The effect of amlodipine and the combination of amlodipine and enalapril on the renin-angiotensin-aldosterone system in the dog.

Excessive aldosterone secretion is detrimental to the heart, vessels and kidneys, contributing to hypertension and the signs and progression of heart failure. Aldosterone secretion, abnormally elevated in heart failure and hypertension, can be blunted with angiotensin-converting enzyme inhibitors. Amlodipine, used to treat hypertension and heart failure, was hypothesized to activate the renin-angiotensin-aldosterone system (RAAS). A study was conducted with six normal adult male beagle dogs. Each dog received amlodipine (0.57 mg/kg b.i.d.) for 6 days, followed by amlodipine (0.57 mg/kg b.i.d.) and enalapril (0.57 mg/kg b.i.d.) for 4 days. Blood pressure, heart rate, serum chemistries and urinary aldosterone excretion, as a measure of RAAS activation, were compared with baseline values. Blood pressure fell by approximately 7% with amlodipine (P = 0.05) and a further 7% with the combination of amlodipine and enalapril (P < 0.01). Blood urea nitrogen increased with the combination (P < 0.05) but only one dog became mildly azotemic. Renin-angiotensin-aldosterone system activation, based on 24 h urinary aldosterone excretion and by aldosterone:creatinine ratio was increased by approximately threefold (P < 0.05) with amlodipine administration. This effect was blunted by enalapril, such that aldosterone excretion was no longer different from that observed under control conditions, although values for 24-h aldosterone excretion did not return to pretreament levels.

Management of drug-resistant cyathostominosis on a breeding farm in central North Carolina.

REASONS FOR PERFORMING STUDY: Possible anthelmintic resistance on a breeding farm where a rapid rotation anthelmintic programme had been implemented for 9 years was investigated. Cyathostomins resistant to fenbendazole and pyrantel were documented by faecal worm egg count reduction test (FWECRT). OBJECTIVES: To 1) manage small strongyle transmission in a herd of horses in which resistance to both pyrantel pamoate and fenbendazole was identified and thereby reduce the risk of clinical disease in the individual animal, 2) monitor the change in resistance patterns over time and 3) monitor the efficacy of ivermectin over the study period. METHODS: Targeted ivermectin treatment of horses on the farm was instituted for mature horses with faecal worm egg counts (FWEC) > 200 eggs/g (epg) and for horses < age 2 years with FWEC > 100 epg. RESULTS: Over a 30 month period, targeted ivermectin treatment achieved acceptable control in mares, as judged by FWEC, and improved control of patent cyathostome infection in consecutive foal crops. Egg reappearance time (ERT) after treatment with ivermectin was < 8 weeks in mares and foals more frequently in the second year of the study than in the first year. Numbers of anthelmintic treatments were reduced by 77.6 and 533% in the mare and foal group, respectively. CONCLUSIONS: Targeted ivermectin treatment may be an economically viable method of managing multiple drug resistant cyathostominosis. POTENTIAL RELEVANCE: Use of ivermectin should be monitored closely for development of resistance.

Pharmacokinetics of azithromycin in foals after i.v. and oral dose and disposition into phagocytes.

The properties of azithromycin suggest that it may be an alternative to erythromycin for treatment of Rhodococcus equi pneumonia in foals. To investigate this possibility, the disposition of azithromycin in plasma, polymorphonuclear leukocytes (PMN), and alveolar cells was examined after a single administration in foals. Azithromycin suspension was administered orally (p.o.) at a dose of 10 mg/kg to five healthy 2-3-month-old foals. Two weeks later, azithromycin for injection was administered by intravenous (i.v.) infusion at a dose of 5 mg/kg to the same foals. Plasma samples were collected after p.o. and i.v. administration. Peripheral blood PMN and bronchoalveolar lavage fluid and alveolar cells were collected after p.o. administration. Azithromycin concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC) with coulometric electrochemical detection. Azithromycin p.o. absorption was variable with a mean systemic availability of 39% (+/-20%). The plasma half-life was 16 and 18.3 h after i.v. and p.o. administration, respectively. Azithromycin had a very large volume of distribution (V(d)) of 11.6 L/kg [V(d(ss))] and 12.4 L/kg [V(d(area))]. The large V(d) can be attributed to high tissue and intracellular concentrations, exhibited by the high concentration of azithromycin in PMN and alveolar cells. The PMN half-life was 49.2 h. Dosage of 10 mg/kg of azithromycin p.o. once daily for foals with R. equi pneumonia is recommended for further study.

Comparison of cefepime pharmacokinetics in neonatal foals and adult dogs.

The pharmacokinetics of cefepime, a new fourth generation cephalosporin with enhanced antibacterial activity, was examined in neonatal foals and adult dogs. Cefepime was administered intravenously (i.v.) at a dose of 14 mg/kg to five neonatal foals and six adult dogs. Blood samples were collected in both groups of animals and plasma cefepime concentrations measured by reverse-phase high-performance liquid chromatography (HPLC). Cefepime concentrations in both groups of animals were described by a two-compartment pharmacokinetic model with elimination half-lives of 1.65 and 1.09 h for the foal and dog, respectively. We tested whether or not pharmacokinetic parameters for cefepime could be scaled across species using principles of allometry. The parameters of elimination half-life (t(1/2)beta), apparent volume of distribution (VDarea), and systemic clearance (CL) were scaled linearly to body weight on a double logarithmic plot with allometric exponents for body weight of 0.26, 1.08 and 0.72, respectively. This study further determined doses for cefepime, a potentially useful antibiotic for neonatal foals and dogs, from the pharmacokinetic values. An i.v. dose of cefepime estimated from this study for treating sensitive bacteria was 11 mg/kg every 8 h for neonatal foals and 40 mg/kg every 6 h for dogs.

Oil fly ash-induced elevation of plasma fibrinogen levels in rats.

Particulate matter air pollution (PM) has been associated with morbidity and mortality from ischemic heart disease and stroke in humans. It has been hypothesized that alveolar inflammation, resulting from exposure to PM, may induce a state of blood hypercoagulability, triggering cardiovascular events in susceptible individuals. Previous studies in our laboratory have demonstrated acute lung injury with alveolar inflammation in rats following exposure to residual oil fly ash (ROFA), an emission source particulate. In addition, increased mortality has been documented following exposure to ROFA in rats with preexistent cardiopulmonary disease. ROFA's toxicity derives from its soluble metal content, which appears also to drive the toxicity of ambient PM. The present study was conducted to test the hypothesis that exposure of rats to a toxic PM, like ROFA, would adversely alter hemostatic parameters and cardiovascular risk factors thought to be involved in human epidemiologic findings. Sixty-day-old male Sprague-Dawley rats were exposed by intratracheal instillation (IT) to varying doses (0.3, 1. 7, or 8.3 mg/kg) of ROFA, 8.3 mg/kg Mt. Saint Helen's volcanic ash (MSH, control particle), or 0.3 ml saline (SAL, control). At 24 h post-IT, activated partial thromboplastin time (APTT), prothrombin time (PT), plasma fibrinogen (PF), plasma viscosity (PV), and complete blood count (CBC) were performed on venous blood samples. No differences from control were detected in APTT and PT in ROFA-exposed rats; however, ROFA exposure did result in elevated PF, at 8.3 mg/kg only. In addition, PV values were elevated in both ROFA and MSH-exposed rats relative to SAL-control rats, but not significantly. Although no changes were detected in APTT and PT, alteration of important hematologic parameters (notably fibrinogen) through PM induction of an inflammatory response may serve as biomarkers of cardiovascular risk in susceptible individuals.

Lung injury from intratracheal and inhalation exposures to residual oil fly ash in a rat model of monocrotaline-induced pulmonary hypertension.

A rat model of monocrotaline (MCT)-induced pulmonary injury/hypertension has been recently used in particulate matter (PM) health effects studies, however, results have been equivocal. Neither the mechanism by which mortality occurs in this model nor the variation in response due to differences in PM exposure protocols (i.e., a bolus dose delivered intratracheally versus a similar cumulative dose inhaled over three days) have been fully investigated. Sprague Dawley rats (SD, 60 d old; 250-300 g) were injected with either saline (healthy) or MCT, 60 mg/kg, i.p. (to induce pulmonary injury/hypertension). Ten days later they were exposed to residual oil fly ash (ROFA), either intratracheally (IT; saline, 0.83 or 3.33 mg/kg) or by nose-only inhalation (15 mg/m3 x 6 h/d x 3 d). Lung histology, pulmonary cytokine gene expression (0 and 18 h postinhalation), and bronchoalveolar lavage fluid (BALF) markers of injury were analyzed (24 and 96 h post-IT; or 18 h post-inhalation). Data comparisons examined three primary aspects, 1) ROFA IT versus inhalation effects in healthy rats; 2) pulmonary injury caused by MCT; and 3) exacerbation of ROFA effects in MCT rats. In the first aspect, pulmonary histological lesions following ROFA inhalation in healthy rats were characterized by edema, inflammatory cell infiltration, and thickening of alveolar walls. Increases in BALF markers of lung injury and inflammation were apparent in ROFA-IT or nose-only exposed healthy rats. Increased IL-6, and MIP-2 expression were also apparent in healthy rats following ROFA inhalation. In regards to the second aspect, MCT rats exposed to saline or air showed perivascular inflammatory cell infiltrates, increased presence of large macrophages, and alveolar thickening. Consistently, BALF protein, and inflammatory markers (macrophage and neutrophil counts) were elevated indicating pulmonary injury. In regards to the third aspect, 58% of MCT rats exposed to ROFA IT died within 96 h regardless of the dose. No mortality was observed using the inhalation protocol. ROFA inhalation in MCT rats caused exacerbation of lung lesions such as increased edema, alveolar wall thickening, and inflammatory cell infiltration. This exacerbation was also evident in terms of additive or more than additive increases in BALF neutrophils, macrophages and eosinophils. IL-6 but not MIP-2 expression was more than additive in MCT rats, and persisted over 18 h following ROFA. IL-10 and cellular fibronectin expression was only increased in MCT rats exposed to ROFA. In summary, only the bolus IT ROFA caused mortality in the rat model of lung injury/hypertension. Exacerbation of histological lesions and cytokine mRNA expression were most reflective of increased ROFA susceptibility in this model.

Chrysotile asbestos and H2O2 increase permeability of alveolar epithelium.

The alveolar epithelium contains tight junctions and provides a barrier to passage of potentially injurious substances into the pulmonary interstitium. Alveolar epithelial injury is hypothesized to be an important early event in the pathogenesis of asbestosis. Mechanisms that may contribute to alveolar epithelial cell injury following asbestos exposure include the physicochemical interactions between asbestos fibers and cells, and the generation of reactive oxygen species such as hydrogen peroxide (H2O2). The present study examined changes in transepithelial resistance (Rt) (a measure of barrier function) and permeability of alveolar epithelium after chrysotile asbestos and H2O2 exposure. Alveolar epithelial cell monolayers, obtained from isolation of rat alveolar type II cells and grown on porous supports, were exposed to chrysotile asbestos or polystyrene beads (control) at concentrations of 5, 10, and 25 micrograms/cm2 for 24 h. In separate experiments, monolayers were exposed to H2O2 at concentrations of 50, 75, and 100 microM for 1 h Rt was measured using a voltohmmeter. Prior to treatment, monolayers had a high Rt (> 2000 ohms.cm2). Permeability was assessed by measuring flux of [3H]sucrose from apical to basolateral compartments. Cytotoxicity was evaluated by lactate dehydrogenase (LDH) and preincorporated [14C]adenine release. The morphological integrity of the monolayers was evaluated by scanning electron microscopy. Chrysotile asbestos and H2O2 exposure resulted in dose-dependent decrease in alveolar epithelial Rt and increases in permeability under conditions that did not result in over cytotoxicity. These results demonstrate that both chrysotile asbestos and H2O2 have effects on alveolar epithelial Rt and permeability and suggest a potential role for the alveolar epithelium in mediation of asbestos-induced pulmonary interstitial disease.

Pharmacokinetics of cefotaxime in neonatal pony foals.

Serum concentrations of cefotaxime and desacetylcefotaxime were measured in 1-week-old pony foals after IV administration of a single dose of cefotaxime. The cefotaxime disposition data conformed to a two-compartment model with elimination half-life of 0.60 hour. The combined cefotaxime and desacetylcefotaxime data was best described by a four-compartment model. The apparent half-life describing the disappearance of desacetylcefotaxime was 1.69 hours. Dosage of 40 mg/kg of body weight given IV every 4 to 6 hours for neonatal foals with gram-negative septicemia and every 2 hours for foals with meningitis is recommended for further study.

Echocardiographic diagnosis of an anomaly of the tricuspid valve in a male pygmy goat.

A 3-year-old male pygmy goat was evaluated because of a grade III/V plateau pansystolic murmur that was auscultated over the tricuspid valve area and a grade II/V plateau pansystolic murmur that was auscultated over the left heart base. Echocardiography revealed a large right atrium and ventricle, an atrial septal defect, and a dysplastic tricuspid valve displaced apically into the right ventricle. Contrast echocardiography and color-flow Doppler echocardiography revealed flow from right to left through the atrial septal defect and severe tricuspid regurgitation. A diagnosis of tricuspid valve dysplasia and severe tricuspid regurgitation was made. This anomaly (Ebstein's anomaly) of the tricuspid valve should be considered in goats that have systolic, with or without diastolic, murmurs over the tricuspic valve. Two-dimensional echocardiography can confirm the diagnosis of the anomaly. The associated tricuspid regurgitation and interatrial right-to-left shunt flow can be detected and semiquantitated by use of contrast, continuous wave, and color-flow Doppler echocardiography.

Azathioprine for treatment of immune-mediated thrombocytopenia in two horses.

Azathioprine, a thiopurine antimetabolite used in the treatment of immune-mediated thrombocytopenia in human beings and dogs, was used in 2 cases of immune-mediated thrombocytopenia in horses that failed to respond to corticosteroid therapy alone. Platelet counts were increased to acceptable values in both horses. One horse returned to a successful racing career, and the other was euthanatized after developing renal disease and mild laminitis.

Ultrasonographic evaluation of horses with thrombophlebitis of the jugular vein: 46 cases (1985-1988).

Medical records of 46 horses with jugular vein thrombophlebitis that were evaluated ultrasonographically were reviewed. The ultrasonographic appearance of the thrombus within the jugular vein was classified as noncavitating if it had uniform low to medium amplitude echoes, or as cavitating if it was heterogenous with anechoic to hypoechoic areas representing fluid or necrotic areas within the thrombus, and/or hyperechoic areas representing gas. Signs of pain on palpation of the affected vein (P less than 0.001), heat over the vein (P = 0.001), and swelling of the vein (P less than 0.05) were significantly associated with the ultrasonographic detection of a cavitating lesion. Ultrasonography also was useful for selecting a site for aspiration of a specimen for bacteriologic culturing and susceptibility testing.