Repeat dose study with oral prednisolone

Prednisolone reduced pruritic behaviours compared to placebo after a single dose and after repeat dosing (Figure 1). On Day 0, the least-square mean (LSM) pruritus score +/- SE for the dogs treated with prednisolone was 43 +/- 7 versus 59 +/- 7 for placebo (P = 0.0656). Following 7 days of twice daily dosing of prednisolone, the LSM pruritus score continued to be reduced compared to the placebo (49 +/- 7 versus 85 +/- 7 for placebo; P = 0.0003).´

Duration of action study after single injection of dexamethasone

Dexamethasone reduced pruritic behaviours in beagle dogs after a single injection when given 10 h prior to the assessment window (P = 0.0150). However, dexamethasone did not reduce pruritic behaviours when injected 1 h prior to the assessment window (P > 0.1) (Figure 2). LSM pruritus scores +/- SE for the treatment groups were 54 +/- 21 (placebo), 52 +/- 21 (dexamethasone given 1 h prior) and 30 +/- 22 (dexamethasone given 10 h prior).

Figure 4. Effect of oclacitinib and oral prednisolone in the IL-31 induced pruritus model. (a) Study design. (b) Pruritus scores of placebo, oclacitinib (0.4 mg/kg, per os), or prednisolone (0.25 mg/kg or 0.5 mg/kg, p.o.) treated animals observed 1–3 h post-dosing. Data represent least-square means (LSM) +/-), N = 8 per group.

Figure 5. Comparison of effect of oclacitinib and dexamethasone in the IL-31-induced pruritus model. (a) Study design. (b) Pruritus scores of placebo, oclacitinib (0.4 mg/kg, p.o.), and dexamethasone (0.2 mg/kg, i.m.) treated animals observed 1–3 h post-dosing. Data represent least-square means (LSM) +/- SE, N = 8 per group.

Duration of action study after single dose of oclacitinib

After a single oral dose of oclacitinib, pruritus was reduced regardless of whether oclacitinib was given 6, 11 or 16 h prior to the observation period for pruritus as compared to placebo (Figure 3; P = 0.0005–0.0015). LSM pruritus scores +/- SE for the treatment groups were 55 +/- 8 (placebo), 17 +/- 8 (oclacitinib given 6 h prior), 21 +/- 8 (oclacitinib given 11 h prior) and 19 +/- 8 (oclacitinib given 16 h prior).

Speed of onset comparison study of oclacitinib and prednisolone

Oclacitinib reduced pruritus compared to placebo during the 1–3 h post-dosing window (P = 0.0202), whereas oral prednisolone evaluated at either dose did not (Figure 4). Additionally, the reduction in pruritus was greater in the oclacitinib-treated animals than in those treated with 0.25 mg/kg prednisolone (P = 0.0101) or 0.5 mg/kg prednisolone (P = 0.0240; Figure 4). LSM pruritus scores +/- SE for the different treatment groups were 57 +/- 12 (placebo), 16 +/- 13 (oclacitinib 0.4 mg/kg, p.o.), 58 +/- 11 (prednisolone 0.25, mg/kg p.o.) and 48 +/- 8 (prednisolone 0.5 mg/kg, p.o.).

Speed of onset comparison study of oclacitinib and dexamethasone

Oclacitinib reduced pruritus compared to the placebo group (P < 0.0001). Dexamethasone also reduced pruritus compared to placebo (P = 0.0650). However, the reduction in pruritus was greater with oclacitinib when compared to dexamethasone (P < 0.0001). LSM pruritus scores +/- SE among the different treatment groups were 75 +/- 7 (placebo), 10 +/- 2 (oclacitinib) and 55 +/- 8 (dexamethasone), and illustrated in Figure 5.

Discussion

An IL-31-induced canine model of pruritus was developed to (i) recapitulate key pathways involved in pruritus due to allergy, (ii) assess acute anti-pruritic responses of novel therapeutics and (iii) benchmark novel agents or formulations against current therapies used by veterinarians in clinical practice. Canine IL-31 was chosen as the pruritogenic agent because of its demonstrated ability to induce pruritus in dogs and due to its presence in dogs with allergic skin conditions including AD.20 Administration of cIL-31 routinely produced a robust but acute pruritic response in normal beagle dogs 20–40 min after infusion, allowing for pruritus to be assessed over an observation window as short as 2 h. Dogs usually returned to baseline levels by 24 h (data not shown), allowing for dogs to be re-used in subsequent studies. Effects of repeat exposure to cIL-31 were not studied extensively, but an increase in pruritus scores were seen after the second exposure to cIL-31 in the Repeat dose study with oral prednisolone (Figure 1), in which cIL-31 was given to dogs twice within 1 week. It is unclear whether this increase represented a real biological change or whether it was variation in the model; however, cIL-31 evaluations in mice have demonstrated that IL-31 can induce the expression of IL-31 receptor A and oncostatin M receptor beta in dorsal root ganglia after repeated administration and increase long-lasting scratching.26 The ability to rapidly and reproducibly induce pruritus in normal animals after a single cIL-31 injection allows for any laboratory beagle dog to potentially be used in studies. The downside to an acute pruritus model is that other endpoints such as skin lesions, erythema, or biomarker analyses such as leukocyte, cytokine or mRNA changes do not make sense to monitor, as skin lesions do not develop. Therefore, this model may be best used as an initial assessment of agents for acute pruritus before evaluation in more complex models where changes associated with allergen sensitization occur naturally, and chronic changes such as immune dysregulation and skin barrier changes can be evaluated clinically or at the cellular and molecular level.

Standard therapies used to control pruritus in allergic skin diseases were effective in reducing pruritus in this model, building confidence that IL-31-induced pruritus may be a relevant model for pruritic allergic skin diseases. Specifically, oral prednisolone, injectable dexamethasone and oral oclacitinib were capable of reducing IL-31- induced pruritus. Oral oclacitinib consistently demonstrated rapid anti-pruritic effects 1–3 h post-dosing in all three studies performed. Oral prednisolone reduced pruritus 10–12 h post-dosing, and injectable dexamethasone reduced pruritus as quickly as 1–3 h post-injection in one study, but responses were variable possibly due to variability in drug bioavailability or pruritic responses in the animal model. A third possibility could be that the null hypothesis may have been incorrectly rejected in one of the studies due to the use of less stringent statistical criteria. Hypothesis testing was done at the 10% significance level due to the acceptance of a higher risk of type I errors for nonclinical studies.

By incorporating objective and quantitative scoring of pruritus, differentiation among drugs could be seen in this model. For example, a single oral dose of oclacitinib demonstrated a faster onset of action than oral prednisolone and produced a greater suppression of pruritus compared to prednisolone or injectable dexamethasone. These findings could be due to differences in pharmacokinetic properties of the drugs, as oclacitinib is shown to have rapid absorption as demonstrated by a tmax of 0.9– 1.2 h.27 Although the tmax has not been reported for prednisolone, drops in eosinophil cell counts in dogs can be detected around 4–6 h after dosing (PrednisTabTM Freedom of Information Summary, Nov 8, 1991). Alternatively, differential responses in the model could reflect differences in how the drugs work, mechanistically. Oclacitinib inhibits the function of the IL-31 cytokine by inhibiting Janus kinase activity directly downstream of the IL-31 receptor,28 whereas glucocorticoids bind an intracellular glucocorticoid receptor in target tissues that then translocates to the nucleus, where the hormone-receptor complex binds specific DNA sequences to alter gene transcription.29 Many of these corticosteroid-responsive genes are involved in decreasing inflammatory mediators. The need to induce gene transcription changes before inhibiting IL-31 function could be contributing to the differences in speed of onset or magnitude of response. Additionally, this study only evaluated two different types of glucocorticoids at commonly used dose levels and formulations; however, there are numerous alternative formulations and dose regimens that can be used based on the needs of the dog that may show a different speed of onset of anti-pruritic activity.30–32 Nevertheless, this model has the potential to detect differential responses between different formulations, doses, regimens or therapies with different mechanisms of action. In summary, the IL-31 pruritus model was able to detect the efficacy of standard anti-pruritus therapies such as glucocorticoids and oclacitinib and to quantitate differences in efficacy responses between them. These findings indicate that the IL-31-induced itch model in dogs represents a potential in vivo assessment that could be used to evaluate novel anti-pruritus compounds or formulations for dogs and to benchmark them against standard therapies used in clinical practice.

References

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23. Cosgrove SB, Wren JA, Cleaver DM et al. A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis. Vet Dermatol 2013; 24: 587–597.

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Resumé

Contexte – Le prurit est un signe clinique caracteristique d’allergie cutanée comme la dermatite atopique (AD) chez le chien. L’IL-31 est une cytokine retrouvee dans le s sérum de certains chiens atopiques qui peut entrainer du prurit chez les beagles de laboratoire.

Hypotheses/Objectifs –Les objectifs etaient de caractériser un modéle de prurit induit par IL-31 en evaluant l’efficacite de la prednisolone, la déxaméthasone et l’oclacitinib, et de comparer la rapidit
e des effets
antiprurigineux de l’oclacitinib contre ceux de la prednisolone et de la dexam
ethasone.

Sujets – Des chiens beagles d’experimentation ont
et
e utilis
es dans toutes les
etudes.

Methodes –
Des etudes contr
ol ^ ees contre placebo, en aveugle et randomis
ees ont
et
e configur
ees pour
evaluer et comparer les propri
et
es antiprurigineuses de la prednisolone, d
exam
ethasone et oclacitinib sui-
vant une simple injection intraveineuse d’IL-31 recombinante canine. Une surveillance video a
et
e utilis
ee
pour enregistrer et noter les comportements de prurit des animaux d’etude.

Resultats – La prednisolone [0.5 mg/kg, per os (p.o.)] diminuait le prurit induit par IL-31 lorsqu’administre
10h avant l’observation. Quand l’intervalle de temps entre le traitement et l’observation etait r
eduit
 a 1h, la dexam
ethasone (0.2 mg/kg, intramusculaire) mais pas la prednisolone (0.25 ou 0.5 mg/kg, p.o.) diminuait le
prurit induit par IL-31. L’oclacitinib (0.4 mg/kg, p.o.) reduisait le prurit lorsqu’administr
e
 a 1, 6, 11 et 16h avant la periode d’observation et l’activit
e antiprurigineuse de l’oclacitinib
etait meilleure lorsque compar
e
 a la prednisolone et  a la dexam
ethasone
 a tous les points evalu
es.

Conclusion et importance clinique – L’efficacite de la prednisolone, de la d
exam
ethasone et de l’oclaciti-
nib dans le modele de prurit induit par IL-31 permet de croire   a la pertinence de ce modele pour le prurit  aigu associe
 a une dermatite allergique comme l’AD; il peut ainsi etre utilis ^ e pour
evaluer de nouveaux
composants ou formulations.

Resumen

Introduccion –
es un signo cl
ınico caracter
ıstico de las condiciones alergicas de la piel incluida la dermatitis
atopica (AD) de la piel en perros. La interleuquina 31 (IL-31) es una citoquina encontrada en el suero de
algunos perros con dermatitis atopica y puede inducir comportamientos indicativos de prurito en perros de
laboratorio de raza Beagle.

Hipotesis/Objetivos –
el objetivo fue caracterizar un modelo de prurito inducido por IL-31 mediante la evaluacion de la eficacia de prednisolona, dexametasona y oclacitinib, y comparar la velocidad de los efectos
anti-pruriginosos de oclacitinib frente a los de la prednisolona y dexametasona

Animales – perros de raza Beagle con este proposito fueron utilizados en todos los estudios.

Metodos –
estudios al azar, ciegos y controlados con placebo fueron designados para evaluar y comparar las propiedades anti pruriginosas de la prednisolona, dexametasona y oclacitinib siguiendo una inyeccion
intravenosa de IL-31 recombinante canina. Se utilizo vigilancia con video para monitorizar y valorar los com-
partimentos pruriginosos en los animales el estudio

Resultados – la prednisolona (0,5 mg/kg, por v
ıa oral (p.o)) redujo el prurito inducido por IL-31 cuando se administro 10 horas antes de la observaci
on. Cuando el intervalo entre el tratamiento y la observaci
on se
hizo m
as corto a una hora, la dexametasona (0,2 mg/kg, intramuscular) pero no la prednisolona (0,25 o 0,5 mg/kg, por v
ıa oral) redujo el prurito inducido por IL-31. Oclacitinib (0,4 mg/kg, por v
ıa oral) redujo el prurito cuando se administro a 1, 6, 11 y 16 horas previas al periodo de observaci
on, y la actividad anti pruriginosa
de oclacitinib fue mayor comparada con la de prednisolona y dexametasona en todos los tiempos evaluados.

Conclusion e importancia cl

ınica – la eficacia de prednisolona, dexametasona y oclacitinib en el control del prurito inducido por IL31 en este modelo aporta mayor confianza de que puede ser un modelo relevante del prurito agudo asociado con la dermatitis alergica, incluida la dermatitis at
opica, y puede ser utilizado
para evaluar compuestos novedosos o formulaciones

Zusammenfassung

Hintergrund – Juckreiz ist ein charakteristisches Symptom allergischer Erkrankungen, wie der atopischen Dermatitis (AD) des Hundes. IL-31 ist ein Zytokin, welches im Serum von einigen Hunden mit AD gefunden wurde und Kratzverhalten bei Laborbeagles auslosen konnte.

Hypothese/Ziele –Die Ziele dieser Studie waren die Darstellung eines durch IL-31 induzierten Juckreizmodells zur Evaluierung von Prednisolon, Dexamethason und Oclacitinib, und ein Vergleich der Geschwindigkeit der juckreizstillenden Wirkung von Oclacitinib im Vergleich zu Prednisolon und Dexamethason.

Tiere – Fur diese Studie wurden f € ur diesen Zweck gez € uchtete Beagles verwendet.

Methoden – Die randomisierten, geblindeten und Plazebo-kontrollierten Studien wurde entworfen, um die juckreizstillende Wirkung von Prednisolon, Dexamethason und Oclacitinib nach einer einzigen intravenosen € Injektion von rekombinantem caninen IL-31 zu evaluieren und zu vergleichen. Videouberwachung wurde € verwendet, um das Juckreizverhalten bei den Versuchstieren zu beobachten und zu bewerten.

Ergebnisse – Prednisolon [0,5 mg/kg, per os (p.o.)] reduzierte den IL-31 induzierten Juckreiz, wenn es 10 h vor der Beobachtung gegeben wurde. Wenn die Zeitspanne zwischen Medikamentengabe und Beginn der Beobachtung auf 1 h verringert wurde, reduzierte Dexamethason (0,2 mg/kg, intramuskul€ ar), aber nicht Prednisolon (0,25 oder 0,5 mg/kg, p.o.) den IL-31 induzierten Juckreiz. Oclacitinib (0,4 mg/kg, p.o.) reduzierte den Juckreiz bei Gabe von 1, 6, 11 und 16 h vor der Beobachtungsperiode und die juckreizstillende Wirkung von Oclacitinib war zu allen verglichenen Zeitpunkten großer als jene von Prednisolon und Dexa- € methason.

Schlussfolgerungen und klinische Bedeutung – Die Wirkung von Prednisolon, Dexamethason und Oclacitinib im IL-31 induzierten Juckreizmodell best€ atigt, dass es sich hier um ein relevantes Modell fur akuten € Juckreiz, welcher mit allergischer Dermatitis inklusive AD einhergeht, handelt und dass es verwendet werden kann, um neue Wirkstoffe oder Formulierungen zu evaluieren.

要約

背景 – そう痒はイヌにおいてアトピー性皮膚炎を含むアレルギー性皮膚疾患に特徴的な臨床症状である。IL-31は一 部のADのイヌの血清中に検出されるサイトカインであり、実験ビーグル犬において痒み行動を誘発することができる。

仮説/目的 – プレドニゾロン、デキサメサゾンおよびオクラシチニブの効果を評価することによって、IL-31誘発そう痒モ デルの特徴を示すこと、オクラシチニブの抗そう痒効果の速度をプレドニゾロン、デキサメサゾンと比較することを目的とし た。

供与動物 – 目的のため繁殖されたビーグル犬をすべての研究で用いた。

方法 – 組み替えイヌIL-31の単回静脈注射後のプレドニゾロン、デキサメサゾンおよびオクラシチニブの抗そう痒特性 を評価、比較することを目的に、ランダム化、盲検化、プラセボ対照試験を作成した。試験動物のモニターおよびそ う痒行動のスコア化をするためにビデオ監視を使用した。

結果 – プレドニゾロン[0.5 mg/kg、経口投与 (p.o.)]は観察の10時間前に投与した際、IL-31誘発そう痒を減少さ せた。薬剤投与と観察の間の時間を1時間に早めた時、プレドニゾロン(0.25あるいは0.5 mg/kg、p.o.)ではなく、 デキサメサゾン(0.2 mg/kg、筋肉内投与)はIL-31誘発そう痒を減少させた。オクラシチニブ(0.4 mg/kg、 p.o.)は 観察時間の1、6、11、および16時間前に投与した時、そう痒を減少させ、オクラシチニブの抗そう痒活性はすべての 評価ポイントでプレドニゾロンとデキサメサゾンと比較し優れていた。

結論および臨床的な重要性 – IL-31誘発そう痒モデルにおけるプレドニゾロン、デキサメサゾンならびにオクラシチニブ の効果により、このモデルがADを含むアレルギー性皮膚炎に関連した急性そう痒に対する現実的なモデルとなり、新規 の化合物や製剤を評価するために使用できるという信頼性が得られる。

摘要

背景 – 瘙痒是过敏性皮肤病的特点,如犬异位性皮炎(AD)。IL-31这种细胞因子会出现在某些AD患犬血清 中,且可导致实验用比格犬的瘙痒行为。

假设/目的 – 通过评估泼尼松龙、地塞米松和奥拉替尼的效果,来描述IL-31诱导的瘙痒模型,并对比奥拉替 尼和泼尼松龙、地塞米松抗瘙痒的起效速度。

动物 – 研究使用的均为实验用比格犬。

方法 – 设计随机、双盲、安慰剂-对照实验。一次静脉注射重组犬IL-31,评估和对比泼尼松龙、地塞米松和 奥拉替尼的抗瘙痒效果。使用视频监视器监测并给实验动物的瘙痒评分。

结果 – IL-31诱导瘙痒的犬,使用泼尼松龙[0.5 mg/kg,每日一次 (口服)] ,在给药后10h见效。当给药时间和 观察时间缩短至1h时,地塞米松(0.2 mg/kg,肌肉注射)组瘙痒有缓解,而泼尼松龙(0.25 或 0.5 mg/kg,口服) 组瘙痒无缓解。奥拉替尼(0.4 mg/kg,口服)在1、6、11及16h观察其瘙痒行为,其在所有时间点的抗瘙痒效 果都强于泼尼松龙和地塞米松。

结论与临床意义 – 在IL-31诱导的瘙痒模型上,泼尼松龙、地塞米松和奥拉替尼的效果显著,这提示我们可建 立其他慢性瘙痒的模型,如AD等过敏性皮肤病,用于评估新型药品或配方。