Characterization and Validation of a Canine Pruritic Model

Åberg, Gunnar; Arulnesan, Nada; Bolger, Gordon T.; Ciofalo, Vincent B.; Pucaj, Kresimir

doi:10.1002/ddr.21261

Cited by 6 publications

(28 citation statements)

References 18 publications

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“…Moreover, the results show the B T / P T and B F / P F for K are greater than for N (Figure ). This suggests that, compared to N, both total and free concentrations of K are greater in the CNS than in plasma supporting a greater sedative effect for K. This is consistent with the highly sedative effect of K and absence of sedative effects of N in dog …”

Section: Discussionsupporting

confidence: 85%

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Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers

Feng

Fawcett

Zhang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Ketotifen (K) and its active metabolite norketotifen (N) exist as optically active atropisomers. They both have antihistaminic and anti‐inflammatory properties but the S‐atropisomer of N (SN) causes less sedation than K and RN in rodents. This study investigated whether this could be related to a lower concentration of SN in brain or a lower affinity of SN for rat brain H1 receptors. Methods Ketotifen and norketotifen atropisomers were quantified using a validated chiral HPLC assay. RBE4 and Caco‐2 cell monolayers were used in uptake and permeability studies, respectively. Free and total brain‐to‐plasma (B/P) ratios were determined after injecting racemic K and N into rat tail veins. Affinity for rat brain H1 receptors (KI) was determined using the [3H]mepyramine binding assay. Key findings Uptake and permeation studies indicate no stereoselective transport for K or N. B/P ratios reveal the brain concentration of N is lower than K with no stereoselective transport into brain. Finally, the [3H]mepyramine binding assay shows SN has the lowest affinity for rat brain H1 receptors. Conclusion The lower sedative effect of SN in rodents is probably due to a combination of a lower uptake of N than K into the brain and less affinity of SN for CNS H1 receptors.

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Section: Discussionsupporting

confidence: 85%

“…After oral administration, K is metabolised to several metabolites including norketotifen (N) (Figure c), which is an active but not major metabolite of K . Interestingly, N has been shown to be significantly less toxic than K in rat after both intravenous and oral administration .…”

Section: Introductionmentioning

confidence: 99%

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers

Feng

Fawcett

Zhang

et al. 2020

Journal of Pharmacy and Pharmacology

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“…administration of CQ (Figure a) to healthy beagle dogs during the observation period of 300 min (Friedman test; CQ1 versus saline_01, P = 0.99 and CQ1 versus saline_02, P = 0.99; CQ2 versus saline_01, P = 0.99 and CQ2 versus saline_02, P = 0.33). Furthermore, there was no significant itch induction within the 180–300 min post‐injection (Figure c; Friedman test; CQ1 versus saline_01, P = 0.99 and CQ1 versus saline_02, P = 0.66; CQ2 versus saline_01 and CQ2 versus saline_02, P = 0.99, respectively), which has been reported previously as the peak time of CQ‐induced itch in healthy dogs …”

Section: Resultssupporting

confidence: 75%

“…CQ/saline acute itch evaluations, video‐recordings were evaluated for the 30 min post‐injection. The duration of CQ/saline video‐recordings resembled previously published CQ‐induced itch study in dogs and mice …”

Section: Methodssupporting

confidence: 61%

“…The present study used video‐recordings to avoid distracting the dogs and influencing their pruritic behaviours. Additionally, the prior study measured pruritic episodes without detailed descriptions for each of the itch behaviours which may have resulted in scoring variability between evaluators . The present study used video‐recordings to avoid direct attention and influence of evaluators presence on the dog behaviours.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of a chloroquine‐induced canine model of pruritus and skin inflammation

Blubaugh

Denley

Banović

2019

Veterinary Dermatology

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Background Chloroquine (CQ) is a prototypical systemic and intradermal pruritogen for histamine‐independent (nonhistaminergic) itch in mice and humans. The predictive validity of this model is poorly documented in dogs. Hypothesis/Objective To determine pruritogenic and inflammatory effects of systemic and i.d. CQ injections in healthy dogs. Animals Ten healthy purpose‐bred laboratory beagles. Methods and materials All dogs were randomized to receive i.d. (200 and 400 µg/site), intravenous (2 mg/kg) and subcutaneous (3 mg/kg) CQ injections. Dogs were video‐recorded for 30 min after i.d. injections and for 300 min after i.v. and s.c. injections. Buffered saline injections served as controls for each route. Global wheal scores were evaluated at 30 min post‐i.d. injection by a blinded investigator. Results All dogs showed wheal and erythema at the CQ i.d. injection sites; global wheal scores of each CQ concentration were significantly increased compared to placebo (P ≤ 0.05). Blinded evaluation revealed no significant increase in generalized pruritic behaviour (pruritic seconds) after i.v. or s.c. administration of CQ. Intradermal injections induced mild localized acute pruritic behaviours at the site of injections at 200 µg (P = 0.06) and 400 µg (P = 0.27) CQ in dogs. Conclusion and clinical significance To the best of the authors’ knowledge, this is the first report which shows that i.d. CQ injections may induce acute inflammation in healthy dogs. By contrast to the systemic CQ‐induced pruritus reported previously in healthy mice and dogs, no significant pruritic behaviours were observed after CQ injection, regardless of the route of administration.

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Ketotifen is a Prodrug. Norketotifen is the active metabolite.

Aberg

Arulnesan

Bolger³

et al. 2021

Drug Development Research

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Evaluation of the in vitro human liver microsome and hepatocyte metabolism of ketotifen demonstrated that norketotifen (NK) is the major demethylated hepatic metabolite of ketotifen. It is here reported that NK is completely devoid of the severe and dose‐limiting sedative effects of ketotifen. Thus, while ketotifen is clinically dose‐limited to 1 mg, bid, there are no dose‐limiting sedative effects elicited by NK, even after the highest single‐dose (16 mg) or after repeat‐doses (8 mg × 7 days) in humans or after the highest doses given to dogs in repeat‐dose toxicological studies (40 mg/kg × 14 days). In addition, NK—but not ketotifen—was found to express potent and dose‐dependent inhibition of the release of the pro‐inflammatory cytokine TNFα from activated human buffy coat preparations. Thus, when used as an anti‐inflammatory drug, ketotifen is the sedating prodrug which is converted to NK a nonsedating metabolite with anti‐inflammatory activity.

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Characterization and Validation of a Canine Pruritic Model

Cited by 6 publications

References 18 publications

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers

Cell-based, animal and H1 receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers

Characterization of a chloroquine‐induced canine model of pruritus and skin inflammation

Ketotifen is a Prodrug. Norketotifen is the active metabolite.

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