Lotilaner   中文名称: 洛替拉纳

GABA receptors

Lotililaner对于果蝇狄氏剂/氟丙隆甲醛抗性形式(DmR2)、鲑鱼虱(Ls)和微小扇头蜱(Rm)的GABACl受体的IC50值分别是38.25±3.75、52.40±4.54和36.79±4.39nM [1-.
洛替拉奈是一种针对螨虫的γ-氨基丁酸门控氯离子通道非竞争性拮抗剂。 抑制GABACl会导致目标生物体产生麻痹作用，从而导致死亡。在体外测试中，洛替拉奈在浓度高达30 µM（约18 µg/mL）时——这大约是人类推荐眼科剂量的1100倍——不会抑制哺乳动物的GABA介导的氯离子通道。 据推测，洛替拉奈在GABACl上的作用位点位于T9'至S15'区域之间的孔道内，这是一个亚基间的区域。一项研究表明，洛替拉奈可能在GABACl的孔道内迁移至其最终位置，从而将通道稳定在关闭状态；然而，这一假说仍需进一步研究。

用于治疗跳蚤和蜱虫感染。 跳蚤和蜱虫必须附着于宿主并开始吸血，才能暴露于活性物质。本兽药产品可作为控制跳蚤过敏性皮炎治疗方案的一部分。
对于犬类： 本兽药产品能立即并持续杀灭跳蚤（猫栉首蚤和犬栉首蚤）以及蜱虫（血红扇头蜱、篦子硬蜱、六角硬蜱和网纹革蜱），效力持续1个月。
对于猫类： 本兽药产品能立即并持续杀灭跳蚤（猫栉首蚤和犬栉首蚤）以及蜱虫（篦子硬蜱），效力持续1个月。
洛替拉奈 是一种异恶唑啉类化合物的体外寄生虫杀灭剂。洛替拉奈主要作为抗寄生虫剂用于兽医学，以治疗动物身上的跳蚤和蜱虫感染。洛替拉奈包含两种对映异构体：S-对映体在体内具有活性，而据报道R-对映体表现出较低的生物活性。洛替拉奈药品中的活性成分是S-对映体。2023年7月25日，美国食品药品监督管理局批准洛替拉奈用于治疗蠕形螨睑缘炎，使其成为该疾病首个且唯一获批的疗法。
洛替拉奈是一种体外寄生虫杀灭剂。
洛替拉奈 是一种小分子药物，其最高临床试验阶段（在所有适应症中）为IV期，于2017年首次获批，适应症为眼部感染，并拥有2个研究中的适应症。

Absorption, Distribution and Excretion
Following a single ocular dose, Tmax was approximately 2 hours after day 1; following the last dose, Tmax was approximately 1 hour after day 42. In healthy subjects, after 42 consecutive days of ocular administration, peak whole blood concentration (Cmax) increased from 0.596 ng/mL to 17.8 ng/mL. Total exposure (AUC0-12) also increased from 5.75 hr x ng/mL to 149 hr x ng/mL. In patients with Demodex blepharitis treated twice daily with loteranal for 42 days, the mean systemic exposure at the end of treatment was 12.0 ng/mL, ranging from 0.4 to 46.1 ng/mL.
No relevant information available.
No relevant information available.
No relevant information available.
Metabolism/Metabolites In cats, the metabolism of loteranal was not observed. Loteranal is not metabolized by CYP enzymes.

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Biological half-life
In healthy subjects, the effective half-life is 264 hours (11 days), calculated based on the cumulative ratio over a 12-hour dosing interval.

Protein Binding
Loteranar exhibits high plasma protein binding in human plasma (>99.9%). The distribution of loteranar in human blood cells is approximately 10% (range 0-20%).

[1]. The novel isoxazoline ectoparasiticide lotilaner (Credelio™): a non-competitive antagonist specific to invertebrates γ-aminobutyric acid-gated chloride channels (GABACls). Parasit Vectors. 2017 Nov 1;10(1):530.

Lotilaner belongs to the isoxazole class of compounds with the structure 4,5-dihydro-1,2-oxazole, substituted at positions 3, 5, and 6 with 4-methyl-5-({2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}carbamoyl)thiophene-2-yl, trifluoromethyl, and 3,4,5-trichlorophenyl (5S-stereoisomer). It is a GABA-gated chloride channel inhibitor with selectivity for mites and is approved for the treatment of Demodex blepharitis. It functions as a GABA-gated chloride channel antagonist, an ophthalmic agent, and an in vitro parasite killer. It is a trichlorobenzene and belongs to the isoxazole, organofluorine, thiophene, and secondary amide classes. Lotilaner is an in vitro parasite killer belonging to the isoxazoline class of compounds. Lotelanar is primarily used as a veterinary antiparasitic drug to treat flea and tick infections in animals. Lotelanar has two enantiomers: the S-enantiomer has in vivo activity, while the R-enantiomer has been reported to have lower biological activity. The active ingredient in lotelanar formulations is the S-enantiomer. On July 25, 2023, lotelanar was approved by the U.S. Food and Drug Administration (FDA) for the treatment of Demodex blepharitis, becoming the first and currently only approved drug for this condition. Lotelanar is an ectoparasitic agent.
Drug Indications
Lotelanar is indicated for the treatment of Demodex blepharitis. It can also be used to treat flea and tick infections. Fleas and ticks must attach to a host and begin feeding to access the active ingredient. This veterinary product can be used as part of a treatment regimen to control flea allergic dermatitis (FAD). Canines: This veterinary drug provides immediate and sustained killing of fleas (Ctenopharynx catii and Ctenopharynx dogii) and ticks (Herba Ursae Majoris, Herba Ricinus communis, Herba Hexagonae, and Herba Reticulatae), with effects lasting up to one month. Cats: This veterinary drug provides immediate and sustained killing of fleas (Ctenopharynx catii and Ctenopharynx dogii) and ticks (Herba Ricinus communis), with effects lasting up to one month. Mechanism of Action: Loteranar is a non-competitive γ-aminobutyric acid (GABA)-gated chloride channel (GABACl) antagonist with selectivity against mites. Inhibition of GABACl leads to paralysis of the target organism, ultimately resulting in death. In vitro studies showed that at concentrations up to 30 µM (18 µg/mL), loteranar was not a mammalian GABA-mediated chloride channel inhibitor, which is approximately 1100 times the recommended human ophthalmic dose. It is hypothesized that loteranal's target in GABACl lies within the pores between the T9' and S15' regions, which belong to the mesenchymal subunit region. One study suggests that loteranal may migrate to its final location within the GABACl pores, thereby stabilizing the channel in a closed state; however, this hypothesis requires further investigation.
Pharmacodynamics
Loteranal is an antiparasitic drug effective against Demodex mites that cause Demodex blepharitis. It is also effective against insects, ticks, and lice. Its activity is arthropod-specific because it does not bind to the same therapeutic targets in mammals.

C20H14CL3F6N3O3S

596.757881641388

594.973

C, 40.25; H, 2.36; Cl, 17.82; F, 19.10; N, 7.04; O, 8.04; S, 5.37

1369852-71-0

76959255

White to off-white solid powder

6.224

108.03

2

11

6

36

868

1

CC1=C(SC(=C1)C2=NO[C@@](C2)(C3=CC(=C(C(=C3)Cl)Cl)Cl)C(F)(F)F)C(=O)NCC(=O)NCC(F)(F)F

HDKWFBCPLKNOCK-SFHVURJKSA-N

InChI=1S/C20H14Cl3F6N3O3S/c1-8-2-13(36-16(8)17(34)30-6-14(33)31-7-19(24,25)26)12-5-18(35-32-12,20(27,28)29)9-3-10(21)15(23)11(22)4-9/h2-4H,5-7H2,1H3,(H,30,34)(H,31,33)/t18-/m0/s1

3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide

Lotilaner; 1369852-71-0; Credelio; XDEMVY; lotilanerum; Xdemvy

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~167.57 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.19 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (3.49 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。