The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.
The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.
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DOI：
10.1038/s41380-018-0064-y
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发表时间：
2020-02
影响因子：
11
通讯作者：
Leggio L
中科院分区：
文献类型：
--
作者：
Lee MR;Tapocik JD;Ghareeb M;Schwandt ML;Dias AA;Le AN;Cobbina E;Farinelli LA;Bouhlal S;Farokhnia M;Heilig M;Akhlaghi F;Leggio L
啮齿类动物的研究表明，胃饥饿素受体阻滞剂可以减少酒精的消耗。然而，没有胃饥饿素受体阻滞剂已被给予大量饮酒的人。因此，我们评估了一种新型胃饥饿素受体反向激动剂PF-5190457与酒精联合给药时的安全性、耐受性、药代动力学（PK）、药效学（PD）和行为效应。我们检测了PF-5190457与酒精联合给药对大鼠自发活动、翻正反射丧失（一种镇静酒精作用的测量方法）和PF-5190457血药浓度的影响。然后，我们对PF-5190457（安慰剂/0 mg b.i.d.，50 mg b.i.d.，100 mg b.i.d.）。12名重度饮酒者在三次相同的访视中完成了酒精管理会话、主观评估、酒精线索反应程序，并提供了用于PK/PD测试的血液样本。在大鼠中，PF-5190457与酒精对自发活动或翻正反射丧失的影响无相互作用。酒精不影响血液PF-5190457浓度。在人类中，所有不良事件均为轻度或中度，无需停药或减量。药物剂量不改变酒精浓度或消除，酒精诱导的刺激或镇静，或情绪在酒精管理。PF-5190457的潜在PD标志物为酰基与总生长素释放肽比值和胰岛素生长因子-1。PF-5190457（100 mg b.i.d.）在线索反应过程中减少对酒精的渴望。本研究首次提供了胃饥饿素受体反向激动剂PF-5190457与酒精联合给药时的安全性和耐受性的翻译证据。PK/PD/行为结果支持继续研究PF-5190457作为治疗酒精使用障碍的潜在药理学药物。
Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of sedative alcohol actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0mg b.i.d., 50mg b.i.d., 100mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss of righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.
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影响因子：
9.8
作者：
Calissendorff, Jan;Danielsson, Olle;Rojdmark, Sven
通讯作者：
Rojdmark, Sven
影响因子：
4.2
作者：
Bhattacharya, Samit K.;Andrews, Kim;Zhang, Yingxin
通讯作者：
Zhang, Yingxin
影响因子：
5.6
作者：
Howick K;Griffin BT;Cryan JF;Schellekens H
通讯作者：
Schellekens H
影响因子：
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作者：
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通讯作者：
Jerlhag, Elisabet
影响因子：
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作者：
Bang, Angela S.;Soule, Steven G.;Pemberton, Chris J.
通讯作者：
Pemberton, Chris J.