imidtarello

EFFICACY OF IMIDOCARB DIPROPIONATE AGAINST
PERIANAL FISTULAS IN 10 DOGS

Walter Tarello, DVM, MRCVS,
C.P. 1644, 06129 PERUGIA, ITALY

SUMMARY
Six dogs from UK (n=2), Australia (n=1) and USA (n=3) with perianal fistulae (PAF) resistant to previous therapies with cyclosporine and ketoconazole, and four dogs from Kuwait (n=3) and Italy (n=1) with no prior medication were treated with imidocarb dipropionate once a week for 4 weeks.

Macroscopic perianal lesions disappeared within 3-8 weeks, concomitantly with collateral signs, such as lethargy, fever, exhaustion and poor appetite in all dogs.

Long-term follow-up confirmed lasting remission in 9 cases and recurrence occurred in only one dog 6 months later. For reasons that still remain to be investigated imidocarb dipropionate can cure dogs with PAF better than cyclosporine, cyclosporine + ketoconazole or azathioprine. The search for underlying agents should not be considered a pre-requisite for the rational treatment of PAF.

INTRODUCTION
Perianal fistulas (PAF) is a severe cutaneous disease of dogs characterized by the presence of single/multiple fistulae in the skin, subcutaneous and dermal tissues surrounding the anus accompanied by swelling, redness, bleeding, diarrhoea, itching and secondary infections due to self traumatic lesions (Mathews and others 1997). The underlying reasons for the occurrence of such condition are not completely understood. However, it has been suggested that secondary cell-mediated immune dysfunctions resulting in decreased T-lymphocyte populations can determine the development of perianal fistulas (Killinwsworth and others 1988).

Cyclosporine administration is considered today useful for the palliative therapy of PAF (House and others 2006). Therapeutic responses of PAF to cyclosporine (Mathews and Sukhiani 1997) or combined treatment with cyclosporine and ketoconazole (Patricelli and others 2002; Mouatt 2002) remain controversial because recurrences are common once treatment is stopped (Mouatt 2002; Patricelli and others 2002). Additionally, no resolution of lesions has been noted in 30-40% of dogs thus treated (Patricelli and others 2002; House and others 2006).

Cyclosporine administration is associated with increased risk of development of lymphoma in humans and dogs as well (Blackwood and others 2004). Moreover, adverse reactions such as transient emesis, diarrhoea, gingival hyperplasia, verruciform lesions and hypertrichosis are seen in dogs thus treated (Guaguere and others 2004). Cost of treatment with cyclosporine is very high and comparable to traditional surgical options (Patricelli and others 2002).

In the recent past, treatment with imidocarb dipropionate in 3 dogs with PAF proved highly and rapidly effective, safe, lasting and cheap (Tarello 2001).

The aim of this study was to determine the response to imidocarb dipropionate in 10 cases of canine PAF, six of which resistant to prior therapy with cyclosporine.

MATERIALS AND METHODS
In 2004, members of an Internet Yahoo/PF-Group, including people from all over the world owning dogs with perianal fistulas (PAF) were asked to voluntarily participate to a trial using imidocarb dipropionate as a therapeutic alternative option for PAF in dogs relapsed or resistant to prior therapy with cyclosporine or cyclosporine + ketoconazole. Six owners from USA (n=3), UK (n=2) and Australia (n=1) agreed to include their dogs in the trial.

Additionally, four dogs with PAF from Kuwait (n=3) and Italy (n=1) were treated with imidocarb dipropionate by this author during the same period. Animals were not submitted to therapy or surgery for PAF during 2 weeks preceding the administration of imidocarb. No search for underlying concurrent diseases was performed.
The animals were treated blindly with imidocarb dipropionate (Carbesia®, Imizol®, Schering-Plough Animal Health Corp, Union, NJ, USA) at the dosage recommended for dogs with babesiosis, i.e. 7.13 mg/kg, thus 1 ml/17 kg, given subcutaneously once a week for 4 weeks. The efficacy of therapy was checked for during weekly controls made until complete clinical resolution was achieved. Follow-up lasted 24-30 months.

RESULTS
History, clinical signs and therapy outcomes are shown in Table 1 and Fig. 1-4.

SIGNALMENT, HISTORY, CLINICAL FINDINGS AND IMIDOCARB DIPROPIONATE THERAPY OUTCOMES IN 10 DOGS DIAGNOSED WITH PERIANAL FISTULAS FROM UK, USA, AUSTRALIA, ITALY AND KUWAIT
Dog	Sex, Age, Breed, Name Country, Date of therapy	History & previous diagnosis	clinical symptons& signs Previous Treatments	Therapy Outcome
1	M, 7 yrs, G. Shepherd, ‘Dudley' USA (Connecticut), Nov 2004	He has a lot of ticks and borreliosis a few years back. Resulted negative for babesiosis by microscopy.	Vomiting, diarrhoea, 8 months PAF Cyclosporine (3 months: no benefit)	Complete recovery within 5weeks No recurrence after 30 months
2	M, 8½ yrs, Pomeranian,‘Ouzo’ UK(Wales),October 2004	No previous diagnosis or test	Lethargy, poor appetite, 1½ yrs PAF Cyclosp.+ketoconazole (6 mo.:recurrence)	Complete recovery within 6 weeks No recurrence after 30 months
3	M, 5 yrs, G. Shepherd, ‘Xebu’ USA (Maine), Nov2004	It was recently tested by microscopy and found positive to babesiosis	Lethargy, anorexia, life-threatening condition Cyclosporine(4months:nobenefit)	Complete recovery within 7 weeks No recurrence after 30 months
4	M,12yrs,Gold.Retriever,‘Puck’ USA(Massachusetts),Oct2004	No previous diagnosis. The owner was diagnosed with babesiosis and ehrlichiosis by DNA testing.	Lethargy, anorexia, diarrhoea, 2 years PAF Cyclosporine (3 months: recurrence)	Complete recovery within 7 weeks No recurrence after 30 months
5	F, 4½ yrs, G. Shepherd, ‘Sabre’ Australia(Queensland),Dec2004	No previous diagnosis	Poor appetite, diarrhoea, 5monthsPAF Cyclosp.+ketoconazole (3 months.: no benefit)	Complete recovery within 4 weeks No recurrence after 30 months
6	M, 7 yrs, Ger. Shepherd, ‘Zedd' UK (South Yorkshire), Oct 2004	No previous diagnosis. Spleen removed Tick infestation 3 years earlier	Almost dead, anorexia, 1 year PAF Cyclosporine(4months:nobenefit)	Complete recovery within 8 weeks Recurrence after 6 mo. (2nd therapy)
7	M, 5 yrs, Ger.Shepherd,‘Marco’ Italy (Rome), May 2005	No previous diagnosis	Lethargy, conjunctivitis, diarrhoea, 6 months PAF Surgery & laser-therapy + antibiotics (no benefit)	Complete recovery within 4 weeks No recurrence after 24 months
8	F, 6 yrs, Pomeranian, ‘Aziza’ Kuwait, June 2003	No previous diagnosis	Lethargy, fever, conjunctivitis, 3 months PAF Broad-spectrum antibiotics (nobenefit)	Complete remission within 3 weeks No recurrence after 24 months
9	M, 5 yrs, G. Shepherd, ‘Rocky’ Kuwait, October 2003	No previous diagnosis	Fever, appetite, conjunctivitis, 1 month PAF Not previously treated for PAF	Complete recovery within 4 weeks No recurrence after 24 months
10	M, 4 yrs, Gold. Retriever, ‘Sarah’ Kuwait (from California) Jan 2004	Previously diagnosed with borreliosis by serology and treated with antibiotics	Fever, lethargy, anorexia, diarrhoea, 1 month PAF No previously treated for PAF	Complete recovery within 4 weeks No recurrence after 24 months

LEGEND: PAF was treated with imidocarb dipropionate (4 injections, one week apart) at doses of 1 ml/17 kg/weekly)

Side effects reported by some members of the Yahoo/PF-Group were drooling for 10 minutes (observed by Jan in dog ‘Dudley’), ‘spacyness’ for a short time after the injection and one member’s dog had a rapid heart beat, according to the owner.

All dogs seemed to sleep for a while after the injections and in some cases there was pain/tenderness at the injection site for a short time afterwards.


Figure 1: dog n. 8 with perianal fistulas, day 1, before therapy with imidocarb	Figure 2: dog n. 8 with advanced remission of perianal fistulas at day 21 after therapy with imidocarb dipropionate.

Transient local pain lasting for few seconds was the only side effect noticed by the author in 4 dogs from Kuwait (n=3) and Italy (n=1). Confirming a previous report (Tarello 2001), treatment of PAF with imidocarb dipropionate in 10 dogs from all over the world proved highly and rapidly effective, safe, lasting and cheap. Efficacy was demonstrated by the quick resolution of clinical signs and rapid remission of lesions observed (Table 1) (Fig. 1-4). Figures 1 and 3 show PAF in cases n. 8 and 10 at day 1 while figures 2 and 4 show the same areas at day 21.


Fig. 3: dog n. 10 with perianal fistulas, day 1, before therapy with imidocarb	Figure 4: dog n. 10 showing complete remission of perianal fistulas at day 21 after therapy with imidocarb dipropionate.

Jan, owner of ‘Dudley’, (Connecticut) commented as follows:” We live in a rural area where New York, Connecticut and Maine meet. There are some human cases of ehrlichiosis in the area, with symptoms such as vomiting, diarrhoea and poly-arthritis. Dudley has had a lot of ticks and Lyme disease a few years back. After the diagnosis of PF, it was tested for babesiosis and came back negative. However, we decided to treat him and our family veterinarian gave the 4 injections of imidocarb dipropionate on a weekly basis with excellent results, I means complete cure”.

Sharon, owner of ‘Ouzo’ (UK, Wales), said:” Ouzo was not tested for babesia and it was given 4 injections by our veterinarian. No side effect could be seen and since receiving the injections Ouzo has enough energy to keep up with a 2 years old dog. Any progress we made before the imidocarb was always short lived and followed by a down turn in his conditions. Now there is no return of old symptoms. All progress since has been good and with no problems”.

Victoria, owner of ‘Xebu’ (USA, Maine), commented:” The dog was diagnosed with babesiosis and had PF! He is very healthy now after his imidocarb treatment. We almost lost him, but he pulled through!”

Jeff, owner of ‘Puck’ (Massachusetts, USA) observed that:” Puck fully recovered after 4 injections of imidocarb. Only the first injection was apparently painful. Puck now is really doing well. I would go for imidocarb treatment if I were the owner of a PF dog. I estimated that Puck had PF for about 2 years and was in very bad shape. Then the big breakthrough came with imidocarb that in the USA is sold under the name Imizol. I had to order it from the manufacturer and do the 4 shots myself as my veterinarian does not believe babesiosis is in the USA. He told me I would have to Africa to get. He would not believe my wife had it along with 3 other tick transmitted diseases and we had to have DNA testing on her blood to find out. The whole bottle cost me 60 $ and it was well worth it. Puck is now doing stuff that he couldn’t do for at least 2 and one half years. He just beat me going down the stairs a little while ago. I think we were the 3rd ones to use the Imizol for treating PF and all of us are really happy we did.”

Valerie, owner of ‘Sabre’ (Queensland, Australia) said:” Sabre healed completely in four weeks. My vet charged me 300 Australian dollars for the four injections of imidocarb that also includes the consultations. When you consider what I was spending on Cyclosporyne and Nyzoral, 310 $ every 3 weeks, is a huge saving”.

Ann, owner of ‘Zedd’ (South Yorkshire, UK) said that:” Zedd has had 2-3 tick bites over the years. It was not tested for babesia before to be treated with 4 imidocarb injections. There were no side effects apart scratching the area for a while. Ann said: ‘Zedd was almost at deaths’ door, he was severely depressed and his recovery is almost like a miracle. Zedd is like a new dog. Cyclosporine just did not work for him and it is very expensive. The imidocarb injections are much cheaper and only 4 are required, the results are quite amazing. We have been extremely happy with the results of the imidocarb injections. Zedd was almost at death’s door and was so depressed, but he is a different dog now, bright, bouncy and full of life. The fistulas appear to still be healing and he is certainly not in anywhere near as much pain. As far as Zedd is concerned we tried cyclosporine, antibiotics and cryosurgery with limited success and he only regained his well being and zest for life after the imidocarb injections.

DISCUSSION
Imidocarb dipropionate (Carbesia®, Imizol®, Schering-Plough Animal Health Corp, Union, NJ, USA) worked better than cyclosporine in the treatment of 6 canine cases of perianal fistulas (PAF) originating from USA (n=3), United Kingdom (n=2) and Australia (n=1), and it was fast and effective in eliminating PAF in 4 dogs from Italy (n=1) and Kuwait (n=3) not previously submitted to therapy with cyclosporine (Table 1). Owners and family veterinarians worldwide witnessed the reported outcomes. It is interesting to note that both drugs are manufactured by the same Company (Schering-Plough Animal Health Corp).

In dogs treated with imidocarb dipropionate, lesions disappeared within 3-8 weeks, and clinical signs such as lethargy, fever, anorexia, vomiting and diarrhoea resolved within 1-2 weeks, thus helping survival in dogs with life-threatening PAF (n. 3 and 6, Table 1). Long-term follow-up (24-30 months) confirmed lasting remission in 9 cases as recurrence occurred in only one dog with no spleen (n.6, Table 1) 6 months later.

These outcomes are intriguing and appear even better than those recently obtained using azathioprine (Harkin and others 2007). In fact, complete remission of perianal fistulas was seen in only eight (57%) of 14 dogs, partial remission occurred in one (7%) dog and no response was detected in five (36%) dogs treated with azathioprine (Harkin and others 2007).

Compared to immunosuppressive drugs such as cyclosporine and azathioprine, imidocarb dipropionate is cheaper, safer, higher effective and exclude the risk of developing lymphoma (Blackwood and others 2004). In accord with the results here reported, in the recent past imidocarb produced complete remission of PAF in 3 dogs showing concurrent underlying babesiosis (Tarello 2001).

As a matter of fact, imidocarb dipropionate is considered a specific anti-babesial drug that works against equine, canine and avian babesiosis as well (Tarello 2006). At present time and for the sake of simplicity, the search for underlying agents (i.e. babesiae) should not be considered a pre-requisite for the rational treatment of PAF using imidocarb, because many canine babesiae remain unknown and new strains of babesiae affecting dogs and humans are discovered every other year in USA and Europe (Zahler and others 2000).

On the other hand it is interesting to note that one dog (n.3) and one owner (n. 4) in this study were diagnosed with babesiosis and that 2 dogs (n.1 and 10, Table 1) resulted positive by serology to borreliosis, a tick-transmitted disease caused by the bacterium Borrelia burgdorferi, which is frequently associated with babesiosis in dogs and humans as well (Hunfeld and others 2002).

These observations and the positive response to imidocarb dipropionate strongly indicate an underlying known or unknown babesial presence in dogs with perianal fistulas. If this will be confirmed by future researches, the use of immunosuppressive drugs should be further avoided since babesiosis is known to cause immuno-depression (Purvis 1977). At present, a large-scale randomized control trial of imidocarb dipropionate is needed and the help of breeders, dogs’ owners and veterinarians should be welcome.

REFERENCES
Harkin, K.R., Phillips, D. & Wilkenson, M. (2007) Evaluation of azathioprine on lesions severity and lymphocyte blastogenesis in dogs with perianal fistulas. Journal of American Animal Hospital Association 43, 21-26.
House, A.K., Guitian, J., Gregory, S.P. & Hardie, R.J. (2006) Evaluation of the effect of two dose rates of cyclosporine on the severity of perianal fistulae lesions and associated clinical signs. Veterinary Surgery 35, 543-549.
Blackwood, L., German, A.J., Stell, A.J. & O’Neill, T. (2004) Multicentric lymphoma in a dog after cyclosporine therapy. Journal of Small Animal Practice 45, 259-262.
Guaguere, E., Steffan, J. & Olivry, T. (2004) Cyclosporin A: a new drug in the field of canine dermatology. Veterinary Dermatology 15, 61-74.
Hunfeld, K.P., Lambert, A., Kampen, H., Albert, S., Epe, C., Brade, V. & Tenter, A.M. (2002) Seroprevalence of Babesia infections in humans exposed to ticks in midwestern Germany. Journal of Clinical Microbiology 40, 2431-6.
Killingsworth, C.R., Walshaw, R., Reimann, K.A. & Rosser, Jr.E.J. (1988) Thyroid and immunologic status of dogs with perianal fistulae. American Journal of Veterinary Research 49, 1742-1747.
Mathews, K.A., Ayres, S.A., Tano, C.A., Riley, S.M., Sukhiani, H.R. & Adams, C. (1997) Cyclosporin treatment of perianal fistulas in dogs. Canadian Veterinary Journal 38, 39-41.
Mathews, K.A. & Sukhiani, H.R. (1997) Randomized controlled trial of cyclosporine for treatment of perianal fistulas in dogs. Journal of American Veterinary Medical Association 211, 1249-1253.
Mouatt, J.G. (2002) Cyclosporin and ketoconazole interaction for treatment of perianal fistulas in the dog. Australian Veterinary Journal 80, 207-211.
Patricelli, A.J., Hardie, R.J. & McAnulty, J.E. (2002) Cyclosporine and ketoconazole for the treatment of perianal fistulas in dogs. Journal of American Veterinary Medical Association 220, 1009-1016.
Purvis, A.C. (1977) Immunodepression in Babesia microti infections. Parasitology 75, 197-205.
Tarello, W. (2001) Babesiosis as an underlying factor influencing the severity and duration of perianal fistulas in three dogs. Revue de Medecine Veterinaire 152, 83-88.
Tarello, W. (2006) Effective imidocarb dipropionate therapy for Babesia shortti in falcons. Veterinary Record 158, 239-40.
Zahler, M., Rinder, H., Schein, E. & Gothe, R. (2000) Detection of a new pathogenic Babesia microti-like species in dogs. Veterinary Parasitology 89, 241-248.

reprinted with kind permission from Walter Tarello, DVM, MRCVS
Zikkos Veterinary Clinic
Larnaca, CYPRUS

The above information is simply informational. It's intent is not to replace the advice of a veterinarian nor to assist you in making a diagnosis of your pet. Please consult with your own veterinarian for confirmation of any diagnosis. Your pets life may depend on it.