Oral Gallium Nitrate Restores Soundness in Horses with Navicular Disease - A Pilot Study
by: George A. Eby
Keywords: horse, navicular disease, navicular pain, caudal heel syndrome, gallium nitrate, inflammation, bone resorption, treatment.
Its main effects are in inhibiting bone resorption through its effects on bone osteoclasts (like TildrenŽ), and second through its effects in stimulating bone formation through action on osteoblasts (bone-forming cells). Both of these benefits are explained in Sections IV A and B of Mechanisms of Therapeutic Activity for Gallium
Pharmacokinetics of gallium nitrate after oral administration in adult horses
Purchase gallium nitrate here: http://galliumnitrate.com.
Navicular disease, also termed navicular syndrome or caudal heel syndrome, in horses cause much foot pain and lameness. Classical treatments often do not provide satisfactory results and the horse remains lame and occasionally the horse must be euthanized. Little is known of the etiology of navicular disease. A hypothesis was advanced that gallium nitrate, a compound reported to have anti-inflammatory, anti-bacterial, anti-hypercalcemic and anti-bone-resorptive activity, would be a safe and effective treatment for navicular syndrome. Horses diagnosed with navicular syndrome, and non-responsive to classical treatments were treated orally with 500 cc of a one percent gallium nitrate (1.36 grams elemental gallium/day) aqueous solution. Treatment reduced mean pain scores fifty percent within 14 days, as measured using a five point scale of observed lameness. Mean pain scores for the second two-week period were statistically lower than the mean pain scores of the first two-week period (p < 0.0001). Complete soundness was achieved in 33 out of 83 horses in less than 28 days, with 24 out of the remaining 50 horses showing improvement in that period, for a total of 57 (69%) horses becoming better. None were worsened and none were euthanized. Most horses remained sound long after treatment ended. No side effects, toxicity or sequela were reported. Oral gallium nitrate is new and effective treatment for navicular syndrome that appears much more effective than previous treatments, and it is becoming a first-line treatment for navicular syndrome. Future trials and field use of gallium nitrate to treat navicular syndrome in horses should follow a continuous dosage protocol, not the two-week on / two-week off protocol described here.
In the horse, the navicular bone is located directly behind the coffin bone of the foot and is held in place by tendons and ligaments. The navicular bone protects the joint and tendons from pressure and concussive forces. It also functions as a pulley for the deep digital flexor tendon, taking some of the stress off the coffin bone during movement. Pathological abnormalities in foot lame horses often involve not only the navicular bone but also the distal sesamoid ligament and navicular bursa. Navicular syndrome have been suggested to be of an arthritic nature. Other possible causes of navicular syndrome include increased pressure inside the bone, adhesions between the navicular bursa and the deep digital flexor tendon and inflammation. The pathogenesis of navicular disease and navicular bone related lameness in horses remain poorly understood and no clear etiology exists despite the high incidence of foot-related lameness in horses.
Diagnosis of navicular syndrome is usually preceded by the horse owner's concern about lameness, and is confirmed upon noting a favorable response to palmar digital nerve block. Classically, lameness from navicular syndrome is treated with rest, hyaluronic acid, anti-inflammatory drugs such as cortisone or phenylbutazone (bute) and isoxsuprine, corrective shoes, neurectomy, and in severe cases euthanization. Often there is little benefit from classical treatment and pain and lameness continues regardless of treatment.
In 1996 the author's horse was diagnosed with severe navicular syndrome. Rest, isoxsuprine, phenylbutazone and corrective shoeing were unsuccessful. The horse remained in severe pain and he was recommended to be euthanized. Since no clear etiology of navicular syndrome existed, a hypothesis was advanced that Aluminum(III) ion contamination of the navicular region from aluminum shoes was the cause of his navicular pain. Aluminum(III) ions are one important, previously unrecognized cause of bone resorption and osteomalacia. This change occurs in all mature vertebrates not associated with Vitamin D deficiency. Aluminum(III) in bone causes bone pain and proximal myopathy in all vertebrate species tested.
On the other hand, Gallium(III) has been shown efficacious in treating bone diseases, especially in the inhibition of bone resorption and bone repair,[4,5,6] and pain prevention suggesting the working hypothesis that Gallium(III) would be effective in treating navicular pain, perhaps by displacing Aluminum(III).
A one percent gallium nitrate solution (5 grams in 500 cc water) given each day on the horse's feed was started. The dosage was prorated from human cancer-related hypercalcemia treatments. Soundness occurred in less than two weeks of treatment. Continued treatment essentially prevented all lameness over the following 10 years. This horse relapsed after 4 to 6 months without gallium nitrate on two occasions, demonstrating the necessity of continued treatment to keep him sound. This horse has severe grooves in the navicular bone of the left front foot, which did not change on X-ray examination during 10 years of gallium treatment. Treatment of other horses with gallium nitrate also appeared successful, meriting this pilot study.
All horses in this study had been diagnosed as having navicular disease or navicular syndrome by veterinarians, and several had navicular disorders in more than one foot and/or had other foot and leg lameness issues, including arthritis, tendinitis and bursitis. Their prognosis had each been described as "poor" by their veterinarians, and their responses to classical treatments had failed. Consequently, their owners sought an alternative medicine treatment in gallium nitrate.
The intention of this investigation was to determine the effects of gallium nitrate in reducing the severity of lameness, and to determine to what extent horses with navicular syndrome and lameness could be made sound within a single two week treatment period. Statistical analysis compared pain scores during the 2-week treatment period against pain scores during the following 2-week off treatment period. After explaining to the horse owners the possible benefits and potential risks based upon the previous observations from use of gallium nitrate to treat navicular syndrome, and of its use in humans for a number of bone-related disorders, informed consent was obtained and this study was performed in an out-patient environment.
MATERIALS AND METHODS
Commercially pure gallium nitrate (99.99%) from Recapture Metals, Inc., Blanding, Utah, USA, was used in this investigation. Each 500 cc bottle contained 70 grams of gallium nitrate (14% gallium nitrate equivalent to 19 grams elemental gallium) in water. The 14% solution had a pH of 1.5.
One hundred owners of horses with navicular disease or navicular pain enrolled their horses in this study. Owners were instructed to dilute the 14% concentrate into fourteen, one-percent gallium nitrate daily doses (equivalent to 1.36 grams of elemental gallium per day) in 500 cc water bottles for each 540 kg (1200 pound) horse. One 500 cc bottle of one-percent gallium nitrate solution per day was to be poured onto the horse's feed for fourteen days, followed by fourteen days without gallium treatment. No placebos were used.
Owners were instructed in filling out their daily diary report form using the following "0" to "4" pain scores:
Soundness observations of each horse were performed each day by the owner. Treatment was to be continued at the owners' discretion for any number of 2-week on-treatment and 2-week off-treatment cycles. Daily diary records were made each day of each 28-day study period. Work was restricted in all horses. To minimize exogenous influences, owners were instructed not to make any changes in their horse's care during the 28 day study other than to give them gallium nitrate.
Complete reports were received for 83 horses. The remaining reports were not received for evaluation. Post study telephone calls revealed that the non responders did not treat their horses with gallium nitrate.
Response to Treatment
Figure one shows the effect of oral gallium nitrate on pain scores in 83 horses during the 28-day reporting period. Analysis of these reports showed that there was more than a fifty percent reduction in pain scores by the fourteenth day of oral gallium nitrate treatment. Upon cessation of gallium on day 14, symptoms severity remained essentially unchanged during the following 14 days, showing the residual effect of gallium nitrate treatment.
Figure 1. Effect of gallium nitrate treatment on mean pain scores with treatment given only during the first 14 days
The response to treatment suggested that gallium nitrate might be curative because pain scores only slightly returned at the end of the two week off treatment period, in support of pre-trial observations. For comparison, the half life of gallium nitrate in human serum is less than one day. Since the same samples were tested against two different treatments (mean pain scores over the 14 days on gallium nitrate vs. mean pain scores over the 14 days off treatment), an ANOVA-Single Factor test was performed, which resulted in p-value < 0.0001. Not only were the results of treatment statistically significant, the benefits of treatment were meaningful.
As shown in Figure 2, by the fourteenth day, 28 horses were sound. Five other horses also became sound during the following 14 days, even though they were off gallium treatment.
Figure 2. Number of horses sound on each day after initiation of gallium nitrate treatment for 14 days
In addition to the 33 (40%) reports which showed complete soundness within the first 28 days, 24 (29%) other reports showed horses had improved, while 26 reports showed remaining lameness had not changed. None worsened. Consequently, more than two-thirds (69%) of the horses had improvement within the 28 day study period.
Examination of some characteristics of these horses showed that nearly 90 percent of them were not being given any other treatment during gallium treatment, with the remainder being also given bute and/or isoxsuprine. Only one had undergone neurectomy prior to gallium. Forty percent of these horses did not have special shoes, 33 percent were fitted with egg bar shoes, 15 percent were barefoot and the remainder had a variety of foot ware. Sixty percent of the horses in this trial were American quarter horses, 14 percent were warmbloods and the remainder were other breeds. The average age was 10, with the youngest being 4 and the oldest being 30. These characteristics appeared to have no effect on the outcome of this investigation.
Side effects from gallium nitrate treatment for navicular syndrome reported were:
There were no harmful side effects reported. However, overly exuberant behavior occurring for a few minutes in newly sound horses was a concern, but this behavior did not result in injury or further lameness to any horse.
No gastrointestinal issues or colic emerged in these or any other gallium-treated horses. There were no instances of infections, diseases or injuries reported to have affected the horses or treatment results. Blood counts remained normal, although low-normal red and white cell counts were observed in several ponies being fed the normal 500 cc dose of the one percent solution. This suggests that dosage be proportionately reduced and increased in horses significantly smaller and larger than 540 kg. The daily dose was often split to reduce feed water content, giving half in the morning and half in the evening. Splitting dosages helped to insure that all gallium nitrate offered was ingested. Although some horses were slow in eating gallium nitrate solution-wetted feed, none refused to eat it. There were no reasons reported to stop gallium treatment.
Navicular disorders may result from an inflammation of the navicular bone and/or bursa. Occasionally, cysts in the navicular bone are evident. Navicular disorders also include degenerative heel lameness, which may involve the navicular bone, navicular bursa, deep digital flexor tendon, and the coffin joint. a.k.a: navicular syndrome, and it is assumed that a variety of these foot disorders were prevalent in these horses. These navicular disorders, although described in various ways, nearly always result in lameness from foot pain, and it limits the utility and value of horses and indirectly limits their life-span. It is hypothesized that some of these disorders are caused by Aluminum(III) contamination. Regardless, gallium nitrate eliminated pain and restored soundness in these horses when other treatments failed.
Data on the effects of gallium nitrate in these horses after the first month, extending in some cases 24 months and in several cases 5 to 10 years, was also collected. However, pain score data from those observations can not be presented here because not all horses were kept on gallium nitrate for more than 14 days because they had become sound and were no longer in the study. These limitations precluded reporting statistically valid data after the first month. Therefore, only an overview of additional observations from those later reports is presented.
Generally, the data and owners' comments showed that gallium nitrate given for 6 months terminated lameness in more than ninety percent of these horses, regardless of the severity of initial lameness. The remaining horses appeared sounder and none were reported to have became worse. However, only one horse presented with an initial pain score of 4.0 and that horse improved only by a single point in 28 days. Horses with very severe navicular disorders required gallium as long as there was a desire for them to remain improved or sound. One normal, quiet foal was conceived, carried and delivered while the mother was being given gallium nitrate, suggesting lack of gestational toxicity.
Mechanisms of Gallium(III) Action
Gallium is a potent inhibitor of bone resorption that acts to maintain and restore bone mass in all vertebrate species.[4, 5, 6] Another inhibitor of bone resorption, tiludronate, has been used effectively to treat navicular disease in horses, restoring soundness in 2 to 6 months.
Gallium(III) has also been shown to inhibit production of inflammatory cytokines, such as IL-1 beta (associated with rheumatoid arthritis), produced by macrophage-like cells.[9, 10] A dose-dependent inhibition of IL-1 beta and tissue-type plasminogen activator (tPA) stimulated MMP activity by gallium nitrate at increasing concentrations occurs, demonstrating that gallium nitrate can be a useful modulator of inflammation in arthritis. Immunosuppression, possibly of inflammatory cytokines, appears involved in these benefits. For example, gallium nitrate suppresses lupus, an autoimmune inflammatory disorder, in mice.
Unlike cortisone and other steroids, gallium(III)-induced immunosuppression is not harmful, because it affects only abnormally activated immune cells, such as macrophages, and abnormal interactions between immune cells, such as between macrophages and T cell lymphocytes. Additionally, corticosteroids cause calcium loss from bones, while gallium rapidly restores calcium to bone, and it is an effective and rapid acting treatment for hypercalcemia and osteoporosis.[4, 5, 6]
The dominant mechanism producing gallium's anti-proliferative and antimicrobial activity is its ability to act as a chemically irreducible ferric iron analog. By this and other mechanisms, gallium inhibits bone resorption, stimulates healthy bone formation, increases Type I collagen production, inhibits excessive parathyroid hormone secretion, and inhibits secretion of interleukin 6 (IL-6) and other pro-inflammatory cytokines. Gallium(III) modulates immune activity and strongly concentrates at sites of both inflammation and infection.
Clearly, gallium has biological activities that help to explain its effectiveness in the treatment of navicular disorders and arthritis. Its benefits extend also to laminitis, which is marked by great increases in IL-1 beta and IL-6, both of which are readily controlled by Gallium(III) in a dose dependent manner.[5, 9, 10]
Some caretakers of these horses reported that their arthritic hands were free of arthritis for years from immersing their hands in gallium nitrate solutions being prepared for horses, prompting a report of the effects of oral and topical gallium nitrate in treating human arthritis. In arthritis, Gallium(III) appears effective as an antibacterial agent, killing iron dependent bacteria and mycobacteria that can cause arthritis, and as an anti-inflammatory agent.
Perhaps there is a microbial component that may be benefited as there is in arthritis, particularly where there is blood in the navicular bursa. As examples of antimicrobial activity, gallium has shown efficacy in treating experimental syphilis in rabbits and eliminating Trypanosoma evansi parasites from infected mice, killing Mycobacterium tuberculosis and Mycobacterium avium complex and killing malarial parasites. Gallium, particularly gallium maltolate, was found to be antibacterial to Rhodococcus equi, which causes foal pneumonia. The anti-bacterial activity of gallium(III) seems very broad, and its activity likely stems from its ability to enter microbes through their iron transport mechanisms, to disrupt their iron metabolism, and to interfere with their DNA and protein synthesis. The ability of transferrin-bound gallium to enter infected cells through the transferrin receptor may be an advantage in treating some intracellular infections.
Gallium is reported to ameliorate hepatocellular injury and protect against necrosis in murine models of septic shock and hepatitis.[15, 16] Similarly, in open field use over a 10-year period to treat navicular pain, there have been no reports of hepatic or renal injury in horses attributable to gallium nitrate. At the time of this writing, over 50,000 daily doses (500 cc of 1% GN) have been administered for navicular pain and other foot pain with no reports of toxicity, performance degradation or injury.
Radioactive gallium-67 has long been used in radiography due to its ability to strongly concentrate in tumors and inflamed tissues. Consequently, the ability of much larger therapeutic doses of non-radioactive gallium(III) to accumulate and remain in inflamed tissues now can be seen as having great importance in the treatment of inflammatory conditions with utility far beyond navicular pain. Any time steroids are indicated, consideration should also be given to gallium, particularly if there is a concern for bone density.
Oral doses identical to those used to treat navicular syndrome were also found to be useful in restoring soundness in a few horses from laminitis, coffin bone separation, tendinitis, bursitis and founder (no data presented), each of which has a strong inflammatory component. Topical application of 14% gallium nitrate solutions to thrushy feet, swollen legs and sole abscesses nearly immediately terminated pain and swelling and restored soundness in one horse each.
Intravenous gallium nitrate is strongly discouraged, due to the potential for kidney damage. Renal toxicity associated with rapid intravenous dosing of gallium nitrate does not appear when gallium nitrate is administered orally, since the gallium becomes protein bound in the serum and is excreted primarily via the intestinal tract and not the kidneys. Nephrotoxicity, if it occurs, should be immediately treated by thorough re-hydration for several days. The pH of gallium nitrate solutions for topical use should not be less than 1.5 to avoid skin irritation. One percent solutions have an astringent mouth-feel in humans, and stronger solutions may not be palatable to horses. Concentrations substantially over 42% and solid gallium nitrate are not suitable for use in veterinary medicine due to the oxidative nature of the nitrate moiety. The gallium nitrate used in this trial was not GaniteŽ, a proprietary, citrated form of gallium nitrate, which is inconsistently termed "gallium nitrate".
Perhaps the hypothesis of Aluminum(III) ion contamination as a cause of some cases of navicular disease and pain is accurate since it is known to cause bone pain, osteomalacia and proximal myopathy in all vertebrate species tested.[3, 18, 19] Adding support to this hypothesis are observations of aluminum horseshoes being associated with navicular discomfort. Not previously considered as a cause of navicular pain, aluminum shoes nailed in place with steel nails create an aluminum-iron battery in wet acidic conditions, which might concentrate aluminum(III) ions in the foot through electrophoretic means. Some of these horses were extremely sensitive to nailed-on aluminum shoes, and could not be made sound with gallium nitrate while wearing them and required 6 weeks without aluminum shoes before gallium became effective. Although this is not yet an indictment of nailed-on aluminum shoes, horses that become lame while using them may be hypersensitive to aluminum ion. Aluminum silicate clay soils also release aluminum(III) in acidic (urine and acid rain) conditions.
Although it is dangerous to ascribe human emotions to animals, the notion of "joy from being pain free" is suggested as being the cause of over exuberant behavior on first turnout.
Gallium nitrate appears to be an effective and safe alternative treatment in the care of horses with painful navicular disorders and related foot pain although the exact mechanism of action remains to be elucidated. Aluminum(III) contamination may be a cause of navicular pain. Future clinical trials and field use of gallium nitrate to treat navicular disease and pain, arthritis, laminitis and related foot conditions in horses should follow a continuous dosage protocol, not the two-week on and two-week off protocol described here. Horses (540 kg bwt) should be given a 500 cc dose of a one percent gallium nitrate solution (1.36 grams elemental gallium per day), with proportional variations in dosage dependent upon weight. Treatment should be given for a minimum of 2 months, and preferably 6 months. Horses may be either maintained or treated prophylactically with gallium nitrate, perhaps at one half the above daily dose. Proper usage of gallium nitrate should rapidly restore soundness and eliminate the need for euthanasia for navicular syndrome, foot pain and associated lameness. If sufficient gallium were an ingredient in horse feed, lameness from navicular pain and other bone/joint inflammatory disorders probably would not occur.
I thank Lawrence R. Bernstein for constructive comments and Karen L. Eby for statistical analyses.
1. Svalastoga E, Nielsen K. Navicular disease in the horse. The synovial membrane of bursa podotrochlearis. Nord Vet Med. 1983;35:28-30.
2. Blunden A, Dyson S, Murray R and Schramme M. Histopathology in horses with chronic palmar foot pain and age-matched controls. Part 1: Navicular bone and related structures. Equine Vet. J. 2006;38:15-22.
3. Alfrey AC. Toxicity of detrimental metal ions - Aluminum. In: Handbook of Metal-Ligand Interactions Biological Fluids - Bioinorganic Medicine, Volume 2, Berthon G (Ed.), Marcel Dekker, Inc., New York. 1995, pp. 735 - 742.
4. Warrell RP Jr. Gallium for Treatment of Bone Diseases. In: Handbook of Metal-Ligand Interactions in Biological Fluids - Bioinorganic Medicine, Volume 2, Berthon G (Ed.), Marcel Dekker, Inc., New York. 1995, pp. 1253 - 1265.
5. Apseloff G. Therapeutic uses of gallium nitrate: past, present, and future. Am J Ther. 1999;6:327-39.
6. Bockman R. The effects of gallium nitrate on bone resorption. Semin Oncol. 2003;30:5-12.
7. Collery P, Keppler B, Madoulet C, Desoize B. Gallium in cancer treatment. Crit Rev Oncol Hematol. 2002;42:283-96.
8. Denoix JM, Thibaud D, Riccio B. Tiludronate as a new therapeutic agent in the treatment of navicular disease: a double-blind placebo-controlled clinical trial. Equine Vet J. 2003; 35:407-13.
9. Bernstein LR. Mechanisms of Therapeutic Activity for Gallium. Pharmacol. Rev. 1998;50:665-682.
10. Panagakos FS, Kumar E, Venescar C, Guidon P. The effect of gallium nitrate on synoviocyte MMP activity. Biochimie. 2000;82:147-51.
11. Apseloff G., Hackshaw KV, Whitacre C, Weisbrode SE, Gerber N. Gallium nitrate suppresses lupus in MRL/lpr mice. Naunyn Schmiedeberg's Arch Pharmacol. 1997;356:517-25.
12. Belknap JK, Gigučre S, Pettigrew A., Cochran AM, Van Eps AW and Pollitt CC. Lamellar pro-inflammatory cytokine expression patterns in laminitis at the developmental stage and at the onset of lameness: innate vs. adaptive immune response. Equine Vet. J. 2006 (in press).
13. Eby G. Elimination of arthritis pain and inflammation for over 2 years with a single 90 min, topical 14% gallium nitrate treatment: case reports and review of actions of Gallium(III). Med Hypotheses. 2005;65:1136-41.
14. Harrington JR, Martens RJ, Cohen ND, Bernstein LR. Antimicrobial activity of gallium against virulent Rhodococcus equi in vitro and in vivo. J Vet Pharmacol & Ther. 2005;29:121-7.
15. Krecic ME, Mullet D, Shepard DR, Apseloff G, Weisbrode SE, Zaveri N. Gallium nitrate inhibits nitric oxide in vitro and attenuates lipopolysaccharide-induced hepatitis in Balb/c mice in vivo. In: Proceedings of 6th INWIN, Geneva, 1995, pp. 101-104.
16. Krecic-Shepard ME, Shepard DR, Mullet D, Apseloff G, Weisbrode SE, Gerber N. Gallium nitrate suppresses the production of nitric oxide and liver damage in a murine model of LPS-induced septic shock. Life Sci. 1999;65:1359-71.
17. Lamoureux F. and Chartrand R. Gallium-67 and its value in the detection of cancerous and inflammatory lesions. Union Med Can. 1977;106:738-43.
18. Berthon G. Aluminum speciation in relation to aluminum bioavailability, metabolism and toxicity. Coord Chem Rev. 2002;228:319-41.
19. Zatta P, Kiss, T, Suwalsky M, Berthon G. Aluminum (III) as a promoter of cellular oxidation. Coord Chem Rev. 2002;228:271-284.