AAntiviral Drugs ntiviral Drugs Treatment of Selected Treatment of Selected

Canine and FelineCanine and FelineViral DiseasesViral Diseases

AAntiviral Drugs ntiviral Drugs Treatment of Selected Treatment of Selected

Canine and FelineCanine and FelineViral DiseasesViral Diseases

Assoc. Prof. Ivan Lambev (www.medpharm-sofia.eu)

About 4000 species of viruses are knownto date, and more than 60% of illnesses in humans are caused by viruses. Currently ≈ 30 antiviral drugs have beenapproved in HM, but the application ofthese drugs in VM often have beenlimited because the etiologic agents of viral diseases vary so widely.

The development of effective antiviral drugs islimited by the latent nature of disease, inherenthost toxicity to viral drugs, and rapid emergenceof viral resistance. Differences in viral diseaseslimits application of human antiviral drugsto animals.

In vitro susceptibility testing of viruses requiressophisticated and expensive techniques such as cell cultures. In vitro inhibitory testing procedureshave not been standardized, and results vary with the assay system, cell type, and viral inoculum.

Viruses are composed of a core genome consisting of either double-stranded or single-stranded DNA or RNA surrounded by a proteinshell known as a capsid. Some viruses are further surrounded by a lipoprotein membraneor envelope. Both the capsid and membranemay be antigenic. Viruses cannot replicateindependently and must usurp the host’smetabolic machinery to replicate. Thereforeviruses are obligate intracellular parasites.

Classification of DNA Viruses by Genome Type

Genomic

Type

Genus

(Virus)

Disease

ssDNA Parvovirus Canine parvovirus (distemper)Feline panleukopenia

dsDNA Adenovirus Canine infectious hepatitis, blue eye (CAV1), respiratory disease (CAV2)

dsDNA Herpes virus Canine herpes virus (CHV)Feline herpes virus (FHV1, rhinotracheitis)

dsDNA Papilloma virus Canine papillomas

Classification of RNA Viruses by Genome Type

Genomic

Type

Genus

(Virus)

Disease

dsRNA(+)ssRN

Coronavirus Canine corona virus (gastroinestinal)Feline infectious peritonitis

dsRNA(+)ssRNA

Vesivirus Feline calicivirus (respiratory)

dsRNA(+)ssRNA

Enterovirus Polio, bovine, and porcine enterovirus

dsRNA(+)ssRNA

Erbovirus Equine rhinitis virus B

Genomic

Type

Genus

(Virus)

Disease

dsRNA(+)ssRNA

Aphthovirus Foot and mouth disease

ssRNA Gammaretrovirus Feline infectious leukemia

ssRNA Lentivirus (HIV, Lentivirus (HIV, FIV)FIV)

Human AIDSHuman AIDSFeline AIDSFeline AIDS

(-)ssRNA Mups virus Mups

(-)ssRNA Morbilli virus MeaslesCanine distemper

Genomic

Type

Genus

(Virus)

Disease

(-)ssRNA Parainfluenzae virus Kennel cough (dog)

(-)ssRNA Influenza A (inc.canine), B, C virus

Canine influenza (respiratory)

(-)ssRNA Newcastle virus Newcastle disease

(-)ssRNA Rabies virus Rabies

ss – single stranded; ds – double stranded (for DNA or RNA);(+) – positive, (-) – negative (for RNA)ss – single stranded; ds – double stranded (for DNA or RNA);(+) – positive, (-) – negative (for RNA)

Antibodies will be generated in response to viralinfection, but these do little to overcome the initialinfection. Rather, in part because viral activity isintracellular and inaccessible to antibodies, theyprotect against subsequent infection. Cell-mediatedimmunity (CMI) plays a critical role in overcomingand preventing viral infection. However, viruses that can avoid an effective CMI response may causelatent or, infected cell is not recognized by T cells. Viruses, causing chronic infections are paramyxo-viruses, selected herpesviruses, and retroviruses.

Potential targets in the viral life cycle that mightbe pharmacologically inhibited are expressed during extracellular stages of viral infection (i.e., penetration), intracellular stages (i.e., replication,assembly, and viral release), and dissemination.Antivirals that diminish penetration of host cells bythe virus are more viral specific and less toxic fromthose that prevent viral replication. Pharmacologic immunomodulation (resp. immunostimulation) mayalso help prevent viral penetration during the earlystages of infection.

Among the toxicities caused by antiviral drug is nephrotoxicity. Acute tubular necrosis has been associated with foscarnet, acyclovir, IFN, and cidofovir. Glomerular disease resulting in proteinuria and the nephrotic syndrome has been mediated by either immuno-mediated complexes (IFN) or crystal deposit (foscarnet). Crystalline deposits in the renal tubule (e.g.,acyclovir, ganciclovir, and indinavir) can cause intrarenal obstruction.Isolated tubular defects may occur; examples include aFanconi-like syndrome (cidofovir, tenofovir), distal tubularacidosis (e.g., acyclic nucleotide phosphonates, foscarnet),and nephrogenic diabetes insipidus (foscarnet).

The structures of antiviral drugs are similarlyto purine or pyrimidine bases of host RNA or DNA.This results inlimited host safety.

H. simplexH. simplex

I. Antiherpetic DrugsThey are prodrugs

– nucleoside analogues.

After phosphorylation nucleoside analogs convertinto active metabolites,which inhibit viral DNApolymerase (reversetranscriptase) and blockviral replication.

Pyrimidine Nucleosides

Pyrimidine nucleosides (halogenated andnonhalogenated) inhibit the replication of herpessimplex viruses with limited host cell toxicity. They substitute pyrimidine with thymidine, causingdefective DNA molecules.

Pyrimidine Thymidine

Idoxuridine (IDU) resembles and is substituted forthymidine. After phosphorylation, it is incorporated intoboth viral and host cell DNA. Resistance to IDU developsrapidly. The ability of IDU to cause neoplastic changes,genetic mutation, and infertility limits its use for treatmentof feline herpetic keratitis. One drop of a 0.1% solutionis usually applied to the affected eye every hour; the 0.5% ointment can be applied every 2 h. Topicalapplication of IDU to the conjunctiva has beenassociated with irritation, pain, pruritus, inflammation, and edema of the conjunctiva.

0.1%

0.5%

Trifluridine (trifluorthymidine – TFT) is a fluorinatedpyrimidine. It has in vitro inhibitory effects against herpessimplex virus (types 1 and 2) and cytomegalovirus. The primary therapeutic indication for TFT is feline herpetic keratitisand it is usually appliedin 1% collyrium 6 to 8times per day. Adverse reactions includediscomfort on applicationand palpebral edema.

Sorivudine has a relative selectivity for varicella-zoster virus (VZV). Inhibitory concentrationsof sorivudine are 1000-fold lower for VZV than arethose of acyclovir. Cellular uptake in cells infectedwith herpes virus is 40-fold greater than in uninfected cells. Clinical resistance has not yet been detected. Sorivudine isavailable in both oraland i.v. preparationsbut only asinvestigational drug.

Purine Nucleosides

Purine Vidarabine

Vidarabine is an analog of adenine. It is phosphorylatedby host enzymes and competitively inhibits viral DNApolymerase. It is substituted for adenine intoDNA. Vidarabine selectively inhibits DNA viruses, particularly herpes viruses. Vidarabine is used for topicaly tretament of herpetic keratitis in the cats as 3% ointment.

Adenine

Acyclovir is is structurally similar to guanosine (purinenucleoside). Valacyclovir is an L-valyl ester prodrug ofacyclovir. Efficacy of acyclovir depends on its activationto monophosphate metabolite by viral thymidine kinase.Subsequent phosphorylation to the diphosphate and thentriphosphate form is mediated selectively by cells infectedwith herpes virus. The drug has a greater affinity for viral(versus host) thymidine synthetase. Antiviral activity of acyclovir is limited essentially to herpes viruses. The in vitro activity of acyclovir is 100 times than of vidarabine.

Aciclovir (INN)(Acyclovir – USAN)Vials (fl.) 500 mg/10 ml i.v.in h. simplex encephalitis

The spectrum of activity of Penciclovir is herpes simplex virus and VZV. Penciclovir is a 100-fold lesspotent than acyclovir but is accumulated to higherconcentrations than is acyclovir in infected cells.Like acyclovir, the drug is well toleratedorally, chronic administrationappears to be tumorigenic, causing testicular toxicity in animals.

Herpes zoster infectionHerpes zoster infection

Ganciclovir is structurally similar to acyclovir. Therapeutic use includes cytomegalovirus retinitis,particularly in humans with AIDS. Ganciclovir is alsoused for treatment of any infection or prevention ofinfection (particularly in transplant recipients) associated with cytomegalovirus. The primary ADRis myelosuppression with neutropenia occurring in up to 40% and thrombocytopenia in 5–20% ofpatients. Myelosuppression more commonly occurswith i.v. administration and is generally reversible by1 week after discontinuation of therapy.

Ribavirin is effective against both DNA and RNAviruses and is a broad-spectrum antiviral drug.Viral resistance to ribavirin is rare. In the cat, in vitro investigations revealed markedantiviral activity against a strain of calicivirus butlittle efficacy for rhinotracheitis.

Other Antiherpetic Drugs

Foscarnet interferes directly with herpes viral DNApolymerase. The drug may also be effective in treatingretroviral infections owing to similar interference withreverse transcriptase. Direct actions preclude intracellular activation. Point mutations in DNApolymerase are responsible for resistance. Major sideeffects in human patients include nephrotoxicity andhypocalcemia. Currently foscarnet is being studied inthe cat for treatment of retroviral infections.

II. ANTIRETROVIRAL DRUGSII. ANTIRETROVIRAL DRUGS

Prof. L. Montagnier (1983)(Nobel prize, 2008)

•BloodBlood•Blood productsBlood products•Sexual secretionsSexual secretions

HIV infections

The HIV lifecycleThe HIV lifecycle

a) Nucleoside analogues ●prodrugs: reverse transcriptase (DNA polymerase) inhibitors

- Abacavir (ABC), - Didanozine, Inosine (?), - Lamivudine, Stavudine, - Zalcitabine - Zidovudine (AZT)

•Retrovir®

caps. 100 mg

Zidovudineanalogue of thymidineAZT (azidothymidine – USA)

Within the virus-infected cell, the 3’-azido group of AZT substitutes for the 3’-hydroxygroup of thymidine. The azido group is thenconverted to a triphosphate form,which is used by retroviral reverse transcriptase and incorporated into DNA transcript. The 3’-substitution prevents DNA chain elongation and insertionof viral DNA into the host cell’s genome, preventing viral replication.

AZT

AZT-MP AZT-TP

(–)

Viral DNAPolymerase

MP – monophosphateTP – 3’-phosphate

...

Treatment with AZT prolongs survival and decreasesthe incidence of opportunistic infections. AZT hasbeen usually combined with didanosine or zalcitabine.The disposition of AZT has been studied in cats. It israpidly absorbed in cats after oral administration.ADRs in cats at 25 mg/kg i.v. were transientrestlessness, mild anxiety, and hemolysis.

Main ADRs of AZT in humans: Bone marrow suppression vomiting, fatigue, headache, insomnia,hepatotoxicity, renaltoxicity.

Zalcitabine is a cytosine nucleoside.•Oral bioavailabilty 86%•Urinary excretion 70%

Unwanted reactions of Zalcitabine•peripheral neuropathies in 23% of patients

•stomatitis stomatitis aftosa aftosa

•skin rashskin rash

Lamivudine. The disposition of the combination of AZT and lamivudine has also been studied innormal and FIV-infected cats.

Didanosine is from 10- to a 100-fold less potentthan AZT. Up to 70% of humans develop pancreatitis. It is approved for treatment of advanced HIV infectionsin patients with intolerance or resistance to AZT.

Stavudine is a thymidine nucleoside – an alternative to AZT therapy for human patients.

CombivirТМ

– Lamivudine– Zidovudine

Trizivir™ – Abacavir– Lamivudine– Zidovudine

Inosine (Isoprinosine) is a nucleoside analog whichinhibits cytopathic effects of several viruses in culture.The mechanism of its antiviral activity involves specificsuppression of viral mRNA. It can also induce T-cell differentiation. Thus inosinemay be more useful as an immunostimulant immunostimulant in immunodeficient patients.

c) HIV-protease inhibitors

• Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir

They prevent cleavage ofprotein precursors essential for HIV infection of new cellsand viral replication.

Indinavir

Ritonavir

ENFUVIRITIDE (Fuzeon®) – s.c.

d) Entry (Fusion) inhibitors:Disrupt the fusion of HIV-1with the target cell

e) Integrase inhibitors – act on the gene level RALTEGRAVIR: p.o.

g) Infective complicationsg) Infective complications of HIV-infectionsof HIV-infections•Pneumocystis carinii pneumonia

high dose co-trimoxazole (21 days i.v./p.o.)is first-line standard therapy

•Tbc: M. avium complex (with Rifabutin p.o.)

•Oropharyngeal candidiasisfluconazole (14 days p.o.)

Kaposi's sarcoma is a tumor caused by infectionwith Human herpes viris 8 (HHV8):

•amantadine(+ antiparkinsonian effect too)•rimantadine

a) Cyclicamines(active against virus A)

(Ag)

(Ag)

III. Drugs used in influenza III. Drugs used in influenza viral infectionviral infection in humansin humans

Amantadine and its derivative rimantadine aresynthetic agents that appear to act on an early stepof viral replication after attachment of virus to cellreceptors. Amantadine also prevents virus assemblyduring virus replication. The main clinical use has been to prevent infection with various strains of influenza A viruses. In humans,however, it also has been found to producesome therapeutic benefit if taken within 48 hafter the onset of illness.

Rimantadine is from two to 8-fold times more active than Amantadine.

Pig flu: Bird flu:Bird flu:

•Rimantadine (Flumadine): p.o.•Vitamin C

•Esberitox N (phytoimmunostimulant)

Indications:prophylaxis and treatmentof influenza A viral infection:А (H5N1)

Rimantadine – adverse effects:•orthostatic hypotension•dizziness, confusion•headache, insomnia•vomiting, xerostomia•urinary retention

b) Neuraminidase inhibitors(active against virus A and B

Zanamivir:•inhibits neuraminidase and prevents replication of influenza-A and B-virus (per inhalationem)

Oseltamivir– Tamiflu®

against virus against virus АА and B and B•A (H5N1): bird or avian flu (influenza)A (H5N1): bird or avian flu (influenza) – – ((2 2 s/78 °C)s/78 °C)•A (H1N1): swine or pig flu (influenza)A (H1N1): swine or pig flu (influenza)

Treatment: 75 mg/12 h 5 daysProphylaxis: 75 mg/24 h about 15 – 30 days

Oseltamivir is an ester prodrug. On release byesterases in the GI tract, the carboxylate form actsas a selective inhibitor of influenza A and B viralneuraminidases. The viruses cannot leave the infected cell and therefore aggregate at the cell surface and are unable to spread. The drug has not yet been studied in dogs or cats despite its anecdotal use for treatment of parvovirus in dogs.

Symptomatic therapy of influenza

ParacetamolMetamizole

Influenza Virus VaccinesInfluenza Virus Vaccines

Against virusAgainst virus А (А (H5N1H5N1)) •FluarixFluarix

•FluogenFluogen

•InflexalInflexal V V •InfluvacInfluvac

•InvivacInvivac

•VaxigripVaxigrip •VaccifluVacciflu

Against virusAgainst virus– – A (H1N1) A (H1N1) :: •CelvapanCelvapan®® •FocetriaFocetria®® •PandemrixPandemrix®® •PrepandrixPrepandrix®®

0,5 ml i.m.0,5 ml i.m.//deep s.c.deep s.c.

It is time to get vaccinated against It is time to get vaccinated against influenza virus Ainfluenza virus A (H1N1)(H1N1)

Please, give me something against influenza.Please, give me something against influenza.

William OslerWilliam Osler (1849 (18491919)1919)

,,Good humor ,,Good humor

helps enormously helps enormously

both in the study both in the study

and practice of and practice of

medicine.”medicine.”

IV. INTERFERONS (IFNs)

They are cytokines (mediatorsof cell growth and function).They are glycoproteins secretedby cells infected with viruses orforeign DNA. < 38 °C< 38 °C

Interferons (IFNs) are cellular glycoproteinsthat interact with cells and render themresistant to infection by a wide variety of RNA- and DNA-containing viruses. IFNs induce the synthesis of new proteinsthat degrade viral mRNA. Human IFNs are classified as α (produced by leukocites),β (by fibroblasts), or γ (by lymphocites).

•IFN gamma has significant immunoregulatory function.•Interferon alfa-2b (Intron) is used in chronic hepatitis, Kaposi’s sarcoma in AIDS, multiple myeloma, etc.•Interferon beta-1b (Betaferon) used s.c. in multiple sclerosisin multiple sclerosis (MS)(MS). MSMS

ADRs of IFNs•fever (influenza-like syndrome)•lympho- and thrombocytopenia•anorexia and weight loss•confusion, tremor, and fits•alopecia•transient hypotension•cardiac arrhythmias•hypothyroidism

A recombinant feline IFN omega(rFeIFN-ω) is a silkworm generated product(Virbagen Omega®)that is licensed for the treatmentof retrovirusinfections in cats.

V. TREATMENT OF SELECTED VIRAL INFECTIONSV. TREATMENT OF SELECTED VIRAL INFECTIONS

Treatment of viral diseases in small animals is nonspecific and seldom includes antiviral drugs. Therapy tends to be supportive,focusing on fluid and electrolyte supplementation, prevention or treatment of secondary bacterial infection, and treatments that support the function and structure of the organ targeted by theinfection. By far, the most important approach to management of viral diseases in dogs and cats is prevention and, in particular,an effective vaccination program. In addition, isolation of infected animals and cleansing of environments contaminated with potentially infecting viruses are important ways to limit the spread of viral infections.

Basic Canine DiseasesBasic Canine Diseases

(1) TREATMENT OF SELECTED CANINE VIRAL INFECTIONS

Canine Parvoviral Enteritis

Parvoviral enteritis, caused by canine parvovirus-2 (CPV-2).Infection reflects contact with infected feces. Animals, humans, and objects can serve as vectors. After exposureviral replication begins in the lymphoid tissue of the GIT anddisseminates to the intestinal crypts of the small intestine. The virus localizes in the epithelium of the tongue, oral andesophageal mucosa, small intestine, and lymphoid tissue. Clinical signs include vomiting, diarrhea, and anorexia, highbody temperature, leukopenia. Myocarditis can develop in patients infected in utero or less than 8 weeks of age.Diagnosis is based on clinical signs, leukopenia, and enzyme-linked immunoassay (ELISA) antigen testing.

Oseltamivir has been used to treat parvovirus(2 mg/kg orally every 12 h) too.

Symptomatic therapy for canine parvoviral enteritis focuses on restoration of fluids and electrolytes and onprevention or treatment of bacteremia or endotoxemia. Fluid therapy is the most important treatment and shouldbe aggressive and continued. Among the antiemetics, metoclopramide was among the most successful. Theondansetron is considered for animals that fail to respond.

Treatment of diarrhea is not indicated. Antimicrobialtherapy should focus on both Gram (–) coliforms andanaerobic organisms. An injectable beta-lactamcombined with an aminoside has proved efficacious.Fluorinated quinolones should not be used becauseof the risk of cartilage damage. Cefazolin is equallyeffective against E. coli. Parvoviruses are extremelystable. Canine parvovirus is susceptible to sodiumhypochlorite (1 part household bleach to 1:32 partswater). Exposure to diluted bleach must be longin duration.

Canine Distemper

Canine distemper virus spreads by aerosolization to the epithelium of the upper respiratory tract. Multiplication intissue macrophages leads to spread to tonsils, bronchiallymph nodes and to lymphatic tissues of the GIT, liver etc.Additional spread generally is hematogenous. Leukopenia characterized by lymphopenia develops as the virus proliferates in lymphoid tissues. In dogs with an insufficient immune response, the virus spreads to othertissues, including the skin. Persistent viral infection ofthe CNS appears to develop in dogs that are not able togenerate circulating IgG antibodies to the viral envelope. Acute encephalitis is more likely in young or immuno-suppressed dogs and reflects direct viral damage.

Demyelinating polioencephalomalacia is characterizedby minimal inflammation. Clinical signs vary with the extent of infection and include general listlessness (apathy); fever; upper respiratory tract infection (similar to kennel cough); keratoconjunctivitis sicca;serous to mucopurulent discharge; and vomiting anddiarrhea, often associated with tenesmus. Animalsmay become severely dehydrated. Neurologic signsgenerally develop after recovery (generally at 1 to 3weeks) and tend to be progressive.

Clinical signs of CNS involve: hyperesthesia, cervicalrigidity, seizures, cerebellar signs, paraparesis ortetraparesis, and myoclonus. Diagnosis is based onimmunologic testing of IgM (ELISA). Measurements of IgG in both serum and CSF may be useful for detecting chronic CNS infections. Treatment continuesto be largely supportive and focuses on prevention ortreatment of bronchopneumonia (usually caused byBordetella bronchiseptica), fluid and electrolytesupport with supplementation of B vitamins, and treatment of neurologic signs. Seizures should be treated with anticonvulsants (diazepam for immediatecontrol, phenobarbital or bromide for long-term control).

Chronic inflammatory forms of distemper (incl. opticneuritis and encephalitis) may require long-termglucocorticoid therapy. Glucocorticoids that are moreeffective in their ability to control oxygen radicals (e.g., methylprednisolone) may offer an advantage. Canine distemper virus is extremely susceptibleto common disinfectants.

Canine Infectious Hepatitis

Infectious canine hepatitis initially localizes in the tonsils and spreads to regional lymph nodes and thento the bloodstream. Cytotoxic effects of the viruscause injury to the liver, kidney, and eye. In immunocompetent animals, infection is cleared within7 days. Acute hepatic necrosis tends to developin immunoncompetent animals. Ocular location of the virus occurs in about 20% ofanimals and can cause severe anterior uveitis andcorneal edema.

Clinical signs in the acute stages of infectious caninehepatitis: enlargement of lymphoreticular tissues, fever, coughing, abdominal tenderness associated with hepatomegaly, and hemorrhagic diathesis. Ocular lesions may be associated with blepharospasm,photophobia and, cloudiness of the cornea. Diagnosis is based on clinical laboratory changes consistent with damage caused by infectious canine hepatitis andserologic testing. Therapy is supportive. Inhibition ofgrowth has been demonstrated toward a number ofviruses by the iron-binding protein lactoferrin.

This endogenous compound is found in mucosal membranes, milk, and other tissues where it impartsantimicrobial effects. Therapy focuses on fluid and electrolyte support (incl. both replacement therapy andanticoagulant therapy), and treatment for hepaticencephalopathy as needed in acute stages. Hypertonicglucose (0.5 mL/kg of a 50% solution given i.v. 5 min)may be helpful in the presence of hypoglycemia.Infectious canine hepatitis is very resistant to many disinfectants. Chemical disinfectants that appear to beuseful include iodine, phenol, and sodium hydroxide.

a) Treat initiating factors to prevents progression (and possibly reverse chronic changes)b) Use drugs non-specifically to reduce inflammation and early fibrosisc) Symptomatic and supportive treatment only. Potenial liver transplantant in man or euthanasia in dog.

Canine Infectious Tracheobronchitis (Kennel Cough)

The most common causative organisms of kennelcough are Canine parainfluenza virus, a ssRNAvirus, and Bordatella bronchiseptica. Viral transmission occurs primarily by aerosol or, for some viruses oronasalcontact. The lack of viral replication in macrophageslimits infection to the upper respiratory tract. Bordatella bronchiseptica preferentially attaches tothe respiratory epithelium, replicates on respiratorycilia, and releases potent toxins that impairphagocytosis and cause ciliostasis, allowing infectionby opportunistic microorganisms.

The clinical signs associated with canine infectioustracheobronchitis (ITB) is paroxysmal nonproductivecoughing, often associated with retching. Edema ofthe vocal folds is responsible for the characteristichonking sound of the cough.Diagnosis is based on history and clinical signs.Culture of the upper airways (by bronchoscopyor transtracheal wash) can support diagnosisof a bacterial component. Rising antibody titers maybe helpful in identifying a specific viral etiology.

Therapy focuses on control of cough and, in casescomplicated by persistent bacterial infection,antimicrobials. Antitussive therapy should include bothperipheral bronchodilators and centrally active drugs.Narcotic derivatives are more likely than non-narcoticsto control cough associated with ITB. Mucolytics, suchas N-acetylcysteine, can usally be given orally.Parainfluenza virus is susceptible to sodium hypochlorite, chlorhexidine, and benzalkonium solution. Vaccines are available; intranasalvaccination may lead to clinical signs typical of ITB.

Canine Papillomavirus

Before treatment After first immunotherapy

Papillomaviruses can cause the growth of small roundskin tumors commonly referred to as warts. Even though dogs can get warts, they are not caused by thesame virus that causes them in humans. Viral papillomashave a rough, almost jagged surface (like a cauliflower). They generally occur on the lips and muzzle of a youngdog (typically less than 2 years of age). Less commonly,papillomas can occur on the eyelids and even the surfaceof the eye or between the toes. They usually occur in groups rather than as solitary growths. These benigntumors are not dangerous. They should go away ontheir own as the dog’s immune system matures. It takes between 1 and 5 months for papillomas to go away.

Some of the individual papillomas may stay permanently.The infection is transmitted via contact with thepapillomas on an infected dog and it takes about 1 to 2months for them to appear. This virus can only be spreadamong dogs, though, so it is not contagious to other petsor to humans. In most cases, treatment is unnecessary. Sometimes, however, a dog will have a large number of tumors, making it difficult to eat. These can be surgicallyremoved or frozen off cryogenically. Occasionally, oralpapillomas can become infected with bacteria. Antibioticswill be needed in these cases to control the pain,swelling, and bad breath.

HPV HPV vaccinesvaccines:: SILGARD®: 0, 2, and 6 month i.m.(from 9 to 26 years old)

CERVARIX®

CervarixCervarix®®

HPV may causes HPV may causes Carcinoma collum uteriCarcinoma collum uteri

Basic Feline DiseasesBasic Feline Diseases

(2) TREATMENT OF SELECTED FELINE VIRAL INFECTIONS

Feline Panleukopenia

ParvovirusParvovirus

Feline panleukopenia is caused by parvovirus transmittedby direct contact between cats or between cats and vehicles acting as vectors. Cells that are rapidly dividingare particularly susceptible to infection, incl. bone marrow,lymphoid tissue, and intestinal mucosal crypt cells. In uteroinfection can cause a number of reproductive disordersin the pregnant cat, ranging from loss of fetuses if infection occurs early in the pregnancy to birth of affectedkittens. Injuries in kittens occur in the cerebellum, optic nerve, and retina. Panleukopenia causes acute signs:fever, depression anorexia, vomiting, dehydration, ulceration, bloody diarrhea and icterus.

Queens (female cats!) infected during pregnancymay be diagnosed with infertility, and dead fetusesmay mummify. Kittens affected in utero present withclassic signs of cerebellar hypoplasia.Diagnosis generally is based on a complete blood count.Therapy is symptomatic and focuses on fluid andelectrolyte replacement (with vitamin B) and maintenance, antiemetics (generally metaclopramide), and broad-spectrum antimicrobials to control secondary infection. The use of antivirals has not been established. Diazepam or other appetite stimulants can be attempted in anorecticcats that are not vomiting. Blood transfusions may be indicated in the presence of severe anemia.

Feline InfectiousPeritonitis (FIP)

CoronavirusCoronavirus

Although caused by a coronavirus, the pathophysiology of infection is complexfor big variety of these viruses. FIP corona virus are at risk to develop some strainswhich appear to rapidly mutate to the virulent form.Virulence may be related to the ability of the virusto infect and replicate within macrophages. The “S” protein on the viral envelope appears to be responsible for viral attachment, membrane fusion, and virus-neutralizing antibody production.

Neutrophil accumulation and subsequent releaseof lysozymes cause vascular necrosis.Effusive FIP causes ascites with or without pleural effusions. Noneffusive FIP tends to bevague in presentation and includes fever, weight loss, anorexia, and depression. Ocular lesions are common, characterized by iritis. Pyogranulomata may be present in the vitreous or the retina.

Neurologic signs include ataxia, nystagmus, andseizures. Meningitis may lead to tremors,hyperesthesia, behavioral changes, or cranialnerve defects. Hydrocephalus also may develop.Investigations into treatment of FIP have focusedon antiviral therapy and control of the immune response. More recent in vitro studies havedemonstrated the potential efficacy of ribavirin or adenine arabinoside. Despite in vitro studies, ribavirin has not been proven effective and appears to be too toxic at doses that are necessary to achieve effective concentrations.

Most recently, efficacy of feline recombinant-omegaIFN (rF-INFω) has been studied. Effusive disease was also treated with glucocoricoids. Effective treatment of FIP remains elusive.

Supportive therapy of FIP includes fluids, antimicrobials, ascorbic acid, vitamin B and A.Options for treatment of ocular FIP include topical and oral glucocorticoids (prednisolone or dexamathasone).Vaccines thus far have proved ineffective becauseantibodies sensitize to rather than protect fromthe disease. Although these viruse is relativelystable in the environment, it is easily destroyed bymost common detergentsincluding diluted sodium hypochlorite solution.

Feline Respiratory Disease

Feline rhinovirus (FRV) and calicivirus (FCV) are themajor viral causes of respiratory disease in the cat, but a number of bacterial organisms contribute to thepathogenesis, incl. B. bronchiseptica, Mycoplasma, andChlamydia psittaci. Rhinovirus is a herpes virus. Naturalroutes for both viral infections are by way of the nasal, oral, and conjunctival mucosae. Viral replication of rhinovirus occurs primarily in the nasal mucosal epithelium and, for calicivirus, throughout the respiratoryepithelium. Lesions reflect necrosis and result in sneezing, pyrexia, depression, and anorexia, salivation, conjunctivitis, oral ulceration.

Similarities between human and feline herpesvirusinfection justifies the potential application of humanantiherpetic drugs to treatment of feline infections. In vitro efficacy of IDU and that of ganciclovir were approximately equivalent and approximately twice that of cidofovir and penciclovir.Oral administration of AZT also should begin early.Other drugs might be considered for treatment of felineviral respiratory infections, although evidence for use is limited. Among those most commonly cited is L-lysine and IFN-ω. Empirical selection should targetthe most likely infecting organisms (fluoroquinolones,doxycycline, azithromycin).

Nasal decongestants are helpful during the acute phases, but note that α-adrenergic decongestants may contributeto nasal mucosal necrosis owing to impaired blood flow. Antihistaminergic products are probably preferable; among them are newer drugs that may have better efficacythan older antihistamines if they preclude mast celldegranulation (cetirizine, 2.5 mg/cat daily). Mucolytic drugs and mucokinetics facilitate movement ofaccumulated respiratory secretions. Acetylcysteine can begiven by injection (125 mg), although oral administration(⅛ tsp sprinkled on food) might be helpful.

Feline Viral Neoplasia: Feline Leukemia Virus (FeLV)

FeLV

FeLV is contagious, with transmission occurring by way of the saliva after close contact between cats.Iatrogenic transmission occurs through contaminatedblood or instruments that penetrate (e.g., needles). Initial infection is characterized by malaise and lymphadenopathy. Cats with an adequate immune response recover. FeLV spreads hematogenously tothe bone marrow. Cats infected with FeLV die as a result of viral-induced neoplasia (lymphoma or leukemia), suppression of the bone marrow (anemia),or infections caused by FeLV-induced immunosuppression.

Bone marrow suppression occurs because FeLV blocksdifferentiation of erythroid progenitors. Immunosuppres-sion reflects disruption of T-cell function, affecting bothcellular and humoral immunity. Glomerulonephritis maybe a sequela. Other disorders include those of the repro-ductive tract (infertility, abortions, endometritis), lympha-denopathy (most severe in submandibular lymph nodes), osteochondromas, and olfactory neuroblastomas. Diagnosis is based on fluorescent antibody testing andELISA. Lymphoma is generally fatal in 1 to 2 months ifnot treated. Prognosis for complete remission isrelatively good.

Treatment focuses on combinations of chemotherapeutic drugs and, for selected cancers(e.g., nasal lymphoma), radiation therapy. Glucocorticoids are palliative only.The most commonly used combination is:cyclophosphamide, vincristine, and prednisone.Other drugs that might be added to this regimeninclude: doxorubicin, L-asparaginase, cytosinearabinoside, and methotrexate. Antiemetics may benecessary, as might appetite stimulants (cyproheptadine, diazepam, megestrol acetate).

Feline Immunodeficiency Virus (FIV)

FIV is transmitted primarily by way of saliva and bloodthrough bite wounds during territorial battles betweenmales. Transmission can occur in utero or throughmilk ingested by nursing infants too. Cats housed exclusively indoors are much less likely to be infected.

FIV and HIV are both lentiviruses; however, neithercan infect the other's usual host: humans cannot beinfected by FIV nor can cats be infected by HIV.FIV can attack the immune system of cats, muchlike the HIV can attack the immune system ofhumans. FIV infects many cell types in its host, incl.CD4+ and CD8+ T lymphocytes, B lymphocytes, andmacrophages. FIV can be tolerated well by cats, but can eventually lead to debilitation of its immunesystem by the infection and exhaustion of T-helper(CD4+) cells.

Several phasesSeveral phases of infection have been describedafter infection with FIV: an acute phase, followedan acute phase, followedby a clinicallyby a clinically asymptomatic phase that variesasymptomatic phase that variesin duration,in duration, and a terminaland a terminal phasephase.. Secondary bacterial infections reflect oppor-tunistic microflora. Infections by fungal (e.g., Cryptococcus) and protozoal (e.g., Toxoplasma)organisms also should be anticipated. Changesin behavior are most commonly reported, followedby seizures, paresis, motor abnormalities, anddisrupted sleep patterns.

Direct damage is the most common cause ofneurologic signs, although secondary infection byToxoplasma or Cryptococcus should be considered.Abnormalities in renal function and wasting diseasealso may reflect either abnormal function or aninflammatory response in the respective organs. Ocular diseases include anterior uveitis (causedby FIV or opportunistic secondary organisms), glaucoma, vitreal changes, retinal degeneration,and retinal hemorrhage. Respiratory diseasegenerally reflects secondary infection.

Neoplasia – a number of tumor types have beenreported in FIV-infected cats, incl. lymphomas (usually B cell) and leukemias. Diagnosis is based on clinical signs and serologic testing.

Therapy of FIV has largely focused on suppor-tive care. Both AZT and Phosphomethoxyethyl adenine (PMEA) have been studied; althoughneither drug thus far has prevented infection, onset to detectable viremia and immunologicchanges can be prolonged.

A trend toward normalization of inverted CD4:CD8ratios and clinical evidence of improvement in diseases such as stomatitis have occurred. AZTis most likely improve the quality of life of a cat withFIV. Benefits of immunomodulators in cats with FIVare not clear. Immunostimulation should be avoided. In human patients with AIDS, highly activeantiretroviral therapy has essentially revolutionizedtherapy, often rendering the lethal disease into a chronic but often manageable disease.

The combination therapy is designed tosuppress viral replication. It generally includes2 or 3 antiretroviral drugs (e.g. AZTor lamivudine),which target early viral replication, with an HIV-1protease inhibitor (e.g. indinavir) that targets laterstages of replication. Other antiretroviraldrugs approved in humans include: didanosine, zalcitabine, stavudine, lamivudine, and abacavir.The protease inhibitors are: saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir.

This approach has proved to be effective indecreasing viral loads and improving the CD4:CD8 ratio in human patients with AIDS.Mortality and morbidity of HIV infection havesubsequently been reduced.

The loss of thymic function in kittens infectedwith FIV appears to reflect an inflammatoryprocess that continues even if viral burdenis significantly reduced.

Using in vitro techniques, viral replication wasdecreased in feline cell lines infected with FIVand subsequently treated rFeINF-ω, but not rFeIFN-γ. Bleomycin inhibits HIV viral replication apparentthrough oxygen-radical generation that alsocharacterizes its anticancer effects. The use ofbleomycin in combination with highly activeantiretroviral therapy, particularly in thosesituations in which resistance has developed,has been recommended.