Safety evaluation of combination CCNU and continuous toceranib phosphate (Palladia®) in tumour‐bearing dogs: a phase I dose‐finding study

While maintaining a standard toceranib dosage [2.75 mg kg^?1, PO, every other day (EOD)], three dose‐escalating CCNU cohorts up to and including 60 mg m^?2, PO, q3wk, were completed. The dose‐limiting toxicities (DLT) for the combination were neutropenia and the maximum tolerated dose (MTD) for CCNU when given with continuous toceranib was determined to be 50 mg m^?2, q3wk. While activity is not a primary objective of phase I trials, we observed one complete (lymphoma) and four partial responses (lymphoma, sarcoma, undifferentiated carcinoma and prostatic carcinoma) and two dogs experienced stable disease for >6 weeks [gastric adenocarcinoma and metastatic multilobulated osteochondrosarcoma (MLO)] for an objective response rate of 38.4% and a biological response rate of 53.8%. Concurrent continuous toceranib (2.75 mg kg^?1, EOD) and pulse dose CCNU (50 mg m^?2, q3wk) was well tolerated. Phase II effectiveness and phase III prospective randomized trials should further interrogate the potential activity of this combination.     

Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour‐bearing dogs: A phase I dose finding study

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low‐dose metronomic and/or anti‐angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose‐finding clinical trial assumed an open‐label 3 + 3 cohort design. Client‐owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg^?1 by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m^?2. A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m^?2. AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG‐CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose‐limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m^?2 IV every 21 days and approximately 2.75 mg kg^?1 PO EOD, respectively. The dose‐limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well‐tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials.     

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia®) in tumour bearing dogs: a phase I dose‐finding study

Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single‐agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose‐finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg^?1 by mouth every other day (PO EOD) while escalating DOX dosage. The dose‐limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m^?2 of DOX q 21 days given concurrently with toceranib 2.75 mg kg^?1 PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti‐tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long‐term AE profiles.     

Evaluation of dexamethasone as a chemoprotectant for CCNU‐induced bone marrow suppression in dogs*

In mice and people, administering corticosteroids before chemotherapy can reduce the severity of myelosuppression without reducing antitumour effects. This study investigated whether pretreatment with dexamethasone would reduce the incidence of grade 4 neutropenia in dogs receiving CCNU. Twenty‐five dogs received dexamethasone [0.1 mg kg^?1 per os (PO) every 12 h] for 5 days and on the sixth day received CCNU (90 mg m^?2 PO). Historical dogs (n = 67) received CCNU alone (90 mg m^?2 PO). Forty‐five percent of historical dogs had grade 4 neutropenia, while 64% of dogs pretreated with dexamethasone had grade 4 neutropenia (P = 0.16). Dexamethasone plasma levels were quantified by enzyme‐linked immunosorbent assay in three healthy dogs. Peak plasma concentrations after a single oral 0.1‐mg kg^?1 dose were <80 ng mL^?1, the minimum level associated with chemoprotective effects of dexamethasone in people. Pretreatment with dexamethasone did not reduce the incidence of grade 4 neutropenia in dogs receiving CCNU.     

Pharmacokinetics and toxicity of the novel oral demethylating agent zebularine in laboratory and tumor bearing dogs

The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC‐MS/MS following an oral zebularine dose of 8 or 4 mg kg^?1. Plasma zebularine clearance was constant. Mean maximum concentration (C_max) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg^?1, respectively. Mean half‐life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg^?1, respectively. A single 8 mg kg^?1 dose was well tolerated. Daily 4 mg kg^?1 treatment in three laboratory dogs resulted in grade 4 neutropenia (n = 3), grade 1 anorexia (n = 2) and grade 1 or 2 dermatologic changes (n = 2). All adverse events resolved with supportive care. A 4 mg kg^?1 dose every 21 days was well tolerated. A follow‐up dose escalation study is in progress with a lower starting dose.     

Phase I Dose Escalation of Single‐Agent Vinblastine in Dogs

Background: Vinblastine (VBL) is commonly used in dogs at a dosage of 2.0 mg/m². The minimal toxicity observed at this dosage indicates that higher dosages might be well tolerated. Hypothesis: The maximum tolerated dosage (MTD) for a single VBL treatment is higher than the previously published dosage of 2.0 mg/m². Animals: Twenty‐three dogs with lymphoma or cutaneous mast cell tumors. Methods: Dogs received 1 single‐agent VBL treatment IV. The starting dosage was 3.0 mg/m², and dosages were increased in increments of 0.5 mg/m² in cohorts of 3 dogs. Hematologic toxicity was assessed with weekly CBCs. Gastrointestinal toxicity was assessed from medical histories from owners. Once the MTD was determined, additional dogs were treated with VBL at that dosage. Dogs whose cancers responded to VBL continued to receive treatments q2–3 weeks. Results: VBL dosages ranged from 3.0 to 4.0 mg/m². Neutropenia was the dose‐limiting toxicity, with the nadir identified 7 days after treatment and resolving by 14 days after treatment. The MTD was 3.5 mg/m². Sixteen dogs were treated at this dosage, and 3 experienced severe toxicity characterized by asymptomatic grade 4 neutropenia, febrile grade 4 neutropenia, and death. Gastrointestinal toxicity was mild and self‐limiting. Preliminary evidence of antitumor activity was identified in 2 of 12 dogs with lymphoma treated at the MTD. Conclusions and Clinical Importance: In dogs, single‐agent VBL is well tolerated at a dosage of 3.5 mg/m² IV. At this dosage, the minimum safe treatment interval is q2 weeks, and adjunct treatment with prophylactic antibiotics should be considered.     

Phase II study of oral docetaxel and cyclosporine in canine epithelial cancer

The goal of the current study was to determine the efficacy of oral docetaxel in combination with cyclosporine in the treatment of canine epithelial cancer. Requirements for eligibility were histological confirmation of epithelial neoplasia, measurable disease, no chemotherapy treatment within 2 weeks, and a life expectancy of ≥3 months. Fifty‐one dogs were enrolled. All dogs received 1.625 mg kg^?1 of docetaxel with 5 mg kg^?1 of cyclosporine (DT/CSA) by gavage. Ten dogs had progressive disease at 2 weeks, one dog died, and one dog was withdrawn from the study. Thirty‐nine dogs were given a second dose of DT/CSA, three each receiving a third or fourth dose. Eight dogs had a dose reduction (1.5 mg kg^?1) and six dogs had treatment delays primarily for gastrointestinal toxicity. The overall response rate was 16.7% (8/48 had a partial response there were no complete responses). The highest response rate was seen in dogs with oral squamous cell carcinoma (50%; 6/12).     

Phase II open‐label study of single‐agent hydroxyurea for treatment of mast cell tumours in dogs*

This prospective study evaluated the efficacy and safety of hydroxyurea (HU) in dogs with measurable mast cell tumours (MCTs). Dogs were treated with HU at 60 mg kg^?1per os q24h for 14 days then 30 mg kg^?1 q24h thereafter or until MCT recurrence. Forty‐six dogs were enrolled. The overall response rate was 28%. Two dogs had a complete response (CR) for 256 and 448 days, respectively. Eleven dogs had a partial response for a median duration of 46 days (range, 28–189 days). Grade 2 to 4 neutropenia occurred in eight dogs and grade 4 thrombocytopenia in two. Grade 3–4 anaemia occurred in seven dogs; overall, there was a significant decrease in haematocrit after treatment with HU. The median drop in haematocrit was 10%. This study demonstrated that HU has activity in the treatment of MCTs with mild anaemia being the primary adverse event.     

Tolerability and pharmacokinetic profile of a novel benzene‐poly‐carboxylic acids complex with cis‐diammineplatinum (II) dichloride in dogs with malignant mammary tumours

The pharmacokinetic profile, tolerability and efficacy of benzene‐poly‐carboxylic acids complex with cis‐diammineplatinum (II) dichloride (BP‐C1) were studied in dogs with mammary cancer. A three‐level response surface pathway designed trial was performed on seven dogs. At each level BP‐C1 was administered subcutaneously daily for 7 days followed by a 7‐day rest period in a dose escalating manner. Adverse events according to VCOG‐CTCAE, performance status and tumour progression were recorded. The pharmacokinetic profile followed a two‐compartment model with rapid absorption, short distribution, and a slow elimination phase. The overall elimination half‐life was 125 h. The maximum tolerated dose of BP‐C1 was estimated to be above 0.46 mg kg^?1. A significant reduction in VCOG‐CTCAE toxicity which correlated negatively with increasing dose was found. The dogs' general performance status remained unchanged. No decrease in total tumour burden was found, although temporary tumour reduction was seen in some target tumours.     

Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma

Background

Idarubicin, a PO bioavailable anthracycline antibiotic‐class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery.

Objectives

The primary objective of this study was to determine the maximally tolerated dose (MTD), dose‐limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD.

Animals

Client‐owned dogs with measurable lymphoma.

Methods

Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines.

Results

The MTD in dogs > 15 kg body weight was 22 mg/m². Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol.

Conclusions and Clinical Importance

PO administered idarubicin was generally well‐tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated‐dose, randomized clinical trials.     

Romifidine and low doses of tiletamine‐zolazepam in dogs

ObjectiveTo evaluate clinical effects of romifidine and low doses of tiletamine‐zolazepam (TZ) in dogs.Study designRandomized “blinded” cross‐over study.AnimalsSix healthy beagle dogs (two males, four females).MethodsIn separate preliminary experiments dogs received intravenous (IV) tiletamine‐zolazepam (TZ) at 1 and 2 mg kg^?1. For the main trial, dogs received romifidine (R) followed 5 minutes later by IV at six dose regimens: R40TZ1, R60TZ1, R80TZ1 (Romifidine at 40, 60, 80 μg kg^?1 and TZ at 1 mg kg^?1), R40TZ2, R60TZ2 and R80TZ2 (Romifidine at 40, 60, 80 μg kg^?1 and TZ at 2 mg kg^?1). Dogs underwent endotracheal intubation, but breathed room air. Cardiorespiratory variables were measured and arterial blood analyzed. Quality of sedation, duration of anaesthesia and time to recovery (TR) were recorded. Data were analysed by anova or Friedman test as relevant.ResultsEndotracheal intubation was possible with all romifidine/TZ combinations but not with TZ alone. Mean times (minutes) from TZ injection to return of pedal reflex were 1–3 minutes for TZ alone, and 9–17 minutes for romifidine combinations. In the main trial (romifidine combinations) mean time (minutes) to standing increased with increasing dosage (R40TZ1 13; R80TZ2 32). Five minutes after TZ administration, when compared with baseline arterial blood pressures and arterial carbon dioxide had increased, and respiratory rate, pH and arterial oxygen tensions decreased, these changes becoming statistically significant with the higher dose rates. One dog in R60TZ2 and three dogs in R80TZ2 became hypoxaemic.Conclusions and clinical relevanceRomifidine improves the quality and lengthens the duration of anaesthesia induced by TZ. The combination provides a suitable protocol for induction of or short‐term anaesthesia in healthy dogs. However, the higher doses cause cardiovascular stimulation and respiratory depression, and precautions should be taken accordingly.     

The clinical use of the neuromuscular blocking agent rocuronium in dogs

Objective The aim of this study was to characterize the onset and duration of action of the aminosteroid muscle relaxant rocuronium in dogs under clinical conditions. Study design Prospective single dose trial. Animals Twenty‐three dogs aged between 6 months and 12 years, weighing between 5.5 and 61.5 kg admitted to the University of Liverpool Small Animal Hospital between January and March 2000, and undergoing elective surgical procedures under general anaesthesia. Materials and methods Following induction of general anaesthesia, neuromuscular function was evaluated using train‐of‐four (TOF) stimulation. An initial dose of 0.4 mg kg^?1 rocuronium was administered intravenously (IV) and neuromuscular blockade was monitored by visually assessing the number of responses (twitches) to TOF stimulation (train‐of‐four count: TOFC). Incremental doses of 0.16 mg kg^?1 rocuronium were administered as indicated, when at least two twitches of the TOFC had returned. Results Rocuronium (0.4 mg kg^?1) abolished all responses to TOF stimulation in all dogs. The mean time to onset of neuromuscular blockade (complete abolition of all twitches) was 98 ± 52 seconds. Neuromuscular blockade (absence of all twitches to return of all four) lasted 32.3 ± 8.2 minutes. Incremental doses of 0.16 mg kg^?1 had a mean duration of action of 20.8 ± 4.9 minutes and up to seven increments were shown to be noncumulative. The effects of rocuronium were readily antagonized with neostigmine and atropine. Small transient increases in arterial blood pressure, which occurred in three dogs after the administration of rocuronium, were the only cardiovascular side‐effects observed. Conclusions Rocuronium is an effective nondepolarizing neuromuscular blocking agent in the dog, with a rapid onset of neuromuscular block after intravenous administration and an intermediate duration of action. Clinical relevance Rocuronium produced a neuromuscular block with similar characteristics to those obtained with vecuronium, thus apparently offering little advantage over vecuronium. However, its availability in aqueous solution and a longer shelf‐life increases convenience.     

A phase II study to evaluate the toxicity and efficacy of alternating CCNU and high‐dose vinblastine and prednisone (CVP) for treatment of dogs with high‐grade,metastatic or nonresectable mast cell tumours

Safety and efficacy of a protocol of alternating 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU; 70 mg m^?2) and vinblastine (3.5 mg m^?2), and prednisone (1–2 mg kg^?1; CVP) in dogs with mast cell tumours (MCT) were evaluated. A total of 17 dogs had nonresectable MCTs and 35 received CVP as adjunctive treatment to locoregional control of metastatic MCTs or grade III MCTs. Neutropenia with fever occurred in 8% of dogs after treatment with vinblastine and in 2% after treatment with CCNU. Persistent elevation of serum alanine transaminase, suggestive of hepatotoxicity, occurred in 9% of the dogs. Response rate in dogs with nonresectable MCTs was 65%; five achieved a complete response (median, 141 days) and six achieved a partial response (median, 66 days). Overall median progression‐free survival (PFS) time in dogs treated in the adjuvant setting was 489 days. Dogs with grade III MCTs had shorter PFS compared with dogs with metastatic grade II MCTs (190 days versus 954 days; P < 0.001). Phase III studies are needed to provide reliable information about the comparative efficacy of this protocol.     

The use of the nondepolarizing neuromuscular blocking drug cis-atracurium in dogs

Objective This clinical trial attempted to evaluate the potency, onset and duration of action of cis‐atracurium in dogs. Animals Twenty dogs aged between 1 and 15 years and weighing between 15 and 85 kg admitted for a variety of elective, surgical procedures under general anaesthesia. Materials and methods Following induction of general anaesthesia, the effects of an intravenous loading dose of cis‐atracurium (0.1 mg kg^?1) were evaluated by counting visual responses to train of four (TOF) nerve stimulation. Incremental doses of 0.02 or 0.04 mg kg^?1 cis‐atracurium were administered when the first of four responses to TOF stimulation was present. Results An initial dose of 0.1 mg kg^?1 eliminated all four TOF responses in 18 out of 20 dogs. The same dose, repeated 10 minutes later in two animals in which blockade was incomplete, abolished all responses. In dogs receiving 0.1 mg kg^?1 cis‐atracurium neuromuscular blockade lasted 27.2 ± 9.3 minutes. Up to six incremental doses were given in individual animals; incremental doses appeared to be noncumulative. No untoward side‐effects were observed with the use of this drug. There was considerable variation between individuals in response to cis‐atracurium. Conclusions Cis‐atracurium is an effective neuromuscular blocking agent in the dog, although its potency varies. Clinical Relevance Further studies are required to determine whether observed differences in potency are related to age, breed or sex. Cis‐atracurium may prove useful in dogs with impaired renal and or hepatic function.     

The echocardiographic effects of romifidine in dogs with and without prior or concurrent administration of glycopyrrolate

Objective To determine the cardiopulmonary response to romifidine (RO) in the dog with or without prior or concurrent administration of glycopyrrolate. Study Design Randomized, cross‐over experimental study. Animals Six (three male, three female) cross‐bred dogs weighing 23 ± 2.4 kg. Methods Two‐dimensional guided M‐mode echocardiography was performed in conscious dogs simultaneously with measurement of systolic arterial blood pressure (SBP) and heart rate (HR). Dimensions of the left ventricle (LVID), interventricular septum (IVS), and left ventricular free wall (LVFW) were obtained in systole (S) and diastole (D). Amplitude of motion (Amp) of the IVS and LVFW were also measured. From these, measures of wall stress (WS) and fractional shortening (FS) of the left ventricle were derived. Baseline echocardiographic measurements were recorded, following which one of the five treatments was administered. Glycopyrrolate (G) 0.01 mg kg^?1, or saline (S) 0.5 mL, was administered IM as pre‐medication (Gp or Sp), or G was administered concurrently (Gc) with romifidine (RO). Treatments were: T₁, Sp + RO (40 μg kg^?1); T₂, Gp + RO (40 μg kg^?1); T₃, Sp + RO (120 μg kg^?1); T₄, Gp + RO (120 μg kg^?1); and T₅, Sp + Gc +RO (120 μg kg^?1). Romifidine or RO + Gc was administered SC 20 minutes after pre‐medication (time 0), and further measurements were taken 10, 20, 30, 60, and 90 minutes after RO. Results Echocardiographic indices of cardiac systolic function (LVID‐S, FS, Amp‐LVFW) and HR were decreased in RO‐sedated dogs (p < 0.0001) . The magnitude of change in cardiac indices was least with low‐dose RO. At most sampling times, high‐dose RO produced significantly more alteration in cardiac indices. Systolic blood pressure increased in all treatment groups, with the greatest increases in those groups receiving G. Glycopyrrolate significantly increased HR; however, cardiac indices were further reduced. Wall stress significantly increased, with a more dramatic increase in groups receiving G. Conclusions Indices of LV systolic function were reduced in RO‐sedated dogs in a dose‐related manner. Glycopyrrolate further reduced these indices and dramatically increased measurements of wall stress in dogs sedated with RO. Clinical relevance Use of low‐dose RO minimizes cardiac dysfunction; however, it should still be used cautiously in dogs with cardiomyopathy or heart failure. The routine use of G is not recommended to alleviate the bradycardia associated with RO in conscious dogs.     

Continuous infusion of propofol in dogs premedicated with methotrimeprazine

Objective To evaluate the cardiopulmonary and clinical effects of three different infusion rates of propofol in dogs premedicated with methotrimeprazine. Study design Randomized experimental trial. Animals Ten healthy adult mixed‐breed male and female dogs, weighing from 14 to 20 kg. Methods Dogs were premedicated with methotrimeprazine [1 mg kg^?1 intravenously (IV)] followed by induction of anesthesia with 4.5 mg kg^?1 of propofol IV and maintenance with propofol for 60 minutes as follows: T1, 0.2 mg kg^?1 minute^?1; T2, 0.3 mg kg^?1minute^?1; and T3, 0.4 mg kg^?1minute^?1. Heart rate (HR), respiratory rate (RR), mean arterial pressure (MAP), end‐tidal CO₂ (P_ETCO₂), arterial hemoglobin O₂ saturation, arterial blood gases, and pedal and cutaneous reflexes were measured before and 5, 10, 20, 30, 45 and 60 minutes after the beginning of the propofol infusion. Statistical analysis was performed using an anova . Results Heart rate increased during anesthesia in all cases and arterial blood pressure decreased only in dogs in the T3 category. Respiratory depression was proportional to the infusion rate of propofol. Muscle relaxation was satisfactory, but analgesia was inadequate in the three treatments. Conclusions The infusion of 0.2–0.4 mg kg^?1 minute^?1 of propofol produced a dose‐dependent respiratory depression. The presence of a pedal withdrawal reflex and marked cardiovascular responses to this noxious stimulus suggests that anesthesia may not be of sufficient depth for surgery to be carried out. Clinical relevance Although several studies have been performed using propofol in animals, few studies have investigated the cardiopulmonary and analgesic effects with different doses. The determination of an adequate propofol infusion rate is necessary for the routine use of this intravenous anesthetic for the maintenance of anesthesia during major surgical procedures in dogs.     

Safety of orally administered,USP‐compliant levothyroxine sodium tablets in dogs

The safety of synthetic levothyroxine sodium tablets (Thyro‐Tabs® Canine; LLOYD , Inc.) in dogs was evaluated in a randomized, sham‐dose controlled, parallel‐group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0×, 2× (0.044 mg/kg), 6× (0.132 mg/kg), or 10× (0.22 mg/kg) the labeled starting dose of 0.022 mg kg^?1 day^?1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose‐dependent increase in serum concentrations of total and free thyroxine with dose‐dependent suppression of the hypothalamic–pituitary–thyroid axis as evidenced by decreased serum thyroid‐stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose–response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10× the labeled starting dose were well tolerated in healthy dogs.     

Effects of acepromazine on the incidence of vomiting associated with opioid administration in dogs

Objective To evaluate the anti‐emetic properties of acepromazine in dogs receiving opioids as pre‐anesthetic medication. Study design Randomized prospective clinical study. Animals One hundred and sixteen dogs (ASA I or II), admitted for elective surgical procedures. The dogs were a mixed population of males and females, purebreds and mixed breeds, 0.25–13.4 years of age, weighing 1.8–57.7 kg. Methods A prospective clinical trial in which the dogs were randomly assigned to one of three groups. All groups received acepromazine (0.05 mg kg^?1 intramuscularly (IM)). Group I received acepromazine 15 minutes prior to opioid administration. Group II received acepromazine in combination with the opioid. Group III received acepromazine 15 minutes after opioid administration. One of three different opioids was administered IM to each dog: morphine sulfate at 0.5 mg kg^?1; hydromorphone hydrochloride at 0.1 mg kg^?1; or oxymorphone hydrochloride at 0.075 mg kg^?1. Results Dogs receiving acepromazine before the opioid (group I) had a significantly lower incidence of vomiting (18%) than dogs in groups II (45%) and III (55%). The degree of sedation was significantly lower in the dogs receiving the combination of acepromazine and the opioid (group II) than in dogs receiving the opioid as the first drug (group III). Conclusions and clinical relevance Acepromazine administered 15 minutes before the opioid lowers the incidence of vomiting induced by opioids.