Sildenafil does not have a significant effect on the portal vein velocity, cross-sectional area, and congestion index in the dog.

In veterinary medicine, sildenafil is most frequently used to treat pulmonary hypertension, but has also been investigated and used as a treatment for congenital megaesophagus and ischemic infarcts. With the increasing use, the effects of sildenafil on the portal vasculature in the dog have not been previously evaluated. The purpose of this study was to evaluate the effects sildenafil has on the portal vasculature, which anecdotally may have caused decreased portal vein pressure in an adult dog. The ultrasound cross-sectional area of the aorta, cross-sectional area of the portal vein, and portal vein blood flow velocity were acquired in dogs prior to administration, and 45, 90, and 120 min after oral administration of sildenafil for the treatment of pulmonary hypertension. Thirteen dogs were enrolled in the study. No statistically significant difference was detected between all measured values and the congestion index at all time points. A trend was identified that demonstrated progressively lower portal vein velocity with each evaluation, but this was not significant. Although this study had a small sample size, sildenafil was not shown to have a significant effect on the size or blood flow velocity of the portal vasculature. The hepatic buffer system, designed to maintain a constant blood flow to the liver, may be a contributing factor, but further studies with a larger sample size will be required for further evaluation.

Analgesic and Cardiopulmonary Effects of Epidural Romifidine and Morphine Combination in Horses.

The study aim is to compare the effects of epidural administration of two different doses of romifidine combined with morphine in horses. A prospective crossover blinded experimental design was used. Five adult healthy horses two males and three females with a mean body weight of 380 ± 45 Kg (335-425 kg), were studied. Treatments consisted of romifidine 30 µg/kg (R30) or 60 µg/kg (R60) combined with morphine 0.1 mg/kg with a washout interval of 72 hours, administered through an epidural catheter placed at the first intercoccygeal space. Heart rate (HR) and respiratory rate (fR), pH, blood gases, arterial blood pressures (mmHg), and threshold for electrical noxious stimulation was evaluated for 120 minutes and after 240 minutes of epidural injection. Data were collected before injections and every 15 minutes for 120 minutes, and at 240 minutes of epidural administration. Significant sedation occurred in both treatments with no statistically significant difference between them. There were significant changes in fR and HR from baseline but no difference between treatments. Arterial blood pressures were significantly lower in R60 treatment from 75 up to 120 minutes post epidural injection. Analgesia was considered moderate for both treatments lasting longer with romifidine at 60 µg/kg. Epidurally administered romifidine and morphine combination in horses produces dose-dependent sedation, arterial hypotension, and antinociceptive effects.

Pharmacokinetics and pharmacodynamics of intravenous continuous rate infusion and repeated intramuscular administration of dexmedetomidine in standing horses.

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an IV bolus followed by CRI dexmedetomidine would have a quicker increase in plasma concentrations compared with repeated IM injections. In a crossover design, eight adult, female horses were randomly placed into two groups: the CRI group (IV bolus dexmedetomidine at 0.005 mg/kg followed by a CRI at 0.01 mg/kg/h for 15 min then 0.005 mg/kg/h for 60 min) and the IM group (dexmedetomidine at 0.01 mg/kg, followed by 0.005 mg/kg in 30-min intervals for 60 min). Clearance and elimination half-life were 134 ± 67.4 ml/kg/min and 44.3 ± 26.3 min, respectively, in the CRI group, and apparent clearance and half-life were 412 ± 306 ml/kg/min (Cl/F) and 38.9 ± 18.6 min, respectively, in the IM group. Analgesia was evaluated using mechanical pressure threshold. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared with IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration. The odds of a decreased GI motility following IV administration was 12.34 times greater compared with IM administration.

Intravenous 15% isoflurane lipid nanoemulsion for general anesthesia in dogs.

OBJECTIVE: To investigate the efficacy of a new intravenous (IV) nanoemulsified isoflurane formulation for maintenance of general anesthesia in dogs. STUDY DESIGN: Prospective, crossover, experimental study. ANIMALS: Seven healthy, mature, mixed-breed dogs, three male and four female, weighing 11.5 ± 1.5 kg. METHODS: Anesthesia was induced with propofol for instrumentation. Measurements were obtained before administration of either inhaled isoflurane (Iso-I) or IV 15% isoflurane-loaded lipid nanoemulsion (Iso-nano). The minimum alveolar concentration (MAC) of isoflurane was determined using the 'up-and-down' technique. A tail clamp was applied every 15 minutes for a total time of 90 minutes and isoflurane administration was adjusted according to the response. Data were recorded at 30, 60 and 90 minutes for end-tidal isoflurane concentration (Fe´Iso), end-tidal carbon dioxide partial pressure (Pe'CO2), inspired isoflurane concentration (FIIso), arterial hemoglobin oxygen saturation (SaO2), peripheral hemoglobin oxygen saturation (SpO2), respiratory rate (fR), heart rate (HR), arterial blood pH, PaCO2, PaO2, base excess (BE), bicarbonate (HCO3-), systemic arterial pressure (sAP), and biochemical variables of blood urea nitrogen, alanine aminotransferase, creatine kinase and creatinine. RESULTS: No significant differences between treatments were detected for HR, fR, SaO2 or any biochemical variables (p > 0.05). In the Iso-nano treatment, sAP was significantly decreased throughout the study. Significant decreases in pH, Pe'CO2, BE and HCO3- were measured in the Iso-nano treatment. Isoflurane MAC was significantly lower in the Iso-nano than the Iso-I treatment. The dose of isoflurane (g hour-1) required to maintain general anesthesia did not differ significantly between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of 15% isoflurane-loaded lipid nanoemulsion IV was effective in maintaining general anesthesia in dogs but did not reduce the amount of isoflurane necessary to maintain general anesthesia. Significant hypotension and nonrespiratory acidosis occurred with the injectable form.

High-resolution melting analysis for detection of a single-nucleotide polymorphism and the genotype of the myostatin gene in warmblood horses.

OBJECTIVE To develop a high-resolution melting (HRM) assay to detect the g.66493737C>T polymorphism in the myostatin gene (MSTN) and determine the frequency of 3 previously defined g.66493737 genotypes (T/T, T/C, and C/C) in warmblood horses. SAMPLES Blood samples from 23 horses. PROCEDURES From each blood sample, DNA was extracted and analyzed by standard PCR methods and an HRM assay to determine the MSTN genotype. Three protocols (standard protocol, protocol in which a high-salt solution was added to the reaction mixture before the first melting cycle, and protocol in which an unlabeled probe was added to the reaction mixture before analysis) for the HRM assay were designed and compared. Genotype results determined by the HRM protocol that generated the most consistent melting curves were compared with those determined by sequencing. RESULTS The HRM protocol in which an unlabeled probe was added to the reaction mixture generated the most consistent melting curves. The genotypes of the g.66493737C>T polymorphism were determined for 22 horses (16 by HRM analysis and 20 by sequencing); 14, 7, and 1 had the T/T, T/C, and C/C genotypes, respectively. The genotype determined by HRM analysis agreed with that determined by sequencing for 14 of 16 horses. The frequency of alleles T and C was 79.5% and 20.5%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that HRM analysis may be a faster and more economical alternative than PCR methods for genotyping. Genotyping results might be useful as predictors of athletic performance for horses.

General anesthesia with an injectable 8% v/v sevoflurane lipid emulsion administered intravenously to dogs.

OBJECTIVE: To evaluate the potential of an intravenous (IV) sevoflurane formulation for maintenance of general anesthesia in dogs. STUDY DESIGN: Prospective crossover design. ANIMALS: Six healthy, mature, mixed-breed dogs, four males and two females, weighing 11.7 ± 3.4 kg. METHODS: Anesthesia was induced and maintained with propofol IV for instrumentation. Baseline measurements were recorded before administration of either sevoflurane in oxygen (Sevo-Inh) or lipid-emulsified sevoflurane 8% v/v in 30% Intralipid IV (Sevo-E), 0.5 mL kg(-1) over 5 minutes followed by an infusion at 0.1-0.3 mL kg(-1)  minute(-1) . Dogs were breathing spontaneously. The 'up-and-down' technique was used to determine the minimum alveolar concentration (MAC) of sevoflurane. Over 120 minutes, a tail clamp was applied every 15 minutes and sevoflurane administration was adjusted depending on the response. End-tidal sevoflurane concentration and variables were recorded at 30, 60, 90, and 120 minutes: heart rate (HR), systemic arterial pressure (sAP), respiratory rate (fR ), end-tidal carbon dioxide tension, hemoglobin oxygen saturation (SaO2 ), arterial pH and blood gases, blood urea nitrogen, alanine aminotransferase, creatine kinase, gamma-glutamyl transferase, and aspartate aminotransferase. RESULTS: There were no significant differences between treatments for HR, sAP, fR , SaO2 , and biochemical variables (p > 0.05). pH and HCO3-were significantly decreased, and PaCO2 increased from baseline in Sevo-E (p < 0.05). MAC was significantly lower for Sevo-E than for Sevo-Inh, although the required dose of sevoflurane (g hour(-1) ) to maintain general anesthesia was not significantly different between treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of 8% v/v sevoflurane lipid emulsion IV was effective in maintaining general anesthesia in dogs, but resulted in moderate cardiopulmonary depression, metabolic and respiratory acidosis. The amount of sevoflurane (g hour(-1) ) required to maintain general anesthesia was significantly lower for inhaled than for IV sevoflurane.

Isoflurane-loaded nanoemulsion prepared by high-pressure homogenization: investigation of stability and dose reduction in general anesthesia.

Isoflurane is a halogenated ether which is used for general anesthesia. To stabilize a new formulation in order to evaluate the potential to reduce the dose required for general anesthesia, an isoflurane-loaded nanoemulsion was proposed. A high-pressure homogenization technique was used to develop drug-loaded nanoemulsions which presented droplet size of 150 +/- 0.78 nm with a narrow size distribution and low polydispersity index (0.08 +/- 0.01). The zeta potential was -18 +/- 2.4 mV and pH was 6.03 +/- 0.04. Rheological analysis showed Newtonian behavior for the formulations, whose physical stability was confirmed by multiple light scattering. It was verified that isoflurane volatilization did not occur in these formulations. The preclinical evaluation, carried out via the end-tidal isoflurane concentration, showed that the dose required for anesthetic maintenance significantly decreased when the nanostructured formulation was administered compared to inhaled isoflurane. There was no significant difference (p < 0.05) between experimental groups (inhaled isoflurane and intravenous isoflurane-loaded nanoemulsion) in terms of the cardiac rate, oxygen hemoglobin saturation, and arterial blood pressure, as well as the biomarkers of renal, hepatic and skeletal muscle system functionalities. Slight tachypnea, edema, and erythema were observed after isoflurane-loaded or unloaded-nanoemulsion. The stability and significant dose reduction observed for drug-loaded nanoemulsion render this formulation a promising option for intravenous delivery of isoflurane.

Spinal anesthetics and analgesics in the horse.

In the past 10 years, there have been many recent advances in spinal techniques in horses, both epidural and subarachnoid, to identify drugs or drug combinations that have sensory effects without motor nerve paralysis, thus providing pain control without these horses becoming recumbent. Opioids, alpha-2 agonists, dissociative drugs, and others have been investigated. Many of these drugs, which have serious side effects when injected systemically in horses, have been shown to have useful analgesic effects when injected spinally. Morphine-like opioids have the greatest potential for spinal use as they produce long-lasting analgesia without motor effects. Often the doses used spinally are significantly lower than those needed for systemic effects.

Pharmacokinetics evaluation of soft agglomerates for prompt delivery of enteric pantoprazole-loaded microparticles.

Soft agglomerates containing pantoprazole-loaded microparticles were developed with the aim of prompt delivery of gastro-resistant particles. The objective was to evaluate the relative bioavailability in dogs after the oral administration of soft agglomerates. Gastro-resistant pantoprazole-loaded microparticles prepared by spray drying were mixed with mannitol/lecithin spray-dried powder and agglomerated by vibration. One single oral dose (40mg) was administered to dogs. Each dog received either a reference tablet or hard gelatin capsules containing the agglomerates. The plasma profiles were evaluated by non-compartmental and compartmental approaches, and the pharmacokinetic parameters were determined. The agglomerates presented 100% of drug particle loading and a production yield of 80.5%. The amount of drug absorbed after oral dosing was similar after reference or agglomerate administration, leading to a relative bioavailability of 108%. The absorption lag-time was significantly reduced after agglomerate administration (from 135.5+/-50.6 to 15.0+/-2.5min). The agglomerated gastro-resistant pantoprazole-loaded microparticles reduced time to peak plasma. The agglomerates were equivalent to the reference tablets in terms of extent but not in terms of rate of absorption, showing that this formulation is an alternative to single-unit oral dosing with enteric coating and with the advantage of reducing time to effect.

Analgesic effects of subarachnoidally administered hyperbaric opioids in horses.

OBJECTIVE: To evaluate the effects of subarachnoidally administered hyperbaric morphine, buprenorphine, and methadone on avoidance threshold to noxious electrical stimulation of the perineal, sacral, lumbar, and thoracic regions in horses. ANIMALS: 6 healthy adult horses. PROCEDURES: Horses were assigned to receive subarachnoid administration of hyperbaric morphine (0.01 mg/kg), buprenorphine (0.001 mg/kg), methadone (0.01 mg/kg), or 10% dextrose solution in equal volumes (5 mL). Electrical stimulation was applied every 10 minutes for 60 minutes and every 30 minutes for 120 minutes after subarachnoid injection over the dermatomes of the perineal, sacral, lumbar, and thoracic regions, and the avoidance threshold voltage was recorded. Heart and respiratory rate, blood gas tensions, serum electrolyte concentrations, and sedative effects were also evaluated. RESULTS: Administration of 10% dextrose solution did not change the avoidance threshold. Morphine and methadone significantly increased the avoidance threshold by 10 minutes after injection, which lasted until 120 minutes after subarachnoid administration in the perineal, sacral, lumbar, and thoracic regions. Profound analgesia (avoidance threshold > 40 V) was achieved in all regions. Buprenorphine also significantly increased the avoidance threshold by 10 minutes (36 V) after injection, which lasted 60 minutes and was considered moderate. Heart rate, blood pressure, respiratory rate, and blood gas tensions stayed within reference range. No ataxia, signs of sedation, or CNS excitement were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Subarachnoid administration of hyperbaric morphine or methadone produces intense analgesia for 120 minutes over the dermatomes of the perineal, sacral, lumbar, and thoracic areas without cardiorespiratory depression, ataxia, or CNS excitement in horses.

Analgesic effects of epidural administration of hydromorphone in horses.

OBJECTIVE: To evaluate the effects of epidural administration of hydromorphone on avoidance threshold to noxious electrical stimulation of the perineal, sacral, lumbar, and thoracic regions in horses. ANIMALS: 6 healthy adult horses. PROCEDURE: Horses were assigned to receive hydromorphone (0.04 mg/kg) or a control solution (20 mL of sterile water) administered epidurally into in the first intercoccygeal space. Treatments were administered at time intervals of > or = 7 days. Electrical stimulation was applied for 6 hours after epidural injection over the dermatomes of the perineal, sacral, lumbar, and thoracic regions, and the avoidance threshold voltage was recorded. RESULTS: Administration of sterile water did not change the avoidance threshold. Hydromorphone significantly increased the avoidance threshold by 20 minutes after injection, which lasted until 250 minutes after epidural administration in the perineal, sacral, lumbar, and thoracic regions. Profound analgesia (avoidance threshold > 40 V) was achieved only in the perineal region at 60 minutes after epidural administration of hydromorphone. Analgesia for all dermatomes was considered moderate for 250 minutes after epidural injection. CONCLUSIONS AND CLINICAL RELEVANCE: Epidural administration of hydromorphone increases the avoidance threshold to noxious electrical stimulation in the perineal, lumbar, sacral, and thoracic regions in horses for 250 minutes after injection. Hydromorphone epidural administration may prove useful in the management of horses with pain of moderate to mild intensity.

Epidural administration of tiletamine/zolazepam in horses.

OBJECTIVES: To evaluate the analgesic, physiologic, and behavioral effects of the epidural administration of tiletamine/zolazepam in horses. STUDY DESIGN: Prospective, double-blind, randomized experimental study. ANIMALS: Five adult, healthy horses aged 10-16 years and weighing (mean +/- SD) 400 +/- 98 kg. METHODS: The horses were sedated with 1.0 mg kg(-1) intravenous (IV) xylazine, and an epidural catheter was placed into the first intercoccygeal intervertebral space. After a 48-hour resting period, epidural tiletamine/zolazepam, 0.5 mg kg(-1) (treatment I) or 1.0 mg kg(-1) (treatment II), diluted up to 5 mL in sterile water, was administered with a 1-week interval between the treatments. Heart rate, respiratory rate, arterial blood pressure, and sedation were evaluated. In order to evaluate the respiratory effects, blood from the carotid artery was withdrawn at time 0 (baseline), and then after 60 and 240 minutes. Analgesia was evaluated by applying a noxious stimulus with blunt-tipped forceps on the perineal region, and graded as complete, moderate, or absent. Data were collected before tiletamine/zolazepam administration and at 15-minute intervals for 120 minutes, and 4 hours after tiletamine/zolazepam administration. Data were analyzed with anova and Bonferroni's test with p < 0.05. RESULTS: The results showed no significant difference between treatments in cardiovascular and respiratory measurements. Sedation was observed with both doses, and it was significantly different from baseline at 60, 75, and 90 minutes in treatment II. Moderate analgesia and locomotor ataxia were observed with both the treatments. CONCLUSIONS AND CLINICAL RELEVANCE: The results suggest that caudal epidural 0.5 and 1.0 mg kg(-1) tiletamine/zolazepam increases the threshold to pressure stimulation in the perineal region in horses. The use of epidural tiletamine/zolazepam could be indicated for short-term moderate epidural analgesia. There are no studies examining spinal toxicity of Telazol, and further studies are necessary before recommending clinical use of this technique.

Effects of epidural opioid analgesics on heart rate, arterial blood pressure, respiratory rate, body temperature, and behavior in horses.

Heart rate, arterial blood pressures, respiratory rate, body temperature, and central nervous system excitement were compared before and after epidural administration of morphine (0.1 mg/kg), butorphanol (0.08 mg/kg), alfentanil (0.02 mg/kg), tramadol (1.0 mg/kg), the k-opioid agonist U50488H (0.08 mg/kg), or sterile water using an incomplete Latin square crossover design in five conscious adult horses. Treatments were administered into the first intercoccygeal epidural space. Significant (P <.05) reductions in respiratory rate were detected after epidural administration of morphine, alfentanil, U50488H, and sterile water. Additionally, significant (P <.05) head ptosis was observed within the first hour after administration of morphine, U50488H, and tramadol, but neither of these changes appeared to be of clinical significance. No treatment-related changes in motor activity or behavior were observed.

Epidural anesthesia and analgesia in horses.

Intercoccygeal, or caudal, epidural injection of local anesthetics is a convenient method of producing analgesia and local anesthesia of the tail and perineal structures in conscious standing horses. This technique has been further developed to provide long duration analgesia and anesthesia by placement of catheters into the epidural space of horses. More recently, opioid, alpha-2 adrenergic agonists, ketamine and other analgesic agents have been administered by caudal epidural injection, providing pain relief in both conscious, standing and anesthetized, recumbent horses. This chapter describes the development of different anesthetic and analgesic epidural techniques in horses, methods for epidural injection and catheterization, and reviews the current literature related to epidural analgesia and pain control in horses.