS tested shared the principle of combining fibrinogen and thrombin, major differences were found between the individual preparations with regard to hemostatic efficacy. Two pre-requisites for successful early hemostasis were identified--adequate clottable protein content and the ability of the application device to effectively mix the fibrinogen and thrombin components of the FS. Factor XIII activity was a key determinant in prevention of re-bleeding and premature clot lysis. Furthermore, FS lacking measurable factor XIII activity formed the weakest, softest clots. CONCLUSIONS: Clearly, all FS are not the same, and their different characteristics may potentially translate into different clinical outcomes. In our studies, while all FS tested performed well on individual parameters, Beriplast P (Aventis Behring) was the foremost FS in consistently providing early hemostasis, minimizing the risk of re-bleeding, and providing strong adhesive clots capable of resisting mechanical forces.

Taurolidine-Fibrin-Sealant-Matrix using spray application for local treatment of brain tumors.

Malignant gliomas tend to recur in the vast majority of cases. Recurrent gliomas may arise from vital tumor cells present in this zone around the resection margin. It appears promising to combine tumor resection with local chemotherapy using an antineoplastic, but non-toxic agent. Taurolidine exerts a selective antineoplastic effect by induction of programmed cell death and has anti-angiogenic activity. Fibrin sealant is completely degradable and firmly adheres to brain tissue, suggesting that it would provide a suitable matrix for taurolidine delivery--a Taurolidine-Fibrin-Sealant-Matrix (TFM)--in the local treatment of brain tumors. The potential of local delivery of taurolidine out of a fibrin sealant matrix was investigated. Taurolidine could be suspended homogeneously in both the thrombin and the procoagulant protein components of the fibrin sealant. The fibrin sealant matrix was a suitable carrier for the suspension of taurolidine at a concentration that ensured the release of therapeutically effective amounts of the drug over a period of 2 weeks in vitro. The antineoplastic action of taurolidine was not affected by embedding in the fibrin sealant matrix. The described drug delivery system may be suitable for local taurolidine treatment of brain tumors following complete or partial resection or of tumors that are non-resectable because of their location.

Resorption of fibrin tissue adhesive sealant by isolated osteoclasts in culture.

The tissue tolerance of fibrin tissue adhesive sealants has been investigated. These materials are increasingly being used to close wounds and to stabilize spongy bone transplants. An in vitro model consisting of isolated osteoclasts in primary cell culture was used. The 2 commercially available tissue adhesive sealant protein solutions differ substantially with regard to the spreading and resorption capacity of the cultivated osteoclasts.

[The pharmacokinetics of a fibrin adhesive agent applied to the rat lung].

PURPOSE: Although fibrin adhesive agents are frequently applied in the clinical setting, their pharmacokinetics in vivo remain to be clarified. We examined the pharmacokinetics of a fibrin adhesive agent applied to the rat lung. MATERIAL AND METHODS: Male Sprague Dawley rats were used. Under general anesthesia, left thoracotomy was performed, and the left lung was incised about 1 cm length and 1 mm depth. This incision was sutured with 9-0 nylon, and a fibrin adhesive agent containing 125I-labeled fibrinogen was applied. On days 1, 3, 7 and 14 after the operation, the left lung, right lung, liver and kidneys were collected. The tissue distribution of radioactivity was examined by determining the 125I levels in each organ as well as calculating the tissue levels of radioactivity. RESULTS: The tissue distribution of radioactivity in the left lung was significantly higher than those in other organs on days 1 and 3. The tissue levels of radioactivity in the left lung was significantly higher than those in other organs on days 1, 3 and 7. Each value rapidly decreased after day 7. CONCLUSION: A fibrin adhesive agent applied to the lung significantly remained at a high level through the inflammatory and proliferative phases followed by a prompt decrease before the phase of cicatrization. Therefore it is considered that a fibrin adhesive agent applied to the lung is satisfactory for the healing of wounds.

[Antitumor effect of MMC mixed in Beriplast P].

We attempted to mix an anticancer drug. MMC, with a fibrinogen preparation, Beriplast P (B. P.). First, we examined how MMC was gradually released from its mixture. As the result, its release depended on the MMC concentration in B. P., and the release rate of 1.0 mg MMC from 100 microliters B. P. was 1.6 mg/30 min. Second, we examined the safety of the conjugated drug for normal tissue, because MMC is one of anticancer drugs causing serious damage to normal tissue. When the conjugation of 100 microliters B. P. and below 1.6 mg MMC was coated within one square centimeter, the drug was safe for the endothelium of artery and vein, and the intestinal wall. Third, we attempted an experiment on both the antitumor effect and the role of survival prolongation of the conjugated drug in a mouse carrying a malignant tumor. MMC conjugated with Beriplast P had a highly antitumor effect, which caused necrosis in the cancer cells in unstable conditions. Also, its conjugation drug could inhibit the growth of cancer cells in stable conditions, and prolonged the survival period. From these results, the mixture of MMC and B. P. was found to possess an MMC releasing effect, was safe for normal tissues, and showed high antitumor effect with prolongation of the survival period.

[Local chemotherapy for malignant brain tumors using methotrexate-containing fibrin glue].

Fibrin glue (FG) is an agent developed for achieving hemostasis and the adhesion of living tissue during surgical operations. Incorporation of a drug into FG may be expected to have a sustained local release. In the present study, methotrexate (MTX) included in FG (FG-MTX) was used. The release of MTX into human plasma and cerebrospinal fluid was studied by in vitro study to confirm the sustained release effect of this preparation, by in vivo study, in which the antitumor effect of FG-MTX was assessed in rats bearing 9L-gliosarcoma subcutaneously; and clinically, FG-MTX therapy was attempted in patients with malignant brain tumors. The in vitro study showed that MTX levels rapidly decreased over 1 to 3 days, but was still detected on days 7 and 14. The results showed the sustained release effect of MTX. The in vivo study showed that in the FG-MTX group, all tumors began to decrease soon after administration and disappeared in four out of five animals (80%) on about day 10. In the clinical study, sustained release for more than one week was found, and tumor decrease occurred in the case of a malignant brain tumor. Thus, FG-MTX appears to provide an effective local chemotherapy.

[The effect of the microenvironment of the liver tissues on the dynamic resorption of hemostatic resorbable materials and of adhesive compositions]. / Vliianie mikrookruzheniia tkanei pecheni na dinamiku rassasyvaniia gemostaticheskikh rassasyvaiushchikhsia materialov i kleevykh kompozitsii.

In experiment there was studied up the cells and tissues reaction on implantation of hemostatic alginate material "Gram-1", "hemostatic gauze" preparation, fibrinous glue composition and sulfoacrylate adhesive glue MK-3.

Determination of porcine fibrinogen in rat and dog plasma after intraperitoneal injection of a porcine-derived fibrin glue by fluorescein-labeled assay method: Comparison with isotope-labeled assay method.

A sensitive and specific fluorescein isothiocyanate (FITC) label coupled with size-exclusion high-performance liquid chromatography-fluorescence detection (SE-HPLC-FLD) method was developed and validated for the estimation of the pharmacokinetic profiles of porcine fibrinogen after intraperitoneal injection of a porcine-derived fibrin glue (FG) to SD rats and beagle dogs with three single doses. Porcine fibrinogen, the major composition of the FG, was labeled with FITC. The FG containing FITC-labeled porcine fibrinogen was intraperitoneally administered to SD rats at three single dosages (100, 200, 400mg/kg of porcine fibrinogen), and the collected plasma was then detected by SE-HPLC-FLD method. The present technique was compared to the previously introduced isotope-labeled assay method for the pharmacokinetic studies in SD rats. The pharmacokinetic studies in SD rats showed that the correlation coefficient between the FITC-labeled assay and (125)I-labeled assay methods was r(2)=0.989. Thus, this FITC-labeled assay method performed well and demonstrated high concordance with the previous (125)I-labeled assay method, suggesting that FITC-labeled assay could substitute the (125)I-labeled assay as a method of choice for quantification in beagle dogs. Then the plasma levels of porcine fibrinogen in beagle dogs were studied by the FITC-labeled assay method with three single doses (15, 30, 60mg/kg of porcine fibrinogen). The method validation showed that the FITC label coupled with SE-HPLC-FLD method was suitable for the quantification of porcine fibrinogen in plasma samples with satisfactory linear (r(2)>0.999), precision (<12%), accuracy (95.5-104.9%) and recovery (>88%). The results showed linear disposition of porcine fibrinogen at the examined dosage range in SD rats or beagle dogs.

Fibrin chain cross-linking, fibrinolysis, and in vivo sealing efficacy of differently structured fibrin sealants.

In this study, we compared the sealing characteristics and efficacy of a fibrin sealant with reduced plasminogen (FS-rplg) and a fibrin sealant with aprotinin as a fibrinolysis inhibitor (FS-apr). The relevant sealing characteristics including clot structure, fibrin chain cross-linking, and clot lysis were tested in the laboratory. The sealing efficacy was then investigated in a follow-up animal model to determine differences in the in vivo sealing properties. A total of 46 animals were available for the final analysis with 23 animals in each treatment arm. In conclusion, we saw differences in vitro between FS-rplg and FS-apr in ultrastructure and α-chain cross-linking rates as well as in the rate of fibrinolysis. These differences may explain the significantly enhanced sealing efficacy in FS-apr compared to FS-rplg shown in vivo in a rabbit intestinal model.

Effect of Tisseel on healing after periodontal flap surgery.

The purpose of this investigation was to evaluate the effect on healing of fast and slow absorbable Tisseel in combination with periodontal flap surgery. Mucoperiosteal flaps were raised on the buccal aspect of maxillary premolars and mandibular premolars and first molars in 4 beagle dogs. The underlying buccal, interproximal and inter-radicular bone was then removed to a level of approximately 5 mm apically to the original bone crest and half way into the interdental spaces and bifurcations. The exposed root surfaces were curetted in order to remove the periodontal ligament tissue, and a notch was made in the root surface at the base of the defects. On the control teeth, the flaps were sutured immediately after creation of the defects, while on the test teeth, a layer of fast (group I) or slow (group II) absorbable Tisseel was applied between the curetted roots and the subsurface of the flaps prior to suturing. Postoperatively, the teeth were brushed 2 x weekly. The dogs were sacrificed after 4 months. Histological analysis revealed that the amounts of new attachment and bone regrowth were similar in the test and control groups, although the results tended to be most favorable for the group of teeth treated with fast absorbable Tisseel (Group I).

Nerve repair using freezing and fibrin glue: immediate histologic improvement of axonal coaptation.

Despite the fine microsurgical techniques available, injuries to peripheral nerves are still a surgical problem. Sutures placed in the epineurium or perineurium cause compression, brushing, and misdirection of endoneural tissue. A technique of nerve repair using freezing to trim the nerve and fibrin glue to coat it before thawing is described. The entire surgical repair procedure is carried out with the nerve stumps frozen. The observed axonal alignment with this technique was much better than that obtained by microsuture alone.