Download Antiviral Drugs. Treatment of Selected Canine and Feline Viral

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.