Systemic antibacterial drug use in dogs in Australia.

A survey of veterinarians' use of antibacterial drugs was conducted by distributing a questionnaire to Australian practitioners. Respondents were asked to indicate their general patterns of use of various systemic antibacterial drugs and drug combinations in dogs and their approach to certain specified clinical disorders. Overall, antibacterials of the beta-lactam type (penicillins and cephalosporins) were most commonly used. Other antibacterials with substantial use were doxycycline, sulphonamide-trimethoprim, metronidazole, fluoroquinolones and clindamycin. Drug selection for different disorders was generally appropriate when compared with recommendations in recent texts, although inappropriate use was evident in some circumstances.

Efficacy of doxorubicin as an induction agent for cats with lymphosarcoma.

OBJECTIVE: To determine the efficacy of doxorubicin when used alone in inducing remission in cats with lymphosarcoma. DESIGN: Prospective multi-institutional study of naturally occurring disease. METHODS: Cases were accrued from veterinary institutions in Australia and New Zealand after obtaining consent from informed owners. Cats were treated with doxorubicin every 3 weeks for three treatments. If there was no response to the first dose of doxorubicin or if the cat relapsed during the doxorubicin regimen, the cat was withdrawn from the trial and either euthanased or treated with other agents. Age, breed, gender and anatomic site of the lymphosarcoma (multicentric, alimentary, mediastinal, extranodal) were recorded for each cat. Clinical remission was assessed before each treatment by physical examination, radiography, ultrasonography and computed tomography where appropriate. Complete remission was defined as the disappearance of all clinical signs and clinically detectable tumour. RESULTS: Twenty-one cases were accrued over a 2-year-period but only 19 were available for data analysis. Young Siamese cats were over-represented and all cats with mediastinal tumours were young Siamese. There was a significant difference between the mean ages of cats with mediastinal or multicentric lymphosarcoma (mean +/- SD: 3.5 +/- 3.0 and 4.3 +/- 2.6 years, respectively) and cats with alimentary or extranodal LSA (11.4 +/- 0.9 and 11.0 +/- 0.9 years, respectively). Of 19 cats treated with doxorubicin alone, 6 (32%) had complete remission, 6 (32%) had partial remission and 7 (36%) did not respond. CONCLUSIONS: The results suggest that doxorubicin cannot be recommended as a single agent for treatment of feline lymphosarcoma because of the rather poor remission rate achieved.

Influence of the oestrous cycle on L-glutamate and L-aspartate transport in rat brain synaptosomes.

Oestrous cycle and sex differences in sodium-dependent transport of L-[3H]glutamate and L-[3H]aspartate were investigated employing well washed synaptosomes prepared from rat brain cortex. Transport was best analysed on the basis of two components, a high and low affinity transport site. Oestrous cycle and sex differences were observed for both substrates. The high affinity transporter displayed highest affinity for glutamate transport in synaptosomes from female rats during proestrous and oestrous. This differed significantly from glutamate transport during dioestrous and in male rats. High affinity aspartate transport displayed highest affinity during oestrous and differed significantly from transport during dioestrous. Maximal velocity of high affinity glutamate transport was higher in synaptosomes from females during dioestrous compared with oestrous and lower in synaptosomes from male rats when compared with female rats in dioestrous and metoestrous. The low affinity sodium-dependent glutamate transporter displayed a 10-fold higher affinity for glutamate during proestrous than during the other three phases of oestrous and in male rats. Exogenously applied oestradiol and progesterone to synaptosomes from male rats showed no effect on glutamate or aspartate transport. No acute effect of oestradiol or progesterone on glutamate currents in oocytes expressing EAAT1 or EAAT2 subtype of glutamate transporter was observed. These results suggest hormonal regulation of high and low affinity sodium-dependent excitatory amino acid transporters over the four day oestrous cycle in synaptosomes from rat cortex. This regulation is unlikely to be due to a direct effect of oestradiol or progesterone on glutamate transporters.

Comparison of methods to assess dog owners' therapeutic compliance.

OBJECTIVE: To compare different methods for assessing the compliance of veterinary clients administering medication to their dogs. PROCEDURE: Thirty-one owners whose dogs were prescribed amoxycillin-clavulanate, twice and thrice daily, for a duration of five to seven days were recruited from three Sydney veterinary hospitals. Compliance was assessed by electronic monitoring devices, return medication counts, client self-reports and veterinarians' estimation of likely compliance. RESULTS: Electronic monitoring showed owners administered on average 84% (range 7 to 104%) of prescribed medication to their dogs. Both return medication counts and client self-reports tended to overestimate therapeutic compliance when compared with electronic monitoring. When questioned, the majority of owners (71%) claimed perfect compliance with the prescribed regimen. No correlation was found between veterinarians' estimates of owner compliance and that assessed electronically. CONCLUSION: Electronic monitoring provided valuable information on dose timing and variation, but proved costly and difficult to employ in veterinary practice. Simplicity and low cost of return medication counts makes this method attractive for use in veterinary compliance studies. Client self-reports reliably detected some noncompliers and permitted identification of individual problems or errors. For practical purposes a combination of return medication counts and client self-reports may have merit in future veterinary compliance studies.

Owner compliance with short term antimicrobial medication in dogs.

The degree to which dog owners complied with instructions to administer a 5 to 10 day course of antimicrobial medication to their pets was assessed using microprocessor based monitoring devices. Twenty two clients gave an average of 84% of prescribed doses of amoxycillin-clavulanate. No difference was found between twice and thrice daily dosing regimens in the overall percentage of prescribed doses given. However, timing of doses was far from ideal in many cases and only 34% of doses were given within the designated optimum time period. Adherence to desired dosing intervals tended to be better with twice daily than with thrice daily dosing, although the difference was statistically insignificant.

Adverse drug reactions: report of the Australian Veterinary Association Adverse Drug Reaction Subcommittee, 1994.

Seventy-seven reports of suspected adverse drug reactions (ADRs) were received by the Adverse Drug Reaction Subcommittee (ADRSc) of the Australian Veterinary Association from April 1993 to December 1994 inclusive. The number of reports received/number of animals involved per species were: dogs (32/44), cats (18/31), horses (17/48), and cattle (10/21). Of these, 49 (64%) were classified as definite ADRs and 9 (12%) as probable ADRs. In 11 (14%) reports an ADR could not be substantiated or there was insufficient information available to make a decision. Eight reports were not classified because the manufacturer and the ADRSc disagreed as to the appropriate classification. Sixteen reports involved apparent hypersensitivity reactions, which resulted in death on 6 occasions. Six reports were associated with 'off label' use and 1 report with use of an expired product. Of the definite, probable and unclassified reports of suspect ADRs, the most frequent types of drugs involved were antimicrobial drugs (13 reports), anthelmintics (13), insecticides (11), vaccines (10), nonsteroidal anti-inflammatory preparations (5), chondroprotective agents (4),anaesthetic/sedative agents (4) and vitamin preparations (2). Single reports concerning definite, probable or unclassified ADRs to a vasodilator, a corticosteroid, a local anaesthetic and a disinfectant were received.

Synaptosomal and brain slice cerebrocortical [3H]L-glutamate uptake in a rat model of chronic hepatic encephalopathy.

Cerebrocortical [3H]L-glutamate uptake was examined using brain slices and synaptosomes obtained from rats with portal vein and bile duct ligation. In addition, the effect of in vitro addition of 5 mM ammonia on glutamate uptake parameters was determined. There was no significant difference in brain slice or synaptosomal glutamate uptake in rats with portal vein and bile duct ligation compared to control rats. In vitro addition of ammonia had no effect on uptake kinetics in either brain slices or synaptosomes. These results suggest that glutamate uptake kinetics are not perturbed in this animal model of chronic hepatic encephalopathy.

L-glutamate and gamma-aminobutyric acid uptake in synaptosomes from the cerebral cortex of dogs with congenital chronic hepatic encephalopathy.

High affinity [3H]gamma-aminobutyric acid (GABA) and [3H]L-glutamate uptake were determined in synaptosomes prepared from the cerebral cortex of dogs with congenital hepatic encephalopathy and control dogs. The Km value for GABA uptake was increased by 35% but there was a concomitant 34% increase in Vmax suggesting that GABA uptake capacity was not changed in HE dogs. In contrast, mean Vmax for glutamate uptake in HE dogs was 85% greater than mean Vmax in control dogs; mean Km was increased by 25% in HE dogs. Therefore, overall synaptosomal high affinity glutamate uptake capacity was increased in HE dogs compared to controls.

Effect of enalapril in dogs with pacing-induced heart failure.

A repeated-measures study was conducted on 5 dogs to clinically, radiographically, and echocardiographically characterize the actions of the angiotensin-converting enzyme inhibitor, enalapril, before and after development of experimentally induced heart failure. Heart failure was artificially induced, using a surgically implanted programmable ventricular pacemaker, which stimulated the heart at a rate of 245 beats/min until a low-output cardiomyopathic state developed. This condition was then stabilized by decreasing the pacing rate to 190 beats/min. Pacing-induced heart failure was successfully induced in a mean +/- SD 4.2 +/- 1.95 weeks. The condition closely resembled the clinical, radiographic, and echocardiographic features of naturally acquired idiopathic dilated cardiomyopathy in dogs. Enalapril was well tolerated by dogs, and clinical adverse reactions did not develop. Results of echocardiographic studies indicated that enalapril treatment during the control period resulted in a significant (P < 0.05) increase in velocity of circumferential fiber shortening and a significant (P < 0.05) decrease in left ventricular ejection time. Therapeutic responses to enalapril were evident after development of heart failure. These included reduced severity of clinical signs of disease, evidence of decreased radiographically determined cardiac size (2 of 5 dogs), radiographic evidence of a reduction in pulmonary edema and congestion (4 of 5 dogs), significant (P < 0.05) reductions in left atrial and ventricular chamber dimensions (left atrial dimension, diastolic left ventricular internal dimension as determined echocardiographically), and improvement in some echocardiographic indices of left ventricular performance (velocity of circumferential fiber shortening and left ventricular ejection time).

Adverse drug reactions: report of the Australian Veterinary Association Adverse Drug Reaction Subcommittee, 1993.

Fifty-nine reports of suspected adverse drug reactions (ADRs) were received by the Adverse Drug Reaction Subcommittee of the Australian Veterinary Association from April 1992-March 1993 inclusive. The number of reports received/number of animals involved per species was: dogs (30/43); cats (11/14); horses (8/10); cattle (9/30); ferret (1/1). Of these, 37 (63%) were classified as definite ADRs and 12 (20%) as probable ADRs. In 10 (17%) reports an ADR could not be substantiated or there was insufficient information available to make a decision. Twenty-three reports involved apparent hypersensitivity reactions and 5 reports were associated with 'off-label' use. Of the definite and probable reports of suspect ADRs the most frequent types of drugs involved were antimicrobials (9 reports), anthelmintics (9 reports), vaccines (7 reports), insecticides (6 reports), vitamin preparations (6 reports), topical anti-inflammatory/antimicrobial/antifungal skin preparations (3 reports) and nonsteroidal anti-inflammatory preparations (3 reports). Single reports concerning definite or probable ADRs to an anticholinergic, an anaesthetic agent, a corticosteroid, an anabolic steroid and a chondroprotective drug were received.

Glutamatergic neurotransmission in hepatic encephalopathy.

There is increasing evidence that glutamatergic neurotransmission is perturbed in hepatic encephalopathy (HE). Studies of the glutamate receptor system suggest that glutamate receptor density is reduced in different animal models of HE. Glutamate release and/or uptake is also believed to be altered in the disorder resulting in increased glutamate concentrations in the synaptic cleft. The relevance of these findings to the pathogenesis of HE remains to be clarified.

Adverse drug reactions: report of the Australian Veterinary Association Adverse Drug Reaction Subcommittee, 1992.

Fifty-nine reports of suspected adverse drug reactions (ADRs) were received by the Adverse Drug Reaction Subcommittee of the Australian Veterinary Association from February 1991-March 1992 inclusive. The number of reports received/number of animals involved per species was: dogs (23/24); cats (20/30); horses (4/4); cattle (7/10); sheep (3/745); poultry (1/580); pigs (1/8). Of these, 38 (64%) were classified as definite ADRs and 9 (15%) as probable ADRs. In 10 (17%) reports an ADR could not be substantiated or there was insufficient information available to make a decision. Two reports involved veterinarians inadvertently overdosing animals. Eighteen reports involved apparent hypersensitivity reactions and 6 reports involved probable drug interactions. Four reports involved the use of drugs at appropriate doses but in inappropriate clinical situations, and 3 reports were associated with 'off-label' use.

Hepatic encephalopathy. Current concepts of the pathogenesis.

Hepatic encephalopathy occurs in a number of different species as a result of either congenital portacaval shunts or acquired liver disease. Despite intensive research, the neurochemical basis of the disorder has not been defined. Theories to explain the cerebral dysfunction that accompanies acute or chronic hepatic failure include 1) ammonia acting as the putative neurotoxin, 2) perturbed monoamine neurotransmission as a result of altered plasma amino acid metabolism, 3) an imbalance between excitatory amino acid neurotransmission, mediated by glutamate, and inhibitory amino acid neurotransmission, mediated by gamma-aminobutyric acid, and 4) increased cerebral concentrations of an endogenous benzodiazepine-like substance.

Congenital deficiency of all vitamin K-dependent blood coagulation factors due to a defective vitamin K-dependent carboxylase in Devon Rex cats.

Two Devon Rex cats from the same litter, which had no evidence of liver disease, malabsorption of vitamin K or chronic ingestion of coumarin derivatives, were found to have plasma deficiencies of factors II, VII, IX and X. Oral treatment with vitamin K1 resulted in the normalization of these coagulation factors. After taking liver biopsies it was demonstrated that the coagulation abnormality was accompanied by a defective gamma-glutamyl-carboxylase, which had a decreased affinity for both vitamin K hydroquinone and propeptide. This observation prompted us to study in a well-defined in vitro system the possible allosteric interaction between the propeptide binding site and the vitamin K hydroquinone binding site on carboxylase. It was shown that by the binding of a propeptide-containing substrate to gamma-glutamylcarboxylase the apparent KM for vitamin K hydroquinone is decreased about 20-fold. On the basis of these in vitro data the observed defect in the Devon Rex cats can be fully explained.

Correction of cervical esophageal stricture in a dog by creation of a traction diverticulum.

A cervical esophageal stricture was corrected in a dog by creation of a traction diverticulum. Although abnormal esophageal motility persisted in the portion of the esophagus cranial to the stricture, the clinical effects of the stricture were ameliorated by the simple surgical procedure.

Erythrocyte protoporphyrin concentrations in clinically normal cats and cats with lead toxicity.

Erythrocyte protoporphyrin (EPP) and blood lead concentrations were determined in 91 clinically healthy cats living in the inner suburban area of Sydney, Australia. The mean EPP concentration was 223.4 +/- 186.1 micrograms litre-1 whole blood and the mean blood lead concentration 0.62 +/- 0.25 mumol litre-1. EPP concentrations were also monitored in three cats with confirmed lead toxicity--at the time of diagnosis and one week and one month after chelation therapy with calcium EDTA. EPP concentrations were elevated in two cats and within the normal range in the third cat at the time of diagnosis. EPP concentration were higher in two cats one week after treatment than at the time of diagnosis. One month after chelation therapy, EPP concentrations were normal in two cats but still substantially elevated in the third cat although its blood lead concentration had returned to normal and all clinical signs of lead toxicity had resolved. It was determined that the predominant form of protoporphyrin present in cats with lead toxicity was zinc protoporphyrin. The EPP assay may have limited value in the diagnosis of acute lead toxicity and in monitoring the success of chelation therapy in cats.

CNQX binding to non-NMDA glutamate receptors in canine cerebro-cortical crude synaptosomal membranes: pharmacological characterization and comparison of binding parameters in dogs with congenital portosystemic encephalopathy and control dogs.

The pharmacological profile and binding characteristics of the non-NMDA antagonist of glutamate receptors [3H]6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), were investigated in triton-washed crude synaptosomal membranes prepared from canine cerebral cortex. [3H]CNQX binding was inhibited by various glutamate agonists and antagonists, the rank order of potency being CNQX greater than alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) = quisqualate = kainate greater than glutamate. Two binding sites for [3H]CNQX were apparent when non-specific binding (NSB) was defined with unlabelled CNQX. In contrast, when NSB was defined with saturating concentrations of unlabelled AMPA and kainate, only one binding site was identified which corresponded to the high affinity site identified when CNQX was used to define NSB. No physiologically relevant differences were found in binding parameters for [3H]CNQX membranes from dogs with congenital portosystemic encephalopathy (PSE) when compared with control dogs. The affinity constant (Ki) of AMPA displacement of [3H]CNQX binding was not significantly different in PSE dogs compared with control dogs. These results suggest that the antagonist site on cortical non-NMDA receptors is not perturbed in dogs with congenital PSE.

Neurochemical studies of hepatic encephalopathy.

Despite intensive research, the neurochemical basis of hepatic encephalopathy (HE) has not been defined. Theories that are currently favoured to explain the cerebral dysfunction that accompanies acute or chronic hepatic failure include: (1) ammonia acting as the putative neurotoxin; (2) perturbed monoamine neutrotransmission as a result of altered plasmo amino acid metabolism; (3) an imbalance between excitatory amino acid neurotransmission, mediated by glutamate, and inhibitory amino acid neurotransmission, mediated by gamma-aminobutyric acid (GABA); and (4) increased cerebral concentrations of an endogenous benzodiazepine-like substance. Studies of amino acid neurotransmitter receptors in HE have yielded conflicting results. The majority of studies in different animal models of acute and chronic HE and in patients have reported that brain GABA receptor density and affinity are unchanged. There have been fewer studies of excitatory amino acid receptors and these have also yielded conflicting results. However, the majority suggest that components of the glutamate receptor system are perturbed in HE. Further investigation is required to determine the significance of these findings to the pathogenesis of HE.

Alterations in cortical [3H]kainate and alpha-[3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding in a spontaneous canine model of chronic hepatic encephalopathy.

Excitatory amino acid receptor binding parameters were investigated in a spontaneous dog model of chronic hepatic encephalopathy. L-[3H]Glutamate, (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK-801), [3H]kainate, and alpha-[3H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding experiments were performed using crude cerebrocortical synaptosomal membrane preparations from dogs with congenital portosystemic encephalopathy (PSE) and control dogs. There was no change in the affinity or density of L-[3H]-glutamate or [3H]MK-801 binding sites in dogs with congenital PSE compared with control dogs. However, in the PSE dogs there was a significant reduction in the density of [3H]kainate binding sites compared with control dogs and abolition of the low-affinity [3H]AMPA binding site. The relative binding capacity of PSE synaptosomal membranes for [3H]kainate and [3H]AMPA was expressed as the ratio Bmax/KD. There was a significant inverse correlation between the Bmax/KD ratio for [3H]AMPA binding and the worst grade of encephalopathy experienced by each dog. These results suggest that there is a significant perturbation of cerebrocortical non-N-methyl-D-aspartate receptor binding in dogs with congenital PSE which may have relevance to the pathogenesis of hepatic encephalopathy.