Selamectin is a potent substrate and inhibitor of human and canine P-glycoprotein

The transport of the antiparasitic agents, ivermectin, selamectin and moxidectin was studied in human intestinal epithelial cell monolayers (Caco-2) and canine peripheral blood lymphocytes (PBL). Both models expressed the mdr1-coded 170 kDa ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Fluxes of the P-gp substrate rhodamine-123 (Rh-123) across Caco-2 monolayers showed that ivermectin and selamectin acted as potent P-gp inhibitors with IC50 values of 0.1 microm. In contrast, moxidectin was a weaker P-gp inhibitor with an IC50 of 10 microm. The transport of radiolabelled ivermectin, selamectin and moxidectin through Caco-2 monolayers showed that ivermectin, selamectin and moxidectin were P-gp substrates with secretory/absorptive ratios of 7.5, 4.7 and 2.6 respectively. Secretory transport of [3H]-ivermectin and [3H]-selamectin was blocked by the P-gp inhibitor, verapamil. Ivermectin and selamectin inhibited the efflux of Rh-123 from PBL and the concentration of inhibition was similar to that of verapamil. In contrast, moxidectin did not have a significant effect on Rh-123 efflux from PBL. The data suggest that ivermectin and selamectin are potent P-gp substrates, while moxidectin is a weak one.     

Frequency of the nt230 (del4) MDR1 mutation in Collies and related dog breeds in Germany

MDR1 (ABCB1) P-glycoprotein exerts a protective function in the blood–brain barrier thereby limiting the entry of many drugs and other xenobiotics to the central nervous system. A nonsense mutation has been described for Collies and related dog breeds which abolishes this function and is associated with increased susceptibility to neurotoxic side effects of several drugs including ivermectin, moxidectin and loperamide. In order to evaluate the occurrence and frequency of this nt230 (del4) MDR1 mutation in Germany, we screened 1500 dogs. Frequency of the homozygous mutated genotype was highest for Collies (33.0%), followed by Australian Shepherd (6.9%) and Shetland Sheepdog (5.7%). Thirty-seven percent of the Wäller dogs and 12.5% of the Old English Sheepdogs were heterozygous for the mutant MDR1 (−) allele. Considering the predominant role of MDR1 P-glycoprotein in drug disposition and in particular for blood–brain barrier protection, MDR1 genotype-based breeding programs are recommended for improving the safety of drug therapy in these canine breeds.     

Biliary excretion of technetium-99m-sestamibi in wild-type dogs and in dogs with intrinsic (ABCB1-1Δ mutation) and extrinsic (ketoconazole treated) P-glycoprotein deficiency

P-glycoprotein (P-gp), the product of ABCB1 gene, is thought to play a role in the biliary excretion of a variety of drugs, but specific studies in dogs have not been performed. Because a number of endogenous (ABCB1 polymorphisms) and exogenous (pharmacological P-gp inhibition) factors can interfere with normal P-gp function, a better understanding of P-gp's role in biliary drug excretion is crucial in preventing adverse drug reactions and drug–drug interactions in dogs. The objectives of this study were to compare biliary excretion of technetium-99m-sestamibi (^99mTc-MIBI), a radio-labelled P-gp substrate, in wild-type dogs (ABCB1 wild/wild), and dogs with intrinsic and extrinsic deficiencies in P-gp function. Dogs with intrinsic P-gp deficiency included ABCB1 mut/mut dogs, and dogs with presumed intermediate P-gp phenotype (ABCB1 mut/wild). Dogs with extrinsic P-gp deficiency were considered to be ABCB1 wild/wild dogs treated with the P-gp inhibitor ketoconazole (5 mg/kg PO q12h × 9 doses). Results from this study indicate that ABCB1 mut/mut dogs have significantly decreased biliary excretion of ^99mTc-MIBI compared with ABCB1 wild/wild dogs. Treatment with ketoconazole significantly decreased biliary excretion of ^99mTc-MIBI in ABCB1 wild/wild dogs. P-gp appears to play an important role in the biliary excretion of ^99mTc-MIBI in dogs. It is likely that concurrent administration of a P-gp inhibitor such as ketoconazole will decrease P-gp-mediated biliary excretion of other substrate drugs as well.     

The relation between the birth process and the condition of the newborn piglet and calf

Fluxes of the anti-parasitic agents, [³H]-ivermectin, [³H]-selamectin and [³H]-moxidectin were studied across non-transfected and transfected canine kidney epithelial monolayers, MDCK II/wt, MDCK II-MDR1, MDCK II-MRP1 and MDCK II-MRP2. All four lines surprisingly expressed significant levels of P-glycoprotein (P-gp), coded for by MDR1, but MDCK II-MDR1 expressed increased levels compared to the other lines. MDCK II-MRP1 and MDCK II-MRP2 expressed increased levels of MRP1 and MRP2 respectively. Fluxes of [³H]-ivermectin, [³H]-selamectin, [³H]-moxidectin, and the P-gp substrates, rhodamine-123 and DiOC₂, were polarized in the basolateral-to-apical (secretory) direction across the four lines. Selected MRP inhibitors used in relevant pharmacological concentrations did not block the secretory fluxes of either [³H]-ivermectin or [³H]-selamectin in either the non-transfected or MRP-transfected lines. In contrast, secretory fluxes of ivermectin and selamectin were inhibited in all four lines by the P-gp inhibitor, verapamil. These data confirm that ivermectin and selamectin are substrates for P-gp in four additional cell lines, but suggest that they are not significant substrates for MRP1 or MRP2 where there is background expression of P-gp. Since this pattern of expression also pertains on the blood-brain barrier, it is unlikely that MRP1 and MRP2 play a significant role in ivermectin and selamectin blood: brain distribution in vivo.     

Clinical, immunological and histopathological findings in a subpopulation of dogs with pododermatitis

Abstract   Clinical, immunological and histopathological findings in 20 adult dogs of varying breeds with chronic (≥ 6 months) inflammation confined to the pedal skin were compared over a 2-year period with those of a group of age-matched controls ( n  = 20). All affected dogs were pruritic but systemically well. Lesions were present on all four feet in 18/20 cases. Affected feet were characteristically erythematous, swollen, painful and alopecic. Sinus tracts were evident in 4/20 dogs. Despite a methodical series of diagnostic tests, no underlying cause was identified. None of the dogs responded to antimicrobial therapy administered for 8 weeks, none had evidence of ectoparasitism and none satisfied the criteria for atopic dermatitis. There was no response to a dietary trial using a novel protein source. The condition was characterized histopathologically by epidermal hyperplasia, hyperkeratosis, spongiosis, dermal oedema and perivascular aggregates of lymphocytes and plasma cells. Clinical signs did not correlate with histopathological findings. Affected dogs had significantly elevated serum IgG and IgM concentrations. The results of lymphocyte proliferation assays and phenotypic studies to determine the relative percentage of CD3⁺, CD4⁺, CD8⁺ and CD21⁺ lymphocyte subsets, and the ratio of CD4⁺/CD8⁺ cells were not significantly different between groups. No age, sex or seasonal predilections were noted. All dogs subsequently responded to immunosuppressive doses of prednisolone or cyclosporin. The term immunomodulatory-responsive lymphocytic–plasmacytic pododermatitis is proposed to denote what may be a previously unrecognized condition in some dogs with pododermatitis of undetermined aetiology.     

Carprofen inhibition of flare in the dog measured by laser flare photometry

The purpose of this study was to determine whether oral carprofen (Rimadyl®) treatment in dogs could prevent or decrease the breakdown of the blood–aqueous barrier. The topical pilocarpine irritative model was used to induce breakdown and cause flare. Pilocarpine was instilled in both eyes of seven dogs at time zero and again 5 h later. At 7 h, laser flare photometry was used to measure the flare concentration in each eye using the Kowa FC-1000 laser flare cell meter. All treatments were then discontinued. Two days later, carprofen was administered to the same dogs for a total of three doses. After the last dose of carprofen, pilocarpine treatments and flare measurements were repeated. Carprofen pretreatment resulted in a 68% inhibition of flare, which was highly significant ( P < 0.01). The pilocarpine group had a mean of 16.1 photon counts per millisecond (PC ms⁻¹) ± 2.2 SE, and the carprofen group had a mean of 7.0 PC/ms ± 1.2 SE. These results compare favorably with previous studies measuring increased protein or fluorescein concentrations in the aqueous humor after blood–aqueous barrier breakdown in the dog. These results suggest that carprofen may be effectively used as a systemically administered ocular anti-inflammatory drug. Carprofen has the added benefit of fewer reported side effects.     

ABCB1-1Δ (MDR1-1Δ) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis

Twenty-two dogs diagnosed with generalized demodicosis were treated with milbemycin oxime (MO) because of poor response to previous therapies or because the dog was a breed known to be susceptible to ivermectin toxicosis. Fifteen of the 22 dogs were herding breeds. Doses of MO ranged from 1.0 to 2.2 mg kg⁻¹ day⁻¹ per os. Cheek swab samples were obtained in order to determine each dog's ABCB 1 genotype. Adverse drug reactions were recorded for each dog by the owners and/or veterinarians. The ABCB 1-1Δ genotype was significantly associated with the development of an adverse reaction (neurological toxicity) after treatment with MO. None of the 19 dogs with the wild-type ABCB1 allele experienced adverse reactions, whereas two dogs homozygous for the ABCB1-1Δ mutation developed ataxia. Assessing the ABCB1-1Δ genotype prior to MO administration may prevent neurological toxicity in these patients.     

Evaluation of the Perkins® handheld applanation tonometer in the measurement of intraocular pressure in dogs and cats

Objective  To evaluate and to validate the accuracy of the Perkins^® handheld applanation tonometer in the measurement of IOP in dogs and cats.
Animals  Twenty eyes from 10 dogs and 10 cats immediately after sacrifice were used for the postmortem study and 20 eyes from 10 clinically normal and anesthetized dogs and cats were used for the in vivo study. Both eyes of 20 conscious dogs and cats were also evaluated.
Procedure  Readings of IOP postmortem and in vivo were taken using manometry (measured with a mercury column manometer) and tonometry (measured with a Perkins^® handheld applanation tonometer). The IOP measurement with Perkins^® tonometer in anesthetized and conscious dogs and cats was accomplished by instillation of proxymetacaine 0.5% and of 1% fluorescein eye drops.
Results  The correlation coefficient ( r ²) between the manometry and the Perkins^® tonometer were 0.982 (dogs) and 0.988 (cats), and the corresponding linear regression equation were y  = 0.0893 x  + 0.1105 (dogs) and y  = 0.0899 x  + 0.1145 (cats) in the postmortem study. The mean IOP readings with the Perkins^® tonometer after calibration curve correction were 14.9 ± 1.6 mmHg (range 12.2–17.2 mmHg) in conscious dogs, and were 15.1 ± 1.7 mmHg (range 12.1–18.7 mmHg) in conscious cats.
Conclusion  There was an excellent correlation between the IOP values obtained from direct ocular manometry and the Perkins^® tonometer in dogs and cats. The Perkins^® handheld tonometer could be in the future a new alternative for the diagnosis of glaucoma in veterinary ophthalmology.     

Prothrombotic and Inflammatory Effects of Intravenous Administration of Human Immunoglobulin G in Dogs

Background: Intravenous administration of human immunoglobulin G (hIVIgG) has been suggested to potentiate thromboembolism in dogs, but supportive scientific reports are lacking.
Objectives: To determine if hIVIgG therapy promotes hypercoagulability and inflammation in dogs.
Animals: Twelve healthy Beagle dogs.
Methods: Prospective, experimental trial. An hIVIgG/saline solution was infused IV at 1 g/kg BW over 8 hours to 6 dogs, and physiological saline was infused to the other 6 dogs. Blood samples were drawn before, during, and after infusion for serial measurement of indicators of coagulation and inflammation. Data were analyzed by 2-way repeated measures analysis of variance.
Results: Dogs administered hIVIgG developed mildly decreased blood platelet concentrations without thrombocytopenia (median, 200 × 10³/μL; range, 150–302 × 10³/μL; P < .01), leukopenia (median, 3.5 × 10³/μL; range, 20–62 × 10³/μL; P < .001), and mildly increased plasma total protein concentrations (median, 6.3 g/dL; range, 5.6–6.7 g/dL; P < .001). Administration of hIVIgG was also associated with increases in fibrin/fibrinogen degradation products in all dogs (either 5 μg/mL or 10 μg/dL), thrombin-antithrombin III complexes (median, 7.2 ng/mL; range, 4.9–14.2 ng/mL; P < .001), and C-reactive protein concentrations (median, 2.5 mg/dL; range, 0.5–4.3 mg/dL; P < .01).
Conclusion and Clinical Importance: Administration of hIVIgG to dogs promotes hypercoagulability and an inflammatory state. This should be further evaluated and considered when using hIVIgG in dogs with IMHA or other prothrombotic conditions.     

Neurotoxic effects of ivermectin administration in genetically engineered mice with targeted insertion of the mutated canine ABCB1 gene

Objective-To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies. Animals-14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted. Procedures-Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration. Results-After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin. Conclusions and Clinical Relevance-The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1-1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.     

Absorption, distribution, metabolism, and excretion of dirlotapide in the dog

Three once-daily oral doses of 0.2 mg/kg [¹⁴C]dirlotapide were administered to beagle dogs to study the absorption, distribution, metabolism, and excretion of dirlotapide. Mean ¹⁴C recovered at 2.5 and 4.5 h after the last dose was 90%. Mean ¹⁴C in urine, bile, and feces was <1%, 1.7%, and 56% of the dose, respectively. In tissues, 26% of the ¹⁴C dose was present in the gastrointestinal tract, 6.0% in liver, and <1% each in kidney, gall bladder, heart, and brain. To further characterize drug disposition, a single 2.5-mg/kg oral dose of [¹⁴C]dirlotapide was administered to beagle dogs. More than 84% of the dose had been eliminated by 72 h in feces, with 21% of the dose present in feces as parent dirlotapide. Less than 1% of the dose was excreted in urine. In bile collected during the first 24-h postdose from three dogs, 32% and 11% of the ¹⁴C dose was present in samples from male and female dogs, respectively. Based upon metabolite profiling of plasma, excreta, and bile samples, dirlotapide was extensively metabolized to more than 20 metabolites. Biliary/fecal excretion and the potential for enterohepatic recycling of metabolites are suggested.     

Brain penetration of emodepside is increased in P‐glycoprotein‐deficient mice and leads to neurotoxicosis

The antiparasitic drug emodepside (EMO) is a substrate of the P‐glycoprotein multidrug efflux carrier (P‐gp; syn. MDR1, ABCB1), which has an important function in protecting the brain from potentially toxic compounds by functional drug efflux at the blood–brain barrier (BBB). Many dogs of the Collie breed and even dogs of many other breeds have a loss‐of‐function 4‐bp deletion mutation in the MDR1 gene. In these dogs, brain penetration of many P‐gp‐transported drugs is increased and so their therapeutic usage is restricted. To elucidate the role of P‐gp at the BBB for the brain penetration of EMO, we applied EMO at 1 mg/kg to mdr1‐deficient (PGP^mut) and mdr1‐intact (PGP^WT) CF1 mice. Whereas in the brain of the PGP^WT mice, EMO was below the detection level of 10 ng/g, its concentration was at 43.7 ng/g in the PGP^mut mice. Furthermore, appearance of neurological toxicity was analyzed in these mice after application of 1 mg/kg EMO using a rotarod setup. In all PGP^mut mice, but not in the PGP^WT mice, the walking performance on the rotarod was impaired by EMO with clear differences in the degree and duration of neurological toxicity. Some of the mice were completely unable to walk on the rotarod already at 2 h after drug application and showed long‐lasting ataxia over >24 h. Others even showed significantly reduced walking performance, but completely recovered within 1 day. In conclusion, P‐gp restricts brain penetration of EMO and prevents neurological toxicity of this drug in mice.     

Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin

Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in danofloxacin secretion into milk. In addition, the role of potential drug-drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1(-/-) mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of danofloxacin. However, the milk concentration and milk-to-plasma ratio of danofloxacin were almost twofold higher in wild-type compared with Bcrp1(-/-) mice. The in vivo interaction with ivermectin was studied in sheep after co-administration of danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of danofloxacin but significantly decreased danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug-drug interactions mediated by BCRP.     

Improving the estimation of realized effective population sizes in farm animals

Computation of inbreeding rate (Δ F ) must consider that inbreeding is delayed with one generation with respect to the idealized population when addressed using individual inbreeding coefficients. The expression relating inbreeding in generation t with inbreeding rate F _t  = 1 – (1– ΔF ) ^t should be more correctly written in real animal populations as F _t  = 1 – (1– ΔF ) ^{t −1}, as changes in allele frequencies occur in the equivalent co-ancestries in the previous generation. This simple approach is tested on simulated and real pedigrees thus demonstrating that: (i) the adjusted individual increase in inbreeding becomes stable in populations under random mating while the unadjusted parameter does not; (ii) regression of the unadjusted parameter over generations in pedigrees under random mating is highly significant while after correction it is not significant; and (iii) the variance of the adjusted parameter is reduced with the generations.     

Effect of oral administration of 3,3',4,4',5-pentachlorobiphyenl on the intestinal microbiota of Sprague–Dawley rats

The effect of the endocrine-disrupting chemical 3,3',4,4',5-pentachlorobiphyenl (PCB 126) on intestinal microbiota after oral administration, and the improvement of intestinal microbiota and feces quantity by the subsequent administration of Lactobacillus acidophilus or Lactobacillus reuteri was investigated. All the rats were given 100 μg/kg bodyweight of PCB 126. The changes in bacterial counts were confirmed using a culture method. The administration of PCB 126 tended to decrease the bacterial counts of lactobacilli (10^9.6−10^10.2 to 10^8.8−10^9.2) and bifidobacteria (10^5.3−10^6.1 to 10^3.6−10^4.2), and to increase those of Enterobacteriaceae (10^8.2−10^9.1 to 10^9.4−10^10.3) and staphylococci (10^6.6−10^7.4 to 10^7.2−10^8.4) compared to no PCB 126 administration. After administration of PCB 126, L. acidophilus or L. reuteri orally administered to rats caused Enterobacteriaceae and staphylococci counts to decrease, suggesting that the intestinal microbiota was improved by the lactobacilli. The administration of L. acidophilus and L. reuteri improved the balance of intestinal microbiota, and defecation volume returned to its normal level. L. acidophilus and L. reuteri have a remedial effect on intestinal microbiota affected by PCB 126 and can function to lessen accumulated PCB 126 volume.     

P-29 Pustular dermatosis caused by fire ant (Solenopsis invicta) stings in a dog

The purpose of this study was to evaluate 55 clinical cases of canine demodicosis and to compare the results of treatment using amitraz (solution), selamectin (spot-on), ivermectin (injection) and cythioate (oral tablets). Data from the 55 cases was collected and evaluated after clinical and microbiological examination. Treatment was selected depending on the severity of demodicosis and compliance of the owner. The cases were followed for 12 months and the status of the patients was grouped on two levels: recovered (58%), or relapsed (42%). Five dogs (9%) were euthanized. The disease was commonly diagnosed in purebred dogs. Demodicosis was more common in dogs under 2 years of age (65%), in males (64%), and in the short-haired breeds (75%). Demodicosis was generalized in 73% of cases, localised in 23% and affected the feet (pododemodicosis) in 4% of cases. Recovery was the highest in dogs between 1 and 2 years of age (73%), and in the localized cases (92%). Nonspecific treatment with glucocorticoids prior to the diagnosis lowered the rate of recovery (4%), but treatment with glucocorticoids for proven atopic dermatitis improved the rate of recovery (41%). All drugs (amitraz, selamectin, cythioate) administered for the localized form were effective (100% recovered). Recovery in generalized demodicosis was 60% using ivermectin, 55% using amitraz, 44% with the combination of amitraz and selamectin (two treatments with amitraz followed by selamectin), and 43% in cases where selamectin was used alone.
Funding: Pfizer Animal Health.     

Allele-specific polymerase chain reaction diagnostic test for the functional MDR1 polymorphism in dogs

The major multidrug transporter P-glycoprotein (Pgp) contributes to the barrier function of several tissues and organs, including the brain. In a subpopulation of Collies and seven further dog breeds, a 4 base pair deletion has been described in the Pgp-encoding MDR1 gene. This deletion results in the absence of a functional form of Pgp and loss of its protective function. Severe intoxication with the Pgp substrate ivermectin has been attributed to the genetically determined lack of Pgp. An allele-specific polymerase chain reaction (PCR)-based screening method has been developed to detect the mutant allele and to determine if a dog is homozygous or heterozygous for the mutation. Based on this validation, the allele-specific PCR proved to be a robust, reproducible and specific tool, allowing rapid determination of the MDR1 genotype of dogs of at risk breeds using blood samples or buccal swabs.     

Inhibitory effect of dietary anacardic acid supplementation on cecal lesion formation following chicken coccidial infection

Two experiments were conducted to determine the effects on male chicken performance of anacardic acid and cashew nut shell oil as feed supplements during an experimental coccidial infection. Seven-day-old chicks wer e fed a corn-soybean diet containing anacardic acid at 0, 0.4 or 0.8% (Experiment 1), or cashew nut shell oil at 0, 0.1, 0.2 or 0.4% (Experiment 2) for 10 days. On the third day of each experiment, half of the birds fed each diet were individually inoculated orally with 2 × 10³ or 5 × 10⁴ (Experiment 1) and 1 × 10⁴ or 1 × 10⁵ (Experiment 2) Eimeria tenella oocysts. In Experiment 1, body weight gain and cecal length decreased significantly according to the level of oocyst inoculation, while oocyst production per cecum (log value) and cecal lesion score significantly increased. Dietary anacardic acid supplementation had no effect on these parameters except for that of lesion score, which was improved (i.e. decreased) by anacardic acid supplementation of 0.8% at the inoculation level of 2 × 10³ oocysts, and of 0.4 and 0.8% for the higher inoculation (5 × 10⁴ oocysts). Results of Experiment 2 also showed that cashew nut shell oil affected neither cecal length nor oocyst production per cecum (log value) at either of the inoculation levels, but the lesion score was improved by cashew nut shell oil supplementation at 0.2 and 0.4% in the diet at the inoculation level of 1 × 10⁴ oocysts and at 0.4% for the higher inoculation. The present study provides the first evidence of the reducing effects of anacardic acid and cashew nut shell oil on the severity of cecal lesions in chickens during an experimental coccidial infection.     

131‐I therapy for Advanced, Unresectable Thyroid Tumors in Dogs

Introduction:  Greater than 50% of dogs with thyroid tumors present with surgically unresectable disease for which external beam radiotherapy has been reported to prolong survival. The success of ¹³¹I for control of thyroid tumors in cats and in humans suggests such therapy may also play a role in the management of canine thyroid cancer.
Methods:  Thirty‐nine dogs with WHO stage II/III (invasive or ectopic; n = 32) or IV (metastatic; n = 7) thyroid tumors were treated with ¹³¹I alone. Changes in thyroid function, ^99MTc‐pertechnetate (^99MTc) scintigraphic changes, and tumor response were recorded. Dogs with ventral cervical tumors were evaluated for feasibility of surgical resection following ¹³¹I.
Results:  Median overall survival was 839 days and 366 days for dogs with stage II/III and stage IV tumors, respectively. Thyroid hormone status, site and surgical resection were not associated with outcome in dogs with stage II/III tumors. Three dogs developed severe bone marrow suppression.
Conclusions:  These findings suggest ¹³¹I should be investigated more thoroughly in dogs with thyroid tumors not considered surgical candidates to more clearly characterize the indications for therapy and followup recommendations. ¹³¹I dosimetry in dogs with thyroid tumors remains problematic. Administration of ¹³¹I is currently based on empiric recommendations and, in general, the treatment is well tolerated although additional studies are indicated to optimize response and minimize toxicity.     

Canine mdr1 gene mutation in Japan

Frequency of the 4-bp deletion mutant in canine mdr1 gene was examined in 193 dogs of eight breeds in Japan. The mutant allele was found in Collies, Australian Shepherds, and Shetland Sheepdogs, where its respective frequencies were 58.3%, 33.3%, and 1.2%. The MDR1 protein was detected on peripheral blood mononuclear cells (PBMC) from a MDR1/MDR1 dog, but not on PBMC from a mdr1-1Delta/mdr1-1Delta Collie. Rhodamine 123 was extruded from MDR1/MDR1 lymphocytes. That excretion was inhibited by a MDR1 inhibitor, verapamil. On the other hand, Rh123 excretion was not observed from lymphocytes derived from a mdr1-1Delta/mdr1-1Delta Collie. These results indicated that the mutant mdr1 allele also existed in Collie-breed dogs in Japan at high rates and that mdr1-1Delta /mdr1-1Delta dogs have no functional MDR1.