Iohexol-based measurement of intestinal permeability in birds

Background: Iohexol has been successfully used as a marker to assess intestinal permeability in humans and various other mammals. The objective of this study was to evaluate the use of oral iohexol as an intestinal permeability marker in four anatomically and nutritionally diverse bird species. Methods: Three dosages (1 ml/kg, 2 ml/kg, 4 ml/kg) of iohexol (755 mg/ml) were administered orally to each six clinically healthy pigeons and chickens at two-week intervals. Iohexol plasma concentration was determined 45, 90 and 180 minutes after administration. A comparative study was performed by administering iohexol twice to each six clinically healthy cockatiels and falcons, and determining iohexol plasma concentration at 45 or 90 minutes after administration. Results: The recommended iohexol dosage for permeability testing in birds was determined to be 1 ml/kg. Median plasma iohexol concentrations were 27.77 µg/ml in pigeons, 12.97 µg/ml in chickens, 14.24 µg/ml in cockatiels, and 47.81 µg/ml in falcons, 45 minutes after this dosage was administered. At 90 minutes after administration, median plasma iohexol concentrations were 40.68 µg/ml in pigeons, 21.59 µg/ml in chickens, 32.03 µg/ml in cockatiels, and 55.96 µg/ml in falcons. Conclusions and clinical relevance: Oral iohexol was a safe and feasible marker for intestinal permeability assessment in birds. Further investigations are warranted to establish species-specific reference intervals in larger numbers of healthy birds, and to examine the use of iohexol as a permeability marker in birds with disorders associated with altered intestinal permeability.     

Comparison of 51chromium-labeled ethylenediamine tetra-acetic acid and iohexol as blood markers for intestinal permeability testing in Beagle dogs

(51)Chromium-labeled ethylenediamine tetra-acetic acid ((51)Cr-EDTA) is the gold standard probe for assessing intestinal permeability (IP) in dogs, but exposure to radioactivity is a disadvantage. Iohexol is a safe contrast medium commonly used for medical imaging purposes and has been successfully applied more recently for the assessment of IP in animal models and humans. This study aimed at comparing (51)Cr-EDTA and iohexol as IP blood markers in dogs. A test solution containing (51)Cr-EDTA and iohexol was administered intragastrically to seven healthy laboratory Beagle dogs, and percentage recoveries in serum were calculated. The strong linear association (correlation, r=0.76 and linear regression, y=0.03+5.04x) between (51)Cr-EDTA and iohexol supports the potential usefulness of iohexol as an IP blood marker in dogs.     

Evaluation of iohexol clearance used to estimate glomerular filtration rate in clinically normal foals

OBJECTIVE: To determine whether pharmacokinetic analysis of data derived from a single i.v. dose of iohexol could be used to predict creatinine clearance and evaluate simplified methods for predicting serum clearance of iohexol with data derived from 2 or 3 blood samples in clinically normal foals. ANIMALS: 10 healthy foals. PROCEDURE: Serum disposition of iohexol and exogenous creatinine clearance was determined simultaneously in each foal (5 males and 5 females). A 3-compartment model of iohexol serum disposition was selected via standard methods. Iohexol clearance calculated from the model was compared with creatinine clearance. Separate limited-sample models were created with various combinations of sample times from the terminal slope of the plasma versus time profile for iohexol. Correction factors were determined for the limited-sample models, and iohexol clearance calculated via each method was compared with exogenous creatinine clearance by use of method comparison techniques. RESULTS: Mean exogenous creatinine clearance was 2.17 mL/min/kg. The disposition of iohexol was best described by a 3-compartment open model. Mean clearance value for iohexol was 2.15 mL/min/kg and was not significantly different from mean creatinine clearance. A method for predicting serum iohexol clearance based on a 2-sample protocol (3- and 4-hour samples) was developed. CONCLUSIONS AND CLINICAL RELEVANCE: Iohexol clearance can be used to predict exogenous creatinine clearance and can be determined from 2 blood samples taken after i.v. injection of iohexol. Appropriate correction factors for adult horses and horses with abnormal glomerular filtration rate need to be determined.     

Lymphography of the thoracic duct by percutaneous injection of iohexol into the popliteal lymph node of dogs: experimental study and clinical application

OBJECTIVE: To evaluate the efficacy of percutaneous administration of iohexol into the popliteal lymph node as a non-invasive technique for thoracic duct lymphangiography in dogs. STUDY DESIGN: Experimental study and clinical report. ANIMALS: Normal adult dogs (n=4) and 1 dog with recurrent chylothorax. METHODS: For the experimental study, 4 dogs (weight, 8.4-12.3 kg) had 5-10 mL iohexol injected percutaneously into 1 popliteal lymph node and then thoracic radiographs were taken. Popliteal lymph nodes were examined by histopathology 8 days later. One 25-kg dog with recurrent chylothorax had 25 mL iohexol injected into the right popliteal lymph node followed by thoracic radiography. RESULTS: In experimental dogs, the thoracic duct was best visualized on thoracic radiographs after administration of 10 mL iohexol. Clinically, no abnormalities were identified in the injected limb and except for 1 dog that had large numbers of siderocytes and erythrophagocytic macrophages in the injected lymph node, the histopathologic findings in the other injected popliteal lymph nodes were not different from contralateral nodes. In the clinical case, the thoracic duct was visualized, but there was leakage of iohexol around the node. CONCLUSION: The thoracic duct in dogs can be visualized by lymphography after percutaneous injection of iohexol (1 mL/kg at 2 mL/min) into the popliteal lymph node. CLINICAL RELEVANCE: Percutaneous popliteal lymph node administration of iohexol should be considered as an alternative to mesenteric lymph node injection for radiographic identification of the thoracic duct in dogs.     

Intestinal permeability and function in dogs with small intestinal bacterial overgrowth

Small intestinal bacterial overgrowth (SIBO) has been reported to occur commonly in dogs with signs of chronic intestinal disease. There are usually few intestinal histological changes, and it is uncertain to what extent bacteria cause mucosal damage. The aim of this study was to apply a differential sugar absorption test for intestinal permeability and function to the objective assessment of intestinal damage in dogs with SIBO. Studies were performed on 63 dogs with signs of chronic small and, or, large bowel disease, in which SIBO (greater than 10⁵ total or greater than 10⁴ anaerobic colony forming units/ml) was diagnosed by quantitative culture of duodenal juice obtained endoscopically. None of the dogs had evidence of intestinal pathogens, parasites, systemic disease or pancreatic insufficiency. Differential sugar absorption was performed by determining the ratios of urinary recoveries of lactulose/rhamnose (L/R ratio, which reflects permeability) and D-xylose/3-O-methylglucose (X/G ratio, which reflects intestinal absorptive function) following oral administration. Dogs with SIBO comprised 28 different breeds, including 18 German shepherd dogs. SIBO was aerobic in 18/63 dogs (29 per cent), and anaerobic in 45/63 (71 per cent). Histological examination of duode-nal biopsies showed no abnormalities in 75 per cent, and mild to moderate lymphocytic infiltrates in 25 per cent of the dogs. The L/R ratio was increased (greater than 0–12) in 52 per cent, and the X/G ratio reduced (less than 0–60) in 33 per cent of the dogs. Differential sugar absorption was repeated in 11 dogs after their four weeks of oral antibiotic therapy. The L/R ratio declined in all 11 dogs (mean ± SD pre: 0–24 ± 0–14; post: 0–16 ± 0–11; P<0–05), but changes in the X/G ratio were more variable. These findings show that SIBO is commonly associated with mucosal damage, not detected on histological examination of intestinal biopsies, and that changes in intestinal permeability following oral antibiotics may be used to monitor response to treatment.     

Subarachnoid pressures and cardiorespiratory parameters during cisternal myelography in isoflurane anaesthetized dogs

ObjectiveTo measure subarachnoid pressures, systemic circulatory and respiratory effects, and to calculate cerebral perfusion pressure during cisternal myelography.Study designProspective clinical study.AnimalsForty‐three client owned dogs with clinical signs of spinal disease, weighing 6–56 kg.MethodsDogs were premedicated with butorphanol and diazepam intravenously (IV) and anaesthesia was induced with propofol and maintained with isoflurane vaporized in oxygen. Ventilation was spontaneous. Heart and respiratory rates, invasive mean arterial blood pressure (MAP), end tidal carbon dioxide and isoflurane concentration were measured continuously. Initial subarachnoid pressure (SaP₀) was measured in the cisterna magna with a needle pressure gauge. Iohexol 0.3 mL kg^?1 was injected at a rate of 4.1 mL minute^?1 into the cerebellomedullary cistern. The SaP was recorded during and at 120 seconds after contrast administration. The maximum SaP (SaP_max) and minimum calculated cerebral perfusion pressure (CPP_min) were recorded for each case.ResultsPrior to contrast injection, mean ± SD, MAP was 73 ± 20 mmHg and SaP₀ was 10 ± 3 mmHg. The cerebral perfusion pressure (CPP) was 64 ± 20 mmHg. The contrast injection increased the SaP₀ to 73 ± 33 mmHg (SaP_max). After injection, MAP increased to 97 ± 25 mmHg and the CPP decreased to 14 ± 34 mmHg. A negative correlation was found between the lowest CPP and body weight (ρ = ?0.77, p < 0.0001). Nine dogs had bradycardia, apnoea and hypertension, 21 dogs had at least one of these signs. The number of clinical signs showed significant correlation with body weight (ρ = ?0.68, p < 0.0001), SaP_max (ρ = ?0.66, p < 0.0001) and CPP_min (ρ = ?0.73, p < 0.0001).Conclusions and clinical relevanceCerebral perfusion can severely decrease during cisternal myelography using the standard dose of iohexol. Bradycardia, apnoea and systemic hypertension were associated with decreased CPP.     

Risk factors associated with development of seizures after use of iohexol for myelography in dogs: 182 cases (1998)

OBJECTIVE: To determine prevalence of seizures after use of iohexol for myelography and identify associated risk factors in dogs. DESIGN: Retrospective study. ANIMALS: 182 dogs that received iohexol for myelography in 1998. PROCEDURE: Medical records were reviewed for age, breed, sex, weight, dose and total volume of iohexol, injection site, number of injections, lesion type and location, total duration of anesthesia, duration from time of iohexol injection to recovery, presence and number of seizures, and whether surgery followed the myelogram. RESULTS: 39 (21.4%) dogs had at least 1 generalized seizure during or after myelography. Injection site was strongly associated with prevalence of seizures, and risk of seizure was significantly higher after cerebellomedullary injections, compared with lumbar injections. Mean total volume of iohexol administered to dogs that had seizures was significantly higher, compared with that administered to dogs that did not have seizures, although dosage did not differ between groups. Weight was significantly correlated with risk of seizure, and dogs that weighed > 20 kg (44 lb) had higher prevalence of seizures than dogs that weighed < 20 kg. CONCLUSIONS AND CLINICAL RELEVANCE: It is preferential to administer iohexol via the L5-6 intervertebral space to minimize the risk of seizures. Higher prevalence of seizures in large dogs, compared with smaller dogs, may be caused by administration of larger total volumes of contrast agent per volume of CSF.     

Pharmacokinetics of cyclophosphamide after oral and intravenous administration to dogs with lymphoma

Background: Cyclophosphamide is an alkylating chemotherapeutic drug administered IV or PO. It is currently assumed that exposure to the active metabolite, 4‐hydroxycyclophosphamide (4‐OHCP), is the same with either route of administration.

Objectives:

To characterize the pharmacokinetics of cyclophosphamide and 4‐OHCP in dogs with lymphoma when administered PO or IV. Animals: Sixteen client‐owned dogs with substage A lymphoma were enrolled in the study. Eight dogs received cyclophosphamide IV and 8 received it PO. Methods: Prospective randomized clinical trial was performed. Blood was collected from each dog at specific time points after administration of cyclophosphamide. The serum was evaluated for the concentration of cyclophosphamide and 4‐OHCP with mass spectrometry and liquid chromatography. Results: Drug exposure to cyclophosphamide measured by area under the curve (AUC)_0–inf is significantly higher after intravenous administration (7.14 ± 3.77 μg/h/mL) compared with exposure after oral administration (P‐value < .05). No difference in drug exposure to 4‐OHCP was detected after IV (1.66 ± 0.36 μg/h/mL) or PO (1.42 ± 0.64 μg/h/mL) administered cyclophosphamide. Conclusions and Clinical Importance: Drug exposure to the active metabolite 4‐OHCP is equivalent after administration of cyclophosphamide either PO or IV.     

Application of the 51Cr-EDTA urinary recovery test for assessment of intestinal permeability in the horse

Altered intestinal permeability is implicated in the pathogenesis of diverse equine medical conditions including alimentary laminitis and protein-losing enteropathies associated with parasitic infection. The aims of this study were to assess the feasibility of applying the 51Cr-EDTA absorption test for the assessment of intestinal permeability in the horse, and to apply this test in horses with experimentally induced alterations in gastrointestinal function. Four healthy ponies were administered 36 MBq of 51Cr-EDTA via naso-gastric tube, and urine samples were collected into polythene bags strapped to the pony's abdomen. Total urine voided every 6 h was collected during each test, and 1 ml samples were taken for measurement of gamma-radiation. Urinary recovery of 51Cr-EDTA was measured following intravenous atropine sulphate or bethanecol, and following 22 and 46 days of administration of 250,000 third-stage cyathostome larvae. There was no significant difference in urinary 51Cr-EDTA recovery following the control treatment, and following atropine or bethanecol administration, but significant increases were detected in the animals with experimental cyathostome infection consistent with increased permeability of the intestinal membrane. Motility modifying agents (bethanecol and atropine) did not affect absorption of 51Cr-EDTA, suggesting that subtle changes in motility might not affect the ability of this test to detect altered intestinal permeability. The finding of increased urinary recovery of 51Cr-EDTA in ponies with cyathostome infection suggests that 51Cr-EDTA may be a useful marker for assessment of intestinal permeability in the horse.     

Assessment of changes in blood volume in response to resuscitative fluid administration in dogs

Objective: To determine the continuous changes in blood volume in response to fluid administration using an in‐line hematocrit monitor. Design: Prospective study. Setting: Research laboratory. Animals: Four healthy dogs. Interventions: Each dog received intravenous boluses of 80 mL/kg of 0.9% saline (S), 4 mL/kg of 7.5% saline (HS), 20 mL/kg of dextran 70 (D), 20 mL/kg of hetastarch (HES), or no fluids (control, C) on separate occasions. Fluids were administered at 150 mL/min in the S, D, and HES groups, and at 1 mL/kg/min in the HS group. Measurements and main results: Blood volume changes were measured every 20 seconds for 240 minutes using an in‐line hematocrit monitor. There was a rapid rise in blood volume during all infusions. Immediately after the administration of crystalloid fluids, the rapid rise in blood volume ceased. Subsequently, there was a steep decline in blood volume for 10 minutes, and a slower decline thereafter. In contrast, the rise in blood volume continued for at least 10 minutes after the infusion of the colloids was complete, and a plateau was observed for the remainder of the experiment. The blood volume effect, as measured by area under the curve, was significantly greater in the saline group than the other groups during the infusion time and for the 0–240 minutes time period. The areas under the curve for the two colloid solutions were not significantly different from each other during any time periods. The percent increase in blood volume immediately following the infusions was 76.4±10.0 in the S group, 17.1±3.2 in the HS group, 23.0±10.5 in the D group, and 27.2±6.4 in the HES group. At 30 minutes from the start of the infusion, the mean percent increases in blood volumes were 35.2±9.3 in the S group, 12.3±0.9 in the HS group, 35.9±7.3 in the D group, and 36.8±6.5 in the HES group. At 240 h post‐infusion, the mean percent increases in blood volume were 18.0±9.7 in the S group, 2.9±6.1 in the HS group, 25.6±16.1 in the D group, and 26.6±8.6 in the HES group. The C group had a mean percent change in blood volume of ?3.7±3.4 at the end of the experiment. Conclusions: This study indicates that the rapid administration of saline at clinically relevant doses leads to the largest immediate increase in blood volume, although this change is transient because of rapid redistribution of the fluid. Despite a brief increase in blood volume that was almost 3 times the volume administered, hypertonic saline led to the smallest increase in blood volume post‐infusion. The synthetic colloid solutions increased the blood volume by an amount greater than that infused and the effect was sustained for a longer period of time than seen following crystalloid administration, but the maximum increase in blood volume was significantly less than saline. The measurement of continuous changes in blood volume, using an in‐line hematocrit monitor, was a useful means of assessing the dynamic effects of fluid administration in dogs in a research setting.     

Sustained strenuous exercise increases intestinal permeability in racing Alaskan sled dogs

We assessed gastric and intestinal permeability and performed gastroscopy to evaluate the effects of sustained strenuous exercise on the gastrointestinal tract in racing sled dogs. Three teams of racing Alaskan sled dogs were examined approximately 1 week before and 24 hours after the 2003 Iditarod sled dog race (1,100 miles in 10 days). Each examination consisted of the administration of a solution of sucrose, lactulose, and rhamnose to evaluate gastric and intestinal permeability, as well as gastroscopy to visually inspect the gastric mucosa. Of the 54 dogs examined before the race, 16 completed the course and contributed data to the analysis. Sustained strenuous exercise was associated with an increased frequency of gastric erosions or ulcerations seen endoscopically (0% prerace versus 61% postrace). A significant postrace increase occurred in the median lactulose to rhamnose ratio in both serum and urine (0.11 versus 0.165, P = .0363; 0.11 versus 0.165, P = .0090, respectively). No significant differences were found in median serum or urinary sucrose concentrations when pre- and postrace values were compared. No correlation was found between visible gastric lesions and the concentration of sucrose in serum or urine samples obtained 4-5 hours after administration of the sugar solutions. We conclude that sustained strenuous exercise is associated with increased intestinal permeability, but the sucrose permeability test as we performed it did not correlate with visible gastric lesions.     

Evaluation of intestinal permeability and gluten sensitivity in Soft-Coated Wheaten Terriers with familial protein-losing enteropathy, protein-losing nephropathy, or both

OBJECTIVE: To evaluate intestinal permeability and gluten sensitivity in a family of Soft-Coated Wheaten Terriers (SCWT) affected with protein-losing enteropathy (PLE), protein-losing nephropathy (PLN), or both. ANIMALS: 6 affected adult dogs. PROCEDURE: Intestinal biopsy specimens, urine protein-to-creatinine ratio, serum concentrations of albumin and globulin, and concentration of alpha1-protease inhibitor in feces were evaluated before, during, and 13 weeks after daily administration of 10 g of gluten for 7 weeks. Eosinophils and lymphocytes-plasmacytes were enumerated in intestinal biopsy specimens. Intestinal permeability was evaluated before and during the sixth week of gluten administration via cellobiose-mannitol and chromium-EDTA absorption tests. RESULTS: Serum globulin concentration decreased significantly after prolonged administration of gluten. Although not significant, there was an increase in lymphocytes-plasmacytes and a decrease in eosinophils in intestinal biopsy specimens. Furthermore, these counts were greater than those reported for clinically normal dogs. Gluten administration did not increase intestinal permeability. CONCLUSIONS AND CLINICAL RELEVANCE: Daily administration of gluten was associated with a significant decrease in serum globulin concentration in SCWT affected with PLE or PLN, but other variables remained unchanged. Although enhanced wheat-gluten sensitivity may be one factor involved in the pathogenesis of PLE or PLN in SCWT, this syndrome does not appear to be the result of a specific sensitivity to gluten.     

EVALUATION OF IOHEXOL AS A GASTROINTESTINAL CONTRAST MEDIUM IN NORMAL CATS

The non-ionic, iodinated contrast medium, iohexol (240 mg I/ml) was evaluated as a gastrointestinal (GI) contrast medium in cats. Iohexol, both undiluted and diluted with tap water, was administered via a percutaneous endoscopically-placed gastrotomy (PEG) tube to 4 mature clinically normal cats. The dilution of contrast medium administered was 1:1, 1:2, and 1:3, and doses were 10 ml/kg and 5 ml/kg body weight. All combinations of dilution and dose of iohexol provided adequate visualization of the contrast medium column within the GI tract, and results were not significantly different than those observed using 30% w/v barium sulfate. Dehydration and diarrhea were not observed after contrast medium administration, but vomiting occurred within 15–30 minutes after administration of undiluted iohexol in all experimental cats. Renal opacification did not occur on exposures made through a 2 hour period, and dilution in transit was not apparent.     

Validation of a species-optimized enzyme-linked immunosorbent assay for determination of serum concentrations of insulin in dogs

Background: Measurement of canine serum insulin has relied on methods developed to measure human insulin. A species‐optimized test for measurement of serum insulin in dogs is now commercially available. Objective: The purpose of this study was to validate the canine ELISA for determination of serum insulin concentration in dogs. Methods: Precision was determined by evaluating intra‐ and interassay coefficient of variation (CV), and accuracy was determined by dilution and spike recovery studies. A method comparison study with samples from 34 clinically healthy dogs and 73 dogs examined for various illnesses and disorders (“patients”) was performed using the canine ELISA and an ELISA for human insulin. Biologic relevance of the canine assay was evaluated by measuring insulin in samples collected from 8 healthy dogs after administration of glucagon. A stability study was preformed with 6 samples stored at 20°C, 4–8°C, and ?20°C. Results: For the canine ELISA, intra‐ and interassay CVs were 4.3–7.8% and 4.4–7.7%, respectively. Mean recovery after dilution was 99% and recovery after spiking with porcine insulin was 116%. The canine and human ELISAs correlated well (r²=.94 for healthy dogs, r²=.88 for patient samples). After glucagon injection serum insulin concentrations increased significantly in 8 dogs. Insulin was stable for 30 days in 6 serum samples stored at ?20°C and in most samples for 8 days at 4–8°C. Insulin was stable for <3 days at room temperature (20°C). Conclusions: The new canine serum insulin ELISA had good precision and accuracy and correlated well with the previously used assay.     

Measurement of intestinal mucosal permeability in dogs with lymphocytic-plasmacytic enteritis

Lymphocytic-plasmacytic enteritis (LPE) is a type of canine inflammatory bowel disease (IBD). One of its most probable causes is a defect in the mucosal permeability barrier. In the present study, intestinal permeability in LPE dogs was examinated to evaluate its clinical value. Twenty-nine dogs with LPE diagnosed by clinical and histological examinations were included in this study. Intestinal permeability was evaluated by measuring the ratio of the concentrations of two sugars (lactulose (L) and rhamnose (R)) with different molecular weights in urine samples after oral administration of a solution containing them. Biopsy specimens of duodenum were evaluated according to histological criteria. The urinary L:R ratio in the 29 LPE dogs (1.68 +/- 1.17, mean +/- SD) was significantly higher than that in the 10 healthy control dogs (0.75 +/- 0.38, P<0.01). In the LPE dogs, a weak correlation was observed between the histopathological grading score of the duodenum and the urinary L:R ratio (r=0.408, P<0.05). The urinary L:R ratio in the 20 dogs showing hypoalbuminemia (< 2.5 g/dl) was significantly higher than that in the 9 dogs with normal serum albumin levels > 2.5 g/dl (P<0.01). In conclusion, permeability of the intestinal mucosa as determined by the urinary L:R ratio could be a useful laboratory parameter for evaluating intestinal damage in LPE dogs.     

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean ± SD): AUC_(0–∞) 4.20 ± 1.66 μg·h/mL; C_max 6.64 ± 1.38 μg/mL; V_z 4.80 ± 0.91 L/kg; Cl_t 2.64 ± 0.84 L/h·kg; t_½λ 1.35 ± 0.40 h and MRT 1.50 ± 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean ± SD): C_max, 0.30 ± 0.17 and 0.17 ± 0.09 μg/mL; t_max, 1.75 ± 0.76 and 0.69 ± 0.30 h; t_½λ, 2.92 ± 0.79 and 1.53 ± 1.28 h and MRT, 5.10 ± 1.12 and 2.56 ± 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC₉₀ = 0.5 μg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.     

Intra‐articular administration of lidocaine in anaesthetized dogs: pharmacokinetic profile and safety on cardiovascular and nervous systems

The intra‐articular administration of lidocaine is a frequent practice in human orthopaedic surgical procedures, but an eventual absorption of the drug into the bloodstream can lead to toxicity, mainly concerning the central nervous system and the cardiovascular systems. The purpose of this study was to determine the pharmacokinetic profile and the safety, in terms of cardiovascular and CNS toxicity, of lidocaine after intra‐articular administration to anesthetized dogs undergoing arthroscopy. Lidocaine 2% was administered to eight dogs before surgery in differing amounts, depending on the volume of the joints involved, and blood samples were taken at predetermined time points. The maximum serum concentration of lidocaine ranged from 0.50 to 3.01 μg/mL (mean ± SD: 2.18 ± 0.91 μg/mL), and the time to reach it was 28.75 ± 15.74 min. No signs of cardiac toxicity were detected during the entire procedure, and possible signs of CNS toxicity were masked by the anaesthesia. However, concentrations reported in literature as responsible for neurotoxicity in dog were achieved in three of eight investigated subjects. Pending further studies, veterinarians should consider the possibility of side effects occurring following the intra‐articular administration of local anaesthetics.     

Clinical Evaluation of a Novel Liquid Formulation of L-Thyroxine for Once Daily Treatment of Dogs with Hypothyroidism

Background: A liquid solution of levothyroxine (L-T4) is available for treatment of canine hypothyroidism.
Hypothesis: Once daily oral administration of a liquid L-T4 solution is effective and safe for controlling hypothyroidism in dogs.
Animals: Thirty-five dogs with naturally occurring hypothyroidism.
Methods: Dogs received L-T4 solution PO once daily at a starting dosage of 20 μg/kg body weight (BW). The dose was adjusted every 4 weeks, based on clinical signs and peak serum total T4 (tT4) concentrations. Target peak serum tT4 and thyroid stimulating hormone (TSH) concentrations, 4–6 hours posttreatment, were 35–95 nmol/L and < 0.68 ng/mL, respectively. Dogs were followed for up to 22 weeks after establishment of the maintenance dose.
Results: Clinical signs of hypothyroidism improved or resolved in 91% of dogs after 4 weeks of L-T4 treatment at 20 μg/kg once daily. The maintenance dose was established in 76, 94, and 100% of dogs after 4, 8, and 12 weeks of treatment, respectively. This was 20 μg L-T4/kg BW for 79% of the dogs, 30 μg/kg BW for 15%, and 10–15 μg/kg BW in the remaining 6%, once daily. Thereafter, median peak tT4 and TSH concentrations were 51 nmol/L and 0.18 ng/mL, respectively, and remained stable during the 22-week follow-up; clinical signs did not recur.
Conclusions and Clinical Importance: All of the hypothyroid dogs had rapid clinical and hormonal responses to supplementation with the PO-administered L-T4 solution. The starting dosage of 20 μg L-T4/kg BW once daily was suitable for 79% of dogs.     

Absorption kinetics and bioavailability of cephalexin in the dog after oral and intramuscular administration

The pharmacokinetics of cephalexin, a first generation cephalosporin, were investigated in dogs using two formulations marketed for humans, but also often employed by practitioners for pet therapy. Cephalexin was administered to five dogs intravenously and intramuscularly as a sodium salt and by the oral route as a monohydrate. The dosage was always 20 mg/kg of active ingredient. A microbiological assay with Sarcina lutea as the test organism was adopted to measure cephalexin concentrations in serum. The mean residence time (MRT) median values after intravenous (i.v.), intramuscular (i.m.) and oral administration (p.o.) were 86 min, 200 min, and 279 min, respectively. After i.m. and oral dosing the peak serum concentrations (24.2 +/- 1.8 micrograms/mL and 20.3 +/- 1.7 micrograms/mL, respectively) were attained at 90 min in all dogs and bioavailabilities were 63 +/- 10% and 57 +/- 5%, respectively. The time course of the cephalexin serum concentrations after oral administration was best described by a model incorporating saturable absorption kinetics of the Michaelis-Menten type: thus in the gastrointestinal tract of dogs a carrier mediated transport for cephalexin similar to that reported in humans, may exist. The predicted average serum concentrations of cephalexin after repeated i.m. and oral administration indicated that, in order to maintain the therapeutic concentrations, the 20 mg/kg b.w. dosage should be administered every 6-8 h.     

Plasma and serum concentrations of cytarabine administered via continuous intravenous infusion to dogs with meningoencephalomyelitis of unknown etiology

The objective of this study was to evaluate the plasma and serum concentrations of cytarabine (CA) administered via constant rate infusion (CRI) in dogs with meningoencephalomyelitis of unknown etiology (MUE). Nineteen client‐owned dogs received a CRI of CA at a dose of 25 mg/m²/h for 8 h as treatment for MUE. Dogs were divided into four groups, those receiving CA alone and those receiving CA in conjunction with other drugs. Blood samples were collected at 0, 1, 8, and 12 h after initiating the CRI. Plasma (n = 13) and serum (n = 11) cytarabine concentrations were measured by high‐pressure liquid chromatography. The mean peak concentration (C_MAX) and area under the curve (AUC) after CRI administration were 1.70 ± 0.66 μg/mL and 11.39 ± 3.37 h·μg/mL, respectively, for dogs receiving cytarabine alone, 2.36 ± 0.35 μg/mL and 16.91 + 3.60 h·μg/mL for dogs administered cytarabine and concurrently on other drugs. Mean concentrations for all dogs were above 1.0 μg/mL at both the 1‐ and 8‐h time points. The steady‐state achieved with cytarabine CRI produces a consistent and prolonged exposure in plasma and serum, which is likely to produce equilibrium between blood and the central nervous system in dogs with a clinical diagnosis of MUE. Other medications commonly used to treat MUE do not appear to alter CA concentrations in serum and plasma.