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Antiviral Drugs Treatment of Selected Canine and Feline Viral Diseases Assoc. Prof. Ivan Lambev (www.medpharm-sofia.eu) About 4000 species of viruses are known to date, and more than 60% of illnesses in humans are caused by viruses. Currently ≈ 30 antiviral drugs have been approved in HM, but the application of these drugs in VM often have been limited because the etiologic agents of viral diseases vary so widely. The development of effective antiviral drugs is limited by the latent nature of disease, inherent host toxicity to viral drugs, and rapid emergence of viral resistance. Differences in viral diseases limits application of human antiviral drugs to animals. In vitro susceptibility testing of viruses requires sophisticated and expensive techniques such as cell cultures. In vitro inhibitory testing procedures have 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 singlestranded DNA or RNA surrounded by a protein shell known as a capsid. Some viruses are further surrounded by a lipoprotein membrane or envelope. Both the capsid and membrane may be antigenic. Viruses cannot replicate independently and must usurp the host’s metabolic machinery to replicate. Therefore viruses are obligate intracellular parasites. Classification of DNA Viruses by Genome Type Genomic Genus Type (Virus) Disease ssDNA Parvovirus Canine parvovirus (distemper) Feline panleukopenia dsDNA Adenovirus Canine infectious hepatitis, blue eye (CAV1), respiratory disease (CAV2) dsDNA Herpes virus dsDNA Canine herpes virus (CHV) Feline herpes virus (FHV1, rhinotracheitis) Papilloma virus Canine papillomas Classification of RNA Viruses by Genome Type Genomic Genus Type (Virus) dsRNA Coronavirus (+)ssRN dsRNA Vesivirus (+)ssRNA dsRNA Enterovirus (+)ssRNA dsRNA Erbovirus (+)ssRNA Disease Canine corona virus (gastroinestinal) Feline infectious peritonitis Feline calicivirus (respiratory) Polio, bovine, and porcine enterovirus Equine rhinitis virus B Genomic Type dsRNA (+)ssRNA ssRNA Genus (Virus) Aphthovirus Disease Gammaretrovirus Feline infectious leukemia ssRNA Lentivirus (HIV, FIV) Human AIDS Feline AIDS (-)ssRNA Mups virus Mups (-)ssRNA Morbilli virus Measles Canine distemper Foot and mouth disease Genomic Genus Disease Type (Virus) (-)ssRNA Parainfluenzae virus Kennel cough (dog) (-)ssRNA Influenza A (inc. canine), B, C virus (-)ssRNA Newcastle virus Canine influenza (respiratory) (-)ssRNA Rabies virus Rabies Newcastle disease ss – single stranded; ds – double stranded (for DNA or RNA); (+) – positive, (-) – negative (for RNA) Antibodies will be generated in response to viral infection, but these do little to overcome the initial infection. Rather, in part because viral activity is intracellular and inaccessible to antibodies, they protect against subsequent infection. Cell-mediated immunity (CMI) plays a critical role in overcoming and preventing viral infection. However, viruses that can avoid an effective CMI response may cause latent or, infected cell is not recognized by T cells. Viruses, causing chronic infections are paramyxoviruses, selected herpesviruses, and retroviruses. Potential targets in the viral life cycle that might be 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 by the virus are more viral specific and less toxic from those that prevent viral replication. Pharmacologic immunomodulation (resp. immunostimulation) may also help prevent viral penetration during the early stages 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 immunomediated 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 a Fanconi-like syndrome (cidofovir, tenofovir), distal tubular acidosis (e.g., acyclic nucleotide phosphonates, foscarnet), and nephrogenic diabetes insipidus (foscarnet). The structures of antiviral drugs are similarly to purine or pyrimidine bases of host RNA or DNA. This results in limited host safety. I. Antiherpetic Drugs They are prodrugs – nucleoside analogues. H. simplex After phosphorylation nucleoside analogs convert into active metabolites, which inhibit viral DNA polymerase (reverse transcriptase) and block viral replication. Pyrimidine Nucleosides Pyrimidine nucleosides (halogenated and nonhalogenated) inhibit the replication of herpes simplex viruses with limited host cell toxicity. They substitute pyrimidine with thymidine, causing defective DNA molecules. Pyrimidine Thymidine Idoxuridine (IDU) resembles and is substituted for thymidine. After phosphorylation, it is incorporated into both viral and host cell DNA. Resistance to IDU develops rapidly. The ability of IDU to cause neoplastic changes, genetic mutation, and infertility limits its use for treatment of feline herpetic keratitis. One drop of a 0.1% solution is usually applied to the affected eye every hour; the 0.5% ointment can be applied every 2 h. Topical application of IDU to the conjunctiva has been associated with irritation, pain, pruritus, inflammation, and edema of the conjunctiva. 0.1% 0.5% Trifluridine (trifluorthymidine – TFT) is a fluorinated pyrimidine. It has in vitro inhibitory effects against herpes simplex virus (types 1 and 2) and cytomegalovirus. The primary therapeutic indication for TFT is feline herpetic keratitis and it is usually applied in 1% collyrium 6 to 8 times per day. Adverse reactions include discomfort on application and palpebral edema. Sorivudine has a relative selectivity for varicella-zoster virus (VZV). Inhibitory concentrations of sorivudine are 1000-fold lower for VZV than are those of acyclovir. Cellular uptake in cells infected with herpes virus is 40-fold greater than in uninfected cells. Clinical resistance has not yet been detected. Sorivudine is available in both oral and i.v. preparations but only as investigational drug. Purine Nucleosides Purine Adenine Vidarabine Vidarabine is an analog of adenine. It is phosphorylated by host enzymes and competitively inhibits viral DNA polymerase. It is substituted for adenine into DNA. Vidarabine selectively inhibits DNA viruses, particularly herpes viruses. Vidarabine is used for topicaly tretament of herpetic keratitis in the cats as 3% ointment. Acyclovir is is structurally similar to guanosine (purine nucleoside). Valacyclovir is an L-valyl ester prodrug of acyclovir. Efficacy of acyclovir depends on its activation to monophosphate metabolite by viral thymidine kinase. Subsequent phosphorylation to the diphosphate and then triphosphate form is mediated selectively by cells infected with 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 less potent than acyclovir but is accumulated to higher concentrations than is acyclovir in infected cells. Like acyclovir, the drug is well tolerated orally, chronic administration appears to be tumorigenic, causing testicular toxicity in animals. Herpes zoster infection Ganciclovir is structurally similar to acyclovir. Therapeutic use includes cytomegalovirus retinitis, particularly in humans with AIDS. Ganciclovir is also used for treatment of any infection or prevention of infection (particularly in transplant recipients) associated with cytomegalovirus. The primary ADR is myelosuppression with neutropenia occurring in up to 40% and thrombocytopenia in 5–20% of patients. Myelosuppression more commonly occurs with i.v. administration and is generally reversible by 1 week after discontinuation of therapy. Ribavirin is effective against both DNA and RNA viruses and is a broad-spectrum antiviral drug. Viral resistance to ribavirin is rare. In the cat, in vitro investigations revealed marked antiviral activity against a strain of calicivirus but little efficacy for rhinotracheitis. Other Antiherpetic Drugs Foscarnet interferes directly with herpes viral DNA polymerase. The drug may also be effective in treating retroviral infections owing to similar interference with reverse transcriptase. Direct actions preclude intracellular activation. Point mutations in DNA polymerase are responsible for resistance. Major side effects in human patients include nephrotoxicity and hypocalcemia. Currently foscarnet is being studied in the cat for treatment of retroviral infections. II. ANTIRETROVIRAL DRUGS Prof. L. Montagnier (1983) (Nobel prize, 2008) HIV infections •Blood •Blood products •Sexual secretions The HIV lifecycle a) Nucleoside analogues ●prodrugs: reverse transcriptase (DNA polymerase) inhibitors - Abacavir (ABC), - Didanozine, Inosine (?), - Lamivudine, Stavudine, - Zalcitabine - Zidovudine (AZT) Zidovudine analogue of thymidine AZT (azidothymidine – USA) ® •Retrovir caps. 100 mg Within the virus-infected cell, the 3’-azido group of AZT substitutes for the 3’-hydroxy group of thymidine. The azido group is then converted to a triphosphate form, which is used by retroviral reverse transcriptase and incorporated into DNA transcript. The 3’-substitution prevents DNA chain elongation and insertion of viral DNA into the host cell’s genome, preventing viral replication. AZT-MP ... AZT-TP MP – monophosphate TP – 3’-phosphate AZT (–) Viral DNA Polymerase Treatment with AZT prolongs survival and decreases the incidence of opportunistic infections. AZT has been usually combined with didanosine or zalcitabine. The disposition of AZT has been studied in cats. It is rapidly absorbed in cats after oral administration. ADRs in cats at 25 mg/kg i.v. were transient restlessness, 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 aftosa •skin rash Lamivudine. The disposition of the combination of AZT and lamivudine has also been studied in normal and FIV-infected cats. Didanosine is from 10- to a 100-fold less potent than AZT. Up to 70% of humans develop pancreatitis. It is approved for treatment of advanced HIV infections in patients with intolerance or resistance to AZT. Stavudine is a thymidine nucleoside – an alternative to AZT therapy for human patients. ТМ Combivir – Lamivudine – Zidovudine Trizivir™ – Abacavir – Lamivudine – Zidovudine Inosine (Isoprinosine) is a nucleoside analog which inhibits cytopathic effects of several viruses in culture. The mechanism of its antiviral activity involves specific suppression of viral mRNA. It can also induce T-cell differentiation. Thus inosine may be more useful as an immunostimulant in immunodeficient patients. c) HIV-protease inhibitors They prevent cleavage of protein precursors essential for HIV infection of new cells and viral replication. • Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir Indinavir Ritonavir d) Entry (Fusion) inhibitors: Disrupt the fusion of HIV-1 with the target cell ENFUVIRITIDE (Fuzeon®) – s.c. e) Integrase inhibitors – act on the gene level RALTEGRAVIR: p.o. g) Infective complications of 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 candidiasis fluconazole (14 days p.o.) Kaposi's sarcoma is a tumor caused by infection with Human herpes viris 8 (HHV8): III. Drugs used in influenza viral infection in humans (Ag) (Ag) a) Cyclic amines (active against •amantadine virus A) (+ antiparkinsonian effect too) •rimantadine Amantadine and its derivative rimantadine are synthetic agents that appear to act on an early step of viral replication after attachment of virus to cell receptors. Amantadine also prevents virus assembly during 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 produce some therapeutic benefit if taken within 48 h after the onset of illness. Rimantadine is from two to 8-fold times more active than Amantadine. Pig flu: Bird flu: Indications: prophylaxis and treatment of influenza A viral infection: А (H5N1) (Flumadine ): •Rimantadine p.o. •Vitamin C •Esberitox N (phytoimmunostimulant) 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 А and B •A (H5N1): bird or avian flu (influenza) – (2 s/78 °C) •A (H1N1): swine or pig flu (influenza) Treatment: 75 mg/12 h 5 days Prophylaxis: 75 mg/24 h about 15 – 30 days Oseltamivir is an ester prodrug. On release by esterases in the GI tract, the carboxylate form acts as a selective inhibitor of influenza A and B viral neuraminidases. 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 Paracetamol Metamizole Influenza Virus Vaccines Against virus А (H5N1) •Fluarix •Fluogen •Inflexal V •Influvac •Invivac •Vaxigrip •Vacciflu 0,5 ml i.m./deep s.c. Against virus – A (H1N1) : •Celvapan® •Focetria® •Pandemrix® •Prepandrix® It is time to get vaccinated against influenza virus A (H1N1) Please, give me something against influenza. ,,Good humor helps enormously both in the study and practice of medicine.” William Osler (1849-1919) IV. INTERFERONS (IFNs) They are cytokines (mediators of cell growth and function). They are glycoproteins secreted by cells infected with viruses or foreign DNA. < 38 °C Interferons (IFNs) are cellular glycoproteins that interact with cells and render them resistant to infection by a wide variety of RNA- and DNA-containing viruses. IFNs induce the synthesis of new proteins that 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 sclerosis (MS). MS 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 treatment of retrovirus infections in cats. V. 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 the infection. 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 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 exposure viral replication begins in the lymphoid tissue of the GIT and disseminates to the intestinal crypts of the small intestine. The virus localizes in the epithelium of the tongue, oral and esophageal mucosa, small intestine, and lymphoid tissue. Clinical signs include vomiting, diarrhea, and anorexia, high body 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 on prevention or treatment of bacteremia or endotoxemia. Fluid therapy is the most important treatment and should be aggressive and continued. Among the antiemetics, metoclopramide was among the most successful. The ondansetron is considered for animals that fail to respond. Treatment of diarrhea is not indicated. Antimicrobial therapy should focus on both Gram (–) coliforms and anaerobic organisms. An injectable beta-lactam combined with an aminoside has proved efficacious. Fluorinated quinolones should not be used because of the risk of cartilage damage. Cefazolin is equally effective against E. coli. Parvoviruses are extremely stable. Canine parvovirus is susceptible to sodium hypochlorite (1 part household bleach to 1:32 parts water). Exposure to diluted bleach must be long in duration. Canine Distemper Canine distemper virus spreads by aerosolization to the epithelium of the upper respiratory tract. Multiplication in tissue macrophages leads to spread to tonsils, bronchial lymph 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 other tissues, including the skin. Persistent viral infection of the CNS appears to develop in dogs that are not able to generate circulating IgG antibodies to the viral envelope. Acute encephalitis is more likely in young or immunosuppressed dogs and reflects direct viral damage. Demyelinating polioencephalomalacia is characterized by 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 and diarrhea, often associated with tenesmus. Animals may become severely dehydrated. Neurologic signs generally develop after recovery (generally at 1 to 3 weeks) and tend to be progressive. Clinical signs of CNS involve: hyperesthesia, cervical rigidity, seizures, cerebellar signs, paraparesis or tetraparesis, and myoclonus. Diagnosis is based on immunologic testing of IgM (ELISA). Measurements of IgG in both serum and CSF may be useful for detecting chronic CNS infections. Treatment continues to be largely supportive and focuses on prevention or treatment of bronchopneumonia (usually caused by Bordetella bronchiseptica), fluid and electrolyte support with supplementation of B vitamins, and treatment of neurologic signs. Seizures should be treated with anticonvulsants (diazepam for immediate control, phenobarbital or bromide for long-term control). Chronic inflammatory forms of distemper (incl. optic neuritis and encephalitis) may require long-term glucocorticoid therapy. Glucocorticoids that are more effective in their ability to control oxygen radicals (e.g., methylprednisolone) may offer an advantage. Canine distemper virus is extremely susceptible to common disinfectants. Canine Infectious Hepatitis Infectious canine hepatitis initially localizes in the tonsils and spreads to regional lymph nodes and then to the bloodstream. Cytotoxic effects of the virus cause injury to the liver, kidney, and eye. In immunocompetent animals, infection is cleared within 7 days. Acute hepatic necrosis tends to develop in immunoncompetent animals. Ocular location of the virus occurs in about 20% of animals and can cause severe anterior uveitis and corneal edema. Clinical signs in the acute stages of infectious canine hepatitis: 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 and serologic testing. Therapy is supportive. Inhibition of growth has been demonstrated toward a number of viruses by the iron-binding protein lactoferrin. This endogenous compound is found in mucosal membranes, milk, and other tissues where it imparts antimicrobial effects. Therapy focuses on fluid and electrolyte support (incl. both replacement therapy and anticoagulant therapy), and treatment for hepatic encephalopathy as needed in acute stages. Hypertonic glucose (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 be useful 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 fibrosis c) 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 kennel cough are Canine parainfluenza virus, a ssRNA virus, and Bordatella bronchiseptica. Viral transmission occurs primarily by aerosol or, for some viruses oronasal contact. The lack of viral replication in macrophages limits infection to the upper respiratory tract. Bordatella bronchiseptica preferentially attaches to the respiratory epithelium, replicates on respiratory cilia, and releases potent toxins that impair phagocytosis and cause ciliostasis, allowing infection by opportunistic microorganisms. The clinical signs associated with canine infectious tracheobronchitis (ITB) is paroxysmal nonproductive coughing, often associated with retching. Edema of the vocal folds is responsible for the characteristic honking sound of the cough. Diagnosis is based on history and clinical signs. Culture of the upper airways (by bronchoscopy or transtracheal wash) can support diagnosis of a bacterial component. Rising antibody titers may be helpful in identifying a specific viral etiology. Therapy focuses on control of cough and, in cases complicated by persistent bacterial infection, antimicrobials. Antitussive therapy should include both peripheral bronchodilators and centrally active drugs. Narcotic derivatives are more likely than non-narcotics to control cough associated with ITB. Mucolytics, such as N-acetylcysteine, can usally be given orally. Parainfluenza virus is susceptible to sodium hypochlorite, chlorhexidine, and benzalkonium solution. Vaccines are available; intranasal vaccination may lead to clinical signs typical of ITB. Canine Papillomavirus Before treatment After first immunotherapy Papillomaviruses can cause the growth of small round skin tumors commonly referred to as warts. Even though dogs can get warts, they are not caused by the same virus that causes them in humans. Viral papillomas have a rough, almost jagged surface (like a cauliflower). They generally occur on the lips and muzzle of a young dog (typically less than 2 years of age). Less commonly, papillomas can occur on the eyelids and even the surface of the eye or between the toes. They usually occur in groups rather than as solitary growths. These benign tumors are not dangerous. They should go away on their 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 the papillomas on an infected dog and it takes about 1 to 2 months for them to appear. This virus can only be spread among dogs, though, so it is not contagious to other pets or 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 surgically removed or frozen off cryogenically. Occasionally, oral papillomas can become infected with bacteria. Antibiotics will be needed in these cases to control the pain, swelling, and bad breath. HPV vaccines: SILGARD®: 0, 2, and 6 month i.m. (from 9 to 26 years old) CERVARIX® HPV may causes Carcinoma collum uteri Cervarix® Basic Feline Diseases (2) TREATMENT OF SELECTED FELINE VIRAL INFECTIONS Feline Panleukopenia Parvovirus Feline panleukopenia is caused by parvovirus transmitted by direct contact between cats or between cats and vehicles acting as vectors. Cells that are rapidly dividing are particularly susceptible to infection, incl. bone marrow, lymphoid tissue, and intestinal mucosal crypt cells. In utero infection can cause a number of reproductive disorders in the pregnant cat, ranging from loss of fetuses if infection occurs early in the pregnancy to birth of affected kittens. 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 pregnancy may be diagnosed with infertility, and dead fetuses may mummify. Kittens affected in utero present with classic signs of cerebellar hypoplasia. Diagnosis generally is based on a complete blood count. Therapy is symptomatic and focuses on fluid and electrolyte replacement (with vitamin B) and maintenance, antiemetics (generally metaclopramide), and broadspectrum antimicrobials to control secondary infection. The use of antivirals has not been established. Diazepam or other appetite stimulants can be attempted in anorectic cats that are not vomiting. Blood transfusions may be indicated in the presence of severe anemia. Feline Infectious Peritonitis (FIP) Coronavirus Although caused by a coronavirus, the pathophysiology of infection is complex for big variety of these viruses. FIP corona virus are at risk to develop some strains which appear to rapidly mutate to the virulent form. Virulence may be related to the ability of the virus to 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 release of lysozymes cause vascular necrosis. Effusive FIP causes ascites with or without pleural effusions. Noneffusive FIP tends to be vague 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, and seizures. Meningitis may lead to tremors, hyperesthesia, behavioral changes, or cranial nerve defects. Hydrocephalus also may develop. Investigations into treatment of FIP have focused on antiviral therapy and control of the immune response. More recent in vitro studies have demonstrated 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-omega IFN (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 because antibodies sensitize to rather than protect from the disease. Although these viruse is relatively stable in the environment, it is easily destroyed by most common detergents including diluted sodium hypochlorite solution. Feline Respiratory Disease Feline rhinovirus (FRV) and calicivirus (FCV) are the major viral causes of respiratory disease in the cat, but a number of bacterial organisms contribute to the pathogenesis, incl. B. bronchiseptica, Mycoplasma, and Chlamydia psittaci. Rhinovirus is a herpes virus. Natural routes 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 respiratory epithelium. Lesions reflect necrosis and result in sneezing, pyrexia, depression, and anorexia, salivation, conjunctivitis, oral ulceration. Similarities between human and feline herpesvirus infection justifies the potential application of human antiherpetic 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 feline viral respiratory infections, although evidence for use is limited. Among those most commonly cited is L-lysine and IFN-ω. Empirical selection should target the most likely infecting organisms (fluoroquinolones, doxycycline, azithromycin). Nasal decongestants are helpful during the acute phases, but note that α-adrenergic decongestants may contribute to nasal mucosal necrosis owing to impaired blood flow. Antihistaminergic products are probably preferable; among them are newer drugs that may have better efficacy than older antihistamines if they preclude mast cell degranulation (cetirizine, 2.5 mg/cat daily). Mucolytic drugs and mucokinetics facilitate movement of accumulated respiratory secretions. Acetylcysteine can be given 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 contaminated blood 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 to the 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 blocks differentiation of erythroid progenitors. Immunosuppression reflects disruption of T-cell function, affecting both cellular and humoral immunity. Glomerulonephritis may be a sequela. Other disorders include those of the reproductive tract (infertility, abortions, endometritis), lymphadenopathy (most severe in submandibular lymph nodes), osteochondromas, and olfactory neuroblastomas. Diagnosis is based on fluorescent antibody testing and ELISA. Lymphoma is generally fatal in 1 to 2 months if not treated. Prognosis for complete remission is relatively 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 regimen include: doxorubicin, L-asparaginase, cytosine arabinoside, and methotrexate. Antiemetics may be necessary, as might appetite stimulants (cyproheptadine, diazepam, megestrol acetate). Feline Immunodeficiency Virus (FIV) FIV is transmitted primarily by way of saliva and blood through bite wounds during territorial battles between males. Transmission can occur in utero or through milk ingested by nursing infants too. Cats housed exclusively indoors are much less likely to be infected. FIV and HIV are both lentiviruses; however, neither can infect the other's usual host: humans cannot be infected by FIV nor can cats be infected by HIV. FIV can attack the immune system of cats, much like the HIV can attack the immune system of humans. FIV infects many cell types in its host, incl. CD4+ and CD8+ T lymphocytes, B lymphocytes, and macrophages. FIV can be tolerated well by cats, but can eventually lead to debilitation of its immune system by the infection and exhaustion of T-helper (CD4+) cells. Several phases of infection have been described after infection with FIV: an acute phase, followed by a clinically asymptomatic phase that varies in duration, and a terminal phase. Secondary bacterial infections reflect opportunistic microflora. Infections by fungal (e.g., Cryptococcus) and protozoal (e.g., Toxoplasma) organisms also should be anticipated. Changes in behavior are most commonly reported, followed by seizures, paresis, motor abnormalities, and disrupted sleep patterns. Direct damage is the most common cause of neurologic signs, although secondary infection by Toxoplasma or Cryptococcus should be considered. Abnormalities in renal function and wasting disease also may reflect either abnormal function or an inflammatory response in the respective organs. Ocular diseases include anterior uveitis (caused by FIV or opportunistic secondary organisms), glaucoma, vitreal changes, retinal degeneration, and retinal hemorrhage. Respiratory disease generally reflects secondary infection. Neoplasia – a number of tumor types have been reported 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 supportive care. Both AZT and Phosphomethoxyethyl adenine (PMEA) have been studied; although neither drug thus far has prevented infection, onset to detectable viremia and immunologic changes can be prolonged. A trend toward normalization of inverted CD4:CD8 ratios and clinical evidence of improvement in diseases such as stomatitis have occurred. AZT is most likely improve the quality of life of a cat with FIV. Benefits of immunomodulators in cats with FIV are not clear. Immunostimulation should be avoided. In human patients with AIDS, highly active antiretroviral therapy has essentially revolutionized therapy, often rendering the lethal disease into a chronic but often manageable disease. The combination therapy is designed to suppress viral replication. It generally includes 2 or 3 antiretroviral drugs (e.g. AZTor lamivudine), which target early viral replication, with an HIV-1 protease inhibitor (e.g. indinavir) that targets later stages of replication. Other antiretroviral drugs 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 in decreasing viral loads and improving the CD4:CD8 ratio in human patients with AIDS. Mortality and morbidity of HIV infection have subsequently been reduced. The loss of thymic function in kittens infected with FIV appears to reflect an inflammatory process that continues even if viral burden is significantly reduced. Using in vitro techniques, viral replication was decreased in feline cell lines infected with FIV and subsequently treated rFeINF-ω, but not rFeIFN-γ. Bleomycin inhibits HIV viral replication apparent through oxygen-radical generation that also characterizes its anticancer effects. The use of bleomycin in combination with highly active antiretroviral therapy, particularly in those situations in which resistance has developed, has been recommended.