Anticoagulant effects of low-molecular-weight heparins in healthy cats

BACKGROUND: Low-molecular-weight heparin (LMWH) has potential benefit in cats at risk for thromboembolic disease. However, LMWH pharmacokinetics has not been characterized in the cat. Drug effect with LMWH may be evaluated with analysis of factor Xa inhibition (anti-Xa) or thromboelastography (TEG). HYPOTHESIS: Administration of LMWH at previously recommended dosages and schedules to healthy cats will result in inhibition of factor Xa and hypocoagulable TEG. ANIMALS: In vivo research with heparin was performed in 5 purpose-bred cats. METHODS: In a prospective study with randomized crossover design, heparin or placebo was administered. Treatments were unfractionated heparin (UFH), 250 IU/kg q6h; dalteparin, 100 IU/kg q12h; enoxaparin, 1 mg/kg q12h; or 0.9% saline, 0.25 mL/kg q6h. Each drug was administered for 5 consecutive days followed by a minimum washout of 14 days. Baseline and post-treatment analyses included anti-Xa, TEG, and prothrombin time/activated partial thromboplastin time. RESULTS: Mean anti-Xa activity 4 hours after enoxaparin (0.48 U/mL) approached the human therapeutic target (0.5-1.0 U/mL); however, mean trough anti-Xa activity was below detection limits. Mean anti-Xa activity 4 hours after dalteparin was lower, and only 1 cat attained therapeutic target at a single time point. Cats receiving UFH attained target anti-Xa activity and changes in TEG at trough and 4 hours. CONCLUSIONS: Cats have rapid absorption and elimination kinetics with LMWH therapy. On the basis of pharmacokinetic modeling, cats will require higher dosages and more frequent administration of LMWH to achieve human therapeutic anti-factor Xa activity of 0.5-1 U/mL. Peak anti-Xa activity is predicted at 2 hours after administration of LMWH.     

Low dose calcium heparin in horses: plasma heparin concentrations, effects on red blood cell mass and on coagulation variables

Low dose calcium heparin was administered subcutaneously at 12 hourly intervals to six healthy horses at an initial dose of 150 iu of heparin/kg bodyweight (bwt) and at a maintenance dose of 120 iu/kg bwt. All injections were given at 0900 and 2100 h. Blood samples for monitoring plasma heparin concentrations were obtained prior to, at 2 hourly intervals for 84 h (treatment period), and at Hours 24, 32, 48 and 96 of the control period. Blood samples for monitoring red blood cell (RBC) mass, plasma antithrombin III activity (AT III), activated partial thromboplastin time (APTT), and thrombin time (TT) were taken at 8 hourly intervals during the treatment period and at all of the Control Period Hours. Mean plasma heparin concentrations increased significantly (P less than 0.01) from 2 h after the first to 32 h after the last (seventh) injection. Mean values corresponding to the desired range of heparin in plasma (0.05 to 0.20 iu/ml) were achieved at 21 h after initiation of heparin treatment and were maintained during the following 81 h. Great individual variations in the sensitivity to heparin among horses, cumulation of heparin in plasma with prolonged administration and a marked circadian periodicity in the disposition of heparin affected actually measured plasma heparin values. A chronodiagram revealed peak values around 1300 h, trough values around 0500 h. The peak-trough difference amounted to about 50 per cent. Increasing plasma heparin concentrations were associated with erratic prolongations of mean APTT and TT values. The AT III curve was not affected significantly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of an adapted intravenous amiodarone treatment protocol in horses with atrial fibrillation

REASON FOR PERFORMING STUDY: Good results have been obtained with a human amiodarone (AD) i.v. protocol in horses with chronic atrial fibrillation (AF) and a pharmacokinetic study is required for a specific i.v. amiodarone treatment protocol for horses. OBJECTIVES: To study the efficacy of this pharmacokinetic based i.v. AD protocol in horses with chronic AF. METHODS: Six horses with chronic AF were treated with an adapted AD infusion protocol. The protocol consisted of 2 phases with a loading dose followed by a maintenance infusion. In the first phase, horses received an infusion of 6.52 mg AD/kg bwt/h for 1 h followed by 1.1 mg/kg bwt/h for 47 h. In the second phase, horses received a second loading dose of 3.74 mg AD/kg bwt/h for 1 h followed by 1.31 mg/kg bwt/h for 47 h. Clinical signs were monitored, a surface ECG and an intra-atrial electrogram were recorded. AD treatment was discontinued when conversion or any side effects were observed. RESULTS: Three of the 6 horses cardioverted successfully without side effects. The other 3 horses did not convert and showed adverse effects, including diarrhoea. In the latter, there were no important circulatory problems, but the diarrhoea continued for 10-14 days. The third horse had to be subjected to euthanasia because a concomitant Salmonella infection worsened the clinical signs. CONCLUSION: The applied treatment protocol based upon pharmacokinetic data achieved clinically relevant concentrations of AD and desethylamiodarone. POTENTIAL RELEVANCE: Intravenous AD has the potential to be an alternative pharmacological treatment for AF in horses, although AD may lead to adverse drug effects, particularly with cumulative dosing.     

Attenuation of ischaemic injury in the equine jejunum by administration of systemic lidocaine

REASONS FOR PERFORMING STUDY: Absorption of endotoxin across ischaemic-injured mucosa is a major cause of mortality after colic surgery. Recent studies have shown that flunixin meglumine retards mucosal repair. Systemic lidocaine has been used to treat post operative ileus, but it also has novel anti-inflammatory effects that could improve mucosal recovery after ischaemic injury. HYPOTHESIS: Systemic lidocaine ameliorates the deleterious negative effects of flunixin meglumine on recovery of mucosal barrier function. METHODS: Horses were treated i.v. immediately before anaesthesia with either 0.9% saline 1 ml/50 kg bwt, flunixin meglumine 1 mg/kg bwt every 12 h or lidocaine 1.3 mg/kg bwt loading dose followed by 0.05 mg/kg bwt/min constant rate infusion, or both flunixin meglumine and lidocaine, with 6 horses allocated randomly to each group. Two sections of jejunum were subjected to 2 h of ischaemia by temporary occlusion of the local blood supply, via a midline celiotomy. Horses were monitored with a behavioural pain score and were subjected to euthanasia 18 h after reversal of ischaemia. Ischaemic-injured and control jejunum was mounted in Ussing chambers for measurement of transepithelial electrical resistance (TER) and permeability to lipopolysaccharide (LPS). RESULTS: In ischaemic-injured jejunum TER was significantly higher in horses treated with saline, lidocaine or lidocaine and flunixin meglumine combined, compared to horses treated with flunixin meglumine. In ischaemic-injured jejunum LPS permeability was significantly increased in horses treated with flunixin meglumine alone. Behavioural pain scores did not increase significantly after surgery in horses treated with flunixin meglumine. CONCLUSIONS: Treatment with systemic lidocaine ameliorated the inhibitory effects of flunixin meglumine on recovery of the mucosal barrier from ischaemic injury, when the 2 treatments were combined. The mechanism of lidocaine in improving mucosal repair has not yet been elucidated.     

Cardiorespiratory effects of enoximone in anaesthetised colic horses

Reasons for performing study: No studies have been reported on the effects of enoximone in anaesthetised colic horses. Objective: To examine whether enoximone improves cardiovascular function and reduces dobutamine requirement in anaesthetised colic horses. Methods: Forty‐eight mature colic horses were enrolled in this prospective, randomised clinical trial. After sedation (xylazine 0.7 mg/kg bwt) and induction (midazolam 0.06 mg/kg bwt, ketamine 2.2 mg/kg bwt), anaesthesia was maintained with isoflurane in oxygen and a lidocaine constant rate infusion (1.5 mg/kg bwt, 2 mg/kg/h). Horses were ventilated (PaCO₂<8.00 kPa). If hypotension occurred, dobutamine and/or colloids were administered. Ten minutes after skin incision, horses randomly received an i.v. bolus of enoximone (0.5 mg/kg bwt) or saline. Monitoring included respiratory and arterial blood gases, heart rate (HR), arterial pressure and cardiac index (CI). Systemic vascular resistance (SVR), stroke index (SI) and oxygen delivery index (DO₂I) were calculated. For each variable, changes between baseline and T10 within each treatment group and/or colic type (small intestines, large intestines or mixed) were analysed and compared between treatments in a fixed effects model. Differences between treatments until T30 were investigated using a mixed model (α= 0.05). Results: Ten minutes after enoximone treatment, CI (P = 0.0010), HR (P = 0.0033) and DO₂I (P = 0.0007) were higher and SVR lower (P = 0.0043) than at baseline. The changes in CI, HR and SVR were significantly different from those after saline treatment. During the first 30 min after enoximone treatment, DO₂I (P = 0.0224) and HR (P = 0.0003) were higher than after saline administration. Because the difference in HR between treatments was much clearer in large intestine colic cases, an interaction was detected between treatment and colic type in both analyses (P = 0.0076 and 0.0038, respectively). Conclusions: Enoximone produced significant, but short lasting, cardiovascular effects in colic horses. Potential relevance: Enoximone's cardiovascular effects in colic horses were of shorter duration than in healthy ponies.     

Evaluation of low-molecular-weight heparin for the prevention of equine laminitis after colic surgery

Objectives – The aim of this study is to describe the prevalence of postoperative laminitis in colic cases and to determine if low-molecular-weight heparin (LMWH) is effective in preventing this complication.
Design – Retrospective clinical study.
Animals – Client-owned horses.
Interventions – SC administration of enoxaparin during the postoperative period.
Measurements and Main Results – Medical records of 360 horses undergoing surgery for colic and surviving at least 3 days were evaluated. Fifty-six horses admitted before 1995 did not receive LMWH (control group) and 304 admitted after 1995 received LMWH as a prophylaxis for laminitis (treatment group). Three grades of severity were defined for laminitis. Prevalence and severity of laminitis were compared between the 2 groups. Several parameters recorded on admission (sex, age, breed, site and nature of the disease, heart rate, PCV, gravity score, and shock score) and the administration of LMWH were tested as risk factors in the development of laminitis in a logistic regression procedure. Prevalence and grade of laminitis were significantly lower in the treatment group. Only the absence of LMWH was recognized as a significant risk factor in the logistic regression model.
Conclusions – The administration of LMWH appears to be effective in the prophylaxis of laminitis following colic surgery and may be useful in the postoperative management of these horses.     

Use of intravenous flecainide in horses with naturally-occurring atrial fibrillation

REASONS FOR PERFORMING STUDY: It has been reported that i.v. flecainide has a high efficacy for the treatment of experimentally-induced acute atrial fibrillation (AF) in horses and that its use is associated with minimal toxic side effects. OBJECTIVES: The objectives were to study the efficacy of i.v. flecainide as a treatment for atrial fibrillation in horses with naturally-occurring AF. METHODS: Ten horses with naturally-occurring AF were treated with 2 mg/kg bwt flecainide i.v. at a rate of 0.2 mg/kg bwt/min. In 3 horses, the infusion was continued at 0.05-0.10 mg/kg bwt/min until a total dose of 3.0 mg/kg bwt had been administered. Heart rate, QRS duration and average interval between fibrillation waves were measured before, during and following flecainide infusion. If conversion to normal sinus rhythm was not achieved, horses were treated with quinidine sulphate per os at a dose of 22 mg/kg bwt given every 2 h. RESULTS: None of the horses with chronic AF (n = 9) converted to sinus rhythm with flecainide i.v. The only horse treated successfully had acute AF of 12 days' duration. The QRS duration and fibrillation cycle length increased significantly (P = 0.006 and 0.002, respectively) during and following flecainide infusion. Heart rate did not increase significantly over time however, 3 horses developed heart rates in excess of 100 beats/min. Two horses developed a potentially dangerous ventricular dysrhythmia during the first 15 mins of treatment. Quinidine sulphate given per os restored sinus rhythm in 8 out of 9 horses, with minimal adverse effects. CONCLUSIONS: Although flecainide might be efficacious in cases of acute AF, it was not possible to restore sinus rhythm in horses with naturally-occurring chronic AF at the dosages used in this study. In 2 horses, 2.0 mg/kg bwt flecainide was associated with potentially dangerous dysrhythmias. POTENTIAL CLINICAL RELEVANCE: Intravenous administration of 2 mg/kg bwt flecainide is unlikely to convert chronic AF in horses and could induce dangerous dysrhythmias.     

Prevention of ischaemia-induced small intestinal adhesions in foals

REASONS FOR PERFORMING STUDY: Treatments addressing variously theorised pathophysiological mechanisms of small intestinal adhesions have been reported. This study applied those classes of treatments to the most clinically relevant aetiology of post operative adhesions. HYPOTHESIS: Treatments addressing the pathophysiology of ischaemia-reperfusion induced adhesions would accordingly reduce the incidence of adhesions from this model. METHODS: Four classes of treatments were administered for 72 h to 16 foals subjected to complete ischaemia followed by reperfusion to create peritoneal adhesions. These groups were: 1) FPG group--flunixin meglumine (1.1 mg/kg bwt i.v., divided q.i.d.), potassium penicillin G (22,000 iu/kg bwt i.v., q.i.d.) and gentamicin (2.2 mg/kg bwt i.v., t.i.d.); 2) HEP group--heparin (80 iu/kg bwt subcut., b.i.d.); 3) DMSO group--dimethylsulphoxide (DMSO) (20 mg/kg bwt [diluted in 500 ml normal saline] i.v., b.i.d.); and 4) SCMC group--sodium carboxymethylcellulose (500 ml 3% sterile solution intraperitoneally, administered only at the beginning of surgery). RESULTS: Post operative intestinal obstruction did not occur in any foal. After 10 days, necropsy revealed bowel-to-bowel adhesions in none of the FPG or DMSO groups, in 2/4 of the SCMC group, in 3/4 of the HEP group and 5/6 foals subjected to the procedure without treatment (UIR group). CONCLUSIONS: Inhibition of the inflammation associated with ischaemia and reperfusion in foals treated with FPG or DMSO decreased small intestinal adhesions in foals. POTENTIAL RELEVANCE: Although anti-inflammatory therapy was shown to eliminate bowel-bowel adhesions in this controlled study, it must be remembered that clinical cases are without control. These therapies are advised to improve the result but are unlikely to eliminate the problem.     

Theophylline does not potentiate the effects of a low dose of dexamethasone in horses with recurrent airway obstruction

REASONS FOR PERFORMING STUDY: Theophylline has been shown to have corticosteroid-sparing effects for the treatment of human asthma. A similar effect, if present in horses, would allow diminishing the dose of corticosteroids administered to equine patients with inflammatory airway diseases. OBJECTIVES: To evaluate whether theophylline potentiates the effects of a low dose of dexamethasone when treating horses with recurrent airway obstruction (RAO). HYPOTHESIS: Theophylline has steroid-sparing effects in horses with RAO. METHODS: Ten mature mixed breed horses in clinical exacerbation of RAO were studied. Using an incomplete crossover design and 3 experimental periods of 7 days duration, horses were distributed randomly in 5 treatment groups; and administered dexamethasone s.i.d., at either 0.05 mg/kg bwt i.v. or per os, or 0.02 mg/kg bwt alone or combined with theophylline at 5 mg/kg bwt per os b.i.d. A fifth group was treated with theophylline alone at the above dosage. Lung function was evaluated prior to drug administration and then 3 and 7 days later. RESULTS: Oral administration of dexamethasone alone or combined with theophylline failed to improve lung function significantly in RAO affected horses. Theophylline alone also failed to improve lung function in all treated horses. Conversely, dexamethasone administration at 0.05 mg/kg bwt i.v. resulted in a significant improvement in lung function starting on Day 3. CONCLUSIONS AND POTENTIAL RELEVANCE: Oral theophylline for 7 days did not improve the effects of a low dose of dexamethasone for the treatment of horses with RAO.     

Low‐Molecular‐Weight Heparin Dosage in Newborn Foals

Background: Heparin is used in humans as prophylaxis of hypercoagulable states and disseminated intravascular coagulation (DIC). However, babies need a higher heparin dose than do adults. Septic neonate foals are at high risk of hypercoagulable state and DIC, and there is limited objective information about heparin dose for equine neonates. Objective: To assess whether neonate foals require higher dosages of low‐molecular‐weight heparin (LMWH) than adults. Animals: Eighteen healthy and 11 septic neonate foals. Methods: Experimental and clinical studies. Firstly, healthy foals were randomly distributed in 2 groups, 1 receiving 50 IU/kg SC of dalteparin and the 2nd group receiving 100 IU/kg SC of dalteparin, once daily for 3 days. Blood samples were collected before and 3, 6, 27, and 51 hours after the 1st LMWH administration. Plasma antifactor‐Xa activity was measured, together with hemostatic and hematologic parameters used to assess the risk of bleeding. Subsequently, septic foals were treated blindly either with placebo (saline) or 100 IU/kg of dalteparin for 3 days. Plasma antifactor‐Xa activity and other hemostatic parameters were determined before and after treatment. Results: Plasma antifactor‐Xa activity in healthy foals was below prophylactic activity when using the adult dosage (50 IU/kg), whereas prophylactic activities were achieved when using the double dosage (100 IU/kg). No hemorrhagic events and erythrocyte‐related complications were observed with either dosage. In the clinical study, only 4/6 septic foals had plasma antifactor‐Xa activity adequate for prophylaxis. Conclusions and Clinical Importance: Equine neonates require higher dosages of LMWH compared with adults to reach prophylactic heparinemia.     

Preliminary safety and biological efficacy studies of ethyl pyruvate in normal mature horses

Reasons for performing the study: Endotoxaemia causes substantial morbidity and mortality in horses with colic and sepsis. Ethyl pyruvate is a novel anti‐inflammatory medication that improved survival in preclinical models of severe sepsis endotoxaemia and intestinal ischaemia and reperfusion in rodents, swine, sheep and dogs and may be a useful medication in horses. Hypothesis: Ethyl pyruvate has no adverse effects in normal horses and is biologically active based on suppression of proinflammatory gene expression in endotoxin stimulated whole blood, in vitro. Methods: Physical and neurological examinations, behaviour scores, electrocardiograms and clinicopathological tests were performed on 5 normal healthy horses receiving 4 different doses of ethyl pyruvate. Doses included 0, 50, 100 and 150 mg/kg bwt administered in a randomised crossover design with a 2 week washout period between doses. Biological efficacy was assessed by stimulating whole blood with endotoxin from the horses that received ethyl pyruvate prior to and 1 and 6 h after drug infusion. Gene expression for TNFα, IL‐1β and IL‐6 was assessed. Results: There were no effects of drug or dose (0, 50, 100 or 150 mg/kg bwt) on any of the physical or neurological examination, behaviour factors, electrocardiogram or clinical pathological results collected from any of the horses. All parameters measured remained within the normal reference range. There was a significant reduction in TNFα, IL‐1β and IL‐6 gene expression in endotoxin stimulated whole blood from horses 6 h after receiving 150 mg/kg bwt ethyl pyruvate. There were no detectable effects on gene expression of any of the other doses of ethyl pyruvate tested. Conclusion: We were unable to detect any detrimental effects of ethyl pyruvate administration in normal horses. Ethyl pyruvate significantly decreased proinflammatory gene expression in endotoxin stimulated blood 6 h after drug administration. Clinical relevance: Ethyl pyruvate may be a safe, effective medication in endotoxaemic horses.     

Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses

Reasons for performing the study: Endotoxaemia contributes to morbidity and mortality in horses with colic due to inflammatory cascade activation. Effective therapeutic interventions are limited for these horses. Ethyl pyruvate (EP), an anti‐inflammatory agent that alters the expression of proinflammatory cytokines, improved survival and organ function in sepsis and gastrointestinal injury in rodents and swine. Therapeutic efficacy of EP is unknown in endotoxaemic horses. Objectives: Determine the effects of EP on signs of endotoxaemia and expression of proinflammatory cytokines following administration of lipopolysaccharide (LPS) in horses. Methods: Horses received 30 ng/kg bwt LPS in saline to induce signs of endotoxaemia. Next, horses received lactated Ringer's solution (LRS), (n = 6), 150 mg/kg bwt EP in LRS, (n = 6), or 1.1 mg/kg bwt flunixin meglumine (FM), (n = 6). Controls received saline followed by LRS (n = 6). Physical examinations, behaviour pain scores and blood for clinical pathological testing and gene expression were obtained at predetermined intervals for 24 h. Results: Lipopolysaccharide infusion produced clinical and clinicopathological signs of endotoxaemia and increased expression of tumour necrosis factor alpha (TNFα), interleukin 6 (IL‐6) and IL‐8 (P<0.001) compared with controls. Leucopenia and neutropenia occurred in all horses that received LPS. Horses treated with EP and FM had significantly (P<0.0001) reduced pain scores compared with horses receiving LPS followed by LRS. Flunixin meglumine was significantly more effective at ameliorating fever compared with EP. Both EP and FM significantly diminished TNFα expression. Ethyl pyruvate significantly decreased, but FM significantly increased, IL‐6 expression. Neither EP nor FM altered IL‐8 expression. Conclusions and potential relevance: Ethyl pyruvate administered following LPS diminished the clinical effects of endotoxaemia and decreased proinflammatory gene expression in horses. Ethyl pyruvate suppressed expression of proinflammatory cytokines better than FM. However, FM was a superior anti‐pyretic compared with EP. Ethyl pyruvate may have therapeutic applications in endotoxaemic horses.     

Multicentre,controlled, randomised and blinded field study comparing efficacy of suxibuzone and phenylbutazone in lame horses

Reasons for performing study: In horses, it has been demonstrated that suxibuzone (SBZ) has a lower gastric ulcerogenic effect than phenylbutazone (PBZ). However, no field trials have been reported comparing the efficacy of the drugs in alleviating lameness. Objectives: To compare the therapeutic effect of SBZ to that of PBZ when administered orally in lame horses. Acceptability of both products was also compared. Methods: Lame horses (n = 155) were used in a multicentre, controlled, randomised and double‐blinded clinical trial. Horses were treated orally with either SBZ or PBZ at equivalent therapeutic dosages. PBZ was given to 79 horses at a dose of 4.4 mg/kg bwt/12 h for 2 days, followed by 2.2 mg/kg bwt/12 h for 6 days. SBZ was given to 76 horses at 6.6 mg/kg bwt/12 h for 2 days, followed by 3.3 mg/kg bwt/12 h for 6 days. Efficacy of treatments was evaluated by clinicians in equine practices according to lameness progression throughout the study. Product ingestion was checked daily to evaluate product acceptability. Results: Although SBZ showed a statistically significant tendency to have a better efficacy than PBZ (Odds ratio = 2.7; P = 0.016), significance dissipated once the analysis was adjusted for some imbalanced baseline covariates, confirming that they were actually related to the apparent advantage of SBZ over PBZ. Product acceptability was significantly higher in the SBZ group than in the PBZ group (96.1% vs. 77.2%; P = 0.001). Conclusions: SBZ and PBZ did not show significant differences in alleviating lameness in horses. However, SBZ had better product acceptability when administered orally with some food. Potential relevance: SBZ is a good therapeutic alternative to PBZ in horses since there is no significant difference in alleviating lameness between the 2 therapies.     

Intravenous and intratracheal administration of trimetoquinol, a fast-acting short-lived bronchodilator in horses with 'heaves'

REASON FOR PERFORMING STUDY: Trimetoquinol (TMQ) is a potent beta-adrenoceptor agonist bronchodilator used in human medicine but has not been evaluated for potential use as a therapeutic agent for horses with 'heaves'. OBJECTIVES: To assess the pharmacodynamics of TMQ in horses with 'heaves' to determine potential therapeutic effects. METHODS: Increasing doses of TMQ were administered to horses with 'heaves' by i.v. and intratracheal (i.t.) routes. Doses ranged 0.001-0.2 microg/kg bwt i.v. and 0.01-2 microg/kg bwt i.t. Cardiac and airways effects were assessed by measurement of heart rate (HR) and maximal change in pleural pressure (deltaPplmax), respectively. Side effects of sweating, agitation and muscle trembling were scored subjectively. Duration of action to i.v. (0.2 microg/kg bwt) and i.t. (2 microg/kg bwt) TMQ was evaluated over 6 h. RESULTS: Intravenous TMQ was an exceptionally potent cardiac stimulant. Heart rate increased at 0.01 microg/kg bwt, and was still increasing after administration of highest dose, 0.2 microg/kg bwt. Airway bronchodilation, measured as a decrease in deltaPplmax, also commenced at 0.01 microg/kg bwt. By the i.t. route, TMQ was 50-100-fold less potent than by i.v. Side effects included sweating, agitation and muscle trembling. Overall, the onset of HR and bronchodilator effects was rapid, within about 3 min, but effects were over at 2 h. CONCLUSION: When administered i.v. and i.t., TMQ is a highly potent cardiac stimulant and a modest bronchodilator. It may not be an appropriate pharmacological agent by i.v. and i.t. routes for the alleviation of signs in horses with 'heaves'. Further studies of TMQ by oral and aerosol routes are necessary. POTENTIAL RELEVANCE: In horses, TMQ is a fast-acting bronchodilator with a short duration of action. It could be used as a rescue agent during an episode of 'heaves'. The i.v. and i.t. administration of TMQ is associated with side effects, similar to those reported for all other beta-agonists. However, other routes, such as aerosol and oral, may prove useful and safe for the alleviation of bronchoconstriction typical of 'heaves'.     

Efficacy of oral and intravenous dexamethasone in horses with recurrent airway obstruction

REASONS FOR PERFORMING STUDY: Although the efficacy of dexamethasone for the treatment of recurrent airway obstruction (RAO) has been documented, the speed of onset of effect and duration of action are unknown, as is the efficacy of orally administered dexamethasone with or without fasting. OBJECTIVES: To document the time of onset of effect and duration of action of a dexamethasone solution i.v. or orally with and without fasting. METHODS: Protocol 1 used 8 RAO-affected horses with airway obstruction in a crossover design experiment that compared the effect of i.v. saline and dexamethasone (0.1 mg/kg bwt) on pulmonary function over 4 h. Protocol 2 used 6 similar horses to compare, in a crossover design, the effects of dexamethasone i.v. (0.1 mg/kg bwt), dexamethasone per os (0.164 mg/kg bwt) with and without prior fasting, and dexamethasone per os (0.082 mg/kg) with fasting. RESULTS: Dexamethasone i.v. caused significant improvement in lung function within 2 h with a peak effect at 4-6 h. Dexamethasone per os was effective within 6 h with peak effect at 24 h at a dose of 0.164 mg/kg bwt prior to feeding. The duration of effect was, for all dexamethasone treatments, statistically significant for 30 h when compared to saline and tended to have a longer duration of effect when used orally. Dexamethasone per os at a dose of 0.164 mg/kg bwt to fed horses had mean effects comparable to dexamethasone at a dose of 0.082 mg/kg bwt per os given to fasted horses, indicating that feeding decreases bioavailability. CONCLUSIONS: Dexamethasone administered i.v. has a rapid onset of action in RAO-affected horses. Oral administration of a bioequivalent dose of the same solution to fasted horses is as effective as i.v. administration and tends to have longer duration of action. Fasting horses before oral administration of dexamethasone improves the efficacy of treatment. POTENTIAL RELEVANCE: Oral administration to fasted horses of a dexamethasone solution intended for i.v. use provides an effective treatment for RAO-affected animals.     

Pharmacokinetics of recombinant hirudin in healthy horses

REASONS FOR PERFORMING STUDY: Recombinant (r)-hirudin is a specific inhibitor of thrombin that is independent of the activity of antithrombin. OBJECTIVES: To evaluate pharmacokinetic properties and coagulatory changes of r-hirudin in healthy horses. METHODS: Two clinically healthy horses received a single i.v. bolus of 0.4 mg/kg bwt r-hirudin and 6 clinically healthy horses received the same dose subcutaneously (subcut.) q. 12 h for 3 days. Coagulation times and r-hirudin plasma concentration were determined over 720 mins and 3 days after i.v. and subcut. administration, respectively. RESULTS: In all horses, treatment with r-hirudin was not associated with systemic or local side effects. After i.v. injection, the 2 horses showed an elimination half-life of 58 and 80 mins, respectively. After subcut. administration, maximum plasma concentration of r-hirudin occurred at 128 +/- 55 mins and declined with a terminal half-life of 561 +/- 364 mins. Maximum response of activated partial thromboplastin time (aPTT) occurred 1.5 h after administration of r-hirudin. A prolongation of 1.9 +/- 0.2 times the pretreatment value was noted. CONCLUSIONS: Pharmacokinetics of r-hirudin in healthy horses were similar to those in man and other animal species. POTENTIAL RELEVANCE: The results of this study indicate that r-hirudin can be used in horses, but further studies should be performed in order to prove its effectiveness in diseased horses.     

The evaluation of isoxsuprine hydrochloride for the treatment of navicular disease: a double blind study

A randomised double-blind clinical trial of 28 horses was undertaken to evaluate the efficacy of isoxsuprine hydrochloride at four different doses:- 0.0 mg/kg bodyweight (bwt) (placebo), 0.6 mg/kg bwt, 1.2 mg/kg bwt and 1.8 mg/kg bwt for treatment of navicular disease. The results showed that horses treated with isoxsuprine hydrochloride (N = 22) responded significantly with respect to clinical assessment score (P less than 0.01) when compared with the control group (N = 6). Furthermore, there were no dose-related differences in the responses of the horses treated with increasing levels of isoxsuprine. No correlation was found between radiological evidence of the extent of navicular disease and severity of lameness or response to treatment.     

Effects of phenylbutazone alone or in combination with flunixin meglumine on blood protein concentrations in horses

OBJECTIVE: To assess effects of treatment with phenylbutazone (PBZ) or a combination of PBZ and flunixin meglumine in horses. ANIMALS: 24 adult horses. PROCEDURE: 13 horses received nonsteroidal antiinflammatory drugs (NSAIDs) in a crossover design. Eleven control horses were exposed to similar environmental conditions. Treated horses received PBZ (2.2 mg/kg, PO, q 12 h, for 5 days) and a combination of PBZ and flunixin meglumine (PBZ, 2.2 mg/kg, PO, q 12 h, for 5 days; flunixin meglumine, 1.1 mg/kg, IV, q 12 h, for 5 days). Serum samples were obtained on day 0 (first day of treatment) and day 5, and total protein, albumin, and globulin were measured. RESULTS: 1 horse was euthanatized with severe hypoproteinemia, hypoalbuminemia, and colitis during the combination treatment. Comparisons revealed no significant difference between control horses and horses treated with PBZ alone. There was a significant difference between control and treated horses when administered a combination of PBZ and flunixin meglumine. Correction for horses with values >2 SDs from the mean revealed a significant difference between control horses and horses administered the combination treatment, between control horses and horses administered PBZ alone, and between horses receiving the combination treatment and PBZ alone. Gastroscopy of 4 horses revealed substantial gastric ulcers when receiving the combination NSAID treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of results of the study indicates the need for caution when administering a combination NSAID treatment to horses because the detrimental effects may outweigh any potential benefits.     

Upper respiratory signs associated with Anaplasma phagocytophilum infection in two horses

An adult Quarter Horse gelding (Case 1) was evaluated for tachypnoea and acute dysphagia. A 20-year-old Quarter Horse gelding (Case 2) was evaluated for respiratory stertor and severe, acute swelling of the head in the submandibular region. A physical examination, complete blood count, blood chemistry, upper airway endoscopy, and peripheral blood Anaplasma phagocytophilum polymerase chain reaction were completed for both horses. Both horses tested positive for A. phagocytophilum. The upper airway endoscopy for Case 1 revealed a feed contaminated pharynx, absent swallowing reflex, and left laryngeal hemiplagia. The upper airway endoscopy for Case 2 revealed severe diffuse pharyngeal swelling occluding the airway. Due to increased respiratory effort in Case 2, a tracheotomy was performed. In both horses, treatment consisted of intravenous oxytetracycline 6.6 mg/kg bwt i.v. q. 24 h for 2–3 days followed by minocycline 4 mg/kg bwt per os q. 12 h for 10–14 days. Both horses made full recoveries.     

Pharmacokinetics and pharmacodynamics of a therapeutic dose of unfractionated heparin (200 U/kg) administered subcutaneously or intravenously to healthy dogs

BACKGROUND: Heparin treatment has been recommended for dogs in hypercoagulable states such as disseminated intravascular coagulation, however, potential benefits have to be balanced against the bleeding risk if overdosage occurs. A better understanding of the pharmacology of heparin and tests to monitor heparin therapy in dogs may help prevent therapeutic hazards. OBJECTIVES: The purpose of this study was to evaluate the effects of 200 U/kg of sodium unfractionated heparin (UFH) on coagulation times in dogs after intravenous (IV) and subcutaneous (SC) administration and to compare these effects with plasma heparin concentrations assessed by its antifactor Xa (aXa) activity. METHODS: 200 U/kg of UFH were administered IV and SC to 5 healthy adult Beagle dogs with a washout period of at least 3 days. Activated partial thromboplastin time (APTT), prothrombin time (PT), and plasma aXa activity were determined in serial blood samples. RESULTS: After IV injection, PT remained unchanged except for a slight increase in 1 dog; APTT was not measurable (>60 seconds) for 45-90 minutes, and then decreased gradually to baseline values between 150 and 240 minutes. High plasma heparin concentrations were observed (maximal concentration = 4.64 +/-1.4 aXa U/mL) and decreased according to a slightly concave-convex pattern on a semilogarithmic curve, but returned to baseline slightly more slowly (t240-t300 minutes) than did APTT. After SC administration, APTT was moderately prolonged (by a ratio of 1.55 +/-0.28 APTT t0, range 1.35-2.01) between 1 and 4 hours after administration. Plasma aXa activity reached a maximum of 0.56 +/-0.20 aXa U/mL (range 0.42-0.9 U/mL) after 132 +/-26.8 minutes; this lasted for 102 +/-26.8 minutes. Prolongation of APTTs of 120-160% corresponded to plasma heparin concentrations of 0.3-0.7 aXa U/mL. CONCLUSIONS: As in humans, the pharmacokinetics of UFH in dogs was nonlinear. Administration of 200 U/kg of UFH SC in healthy dogs resulted in sustained plasma heparin concentrations in accordance with human recommendations for thrombosis treatment or prevention, without excessively increased bleeding risks. In these conditions, APTT can be used as a surrogate to assess plasma heparin concentrations. These findings need to be confirmed in diseased animals.