Pharmacokinetics and tolerance of repeated oral administration of 5-fluorocytosine in healthy dogs.

BACKGROUND: 5-fluorocytosine is a pyrimidine and a fluorinated cytosine analog mainly used as an antifungal agent. It is a precursor of 5-fluorouracil, which possesses anticancer properties. To reduce systemic toxicity of 5-fluorouracil during chemotherapy, 5- fluorocytosine can be used as a targeted anticancer agent. Expression of cytosine deaminase by a viral vector within a tumor allows targeted chemotherapy by converting 5-fluorocytosine into the cytotoxic chemotherapeutic agent 5-fluorouracil. However, little is known about the tolerance of 5-fluorocytosine in dogs after prolonged administration. RESULTS: In three healthy Beagle dogs receiving 100 mg/kg of 5-fluorocytosine twice daily for 14 days by oral route, non-compartmental pharmacokinetics revealed a terminal elimination half-life of 164.5 ± 22.5 min at day 1 and of 179.2 ± 11.5 min, after 7 days of administration. Clearance was significantly decreased between day 1 and day 7 with 0.386 ± 0.031 and 0.322 ± 0.027 ml/min/kg, respectively. Maximal plasma concentration values were below 100 µg/ml, which is considered within the therapeutic margin for human patients. 5-fluorouracil plasma concentration was below the limit of detection at all time points. The main adverse events consisted of depigmented, ulcerated, exudative, and crusty cutaneous lesions 10 to 13 days after beginning 5-fluorocytosine administration. The lesions were localized to the nasal planum, the lips, the eyelids, and the scrotum. Histological analyses were consistent with a cutaneous lupoid drug reaction. Complete healing was observed 15 to 21 days after cessation of 5-fluorocytosine. No biochemical or hematological adverse events were noticed. CONCLUSIONS: Long term administration of 5-fluorocytosine was associated with cutaneous toxicity in healthy dogs. It suggests that pharmacotherapy should be adjusted to reduce the toxicity of 5-fluorocytosine in targeted chemotherapy.

[Intradermal versus intramuscular vaccine application in suckling piglets - Comparison with regard to dermal reactions, performance and procedural aspects]. / Intradermale versus intramuskuläre Impfstoffapplikation bei Saugferkeln.

OBJECTIVE: The aim of this study was the scientific evaluation of an intradermal vaccination method in comparison to an intramuscular vaccination against Mycoplasma hyopneumoniae in suckling piglets with regard to skin reactions, performance parameters and procedural aspects. Possible effects on animal welfare should be deduced. MATERIAL AND METHODS: Under field conditions, 672 suckling piglets in three batches were vaccinated; 338 intradermally and 334 intramuscularly. In addition to a detailed scoring of the integument, the injection site with the local reaction was evaluated, scoring the swelling size (score 0-5), and rubor and incrustation (score 0-3). Moreover, piglets were weighed individually 1 day before vaccination and 8 days later. In addition, the time required for each vaccination was documented. RESULTS: On the first day after vaccination, 71.3 % of the intramuscularly vaccinated piglets and 2.7 % of the intradermally vaccinated piglets displayed no swelling at the vaccination site. No differences remained by the 7th day after vaccination. Daily weight gain did not differ significantly between the piglets in the intramuscularly (248 g) and intradermally (258 g) vaccinated groups. Intradermal vaccination took a mean of 11 seconds per piglet, while 17 seconds were required for intramuscular vaccination. CONCLUSIONS AND CLINICAL RELEVANCE: In this first study, no negative effects of the intradermal vaccination on performance parameters and no long-standing skin reactions were detected in the suckling piglets. Skin reactions were related to the desired immune reaction of the intradermal vaccination, but were no longer present after 7 days. Moreover, with regard to procedural aspects, the intradermal vaccination offered time saving advantages. To evaluate further possible effects on animal welfare, further analyses via video recordings are required.

Drug-induced panniculitis due to deworming in a dog ­ case report / Paniculite farmacodérmica decorrente de vermifugação em um cão - relato de caso

Outpatient clinics, clinics, and veterinary hospitals in the state of São Paulo and other Brazilian states commonly prescribe broad-spectrum vermicidal agents. The prescriptions are not based on coproparasitological examination results and drugs, including those used for the elimination of enteric parasites, are not innocuous and can potentially cause health hazards. Therefore, we report a clinical case of drug-induced panniculitis caused by deworming and show the actual occurrence of endoparasites in canine and feline outpatients at HOVET-USP.(AU)

É prática corrente em ambulatórios, consultórios, clínicas e hospitais veterinários paulistas, por não dizer brasileiros, a prescrição de ativos com ação vermicida, no senso lato, sem o embasamento do, hoje até prosaico, exame coproparasitológico. É sabido há muito que todo e qualquer fármaco não é inócuo e pode potencialmente acarretar agravos à saúde, e dentre estes incluem-se os ativos destinados à erradicação de parasitos entéricos. Decidiu-se assim por se relatar um caso clínico de paniculite farmacodérmica decorrente de vermifugação, bem como situar a real ocorrência de endoparasitas em pacientes, caninos e felinos, trazidos para atendimento ambulatorial no HOVET-USP.(AU)

Cutaneous adverse drug reaction in a dog associated with imepitoin.

BACKGROUND: The macroscopic appearance of cutaneous adverse drug reactions can be similar to a plethora of skin diseases and in particular may resemble autoimmune and immune-mediated disorders. The reaction can occur after single or multiple administrations, with the latter varying in durations of up to years of treatment. These reactions are mostly self-limiting with cessation of the offending drug. OBJECTIVES: To report a cutaneous adverse drug reaction associated with chronic administration of imepitoin. CASE REPORT: A 4-year-old, Jack Russell terrier dog was presented with progressive skin lesions of 1-week duration. The dog had a 6 month history of idiopathic epilepsy treated with imepitoin for the previous 5 months. Imepitoin is an anti-epileptic drug that acts as a low-affinity partial agonist of the benzodiazepine site at the GABAA receptor. The dosage of imepitoin was increased from 20 mg/kg twice daily to 30 mg/kg twice daily, 3 days before the onset of skin lesions, due to uncontrolled seizures. [Correction added on 15 February 2016 after first online publication: In the preceding sentence, the dosage of imepitoin was previously incorrect and has been amended in this current version.] Dermatological examination revealed erythema and exfoliation at the mucocutaneous junctions of the lips, lip folds, philtrum, ears, axillae and the ventral abdomen. Small erosions and depigmentation were visible on the oral mucosa, lip folds and philtrum. Histopathology was supportive of a lupoid drug reaction. Complete resolution of skin lesions was seen after discontinuation of imepitoin and low dose of prednisolone during a period of 4 weeks. No recrudescence of skin lesions was observed during a 6 month follow-up period. CONCLUSION AND CLINICAL IMPORTANCE: Imepitoin may result in cutaneous adverse drug reactions in dogs.

Phase I dose escalation of doxorubicin chemotherapy in tumor-bearing equidae.

BACKGROUND: There is no information on the use of doxorubicin in horses with tumors. OBJECTIVE: To determine dose-limiting toxicosis (DLT) and maximum tolerated dose (MTD) of doxorubicin in tumor-bearing horses. ANIMALS: Seventeen horses with 34 localized or multicentric advanced tumors. METHODS: Two-stage dose-ranging design involving intrapatient and interpatient dose escalation. Treatment protocol included 6 treatment cycles given at 3-week intervals with dosages ranging from 40 to 85 mg/m(2). Clinical signs, hematologic, and nonhematologic changes were evaluated. RESULTS: Total doses ranged from 1,127 to 2,900 mg in 12 horses that completed the assigned treatment protocols. The MTD was 75 mg/m(2). Hypersensitivity reactions and neutropenia were dose limiting. Hypersensitivity was dose-dependent but schedule invariant. Neutropenia was dose- and cycle-dependent but dose-escalation schedule invariant. Cardiotoxicity was not observed. CONCLUSION AND CLINICAL RELEVANCE: The recommended dosage of doxorubicin to treat horses is 70 mg/m(2) given at 3-week intervals as single agent. Adjunctive treatment with antihistamines and nonsteroidal anti-inflammatory drugs is recommended to control hypersensitivity.

Idiosyncratic drug toxicity affecting the liver, skin, and bone marrow in dogs and cats.

Idiosyncratic drug toxicity reactions are, by definition, uncommon, but can lead to serious or even fatal organ toxicity. The liver, skin, and peripheral blood cells/bone marrow are common targets. Most of these reactions are the result of reactive metabolites, which may cause local cell or organelle damage, or may be amplified by a systemic immune response. Individual risk may depend on differences in drug biotransformation, levels of oxidative stress, or antigen presentation.

Vesiculobullous skin reaction temporally related to firocoxib treatment in a white rhinoceros (Ceratotherium simum).

A 40 yr-old female white rhinoceros (Ceratotherium simum) suffered from chronic nail-bed abscesses. Due to worsening of clinical signs, the animal's nonsteroidal anti-inflammatory treatment was switched to firocoxib. Approximately 7 days after this change, the animal developed multifocal vesicles and bullae along the lateral aspects of the thorax and abdomen, the dorsum, and the proximal limbs. Cytology and culture did not identify an infectious etiology. Histologically, the lesions consisted of a severe, subacute vesiculobullous dermatitis with intraepidermal to subepidermal clefting with areas of individual keratinocyte necrosis and minor neutrophilic epidermal infiltrates. These findings are similar to those seen in some drug reactions in people; therefore an adverse drug reaction to the firocoxib was suspected.

Antibiotic treatments of a methicillin-resistant Staphylococcus pseudintermedius infection in a dog: a case presentation.

We report the antibiotic treatments administered to a female dog with mastitis and successive pyoderma. Microbiological investigations allowed the identification of Staphylococcus pseudintermedius after 54 days of various antibiotic treatments. The isolate carried the mecA gene and was resistant to 9 of 15 tested antibiotics. Consistent antibiotic treatment of the infection was possible only after accurate microbiological diagnosis.

Long-term management of vaccine-induced refractory ischemic dermatopathy in a Miniature Pinscher puppy.

A 2-month-old intact female Miniature Pinscher puppy presented with footpad swelling and crusted pustules of ear pinnae. The dog had been vaccinated with a polyvalent canine vaccine 5 days prior to the onset of clinical signs. With the history of recent vaccination, the clinical presentation and the histopathological observations were suggestive of ischemic dermatopathy. Treatment involved oral prednisolone, azathioprine, and other immune modulating drugs, which did not work. Chlorambucil plus cyclosporine therapy was initiated for vigorous immune suppression after rush therapy using intravenous immunoglobulin. Clinical signs again gradually improved with no relapse or side effects, even at a 4-month follow-up. The case report is suggested ischemic dermatopathy refractory to conventional therapy and suggests effective approaches to long-term management of the disease.

Staphylococcus pseudintermedius exfoliative toxin EXI selectively digests canine desmoglein 1 and causes subcorneal clefts in canine epidermis.

Staphylococcal exfoliative toxins are known to digest desmoglein (Dsg) 1, a desmosomal cell-cell adhesion molecule, thus causing intraepidermal splitting in human bullous impetigo, staphylococcal scalded skin syndrome and swine exudative epidermitis. Recently, a novel exfoliative toxin gene (exi), whose sequence shares significant homology with previously identified exfoliative toxins, was isolated from Staphylococcus pseudintermedius. Little is known about the pathogenic involvement of this toxin in canine pustular diseases such as impetigo. The aim of this study was to determine whether EXI, the product of the exi gene, digests canine Dsg1 and causes intraepidermal splitting in canine skin. An exi gene was isolated from chromosomal DNA of an S. pseudintermedius strain obtained from a pustule of a dog with impetigo, and was used to produce a recombinant EXI by Escherichia coli expression. When purified recombinant EXI was injected intradermally into normal dogs, it caused the development of vesicles or erosions with superficial epidermal splitting. In addition, the EXI abolished immunofluorescence for Dsg1, but not for Dsg3, at the injection sites. Moreover, the EXI directly degraded baculovirus-secreted recombinant extracellular domains of canine Dsg1, but not that of canine Dsg3, in vitro. The EXI also degraded mouse Dsg1α and swine Dsg1, but not human Dsg1, mouse Dsg1ß and Dsg1γ. Conversely, recombinant SIET, previously designated as S. intermedius exfoliative toxin, did not cause intraepidermal splitting or degradation of any Dsgs. These findings indicate that EXI has a proteolytic activity that digests canine Dsg1, and this characteristic might be involved in the pathogenesis of intraepidermal splitting in canine impetigo.

Effect of spironolactone on diastolic function and left ventricular mass in Maine Coon cats with familial hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis occurs in cats with hypertrophic cardiomyopathy (HCM), and is one factor that leads to diastolic dysfunction. Spironolactone (SPIR) reduces myocardial fibrosis in several models of HCM and in humans with cardiac disease. HYPOTHESIS: SPIR will improve diastolic function and reduce left ventricular (LV) mass in Maine Coon cats with HCM. METHODS: Maine Coon cats with familial HCM were included if there was concentric hypertrophy (> or =6 mm end diastolic wall thickness) and decreased early lateral mitral annular velocity (Em) or summated early and late mitral annular velocity (EAsum) measured by pulsed wave tissue Doppler imaging echocardiography. Cats were paired by Em-EAsum and randomized to receive 2 mg/kg SPIR (n = 13) or placebo (n = 13) PO q12 h for 4 months. Em-EAsum, systolic velocity, LV mass, and the ratio of left atrial to aortic diameter were measured at baseline, 2 months, and 4 months. Statistical analysis included 2-way repeated measures analysis of variance and the Student's t-test. RESULTS: Plasma aldosterone concentration increased in cats treated with SPIR (235 ng/mL, baseline; 935 ng/mL, 2 months; 1,077 ng/mL, 4 months; P < .001 at 2 and 4 months). No significant treatment effect was identified for early or early-late summated diastolic mitral annular velocity or any other variable except plasma aldosterone concentration. Severe facial ulcerative dermatitis developed in 4 of 13 cats treated with SPIR, requiring discontinuation of the drug. CONCLUSION: SPIR did not improve Em or EAsum of the lateral mitral annulus or alter LV mass over 4 months. One third of cats treated with SPIR developed severe ulcerative facial dermatitis.

Pemphigus foliaceus-like drug reaction in a 3-month-old crossbreed dog treated for juvenile cellulitis.

Two weeks after administration of routine vaccinations, a 3-month-old, male crossbreed dog developed cutaneous lesions that were clinically and histopathologically consistent with a diagnosis of juvenile cellulitis. The patient was treated with systemic antibacterial, antibacterial ophthalmic ointment and nonsteroidal anti-inflammatory drugs. Within 1 week, new skin lesions that were clinically, histopathologically and immunohistochemically consistent with pemphigus foliaceus developed. The latter completely resolved following drug withdrawal, suggesting a pemphigus foliaceus-like drug reaction. However, the initial lesions persisted and required glucocorticoid therapy to effect resolution. To the authors' knowledge, this is the first reported case of a puppy developing juvenile cellulitis followed by a pemphigus foliaceus-like reaction shortly thereafter, in response to drug therapy.

Cutaneous and ocular adverse reactions in a dog following meloxicam administration.

The present report addresses the development of cutaneous and ocular reactions possibly related to meloxicam administration in a dog. Based on clinical signs and absence of laboratory data compatible with the other differential diagnoses considered, the possibility of an adverse drug reaction (ADR) due to meloxicam was considered. Skin biopsy revealed haemorrhage of the superficial and deep dermis, associated with hyperplasia of endothelial cells and epidermal sloughing. Vasculitis in the deep dermis was also noted. Such lesions were considered compatible with an ADR. Although the owner was not aware of any previous allergic reaction to drugs, the animal had a clinical history of atopic dermatitis. Meloxicam is a nonsteroid anti-inflammatory drug (NSAID) in the oxicam family, indicated for the control of inflammation and pain in acute and chronic musculoskeletal disorders in dogs. Although meloxicam is usually well tolerated, the present clinical case represents an alert to practitioners about the potential role of NSAIDS in ADRs in dogs with a history of allergic cutaneous diseases.

Treatment of severe adverse cutaneous drug reactions with human intravenous immunoglobulin in two dogs.

Severe adverse cutaneous reactions were documented in two dogs with acute skin lesions and systemic signs after exposure to several oral and injectable drugs. Because of the high morbidity and mortality rates of many severe cutaneous drug reactions and a poor response to supportive care, wound management, and conventional immunosuppressive therapy, human intravenous immunoglobulin (IVIG) was infused on 2 consecutive days (1 g/kg per day) after informed consent was received. Human IVIG, with supportive care, resulted in rapid resolution of dermatological and systemic signs in both dogs; this treatment may be considered in other cases of severe cutaneous drug reactions.

Neutrophilic dermatitis and immune-mediated haematological disorders in a dog: suspected adverse reaction to carprofen.

This report describes the clinical and pathological findings of a suspected idiosyncratic adverse drug reaction in a young dog. The patient presented with sudden onset, severe skin lesions together with episodes of collapse. Investigations revealed a neutrophilic dermatitis with vasculitis, immune-mediated haemolytic anaemia and thrombocytopenia. Similar pathology has been described in human cases of Sweet's syndrome. The chronology of events suggested an adverse drug reaction to carprofen, although two antibiotics had been prescribed within the dog's recent history. Lymphocyte transformation tests were performed and tended to exclude both antibiotics as the cause of the reaction. To the authors' knowledge, lymphocyte transformation tests have not previously been described with regard to drug hypersensitivity assessment in the veterinary literature, and this is the first peer-reviewed case report of neutrophilic dermatitis and vasculitis with immune-mediated haemolytic anaemia and thrombocytopenia occurring as a suspected adverse drug reaction to carprofen in the dog.