Dermal safety study with imidacloprid/moxidectin topical solution in the ivermectin-sensitive collie

Paul, Allan; Hutchens, Douglas E.; Firkins, Lawrence D.; Borgstrom, Mark

doi:10.1016/j.vetpar.2004.03.005

Cited by 27 publications

(11 citation statements)

References 6 publications

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“…This result is consistent with previous work reporting an IVM LD 50 of 0.6–0.8 µmol/kg bw in Mdr1a-deficient mice which had been mutated on only the abcb1a gene and had a compensatory increase in expression of the abcb1b gene [3]. Further, our results in the Mdr1ab−/− mice are consistent with observations that MOX did not induce any signs of toxicosis in IVM-sensitive dogs, which are P-gp-deficient [17], [19].…”

Section: Discussionsupporting

confidence: 93%

“…In another study, P-gp-deficient dogs that were sensitive to 120 µg/ml of IVM (20× the therapeutic dose rate (6 µg/kg) for IVM as a monthly heartworm preventative) did not produce signs of toxicosis following exposure to MOX at 100 µg/kg (more than the molar equivalent to 120 µg/ml IVM, and 33-fold the therapeutic dose rate (3 µg/kg) for MOX as a monthly heartworm preventative) given daily for 7 days [18]. In fact, MOX has been safely used on P-gp-deficient Collie dogs up to 32.5 mg/kg by spot-on application [19]. However, in addition to dose rate, route of administration can markedly affect toxicity and topical application is known to produce low bioavailability.…”

Section: Introductionmentioning

confidence: 97%

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Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

et al. 2012

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The anthelmintics ivermectin (IVM) and moxidectin (MOX) display differences in toxicity in several host species. Entrance into the brain is restricted by the P-glycoprotein (P-gp) efflux transporter, while toxicity is mediated through the brain GABA(A) receptors. This study compared the toxicity of IVM and MOX in vivo and their interaction with GABA(A) receptors in vitro. Drug toxicity was assessed in Mdr1ab(−/−) mice P-gp-deficient after subcutaneous administration of increasing doses (0.11–2.0 and 0.23–12.9 µmol/kg for IVM and MOX in P-gp-deficient mice and half lethal doses (LD50) in wild-type mice). Survival was evaluated over 14-days. In Mdr1ab(−/−) mice, LD50 was 0.46 and 2.3 µmol/kg for IVM and MOX, respectively, demonstrating that MOX was less toxic than IVM. In P-gp-deficient mice, MOX had a lower brain-to-plasma concentration ratio and entered into the brain more slowly than IVM. The brain sublethal drug concentrations determined after administration of doses close to LD50 were, in Mdr1ab(−/−) and wild-type mice, respectively, 270 and 210 pmol/g for IVM and 830 and 740–1380 pmol/g for MOX, indicating that higher brain concentrations are required for MOX toxicity than IVM. In rat α1β2γ2 GABA channels expressed in Xenopus oocytes, IVM and MOX were both allosteric activators of the GABA-induced response. The Hill coefficient was 1.52±0.45 for IVM and 0.34±0.56 for MOX (p<0.001), while the maximum potentiation caused by IVM and MOX relative to GABA alone was 413.7±66.1 and 257.4±40.6%, respectively (p<0.05), showing that IVM causes a greater potentiation of GABA action on this receptor. Differences in the accumulation of IVM and MOX in the brain and in the interaction of IVM and MOX with GABA(A) receptors account for differences in neurotoxicity seen in intact and Mdr1-deficient animals. These differences in neurotoxicity of IVM and MOX are important in considering their use in humans.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 97%

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

et al. 2012

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“…This confirms the safety of the spot-on treatment with imidacloprid/moxidectin which was also proven in ivermectin-sensitive collies (Paul et al 2004).…”

Section: Discussionsupporting

confidence: 79%

Evaluation of the efficacy and safety of imidacloprid 10% plus moxidectin 2.5% spot–on in the treatment of generalized demodicosis in dogs: results of a European field study

Heine

Krieger

Dumont³

et al. 2005

Parasitol Res

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Efficacy and safety of the test product imidacloprid 10%+moxidectin 2.5% spot on (Advocate, Advantage multi) in the treatment of canine generalized demodicosis were evaluated in a multi-centre, controlled, randomized, blinded field study in Albania, France, and Germany. The study was conducted according to a non-inferiority design to demonstrate that the efficacy of the test product is not inferior to that of a control product containing milbemycin oxime (Interceptor, tablets for oral application). Of the 72 dogs enrolled, all of which expressed clinical signs of generalized demodicosis, 63 completed the study. Of these, 30 dogs were treated 2-4 times, at 4-week intervals, with the test product at the recommended dose of at least 0.1 ml/kg body weight. Thirty-three dogs were treated daily for two to four periods of 4 weeks with the control product according to label instructions (0.5-1 or 1-2 mg/kg body weight). Presence of mites in deep skin scrapings and clinical improvement were assessed 3-6 times at each inspection at 4-week intervals. Treatment was discontinued in dogs negative for mites on two subsequent examinations 4 weeks apart or at the last examination on day 84. At the end of the trial, dogs in both groups showed a similar clinical improvement. No Demodex mites were detected in 26 of 30 dogs treated with imidacloprid/moxidectin and in 29 of 33 dogs treated with milbemycin oxime. Statistical evaluation confirmed that the efficacy of the test product in the treatment of generalized canine demodicosis was not inferior to that of milbemycin oxime.

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“…It is unknown if imidacloprid serves as a substrate for ABCB1 or other MDR proteins. However, studies of imidacloprid absorption by the human intestinal epithelial Caco‐2 cell line suggest lack of involvement of classical ABC transport systems,24 and ivermectin‐sensitive Collies do not demonstrate any observable toxicologic effects of topical treatment with imidacloprid 25…”

Section: Discussionmentioning

confidence: 99%

Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case‐Control Study

Gookin

Correa

Peters

et al. 2015

Veterinary Internal Medicne

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BackgroundThe cause of gallbladder mucocele (GBM) formation in dogs currently is unknown. Many available drugs represent a newer generation of xenobiotics that may predispose dogs to GBM formation.ObjectiveTo determine if there is an association between the histologic diagnosis of GBM in dogs and administration of selected drugs.AnimalsEighty‐one dogs with a histologic diagnosis of GBM and 162 breed, age, and admission date‐matched control dogs from a single referral institution.MethodsMedical records of dogs with GBM and control dogs from 2001 to 2011 were reviewed. Owner verification of drug history was sought by a standard questionnaire. Reported use of heartworm, flea, and tick preventatives as well as nonsteroidal anti‐inflammatory drugs, analgesics, corticosteroids, or medications for treatment of osteoarthritis was recorded.ResultsDogs with GBM were 2.2 times as likely to have had reported use of thyroxine (as a proxy for the diagnosis of hypothyroidism) as control dogs (95% confidence interval [CI], 0.949–5.051), 3.6 times as likely to have had reported treatment for Cushing's disease (95% CI, 1.228–10.612), and 2.3 times as likely to have had reported use of products containing imidacloprid (95% CI, 1.094–4.723). Analysis of a data subset containing only Shetland sheepdogs (23 GBM and 46 control) indicated that Shetland sheepdogs with GBM formation were 9.3 times as likely to have had reported use of imidacloprid as were control Shetland sheepdogs (95% CI, 1.103–78.239).Conclusions and Clinical ImportanceThis study provides evidence for an association between selected drug use and GBM formation in dogs. A larger epidemiologic study of Shetland sheepdogs with GBM formation and exposure to imidacloprid is warranted.

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Dermal safety study with imidacloprid/moxidectin topical solution in the ivermectin-sensitive collie

Cited by 27 publications

References 6 publications

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

Relative Neurotoxicity of Ivermectin and Moxidectin in Mdr1ab (−/−) Mice and Effects on Mammalian GABA(A) Channel Activity

Evaluation of the efficacy and safety of imidacloprid 10% plus moxidectin 2.5% spot–on in the treatment of generalized demodicosis in dogs: results of a European field study

Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case‐Control Study

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