Chymopapain Injection Research Articles

A review of chymopapain for chemonucleolysis of lumbar disc herniation

The purpose of this review was to examine the available literature regarding the efficacy of chymopapain for chemonucleolysis of symptomatic lumbar disc herniation. Recent literature reviews demonstrate that there are few well-designed studies investigating this once more popular treatment modality. There are two landmark papers published by Couto and Gibson that pool the available data and perform meta-analyses to give reasonable conclusions regarding the efficacy of chymopapain for chemonucleolysis. Based on the meta-analyses, injection of chymopapain into the disc has proven to be more effective than placebo. The results of chemonucleolysis with chymopapain and collagenase are similar. Most randomized trials show consistently poorer results with chymopapain compared with surgery, but the results of the meta-analyses do not reach statistical significance. Therefore, no definitive results can be drawn from the available data. Further research and refinement in this modality will be needed before chymopapain therapy can be recommended for widespread clinical use.

Never Get Ahead of Others

We physicians have been expected to be the elite and leaders of our society. We have recognized ourselves or have been considered by others as more intelligent and gifted than ordinary people in every aspect of life. Hence, you may wonder why we should not get ahead of others. What I mean is that we should not be competitive at least in treating patients and performing surgery. No one can deny that we should go the extra mile with research and publication. However, I doubt whether taking an aggressive stance with regard to patient care would be beneficial. I would like to make it clear that I do not intend to depreciate the efforts by doctors or hospitals to explore or implement a new treatment. However, it is another matter whether we should jump on the bandwagon for innovative treatments. Newly developed treatments are not rigorously tested for safety and efficacy in most cases. So they should be publicized and recommended to the public only when their safety and efficacy are proved by several years of follow-up. Let me site an example of spinal surgery, and especially disc surgery, which I specialize in. Between the 1980s and 1990s, chymopapain injection was praised as a simple and effective treatment for lumbar disc herniation. However, it is no longer in use since it caused severe side effects. Thereafter, laser disc surgery and nuecleotome became popular, which were known for involving a minimal skin incision, but they have turned out to be less effective than the established techniques and they have gone the same way as chymopapain injection and the Dodo bird, that is, into oblivion. It is worrisome that new treatments become popular due to the media publicity, but they are without scientific evidence and then they just disappear when their side effects are revealed. Considering that medicine is about treating human beings, extreme care should be taken with using a new treatment. Most importantly, the short-term treatment results observed in some patients should not be described as if they were obtained from all of the patients with the same disease. A doctor's personal experience with some limited number of patients is just an anecdotal episode. People tend to see what they want to see. No wonder then, that we often find ourselves generalizing results based on our anecdotal episodes. This can pose a danger in the field of medicine. That is why only results proven through objective and statistical analyses and comparisons are accepted in the field of medicine. Introducing short-term results obtained from some patients as a proof of successful treatment is an irresponsible act that can lead to a variety of problems. We should also guard against simply implementing a new method even when it is proven to be far more effective than the established techniques. Every surgery has its own learning curve, which represents the period needed to learn from a skilled person. The learning curve is long for difficult surgical procedures. New operative methods based on new ideas or using new devices usually require a long and complex learning curve. You will probably experience difficulties before being accustomed to a method and finally mastering it. Unexpected events often occur in the operating room for surgeons who are armed only with knowledge acquired from books and a complete picture of the surgery. In this situation, the safest and easiest way is to get assistance from an experienced person who can come to the rescue with a solution that cannot be learned from books. Therefore, being the first person to try out a new surgical method means enduring hardship in first few cases without a guarantee of successful outcomes. Accordingly, it would be the best to wait for others to be experienced with the method you have in mind and later learn from them. You do not have to feel ashamed when you have to learn a new method or technique from someone of the same age or a few years junior to you. Rather, you can learn not only the surgical technique, but also the possible complications without paying a price. So, never get ahead of others. That's the wisest way.

Animal experiment studies of the diagnosis and therapy of chymopapain-induced spinal complications

Short and long-term effects of chymopapain on nervous transmission were studied in rats. The drug was injected into the lumbar spinal canal. Action potentials evoked by electrical stimulation of the sciatic nerve were recorded at the dorsal root entry zone of the lumbar cord. One group of rats was pre-treated with dexamethasone. Chymopapain prolongs impulse latency compared to that of control rats treated with isotonic saline. The effect is dose dependent and can last for several weeks. Rats pre-treated with dexamethasone showed milder impairment of nervous transmission after chymopapain injection compared to the rats treated only with papain.

Spinal balloon nucleoplasty: A hypothetical minimally invasive treatment for herniated nucleus pulposus

Low back pain is the most common cause of disability under the age of 45. The annual incidence of back pain is estimated to be 5% and the lifetime prevalence is 80%. Majority of the patients with persistent symptoms are suffering from radiculopathy that is mainly caused by a herniated nucleus pulposus (HNP). HNP can heal spontaneously due to spontaneous resorption. Besides pressure nucleus pulposus, without any compression, may induce similar changes when applied epidurally to the nerve roots. Nevertheless, combination of chronic mechanical compression and application of nucleus pulposus causes a more pronounced nerve injury. When dual pathophysiology (pressure and inflammatory reaction), spontaneous resorption, and natural course of HNP are taken into account, any treatment modality that eliminates both the pressure and contact of the nucleus pulposus with the nerve root via creating extra time for healing to take place might prove beneficial. These requirements can be provided by spinal balloon nucleoplasty (SBN), which can be used in combination with other treatment modalities such as chymopapain injection. In this hypothetical method, epidural access to the subarachnoid space is established via epidural needles, thereafter a specially designed balloon tipped catheter is advanced. When the catheter is ideally placed with the help of CT or MRI, the balloon at the tip is inflated to relieve pressure and to prevent contact of the nerve root with HNP. The answer to the question, will SBN find a place in clinical practice? is obscure. But a homology can be established with uterine fibroid embolization, which has found clinical use in a period of 30 years approximately.

Intradiscal Therapies for Discogenic Pain

Since the first injection of chymopapain in 1963, percutaneous intradiscal therapies have been used to treat discogenic back and leg pain. The percutaneous discectomy techniques treat contained disc herniations not by resecting the prolapsed disc material but rather through central decompression of the disc. By removing a small volume of tissue from the disc nucleus, a large reduction in overall disc pressure is achieved with consequent relief of neural compression. DISC Nucleoplasty and Dekompressor are the two leading percutaneous discectomy technologies currently. Although rigorous clinical testing of their efficacy is ongoing, there has now been a 40-year history confirming the concept of percutaneous disc decompression, and initial results are very promising. Discogenic low back pain can also arise from annular tears and other forms of internal disc derangement (IDD). Annuloplasty techniques, such as IntraDiscal Electrothermal Therapy (IDET) and discTRODE, have been developed over the past decade that thermally treat the lesions of IDD. Although the therapeutic mechanisms of thermal annuloplasty have yet to be fully elucidated, research studies demonstrate that the procedure can be effective for appropriately selected patients with degenerative disc disease characterized by discographically proven painful annular fissures. Other novel intradiscal therapies are emerging for percutaneous treatment of discogenic pain and await more widespread clinical evaluation.

Spinal flexibility increase after chymopapain injection is dose dependent: a possible alternative to anterior release in scoliosis.

Experimental animal study. To investigate whether the increase in spinal flexibility after chymopapain injection is dose dependent and determine the "optimal" dosage of chymopapain to increase spinal flexibility in a rabbit model. Spinal instability after chymopapain injection may result in severe back pain. However, this undesired mechanical effect in treating disc herniation may provide a safe minimally invasive approach for anterior spinal release in scoliosis correction. A total of 138 lumbar intervertebral discs from 46 New Zealand white rabbits were randomly injected with chymopapain at 6.25, 12.5, 25, 50, 75, and 100 picokatals (pKats)/0.05 mL/disc. The rabbits were killed 1 week after the injection, and the lateral bending stiffness of the spinal segments without posterior elements was determined. The lateral bending spinal stiffness showed no significant change after injection of 6.25 and 12.5 pKats/0.05 mL/disc but reduced significantly following chymopapain injection of 25, 50, 75, and 100 pKats (all P < 0.05 by post hoc least significant difference tests). While the lateral bending stiffness was lowest at the 100-pKats dose, there were no significant differences between the four higher dosages. The reduction in the lateral bending spinal stiffness after chymopapain injection is dose dependent, and an optimal dosage for spinal release existed; doses greater than the optimal dosage did not result in further significant decrease in lateral bending spinal stiffness.

Effect of oral glucosamine on cartilage and meniscus in normal and chymopapain-injected knees of young rabbits.

To determine if oral glucosamine (GlcN) improves joint biology after acute damage by a protease. The effect of 8 weeks of dietary GlcN (20 or 100 mg/kg/day) on knee joint cartilage was evaluated in 2.2-kg male NZW rabbits with and without damage introduced by intraarticular injection of chymopapain (CP). Cartilage was evaluated histologically and scored according to the Mankin scale. Analyses of total hydroxyproline and glycosaminoglycan (GAG) contents and reverse transcription-polymerase chain reaction (RT-PCR) analysis of selected genes were performed. After 8 weeks, there was no effect of GlcN on the GAG content of normal cartilage. Both levels of GlcN treatment significantly increased the sulfated GAG content in the cartilage of the medial femoral condyle in damaged and contralateral knees, but did not change the collagen content. In CP-injected knees, there was still some loss of surface proteoglycan (PG) that was not completely corrected by dietary GlcN. Even after 8 weeks, levels of messenger RNA (mRNA) detected by RT-PCR showed changes indicative of damage and repair, such as elevated type II collagen mRNA, and these levels were not influenced by GlcN treatment. Meniscal GAG content was increased in the contralateral knee of rabbits receiving high-dose GlcN, but was decreased in those receiving no GlcN or low-dose GlcN. Neither diet nor treatment affected the meniscal collagen content. These results suggest that oral GlcN treatment might be useful in a situation where GlcN is limiting, such as where there is a rapid replacement of cartilage PG.

The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage

Objective The purpose of this work was to test the effect of inhibition of bone remodeling, through the use of the bisphosphonate, zoledronic acid, on cartilage matrix damage in an animal model of cartilage matrix damage.Design New Zealand white rabbits were divided into four groups for treatment purposes: (1) untreated controls; (2) injected into one knee joint with the cartilage matrix degradation enzyme, chymopapain; (3) injected into one knee joint with chymopapain and also given subcutaneous injections of the bisphosphonate, zoledronic acid, three times per week until sacrifice at either day 28 or 56 post-chymopapain-injection; (4) received only the zoledronic acid injections. At sacrifice, the knee joints were examined grossly and histologically, and biochemically for proteoglycan content. Urine samples were analysed, at intervals, for levels of collagen cross-links which are biochemical markers of cartilage and bone.Results Animals receiving both intraarticular chymopapain injections and subcutaneous zoledronic acid injections displayed a significantly lower degree of grossly and histologically detectable cartilage degeneration on the tibial articular surfaces (the articular surface displaying the greatest degree of degeneration) than did animals only receiving the chymopapain injections. In addition, urinary levels of collagen cross-links for bone and cartilage were significantly higher in those animals only receiving chymopapain injections.Conclusion The bone resorption observed after chymopapain injection into the rabbit knee joint can be inhibited through the use of the bisphosphonate, zoledronic acid. Furthermore, zoledronic acid does not increase the level of cartilage degeneration and appears to provide some level of chondroprotection in this model.

Urea as a passive transport marker for arthritis biomarker studies.

To develop a method to correct for the unknown dilution of synovial fluid that occurs during lavage of a joint, we evaluated the utility of urea, a molecule that is neither synthesized nor metabolized by joint tissues, as a means of correcting for the dilutional effects of lavage procedures and effusions. Joint fluids were obtained from normal canine joints by direct aspiration (n = 41) and lavage (n = 10). Acute joint injury was induced in 4 joints by intraarticular injection of chymopapain. Serum and joint fluid levels of urea and joint fluid concentrations of glucose, lactate, cartilage oligomeric matrix protein (COMP), and keratan sulfate (KS) were measured in these 55 joints. Urea concentrations in joint fluid were directly proportional to those in serum throughout a wide range of concentrations in normal joints. From this relationship, the dilution factor introduced by joint lavage was determined. This method was applied to quantify biomarker concentrations in synovial lavage fluid and was found to successfully correct for lavage-induced dilution of glucose, lactate, COMP, and KS to levels equivalent to those in samples aspirated directly. In the context of chymopapain-induced joint effusion, urea concentrations continued to be proportional to serum concentrations, but were much lower, enabling an estimation of the change in the volume of distribution (V(d)) of a marker due to a change in joint water content in the setting of inflammation characterized by effusion. Lactate and KS levels rose markedly in response to chymopapain. After adjustment for the V(d), the glucose concentration in the chymopapain-injected joints did not change. Urea provides a robust method of quantifying and correcting for the dilution of synovial fluid due to joint lavage or inflammation. This method is potentially applicable to surrogate marker studies in human arthritis.

Repeat Chemonucleolysis Is Safe and Effective

A review was made of 85 patients who received a second injection of chymopapain because of a recurrent disc herniation between 1980 and 1996. All patients were pretreated for 3 days with H1 and H2 receptor blockers. Immediate sensitivity reactions were not seen. Four Type 1 and one Type 2 reactions were seen after the the second injection. No other complications were seen. In this group of 85 patients, 66 patients received a second injection at the same level as primary treatment after a period of 57.1 months (range, 2-143 months). Two patients were lost to followup. Four patients had surgery, three with good results. Good results and no complications were seen in three patients who had a third chemonucleolysis because of another recurrence after 15, 40, and 56 months, respectively. The remaining 57 patients were interviewed after 64 months (range, 3-143 months). Using the Prolo scale, 51 patients were rated as having excellent or good results, and six patients were rated as having fair or poor results.

Protective effect of exogenous chondroitin 4,6-sulfate in the acute degradation of articular cartilage in the rabbit

The injection of 2.0 mg chymopapain into the adolescent rabbit knee causes severe loss of articular cartilage proteoglycans (PG). Although chondrocytes attempt to restore lost PG, failure to repair ensues. Pure chondroitin 4,6-sulfate (Condrosulf, IBSA Lugano, Switzerland) has been used in clinical studies of human osteoarthritis (OA) as a slow-acting drug for OA (SYSADOA). Using our model of articular cartilage injury, we examined the effects of oral and intramuscular administration of Condrosulf after chymopapain-induced cartilage injury. In this study, animals received an injection of 2.0 mg chymopapain (Chymodiactin, Boots Pharmaceuticals) into the left knee and were sacrificed after 84 days. The contralateral right knee served as a noninjected control. Some animals received oral Condrosulf while others received intramuscular injections of Condrosulf. Serum keratan sulfate (KS) levels were monitored to ensure degradation of the cartilage PG. Those animals not exhibiting at least a 100% increase of serum KS following chymopapain injection were excluded from the study. At sacrifice, cartilage PG contents were markedly reduced in animals receiving an injection of 2.0 mg chymopapain with no further treatment. In contrast, oral administration of Condrosulf beginning 11 days prior to chymopapain injury resulted in significantly higher (P = 0.0036) cartilage PG contents. Intramuscular administration of Condrosulf resulted in higher, but less significantly so (P = 0.0457), cartilage PG contents. These results suggest that daily Condrosulf treatment prior to and continuing after chymopapain injury may have a protective effect on the damaged cartilage, allowing it to continue to re-synthesize matrix PG after the treatment is discontinued.

Chondroitinase ABC (pharmaceutical grade) for chemonucleolysis. Functional and structural evaluation after local application on intraspinal nerve structures and blood vessels.

The effects on nerve tissue and blood vessels of locally applied chondroitinase ABC were studied in two experimental models using chymopapain and the vehicle of chondroitinase ABC for controls. To assess the effects of chondroitinase ABC on blood vessels and nerve tissue after local application. Chondroitinase ABC has been suggested for chemonucleolysis because it has a high specificity for nucleus pulposus matrix, which could mean a high efficiency in dissolving disc tissue combined with a low risk of side effects on other tissues. Chondroitinase ABC or controls were injected intrathecally in the pig, and nerve conduction velocity and histologic changes were assessed after 7 days. The same substances were injected into the hamster cheek pouch and studied for 60 minutes for microvascular effects. The vehicle for the enzyme was used as a negative control and chymopapain in a therapeutic concentration served as a positive control. In all series there was a slight intrathecal fibrotic reaction that was most pronounced after chymopapain injection. The effects on nerve conduction velocity and nerve morphology were similar between chondroitinase ABC and its vehicle. Chymopapain induced a significant reduction in nerve conduction velocity and pronounced histologic changes. In the cheek pouch, chymopapain induced a stand-still of blood flow at the injection site, and microhemorrhage and macromolecular leakage from the vessels at the border of the injection site. Only a slightly reduced blood flow was occasionally found after injection of chondroitinase ABC and controls. In agreement with the current literature, these observations indicate that chondroitinase ABC is safe regarding adverse effects on nerve tissue and blood vessels. The slight reduction in conduction velocity after intrathecal injection of chondroitinase ABC or its vehicle is most likely the result of surgical injury while releasing the nerve roots from the intrathecal fibrous adhesions. Such adhesions may be related to the laminectomy per se, and probably have no pathophysiologic significance.

EXPERIMENTALLY INDUCED ARTICULAR CARTILAGE INJURY

Injection of chymopapain (CP) into the rabbit knee causes rapid depletion of proteoglycans (PGs) in the articular cartilage. Successful repair of the articular cartilage follows injection of only 0.2 mg CP whereas in animals injected with 0.2 mg CP, the repair phase fails leading to cartilage destruction within 21 days. Previous work by the authors indicated that daily oral diclofenac reduced the severity and incidence of CP-induced cartilage injury after 21 days. The present study was designed to determine if administration of diclofenac promoted articular cartilage repair after CP injury over a longer period of time and if coadministration with misoprostol could reduce the concentration of diclofenac needed to promote repair as well as confer protection to the gastric mucosa. Adolescent male New Zealand white rabbits received CP-induced cartilage injury (2.0 mg) followed by daily oral diclofenac, diclofenac/misoprostol or misoprostol. Control animals received diclofenac, diclofenac/misoprostol, or misoprostol or no drug treatment with no cartilage injury. All animals were sacrificed after 2 months. Examination of the stomachs from animals receiving no drug or misoprostol only were completely normal. Most animals receiving diclofenac only had abnormal gastric mucosa. In contrast, coadministration of diclofenac/misoprostol revealed significantly fewer abnormalities. Analysis of the composite histologic score of patellae and measurements of cartilage PG content revealed no significant differences in groups which received CP injury with and without drug treatment. Histology scores and cartilage PG content from animals in groups which did not receive CP injury, but were treated with diclofenac/misoprostol, diclofenac or misoprostol were within normal limits and thus did not differ significantly from untreated control cartilage. The results of this study indicate that daily administration of diclofenac, diclofenac/misoprostol or misoprostol has no protective effect on CP-induced cartilage injury after 2 months. Administration of diclofenac only results in severe gastric abnormalities which are significantly reduced if diclofenac is coadministered with misoprostol. Administration of diclofenac, diclofenac/misoprostol or misoprostol has no effect on PG content of cartilage from otherwise normal joints.

椎間板内薬物注入の実験的研究 再注入例の検討

We investigated the changes in pathology and intradiscal pressure after repeat intradiscal drug injection in the mature rabbit, Chymopahain (500pku/ml) or 10% hypertonic saline was injected into five lumbar intervertebral discs of 9 rabbits. The injection volume was 0.02ml/disc, and a repeat injection was performed 4 weeks after the first injection. Rabbits were sacrificed at 1 week, 4 weeks, and 8 weeks after the repeat injection. They were classified into 3 groups; the HH group received hypertonic saline twice, the HC group was first injected with hypertonic saline and with chymopapain at the second injection, and the CC group received chymopapain twice. The intradiscal pressure changed depending on the degree of disc degeneration and on any regeneration. When hypertonic saline was injected first (HH and HC groups), the degeneration in the disc was slight compared to when chymopapain was injected first (CC group), and the intradiscal pressure was further decreased by the second injection of hypertonic saline (HH group). In comparison, when chymopapain was injected first (CC group), marked degeneration and disc narrowing were observed with a marked decrease in pressure compared to when hypertonic saline was injected first (HH and HC groups). Following a second injection of chymopapain (CC group) there was further degeneration but there was no additional decrease in pressure. Disc regeneration was observed in the HH group, but not in the HC or CC groups.

椎間板内薬物注入の実験的研究 組織学的検討および椎間板内圧測定

We investigated the pathological changes and alterations in intradiscal pressure after an experimental intradiscal injection in the mature rabbit. Thirty intervertebral discs in 6 rabbits were used as controls, and normal pressures were measured. Chymopapain, 10% sodium chloride, or betamethasone were injected separately into 5 intervertebral discs of 9 rabbits. Rabbits were sacrificed at 1 week, 4 weeks, and at 12 weeks after the intradiscal drug injection. The intradiscal pressure changed depending on the degree of disc degeneration and if there was any regeneration. The chymopapain-injected intradiscal pressure decreased significantly at 4 weeks compared with the pressure at 1 week and at 12 weeks (p<0.05, p<0.01 respectively). The intradiscal pressure of the 10% sodium chloride-injected discs decreased at 4 weeks, but by 12 weeks the pressure had recovered to the same level as fourd in the cotrols. Necrotic nucleus pulposus was seen histopathologically at 1 week after chymopapain injection, and at 1 week after the 10% sodium chloride injection. At 12 weeks, there intervertebral discs had regenerated with chondrocytes different from in the normal nucleus pulposus.The pressure of the betamethasone-injected discs was unchanged throughout the 12 weeks with only slight histological changes.

Alteration and recovery of the spatial orientation of the collagen network of articular cartilage in adolescent rabbits following intra-articular chymopapain injection.

We have used polarized light (POL) to monitor changes in the organization of the articular cartilage collagen network and matrix proteoglycans (PGs) after intra-articular injection of chymopapain (CP). POL viewing of sirius red stained sections revealed a loss of normal birefringence suggesting an apparent collapse of the collagen network following intra-articular CP. After 21 days, knees injected with 2.0 mg CP showed no return of normal birefringence, however, normal birefringence was noted in knees injected with only 0.2 mg CP. POL viewing of toluidine blue stained sections revealed a severe loss of matrix PGs followed by PG restoration in animals injected with 0.2 mg CP. The most important inference from the data is that articular cartilage can recover from enzyme-induced alterations in the spatial collapse of its fibrillar network. This is an important finding since it has often been inferred that damage to the collagen network leads invariably to progressive articular cartilage destruction.

Contrast improvement using color-coded radiographs of anatomic specimens.

Radiographs are used in a wide variety of musculoskeletal examinations. Special procedures are required to improve image quality. We report a new radiologic technique that uses monochromatic molybdenum K alpha-radiation together with secondary digital color-coding to produce well contrasted images of supporting tissue. In order to investigate the diagnostic capability of this approach we studied specimens of the intervertebral disc, harvested from cadavers undergoing chemonucleolysis following an injection of chymopapain. Radiographs of the specimen taken using a Mo X-ray tube with a zirconium filter were scanned into a computerised image-processing system and color-coded. This method improves resolution and contrast in the images and allows the differentiation of morphologic changes.

RESULTS OF LUMBAR DISK SURGERY IN A CITY COMPENSATION POPULATION

This is a retrospective analysis of 118 patients who underwent 132 operations in a city compensation setting for the treatment of lumbar disk disease from January 1976 to December 1987. Each of these patients had a work-related injury. There was a minimum 2-year follow up with an average follow up of 6.9 years. No patients were lost to follow up. The purpose was to determine what percentage of patients treated in a work-related setting could be expected to return to a sustained, pre-injury employment state following a carefully executed lumbar spine surgical procedure. Satisfactory surgical results were considered achieved only by those patients who returned to full-duty work status. Only 31 of the 118 patients (26%) returned to full duty and were considered satisfactory. Regarding the number of surgical procedures, 31 of 132 operations (23%) were successful. Sixteen reoperations in 13 patients all resulted in failure. Only 16 of the 64 patients (25%) treated with laminectomy and diskectomy alone had a satisfactory result. When a two-level, posterior lateral spinal fusion was added the success rate was increased to 44%, with 12 of 27 patients returning to work. Six patients with spinal stenosis underwent decompression laminectomy and entry level foraminotomies, and all had unsatisfactory results. Five patients with isthmic spondylisthesis underwent a Gill procedure and fusion. Only one of these patients (25%) returned to work. For a 2-year period chymopapain injection was given to 14 patients. Only two returned to work, with a 14% success rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous Passive Motion Stimulates Repair of Rabbit Knee Articular Cartilage After Matrix Proteoglycan Loss

Continuous passive motion facilitates repair of full-thickness defects in the articular cartilage in rabbits. Studies were conducted to determine whether continuous passive motion would similarly affect the repair process after injection of chymopapain into the rabbit knee. Adolescent rabbits were injected with chymopapain and then given intermittent active motion in the form of free cage activity or continuous passive motion of the injected knee. After injection of either 0.2 or 2 mg chymopapain into the knee, serum keratan sulfate levels rose sharply, indicating proteoglycan loss, and, in all cases, peaked at 24 hours between 200-800% of preinjection levels. Importantly, serum keratan sulfate levels were significantly elevated within 1 hour when joints were submitted to immediate continuous passive motion after the injection. As shown previously, injection of either 0.2 or 2 mg chymopapain into the knee, followed by intermittent active motion, resulted in a pronounced loss of proteoglycans by Day 2, partial restoration of proteoglycans by Day 9, continued proteoglycan synthesis by Day 21 in animals receiving the lower dose, and severe degenerative changes by Day 21 in animals receiving the higher dose. In all animals that received either high or low doses of chymopapain, as well as 2 days of intermittent active motion and then continuous passive motion, the articular cartilage surface was intact by Day 9, and replenishment of proteoglycans had occurred in pericellular and interterritorial areas. By Day 21, the surface of the articular cartilage was still intact, and replenishment of proteoglycans in loaded regions continued in all animals receiving either dose of chymopapain. These results indicate that a period of intermittent active motion followed by continuous passive motion of a chymopapain injected knee may protect and stimulate repair of the articular cartilage matrix after chymopapain-induced injury.

Experimental chemonucleolysis with chymopapain in canine intervertebral disks.

The present study describes the radiological and histological changes in the canine intervertebral disk after the experimental injection of chymopapain as the chemical reagent, and determines the appropriate dose of the enzyme for treatment of herniated disks. By radiography, narrowing of the disk space was observed within 2 weeks after the injection of chymopapain, and recovered to 74.1% in the 0.1 mg group, 61.1% in the 1.0 mg group and 71.7% in the 10.0 mg group at 12 weeks. The disk space recovery showed a tendency to delay with aging. Microscopically, proteoglycan positive matrix appeared and the nuclear space was reduced in each disk at 2 weeks after chymopapain injection. The nucleus pulposus contained an irregularly-defined mass consisting of clusters of degenerated notochordal cells surrounded by proliferated chondrocytes and collagen matrix. In each disk at 12 weeks after chymopapain injection, the center of the nucleus pulposus was replaced by fibrocartilage tissue. In the disk into which 10.0 mg chymopapain was injected, the nuclear space filled with dense fibrocartilage tissue without a regenerated matrix component and narrowing of the disk were maintained. It is suggested that canine chemonucleolysis with 10.0 mg of chymopapain reduces the interdiskal pressure. This treatment may therefore relieve the signs and symptoms of herniation of the nucleus pulposus, and may effect chemical disk decompression.