Gordeeva Е.V.*, Vasilyev I.K.**, Narovlyansky A.N.**, Pronin A.V.,** Sanin А.V.**

*Centre of Veterinary Medicine "Biovet", Ivanovo; **Gamaleya Institute for Epidemiology and Microbiology, Moscow

In recent years, there has been an increased incidence of oral papilloma virus in dogs. Although warts are benign tumors and the disease often ends with spontaneous recovery in few months, the search for effective therapeutic agents is an urgent task. First, the infection often occurs in the latent (hidden) form and the virus carrier poses a significant threat to other dogs. Second, if a sick dog damages the warts eating solid food or playing, bleeding may develop and as a result the disease will be complicated by secondary infection. Finally, there are cases when warts undergo malignant transformation into squamous-cell carcinoma.

In this paper, papillomatosis was treated with Phosprenyl – an immunomodulator with antiviral activity and proven effectiveness for many viral infections in small domestic animals (2,3).

The causative agent of papillomatosis belongs to the group of DNA viruses included in the Papillomaviridae family. They are the smallest of DNA viruses. Papillomavirus virions do not have an outer shell, their diameter is 40-55 nm. Complete virions are composed of the core and the capsid and contain 5 to 7 structural proteins but they do not have lipids and carbohydrates. Replication and maturation occur in the core, virions are released by destruction of cells. The viruses are resistant to high temperatures and esters and are tropic for the epithelium. They cause cell transformation. They are characterized by species specificity (5).

Viral papillomatosis is widespread among many species of mammals. The source of causative agents are sick animals. The mode of transmission is contact. The viruses are most often transmitted when infected animals are kept together with healthy ones. In many cases it has been observed when soon after a puppy infected with papillomatosis appears in the mill, warts begin to develop in other puppies. Typically, the virus enters the body through the damaged skin and mucous membranes. The pathogen can be transferred with injection needles, thought the owner’s clothes and footwear, animal care items, “apports” on the dog playgrounds, etc. The latent period is 1-2 months.

Papillomaviruses are tropic for the mucous and skin epithelium inducing them to develop benign tumors - papillomas and warts, respectively. Typically, entering a crack in the oral mucosa, papillomaviruses first penetrate rapidly in proliferating cells in the basal layer, from where they subsequently come to the surface epithelium. Early viral proteins induce transformation of infected cells that acquire the ability to infinitely divide and maintain the intensive reproduction of viral particles. After transformation of epithelial cells in the oral mucosa (lips, tongue, cheeks, gums) papillary lesions – warts – develop. Lysis of infected cells facilitates further spread of virions, but not all tumor cells contain integrated viral genome. Activation of the integrated genome and transition of the latent infection into the productive form is observed at aging, stresses and different forms of immunosuppression, for example, after chemotherapy or corticosteroid treatment.

Immunity. After spontaneous recovery most dogs acquires immunity to papillomatosis, but some cells retain the viral genome integrated into the cell genome, so immune animals can remain virus carriers posing risk to susceptible ones. Animals administered with a specific anti-serum habing a high titer of virus-neutralizing antibodies acquire passive immunity. Papillomaviruses are weak interferon inducers and role of interferon in this infection has been studied insufficiently. The efficiency of interferon inducing therapy is not always confirmed. Experts believe that an increase in the number of cases when benign papillomas transform into squamous-cell carcinoma is connected with insufficient immunity. Most frequently it occurs in old animals.

Progression and symptoms. In most cases oral papillomatosis in dogs occurs at the age of 1 to 4 years. As a rule, first lesions appears on the lips, then they spread to the mouth and throat. Smooth, pale pink, at first rounded papules later develop into large ragged warts in the mucous membrane resembling sea anemones or cauliflower. They can be few in number, but sometimes warts literally scatter the mucous membrane of cheeks, lips, gums, tongue and throat. Later they can spread to the conjunctiva, eyelids and skin of the animal. In rare cases lesions were noticed around the nose and mouth as well as the esophagus. Oral papillomas can hinder normal eating and drinking. In such cases, halitosis, salivation and minor bleeding in the mouth can be observed. Sometimes a sick dog cannot completely close its jaws, in which case the papillomas can be damaged. In this case bleeding lesions serve as a gate to pathogenic microorganisms – bacteria and fungi (the development of candidiasis is mostly noted).

The disease is usually diagnosed on the basis of clinical symptoms, but it can be confirmed by laboratory tests, in particular, immunohistochemical ones, using an electronic microscope or PCR. Like most papillomaviruses, canine oral papillomavirus does not replicate in cell cultures.

Treatment. As a rule, the disease has a mild form and the animal often recovers spontaneously (on the average within 2-5 months). The use of autologous therapeutic vaccines gives inconsistent results, although some experimental vaccines induce protective immunity.

In the USA, systemic chemotherapy of canine papillomatosis with vincristine, cyclophosphamide, doxorubicin or bleomycin was used with variable success during several years. Typically, this method was used in advanced cases, when warts did not disappear within 5 months or more (6).

Surgery is not always appropriate, since removal of warts can lead to their further spread. However, if the lesions cause discomfort, difficulty in swallowing, their surgical removal is indicated. For this purpose non-invasive methods such as cryosurgery, laser or electrocoagulation are used.

Recently, immunomodulators have been increasingly used for treatment.

In this paper, we used Phosprenyl in the treatment of canine oral papillomatosis. In total, 10 dogs were treated, with the following breeds among them: Labrador Retriever – 5 animals, Golden Retriever – 2, Rottweiler – 1, Dalmatian – 1, Central Asian Shepherd Dog – 1. The age of patients ranged from 1 to 6 years. Five dogs have suffered from chronic papillomatosis for a year. The other five dogs had the beginning stage of the disease.

After doses of the medicine were selected and therapeutic regimens were determined the following treatment course was adopted: Day 1 – 3 ml per 10 kg of body weight; day 2 – 2,5 ml per 10 kg of body weight; day 3–5 – 2 ml per 10 kg of body weight. The injections were administered subcutaneously on the withers. The repeated course began in a week – Phosprenyl was administered in a dose of 2 ml per 10 kg of body weight every day during 5 days.

During the treatment of chronic papillomatosis the warts subsequently became pale, than cracked, decreased in size and completely disappeared in two weeks (Photo 1–5). No case of recurrent papillomatosis was observed during 12 months. During the treatment new warts did not appear.

At the beginning stage of disease, when papillomas are formed, the treatment course was the following: Day 1 – 3 ml per 10 kg of body weight, then 2 ml per 10 kg of body weight during 4 days. In all cases papillomas disappeared within 1-2 weeks.

For the first time, immunomodulators were used for papillomatosis in early 1990s. Thus, during 2 years on the basis of the Department of Veterinary Medicine of the Novosibirsk State Agricultural University a low-molecular interferon superinducer – kamedon (kardanon) – was used. It was indicated when novocaine therapy was ineffective. The authors have shown that nearly in 60% of the animals warts began to destroy after the second administration of the drug and in 15% of cases the recovery occurred on the 7–10th day after the third administration of the drug (1). At the beginning of this century it was found that local Phosprenyl and Novocaine injections under the wart roots were effective. The effect of Phosprenyl was increased in combination with Maxidine (4).

In this paper, we have demonstrated the therapeutic effectiveness of Phosprenyl in subcutaneous injections. Notwithstanding that immunity mechanisms in papillomatosis are slightly studied, it is known that the immunity level is usually crucial for the outcome of the disease. We suppose that the expressed therapeutic effect of Phosprenyl is due to its well-known ability to activate the cell immunity and production a number of key cytokines that play an important role in viral infections.

NOVEL APPROACH TO TREATMENT OF CANINE ORAL PAPILLOMATOSIS

Gordeeva Е.V*, Vasilyev I. K.**, Narovlyansky A.N.**, Pronin A.V.,** Sanin А.V.**

*Centre of Veterinary Medicine "Biovet", Ivanovo; **Gamaleya Institute for Epidemiology and Microbiology, Moscow.

Viral papillomatosis in dogs was treated s.c. with Phosprenyl – immunomodulator with antiviral activity. Altogether 10 patients were studied. Result of the therapy was positive in all cases. Papillomatosis was successfully treated both in chronic cases and at the beginning stage. No recurrent cases were observed following the treatment.

References

1. Gryazin V.N. The Use of Interferon Inducer for the Treatment of Canine Papillomatosis. Topical Issues of Veterinary Medicine. Abstract for the 1st Research and Practice Conference of the Department of Veterinary Medicine of the Novosibirsk State Agricultural University, 1997.

2. Ozherelkov S.V., Sosnovskaya O.Yu., Kozhevnikova T.N., Bekhalo V.A., Nagurskaya Ye.V., Krasota A.Yu., Deeva A.V., Narovlyanskay A.N., Pronin A.V., Sanin A.V., Belousova R.V. Basic Mechanisms of the Antiviral Action of Phosprenyl, a Drug of Natural Origin. VII Kiev International Conference on the Problems of Veterinary Care for Small Domestic Animals. 2-5 October 2002.

3. Sanin A.V. The Use of Immunomodulators in Viral Diseases of Small Domestic Animals. The Russian Journal of Veterinary Medicine. 2005 N1 p.38-42.

4. Sanin A.V., Lipin A.V., Zinchenko Ye. V. Handbook of Traditional and Non-Traditional Methods of Treatment of Dogs. M. Tsentrpoligraf, 2007 595 p.

5. Shulyak B.F. Viral Infections in Dogs. Moscow, Olita, 2004. – 568 p.

6. Calvert CA. Canine viral papillomatosis. In: Greene CE, ed. Infectious diseases of the dog and cat. Philadelphia: WB Saunders, 1990:288-290.

Photo 1. Day 1. Canine oral papillomatosis is diagnosed, Phosprenyl is prescribed.

Photo 2. Day 3 of Phosprenyl therapy; destructive changes in affected cells are clearly visible.

Photo 3. Day 5 of Phosprenyl therapy; recovery of oral epithelial cells.

Photo 4. Repeated course of the Phosprenyl therapy. Day 2.

Photo 5. Repeated course of the Phosprenyl therapy. Day 5 from the beginning of treatment; complete recovery of epithelial cells in the dogs’ mouth.