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Fifteen patients with severe intermittent claudication were treated by therapeutic defibrination with subcutaneous injections of ancrod for 5 weeks. Mean plasma-fibrinogen was maintained below 50% of the initial value throughout the treatment period. This reduction in plasma-fibrinogen was accompanied by a parallel fall in whole-blood viscosity and a pronounced clinical improvement. Objective measurements showed maximum benefit on the 21st day of treatment, when the mean resting ankle/arm pressure index had increased by 37%, the post-exercise pressure index had increased by 50%, and the time taken for the pressure index to return to a resting value after a constant exercise had decreased by 33%. (The claudication-count had increased by 59%).

Chymopapain recently has won approval in the United States for use in chemonucleolysis of herniated intervertebral discs. New research findings will be emerging, but clinicians need criteria by which to assess new results, to evaluate the existing literature, and to strengthen future investigation. Twenty-six original articles on chemonucleolysis were reviewed according to nine criteria of validity and applicability. Common threats to validity were failure to use randomized controls, make blind outcome assessments, assure equal co-treatments, and to calculate statistical power when results were negative. Threats to applicability included wide variations and incomplete reporting of patient selection, procedure technique, and many relevant outcomes. Methods for improving these design features are suggested, and a basic study design is proposed for comparing chemonucleolysis with both surgical and conservative management techniques.

The results of chemonucleolysis in 48 patients with protrusion of the annulus fibrosus or lumbar disc hernia treated over a period of two years are reported. The nucleolysis was performed under local anaesthesia at a single level in all cases, after the pathological state of the disc and nerve roots had been demonstrated by radiography. Satisfactory results, comparable with those following surgical treatment, were obtained in nearly all the patients with small disc herniae and in three-quarters of the patients with herniae of moderate dimensions. The pre-operative neurological defects showed regression in nearly all cases. The only complication was an infection of the disc in one case.

Twenty of 26 consecutive patients with sciatica caused by myelographically proven disc protrusions who were treated by chemonucleolysis with chymopapain made useful recovery. There were no major complications attributable to the procedure. Certain diagnostic and clinical criteria are described which appear to be important in producing a favorable result following chemonucleolysis.

Computerised tomography (CT) was performed in 30 patients with herniated lumbar discs; this was done both before chemonucleolysis and three months after. In 20 of the 28 patients who were CT positive, the compression produced by the herniated disc was eliminated or reduced. Twenty-three of the 28 patients developed diffuse bulging of the annulus. There was good correlation between the clinical results at three months and the alteration in compression as shown by the CT scan. No evidence of alteration in the bony relationship was seen in the scan and none of the patients developed epidural fibrosis. Chemonucleolysis has thus been shown to be an effective treatment of herniated lumbar discs, but it is definitely not indicated in cases where compression of the nerve root or dural sac is due to a bulging annulus.

Fifty-two patients with unilateral sciatica caused by intervertebral disc herniation were selected on strict clinical and radiological criteria. All patients had failed to respond to conservative measures. Patients in this trial group randomly were allocated surgery or Chymopapain. During the same period, a further 71 patients, who were put forward for the trial, and did not fulfill the trial criteria, were offered Chymopapain as an alternative to surgery. Both groups were assessed at one month, three months, and one year--progress being recorded by clinical examination and visual analogs. The failure rate in the two Chymopapain groups were comparable, with 52% and 47%, but were significantly higher than the surgical group (11%). Surgery in the failed Chymopapain group frequently was delayed and unrewarding. Failures can be predicted at one month posttreatment, and early surgery may be indicated to prevent chronic scarring.

Analysis of the data obtained in experimental (971 animals) and clinical (250 patients) studies with various immobilized proteinases and their inhibitors showed that this approach to enzymotherapy is a perspective one. Immobilized enzymes and inhibitors exceeded distinctly the native preparations in therapeutic efficiency and were devoid of their disadvantages (low stability and autolysis of proteinases, inactivation by inhibitors, occurring in blood and tissues, rapid elimination of the inhibitors from the organism). Wide use of immobilized enzymes and inhibitors in medical practice offered new possibilities in surgery, shortened distinctly the duration of patients treatment and enabled to decrease the doses of drugs and consumption of dressing materials.

The urinary excretion of glycosaminoglycans during the 24 hours after intradiscal injection of chymopapain was found to be greater than during the 24 hours before injection when comparison was made either on the basis of a complete 24-hour urine collection or by the use of a glycosaminoglycan/creatinine ratio. Each individual in a group of 14 patients showed this increase after injection. In contrast, no significant increase over the pre-injection levels was detected in serum glycosaminoglycans during the post-injection time periods for which blood samples were available.

A 16-month-old child was born with pulmonic stenosis and a hypoplastic right ventricle. After palliative procedures, the patient began having signs of tricuspid insufficiency and stenosis necessitating a tricuspid valve replacement. A St. Jude Medical valve was implanted. While the child was on aspirin therapy, thrombus formation resulted in valve dysfunction. This thrombus was successfully dissolved with urokinase infusion, and normal valve function was restored.

The results of chemonucleolysis in 48 patients with lumbar disc disease revealed marked improvement in 58%, slight improvement in 23%, and no improvement in 19%. Serious anaphylactic reactions occurred in two patients. These results and those of other neurosurgical and orthopaedic studies are summarized and compared with the 70% improvement rate obtained with a placebo in a recent double blind controlled cooperative study. Only those few investigators participating in the double blind study are now permitted to use intradiscal chymopapain. It is concluded that the ultimate place of chemonucleolysis, if any, in the treatment of ruptured lumbar discs remains to be determined.

Eleven patients were treated for acute pulmonary thromboembolism by perfusion of urokinase in the main pulmonary artery for a period of 12 hr with angiographic control. Clinical and radiologic improvement was achieved in all patients except for one in whom an embolectomy was later performed. The complications were similar to those for intravenous urokinase treatment, the most frequent being hemorrhage.

Recent reports have shown that malignant cells release a variety of factors that modulate the tumor microenvironment. These factors, after release or shedding, work in concert to produce extravasation of fibrinogen from surrounding blood vessels with subsequent fibrin deposition around the tumor cells. This fibrin deposit could act to mask the tumor from the host's immune surveillance system. Fibrin deposits have been observed by investigators in the vicinity of various malignant tumors of man and animals. Although these observations suggest a role for the blood coagulation mechanism in tumor biology, the pathogenesis and significance of fibrin deposits in tumors have not been thoroughly investigated. We have used crotalase, a highly purified defibrinogenating serine proteinase from eastern diamondback rattlesnake venom and a fibrinolytic enzyme from southern copperhead venom to modulate selectively the tumor microenvironment in order to evaluate the role of fibrin(ogen) in tumor growth and dissemination. B16 melanoma, carried in C57BL/6 mice, has been selected as the experimental model system to evaluate the effectiveness of treatment by the venom enzymes. For these studies, solid B16 melanoma was excised from mice and a cell suspension was prepared in serum-free RPMI 1640 medium. Treatment of the cells with crotalase (30 NIH clotting U/ml) produced a dramatic inhibition of growth after subcutaneous injection of cells into C57BL/6 mice. On day 17 after implantation of tumor cells alone, the average tumor weight was 70 mg/mouse. By contrast, mice that received the B16 melanoma cells pretreated with crotalase had an average tumor mass of only 2 mg/mouse.(ABSTRACT TRUNCATED AT 250 WORDS)

The differential effects on primary tumor growth and on the formation of spontaneous pulmonary metastases have been determined for a series of proteinase inhibitors. The substances included the gold compounds, aurothioglucose and aurothiomalate, D(-)penicillamine, phosphoramidon and an egg-white inhibitor of cysteine proteinase (EWI). The i.p. administration of these substances to mice bearing s.c. Lewis lung carcinoma cause varying degrees of antineoplastic effects; the most pronounced effects on metastases are caused by phosphoramidon. The inactivity of EWI on tumor progression is concomitant with an inhibition to 50% of cathepsin B in tumor homogenates. The selective antimetastatic action of phosphoramidon is in agreement with the crucial role proposed for tumor collagenases in tumor dissemination.

38 cases of chemionucleolysis, under neuroleptanalgesia by droperidol-Fentanyl with spontaneous respiration are reported. This technique was satisfactory and allowed the patient to cooperate.

A case report is presented of a 20 year old patient with an acute promyelocytic leukemia. The presenting symptom was a macrohematuria caused by a consumption coagulopathy. Consumption coagulopathy has only been observed in acute promyelocytic leukemia in contrast to other coagulopathies in acute leukemia. The clotting disorder was successfully treated by administration of urokinase.

Sixty nine patients were treated with local intra-arterial urokinase (37,500 U/CTA. hr-1) for recent severe ischemia of lower limbs: 27 (40%) ultimately required amputation. The difference of amputation rate between the groups with and without thrombolysis was not significant (33% v. 42%). A biological study in 6 patients showed that local arterial plasminemia occurred in only 1 patient. Local urokinase does not strongly stimulate "endogenous" thrombolysis and enhances "exogenous" thrombolysis only very inconstantly. A better adaptation of urokinase dosage or the use of an agent with higher affinity for fibrin might improve the efficiency of local thrombolytic therapy.

In the course of a study (now including 53 patients) on the effectiveness of urokinase in the treatment of acute coronary occlusion, coronary angiography was performed in 2 patients before and after the use of this drug. In both instances the angiograms demonstrated obstruction in the coronary-artery branches, with additional narrowing and some collateral circulation. After urokinase therapy, blood flow was restored in the areas previously obstructed. These 2 case reports are presented because they demonstrate this favorable change in coronary blood flow in association with this particular form of therapy. It is hoped that the completed urokinase study may add some information concerning the effect of thrombolysis in the management of myocardial infarction.

Complete aortic occlusion at L2-L3 occurred in an 11-day-old male with hypernatremic dehydration. Attempted thrombolytic therapy using intraarterial urokinase was unsuccessful in inducing either a systemic hyperfibrinolytic state or lysis of the clot. The infant's plasma plasminogen level was low (50-75% of adult levels) and neither fresh frozen plasma nor cryoprecipitate infusion provided adequate plasminogen replacement. Thrombolytic therapy failure was due in part to inadequate generation of plasmin. Alternative means of lytic therapy will need to be devised for this age group.

Compared with streptokinase, thrombolytic treatment with urokinase has the advantages of being better tolerated and of practically unlimited applicability. Its disadvantage is the high cost. A good lytic action can be obtained with a dosage of 150,000 Ploug Units/12 hours for a duration of lysis of 8-14 days combined with heparin, the therapy being monitored by determination of the products of fibrinolysis. This dosage is not possible if the time factor plays a decisive role in the success of the treatment, e.g. in myocardial infarction. Urokinase is indicated when streptokinase cannot be used, or if continuation of the streptokinase therapy is necessary because of extensive thromboses.

Lewis lung carcinoma cells were implanted in the foot-pads of mice and the effects of the plasminogen-plasmin inhibitor tranexamic acid (t-AMCHA) and of the plasminogen activator urokinase on metastasis were examined by electron microscopy. The intravascular tumour cells were not associated with thrombus formation in either control or urokinase-treated mice. Polymerized fibrin deposition around tumour cells and thrombi composed of fibrin and platelets was observed only in the mice given t-AMCHA. This suggests that the inhibition of fibrinolysis by tACC caused fibrin deposition and thrombus formation around intravascular tumour cells, which prevented release of the cells from primary foci to form secondary tumours. On the other hand, fibrinolysis induced by urokinase prevented thrombus formation, and accelerated cell release from primary foci.