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The authors present two cases of septic complications after chemonucleolysis with chymopapain. One patient developed overt aortic valve failure. The second patient suffered an epidural abscess.

A 9- to 12-year follow-up review was conducted in 105 of 124 patients who were treated with chymopapain chemonucleolysis for herniated lumbar disc. The data were obtained from responses to a questionnaire. Seventy-nine patients (75.2%) reported marked improvement, six (5.7%) had slight improvement, and 20 (19.0%) had no improvement. Of the 87 patients not receiving workman's compensation, 70 patients (80.5%) had marked improvement; four (4.6%) had slight improvement; and 13 (14.9%) had no improvement. Of the 18 compensation cases, nine patients (50.0%) had marked improvement; two patients (11.1%) had slight improvement; and seven patients (38.9%) had no improvement. These results are comparable to those reported for surgical discectomy, and confirm that chymopapain chemonucleolysis is an alternative to surgery.

Other investigators have demonstrated fibrin deposition in tumors. Experiments were therefore designed to test whether systemic defibrination would alter tumor growth or tumor response to chemotherapy with cyclophosphamide. Defibrination with Ancrod, a venom extract of Agkistrodon rhodostoma, did not significantly affect tumor sensitivity to chemotherapy. Similarly, defibrination plus fibrinolytic therapy with streptokinase did not affect responsiveness to cyclophosphamide. Long-term defibrination did not affect tumor growth. These results suggest three possible interpretations: (a) the coagulation system may not be important in tumor growth and response to chemotherapy; (b) adequate clearing of fibrin from the tumor was not accomplished in our experiments; or (c) other factors such as platelet deposition may be involved and platelet function was not inhibited by the therapies used in our experiments.

The variations of different antiplasmins were studied in a group of patients suffering from thromboembolic conditions and receiving three different regimens of thrombolytic treatment with streptokinase and urokinase. The evaluation of the antiproteases was carried out by chromogenic substrate and radial immunodiffusion. The different administration patterns of the fibrinolytic agents were followed by a clear drop in fast antiplasmin and alpha 2-macroglobulin, while alpha 1-antitrypsin was increased. Antithrombin-III activity was reduced while its protein rose in the intermittent treatment with streptokinase. In the conventional treatment with streptokinase, both the activity and the protein of antithrombin-III increased. With urokinase both the protein and the activity of antithrombin-III were slightly reduced. Plasminogen and fibrinogen decreased in the different regimens of thrombolytic treatment, being more evident in continuous administration of streptokinase.

Eighteen patients with severe, acute ischemia of the lower limbs were treated with an arterial perfusion of the ischemic leg with Urokinase. This was associated, in thirteen patients, with a limited attempt of revascularization. The result of this treatment was an immediate improvement in twelve cases, which lasted, more than six months, in six patients. The authors insist on the interest of the arteriography performed after the fibrinolytic treatment in order to complete the revascularization.

28 patients with 1 to 6 week old occlusions of the femoral and/or iliac veins as well as the subclavian veins were treated with a standardised urokinase-heparin-scheme. The fibrinolytic therapy was generally performed over a period of 7 to 14 days. In 2 patients, the 1 and 6 weeks respectively old thromboses of the iliac, femoral and tibial veins, and in 4 patients the 5 to 16 days old thromboses of the subclavian veins could be dissolved completely, 16 patients showed clinically and phlebographically a substantial amelioration. In 6 patients no marked success was found.

The therapeutic response to treatment of lumbar disk herniation with chymopapain chemonucleolysis is significantly influenced by the criteria used for patient selection. Although careful clinical selection of patients reduces the frequency of treatment failure, some patients do not achieve satisfactory relief of pain with chemonucleolysis. In an attempt to identify objective pretreatment radiographic findings that might refine selection criteria and further reduce the failure rate of chemonucleolysis, a retrospective correlation of pretreatment radiographs and clinical responses was made of 200 consecutive chemonucleolysis patients. Marked improvement in sciatica occurred in 79.9% and 79.3% of patients at early and late follow-up, respectively. There was a significantly higher response rate, however, in patients who had definite radiographic evidence of focal disk herniation and in those patients with definite radiographic evidence of nerve-root compression (marked nerve-root deviation, nerve-root flattening or edema, root-sleeve amputation) by disk material. Those patients with a preinjection disk height greater than the mean had a slightly better response rate (91.1%) than those whose disk height was smaller than the mean (80.0%). Most cases of treatment failure could be attributed to an incorrect radiographic diagnosis, treatment of patients with equivocal diagnostic studies, the presence of "free" disk fragments, and causes of nerve-root compression unresponsive to chymopapain.

The state of thrombin-plasmin system was studied in 34 rabbits with Masuga nephritis untreated or treated with the use of heparin, urokinase, and uroplasmin. The untreated animals developed long-term activation of thrombinogenesis (hypercoagulation) with simultaneous inhibition of fibrinolysis accompanied by deposition of fibrin-postive substances in the lumens of capillaries and glomerular capsules, along basal membranes, and inside epithelial and endothelial cells. Heparin inoculated prophylactically prevented the development of nephritis and typical changes in the thrombin-plasmin system. Treatment with heparin, urokinase or uroplasmin produced regression of nephritis, elimination of fibrin-positive substances from the kidneys and gradual complete normalization of the functional status of the thrombin-plasmin system. It is suggested that not only heparin but also urokinase and uroplasmin can inhibit the immune process. The experimental results favours the immunocoagulation theory of nephritis pathogenesis.

Two fibrinolytic drugs, streptokinase and urokinase, have undergone extensive clinical evaluation in the past fifteen years. Current evidence suggests that these agents may become the drugs of choice in the treatment of certain patients with venous thrombosis and pulmonary embolism. The ultimate usefulness of fibrinolytic therapy in the treatment of thrombotic conditions other than venous thrombosis and pulmonary embolism has not yet been determined.

Symptoms arising from a herniated disk appear when the nucleus pulposus or soft inner portion of the disk bulges against a nerve root. When conservative treatment fails to help the patient, the enzyme chymopapain is currently being used in the treatment of such conditions. Injected directly into the disk, the chymopapain dissolves the nucleus by enzymatic action which selectively breaks certain bonds within the nucleus. The pressure within the center is decreased, hence the pressure against the nerve root is relieved, alleviating the symptoms. Because back care is particularly important following such treatment, physical therapy is valuable in promoting continued relief. The major emphasis of the therapy back care program is on abdominal strengthening exercises and postural training.

Forty patients with chronic sinusitis were treated orally with sfericase tablets (each tablet = 10,000 units), a proteolytic enzyme preparation, at a daily dosage of six tablets for adults and three tablets for children in three divided doses after each main meal for 4 weeks. As regards subjective symptoms, very favorable results were obtained after 4-week treatment with sfericase as evidenced by an efficacy rate of 81.6% for postnasal rhinorrhea, 66.7% for rhinorrhea, and 43.6% for nasal obstruction. However, with respect to objective symptoms, the efficacy rate was 28.9% for redness and 30.8% for swelling of the nasal mucosa, with a somewhat lower rate than that obtained for subjective symptoms. According to the patient's and physician's global assessments, sfericase was effective in 65 and 57.5% of the cases. None of the cases showed undesirable reactions to sfericase.

To extent the safety information for Chymodiactin (chymopapain for injection), 37 neurologic and orthopedic surgeons conducted an open-label, multicenter, phase 3 clinical study. A total of 1,498 patients with one or two herniated lumbar intervertebral discs were enrolled. Therapeutic results were generally favorable, with the percentages of patients achieving either excellent or good (or successful) results ranging from 79.6% to 88.9%, depending on criteria employed in the tabulation. There were 13 cases of anaphylaxis, and 2 of these patients died of complications of anaphylaxis. Two additional patients experienced serious neurologic problems. The first of these two patients developed transverse myelitis and paraplegia approximately 3 weeks following chemonucleolysis. Transdural discograms at three levels had been done approximately 2 days prior to chemonucleolysis, in violation of the protocol. The second patient developed acute cauda equina syndrome, and, despite emergency laminectomy, had permanent neurologic sequelae. Back spasm and stiffness/soreness were the most frequently encountered adverse experiences.

To update the status of chymopapain in the treatment of herniated intervertebral discs, a review of the current literature and data from an unpublished Texas study are presented. Studies in animals and humans have consistently demonstrated that chymopapain can dissolve the nucleus pulposus. Twenty-eight uncontrolled and unblinded clinical trials involving 2845 patients showed a positive response rate of 75%. Side effects occurred in 2.4% of chymopapain-treated patients. Anaphylaxis, the most serious adverse reaction associated with chemonucleolysis, was noted in less than 1% of patients. No deaths were reported. The first double-blind, placebo-controlled study of chymopapain in the United States demonstrated no significant efficacy, but both the design and execution of the study have been criticized. Two recent double-blind, placebo-controlled studies showed success rates of 73% and 80% for chymopapain, significantly higher than for placebo treatment. Postinjection back pain and muscle spasm were the most common side effects related to chymopapain administration in one of the trials. In the uncontrolled Texas study the success rate in 408 patients treated by chymopapain was 93%. Chemonucleolysis has achieved a success rate comparable with that of surgery in the treatment of symptomatic herniated discs. Appropriate use of chymopapain can result in substantial savings in time and hospital costs.

Previous experimental studies on the canine intervertebral disc treated with chemonucleolysis have shown encouraging results in preserving normal histologic, biomechanical, and radiographic disc appearance. These observations suggest that chemonucleolysis may have significant advantages over surgical disc excision in preserving normal function of the lumbar vertebral motion segment. An experimental canine study was devised to examine and compare the short and long-term effects of chemonucleolysis and surgical disc excision on the entire lumbar motion segment to determine if one treatment modality is superior to the other in providing better maintenance of motion segment function. Twenty adult beagle dogs underwent anterior laparotomy. In ten dogs, Chymodiactin was injected into the L4-5 disc and in the remaining ten, routine surgical discectomies were performed on the L4-5 disc. Preoperative and presacrifice lateral radiographs were obtained. All dogs were allowed to exercise freely. Five dogs that received Chymodiactin (Group A) and five dogs that had surgical excisions (Group B) were killed six weeks postoperatively. Five months postoperatively, five dogs given Chymodiactin (Group C) and 5 having surgery (Group D) were also killed. Mechanical testing was performed on each treated disc sample with a modified MTS machine (MTS Systems Corp., Minneapolis, MN). Axial compression, bending, shear, and torsion were assessed in ten modes. Stiffness values for each mode were calculated. Following the biomechanical tests, the facet joints and the disc with the adjacent endplate were removed intact and analyzed histologically and with high resolution radiography. Six-week biomechanical testing revealed a 50% loss of torsional stiffness, as well as loss of anterior and medial-lateral shear stiffness in the chemonucleolysis group.(ABSTRACT TRUNCATED AT 250 WORDS)

Chemonucleolysis is a procedure in which an enzyme is injected into the intervertebral disc for the purpose of alleviating sciatic pain. This has a reported success rate of 70%-90%. Of the failures, several will benefit from a classic lumbar laminectomy for removal of a free fragment in the spinal canal caused by either improper technique or inadequate enzyme activity. However, in a significant number of cases, the failure is related to either instability or the compression of the nerve roots in the neural foramen. Observations on 17 cases demonstrate that PLIF can relieve pain and other symptoms in cases of failed chemonucleolysis.

The effects of sequential therapy with ancrod followed by streptokinase are reported in a series of patients with thrombotic disease. Measurements have been made in blood coagulation, fibrinolysis and whole blood and plasma viscosity. Intravenous infusion of ancrod resulted in a significant reduction in plasma fibrinogen which was associated with highly significant reduction in both plasma and whole blood viscosity. Sequential therapy with streptokinase resulted in a gradual rise in fibrinogen and a slight but significant rise in whole blood and plasma viscosity. All patients showed clinical improvement and no haemorrhagic complications resulted.

Pre-injection psychological test scores, surgeon ratings, and patient biographical data were evaluated as predictors of success of chymopapain injection therapy in 130 patients who would otherwise have been treated by laminectomy. Three psychological tests were administered to each patient: the Minnesota Multiphasic Personality Inventory, the Cornell Medical Index, and the Quick Test (a measure of mental ability). In addition, the surgeons rated their patients on a five-point scale immediately after injection relative to their suitability for injection therapy and at one year relative to the objective and symptomatic results. The MMPI hysteria and hypochondriasis scales and the surgeon's rating of the psychogenic component of the patient's pain were predictive of the result of chemonucleolysis. The patient's biographical data which consisted of age, sex, marital status, occupation, and education were not related to postoperative outcome.

Immediate anaphylactic reactions after intradiscal chymopapain (CP) injection may occur in 1% of patients undergoing chemonucleolysis (CN). Skin prick testing to CP (10 mg/ml), a prescreening history, and CP serum-specific IgE determinations by the RAST method were performed in order to identify patients presensitized to CP before CN. Follow-up repeat CP skin testing and serum-specific IgE were done 2 to 6 weeks after CN to detect CP IgE-mediated sensitization resulting from the injection. Three of 84 patients who exhibited positive skin tests to CP before CN did not receive CP injections. Only one of the three patients (33%) was detected with elevated CP serum-specific IgE before CN. No immediate severe anaphylactic reactions caused by CP injection were encountered in the remaining 81 patients with negative CP skin tests and RASTs before CN. Eight (10%) nonlife-threatening immediate and late reactions were associated with conversion from negative skin tests and RASTs before CN to positive skin tests or RASTs after CN. Overall, 19 of 52 (37%) patients who returned for follow-up testing developed cutaneous sensitization to CP after CN. Despite the fact that RAST values after CN in these patients were significantly higher (p less than 0.002) than those with negative skin tests after CN, the sensitivity of the RAST was only 72% for identifying patients who developed positive CP skin tests after CN. This study demonstrated that CP skin testing is essential for prescreening patients because it was more sensitive than RAST for identification of CP sensitivity both before and after CN. Late allergic reactions and cutaneous sensitization to CP were common sequelae of CN.

Results in 200 patients with lumbar disk disease who had chemonucleolysis were evaluated by two means. First, the surgeon evaluated the patients clinically from 6 to 30 months after chemonucleolysis by rating each case as excellent, good, fair, or unimproved. Results were judged excellent or good in 91% of the 153 "clean" cases (without previous operation) and in 53% of the 36 with previous operation; 11 patients were lost to follow-up. No patients were clinically worse than before treatment. Scond, a physiatrist did a repeat electromyogram three months or longer after chemonucleolysis. He judged a patient improved if there was a decrease or disappearance of the positive waves and/or fibrillation potentials noted on initial electromyogram. Based on these objective findings, 90.5% of "clean" cases and 85.4% overall showed improvement. Surgeons' clinical evaluations and the independent physiatrical evaluations based on objective electromyographic findings thus correlated closely.

Sixteen patients with arteriosclerosis and pre-gangrene of a lower limb were treated for 5 days by intravenous injection of Arvin. The effects of the injection on plasma fibrinogen, the viscosity of blood and the patient's symptoms were measured. There was a 90 per cent reduction in plasma fibrinogen and a significant reduction in the viscosity of blood. Five patients experienced some relief of pain during the treatment. In only one patient were the symptoms relieved permanently.

Chymopapain degrades the nucleus pulposus portion of the intervertebral disk of rabbits. The degradation is not grossly visible until 15 days post-injection. Depolymerization of the chondromucoprotein and decreases in the ability of a disk to imbibe fluid, is, in effect, a "chemical decompression" of the nucleur pulposus. The enzyme must come into direct contact with the chondromucoprotein complex of the disk material, and to a significant extent also must reach the area of disk material adjacent to the herniated annulus. Rapid depolymerization of the chondromucoprotein complex on a biomechanical level, and "decompression" of disk material on a biomechanical level can be correlated with relief of pain in all types of disk herniation in human beings. A primary biochemical change in the disk material would lead to a secondary decrease in inflammation if the change led to a "decompression" of the chondromucoprotein. Since the primary effect of chymopapain is on the chondromucoprotein of the disk, beneficial results would not be expected if nerve root compression is due to bony impingement or scar tissue following previous surgery. Chymopapain did not seem to possess any anti-inflammatory properties when bone was used as an irritant under a nerve root. However, this was technically difficult to evaluate and the possibility that chymopapain may also interfere with a chemical mediator of pain or interfere directly with an inflammatory reaction secondary to root compression can not be excluded.

The three published randomized clinical trials of chymopapain injection vs. placebo injection for the treatment of herniated lumbar discs are reviewed. Despite some differences, the similarities in selection criteria, technique, and outcome assessment are great enough to justify pooling the results to obtain an overall assessment of chymopapain efficacy. These pooled results suggest that the odds of successful outcome (at least some improvement in symptoms after injection) are 2.6 times as great with chymopapain injection as those after placebo injection. This corresponds to a 50% greater probability of success with chymopapain than with placebo or a 23% increase in the number of patients successfully treated with chemonucleolysis over those successfully treated with placebo. The fact that data from 234 patients evaluated in randomized clinical trials could resolve a controversy over therapeutic efficacy that the uncontrolled evaluation of over 20,000 patients could not answer suggests that the current controversy over the relative efficacy of chymopapain and discectomy should be studied in the same way. The difficulties of such a study are discussed.

Chymopapain chemonucleolysis was performed on 100 patients with primary lumbar intervertebral disc disease. The results were compared with those of 174 patients who underwent laminotomy, foraminotomy, and discectomy. Primary lumbar intervertebral disc disease was arbitrarily divided into degenerative, complex, previous surgical, and simple disc syndromes. No difference was seen between chemonucleolysis and surgery in the first three divisions; between 55 percent and 60 per cent of patients responded successfully to treatment. In the simple disc division 89 per cent of the surgical and 60 per cent of the chemonucleolysis patients had successful results.

Chymopapain was first used for treatment of lumbar disc herniation in 1964 and has been used extensively in Canada and Europe for the last decade, but was recently released for general use in the United States. The enzyme is thought to cause decrease in intradiscal pressure and in disc volume; however, little in vivo evidence exists to support this concept. High resolution computed tomography (CT) scans were performed for diagnosis and at a variable period following chemonucleolysis on 17 randomly selected patients. The results of the study were: disc space narrowing occurred almost invariably; retraction of the prolapsed or extruded disc occurred in many patients; clinical improvement was closely related to retraction of the prolapsed or extruded disc; the best clinical results were obtained in patients who were injected at a single level with a clearly demonstrable disc prolapse or herniation.