Innovative Solutions to Animal Health Problems
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Innovative Solutions to Animal Health Problems
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Reprinted from Journal of Equine Veterinary Science - Non-refereed articles and papers - Volume 8, Number 1, 1988 ANTI-INFLAMMATORY EFFECTS OF AN IMMUNO-MODULATING AGENT Kent Allen Vasko, DVM1 and John McMichael, PhD2 The role of Immuno-modulation as a means of enhancing the body defense mechanisms has been the subject of increasing interest among basic scientists and clinicians for a number of years. The principal areas of interest have been fields of cancer therapy, arthritis, and a variety of immune-mediated diseases involving inflammation and chronic pain. During the past three years we have been doing a series of clinical investigation with one immuno-modulating agent (IMA),2 to determine the potential for use as an anti-inflammatory in a variety of equine neuromuscular and musculoskeletal conditions. These included such clinical entities as myositis, tendonitis, osteoarthritis, fasciitis, and neuritis. In the initial trial, eight horses were selected with problems that were partially or totally refractive to all conventional therapy, including steroids, analgesics and a variety of non-steroidal anti-inflammatory agents. In four of these horse, other modalities including electrotherapy, "soft laser," ultrasound, and a variety of "nutritional therapies" including dimethyl glysine and ascorbic acid. None of these improved the clinical status of these horses. The eight horses were removed from all of the various therapeutic agents for a period of 14 days. A series of subcutaneous injections of the IMA were initiated and continued daily for 14 days. Daily observations were made for changes in the clinical status of the horse. These included status of the inflammatory process (swelling, heat, pain on palpation) and gait alteration (lameness). All but one horse had improvement in both categories within 76 hours. By the end of the 14-day period, 6 of the horses had complete remission of clinical symptoms, one had moderate improvement, and one had no clinical improvement. No horse had signs of undesirable side effects throughout. Se Table 1 for summary of the primary investigation. Because of the 85% efficacy in the initial trial, further preliminary investigations were undertaken. The second trial was conducted in the Netherlands with a group of horses selected by the same criteria of clinical evaluation including lack of response to conventional therapy, the same protocol for treatment and clinical evaluation. The results of the European study and the primary US study were nearly identical. See Table 2 for summary of the European study. Coincident with the second (Netherlands) study, a third study (US) was undertaken. This incorporated the same criteria as the primary study, but the clinical disease entities were limited to chronic myositis, myofascial pain, and /or neuritis. The criteria of "refractory to conventional therapy (ies)" was used. In addition to pre-treatment, treatment, and post-treatment daily observations, blood samples were drawn pre-treatment, daily for 72 hours after treatment, and on the 14th day of treatment. These venous samples were analyzed for hematologic, metabolic, biochemical, and a number of immunologic parameters. All of the control samples had results with specific alterations in enzymes indicative of inflammation. There were specific alterations in several of the immunologic parameters. By the 72-hour samples, all blood parameters had returned to normal levels with the exception of two horses in which alkaline phosphatase decreased, but remained slightly elevated throughout. These tow horses were continued on SQ injections for an additional 14 days at which time all blood parameters were normal. The clinical improvement coincided (6 horses) or preceded by 24 hours (4 horses) the laboratory improvement. Because of the blood parameter, it was possible to identify the specific site in the immune system in which the IMA was effecting an action. This verified the hypothesis of the synthesizer of this IMA as to the site of action. Currently, a double blind study is being carried out in three locations In the US. Each group is made up of 20 horses. Ten in each group are receiving the IMA and 10 are receiving a placebo made up of inactive components of the IMA preparation. To date, 53.33% of the study is complete. Thus far the placebo group has had no clinical response or laboratory improvement with one exception. There was an improvement in one horse, but was probably due to a reduction in the level of exercise, because laboratory values were not consistent with the noted clinical signs. To date, all horses receiving the IMA have complete or nearly complete recovery both clinically and in blood parameters. A laboratory study is continuing to determine whether a subfraction of the IMA may be a more specific immuno-modulator or not. There is no evidence to date to support this hypothesis. Based on the clinical and laboratory results to date there is clear evidence that: 1) Specific immuno-modulation is a realistic approach to anti-inflammatory therapy; 2) A specific IMA is 85% to 90% effective in horses: and 3) There are no undesirable side effects. Further trials are underway to determine the duration of effect and the frequency of therapy that may be required in some cases. In addition to these trials, a feasibility study, using a non-percutaneous form of this IMA is being carried out to ascertain the value of an alternative to injection long term therapy. Authors’ addresses: 1 Equine Sports Medicine, 9170 Hermitage, Chardon, OH 44024; 2 Immuno Therapeutics, PO Box 127, Delanson, NY 12053. 3 CrondolÔ , Eudaemonic Corporation, 7031 N. 16th St. Omaha, NE 68112.
TABLE 1 ITERIM REPORT BIOLOGICAL ANTI-INFLAMMATORY
* This horse has severe carpal disease and was unresponsive after 14 days treatment with agent. Treated for additional 14 days with modified prep sent by Dr. McM with no improvement. ** This pony not only has had a good improvement in movement and increased range of motion of joints, but has had a total remission of the existing chronic bronchitis. TABLE 2
INTERIM REPORT BIOLOGICAL ANTI-INFLAMMATORY
Reprinted from Journal of Equine Veterinary Science - Non-refereed articles and papers - Volume 8, Number 5, 1988 USE OF AN IMMUNO-MODULATING AGENT IN THE TREATMENT OF MYOFASCIAL PAIN Kent Allen Vasko, DVM1; John McMichael, PhD2; W. Burton Smith, DVM3; Alvin L. Smollin, DVM4INTRODUCTION As anticipated by a Veterinary Review Note appearing in a recent issue of this journal1, a multiple-site, double blind clinical trial has been completed in which an immuno-modulating agent (Crondol)5 was evaluated for its safety and efficacy for the treatment of myofascial inflammation in horses. Twenty afflicted horses were enrolled in the trial at each of three test sites -- Florida, where Thorobred race horses in training and competition were used, Nebraska, which employed Quarter Horses in varying levels of activity, and Ohio, at which actively training and competing dressage, three day event horses, and show jumpers were subjects. MATERIALS AND METHODS Horses were evaluated clinically with respect to their degree of myofascial inflammation as determined by pain or palpation over the back and hips, and by severity of gait abnormality, which varied from mild stiffness to unwillingness or inability to move. Horses were assigned a clinical grade of 0 to 3, with 3 representing severe clinical signs while 0 was assigned to horses with no clinical manifestation of the disease. All horses were evaluated daily. Further, blood samples were collected on Days 0,1,2,3, and 14 of the trial and were monitored with respect to hemogram, SMAC21, chemistry profile, plasma cortisol levels, direct Coomb’s test, anti-globulins, and serum protein electrophoresis. Ten Horses at each site were given 14 consecutive daily injections subcutaneously of the test material (Crondol), while the balance received daily injections of a saline placebo. Neither the participating veterinarians nor the horse owners were informed as to the contents of any vial of medicine until the entire trial was completed. RESULTS All horses receiving the immuno-modulating agent showed positive clinical results, with 94% of those declared sound (clinical grade 0) at the conclusion of the trial. The remaining treated horses did experience significant improvement but were not yet to grade 0 (normal) at the conclusion of the trial period. Seventy-five percent of horses receiving the placebo showed no improvement during the trial. The remaining 25% of animals receiving the placebo were rated as being improved or normal (grade 0) at the completion of the trial. All but two horses of this 25% were confined to one study group (Nebraska). These horses were graded 0+ or 1 (very mild myofascial pain) at the onset of the trial and were completely rested during the study. The onset of clinical improvement in the groups receiving the test product was noted as early as 24 hours, and no later than 72 hours, after initiation of therapy. Fifty percent of the treated horses were classified as being clinically normal at 72 hours, and the balance (44%) were graded 0 by Day 6. The remaining treated horses (6%) continued to improve throughout the treatment period, but did not reach grade 0 by the completion of the study period. Laboratory parameters used to monitor renal, hepatic, and bone marrow function showed no differences between Crondol and placebo-treated horses. Of special interest was the observation of a gradual increase in lymphocyte concentration in animals treated with the test agent. This increase leveled off at 72 to 96 hours and coincided with the time that the horses became clinically improved. Also, horses treated with the test immuno-modulating agent showed a consistent drop in alpha-3 globulin levels while those on placebo showed an actual increase in alpha-3 globulin. This suggests that alpha-3 globulin, like the erythrocyte sedimentation rate and C-reactive protein level, might be useful parameter for monitoring degree of inflammation. Summary and Conclusion The results of this multiple-site, double blind study show that this new immuno-modulating agent (Crondol) is both safe and efficacious for the treatment of equine myofascial inflammation. Reference 1. Vasko and McMichael J; Anti-inflammatory effects of an immuno-modulating agent. J Eq Vet Sci 8(1):77, 1988 Authors’ addresses: 19170 Hermitage, Chardon, OH; 2Delanson, NY; 3Elkhorn, NE; 4Pembroke Lake, FL 5 Crondol, Eudaemonic Corporation, 7031 N. 16th St. Omaha, NE 68112
Reprinted from Dressage and CT; April 1992 NEW MEDICAL ADVANCES By Kent Allen Vasko, DVM The role of immunomodulation* as a means of enhancing the body’s own defense mechanisms in a variety of conditions has been the subject of ongoing basic research for many years. Rubeola Virus Immunomodulator (RVI) was developed by an immunologist and a molecular biogeneticist specifically for use in treating immunomediated chronic inflammation and pain. The original hypothesis was that there was a direct effect on suppressor T-cell lymphocytes, which were either blocked or inactivated by an incorrect response in function (not necessarily a decrease in absolute numbers). Suppressor T-cells function primarily as dampeners of the inflammatory response. When the immune system becomes hyperactive, the balance between the components becomes "disoriented ---out of balance," the inflammation becomes chronic, and unless the source (s) of the initial causes of inflammation are removed, the condition remains and may, in fact, worsen. Rest for prolonged periods of time is sometimes effective, but if the initiating causes are not removed, the situation may not improve. If, in fact, it does improve, and the horse returns to work, it is common for the problem to recur rather promptly, much to the frustration of everyone involved. There are many reasons for this, including stress of all kinds, dietary problems, use of certain commonly used drugs, and the long term effects of a variety of viral infections (even though the clinical disease has disappeared, the latent effects of the virus may last indefinitely). This is a very brief overview, and more details will follow from time to time. The basic science research continues, and there is little doubt that this is but the first of many products which will evolve from this and related technologies. I first became involved with RVI in early 1985 when called upon to perform some feasibility studies in horses to see whether it was worth pursuing as a marketable product through the regulatory process. As always, I remained open-minded, because at the time, I (for one) did not fully understand the technology, and, frankly, there was not nearly the amount of hard science available, as there is seven years hence. The initial trial was in light horses with a variety of severe problems---all refractory to conventional therapy and rest. The results were extremely positive in all but one horse, who had severe carpal arthrosis. On this basis, a similar study was undertaken in a group of standardbred horses in the Netherlands, with nearly identical results. The efficacy in the combined trials was 85%. On the basis of these studies, we then embarked on a third study at three separate sites in populations of horses with different types of athletic activities. This time, our cases were limited to chronic myofascial pain with or without accompanying neuritis. The results were even more dramatic (94% effective) and, further, there was no evidence of side effects either clinically or by laboratory analysis of multiple hematologic, biochemical, and immune system tests. From that point, two double blind studies were initiated, one group in each test site receiving the actual medicine and an equal number receiving a placebo. Both test samples were encoded, and none of the clinical investigators were aware which was which. The second set of clinical trials were for safety, since the results of the efficacy study were the same as in the preliminary trials and further supported by laboratory results. The safety study was conducted in the same manner, and at the end of the test period, there was no clinical or laboratory evidence that there were any undesirable side effects. After a long period of time, the medicine is now available through veterinarians and distributed by major veterinary suppliers nationwide. At the time of this writing, field reports indicate that somewhere between eight and ten thousand horses have been treated with RVI with a 90+% efficacy rate and no undesirable side effects. There have been numerous anecdotal reports of improved appearance and coat and improvement in behavior in nervous and unruly horses. I have seen it, and so have many expert clinicians, trainers, and owners. At the moment, the reasons for these favorable effects can only be conjectured, but it does not seem unlikely that bringing the immune system to full strength with elimination of chronic pain and inflammation could allow the horse to return to a normal, healthy state. At least, it is a reasonable working hypothesis for future investigations. Note: Recently, I have received a large number of inquiries from veterinarians and horse owners as to the use of RVI in "tying-up." RVI is not targeted to the classic "tying-up syndrome" but rather to broader use in chronic myofascitis (myofascial pain) and myositis. There are some anecdotal reports that RVI is useful in the prevention of tying-up, but it is unclear whether these cases are truly exertional myopathies or general, severe myofascial pain and myositis due to exercise intolerance. Repeat: RVI is not targeted to the "tying-up syndrome," and results in those cases will not be nearly as consistent and reliable as the use in myofascitis for which RVI is specifically targeted.
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