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GS441524 1355149-45-9
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Introduction
GS-441524现货 1355149-45-9猫传染性腹膜炎
研究小组分别使用了自然感染的猫腹膜巨噬细胞，以及人工感染（使用的是血清型2型的FIP病毒）的猫肾脏细胞（CRFK cell）进行了实验。实验显示，即便在低浓度的情况下，也能产生对FIP病毒繁殖抑制作用。
除了细胞层面的实验，研究小组亦使用了小规模的临床试验。10只实验猫经人工感染FIP，10-18天内出现临床症状，确定患病后分组用药。
不论低剂量组（2mg/kg）还是高剂量组（5mg/kg）在用药后出现快速的改善，高烧减退，淋巴细胞数量快开始恢复正常。这次治疗持续时间是2周。
但在治疗后4-6周，高剂量组、低剂量组各出现了一只猫复发。这两只猫再次进行了为期两周的GS441524治疗，效果依旧优秀。
此后超过8个月这些猫依旧健康没有再出现复发。明显的药物毒性也没有发现。
实验比GC376的效果好，有望成为新的治疗猫传染性腹膜炎的药。
WHERE WE ARE WITH UNDERSTANDING THE CAUSE OF FELINE INFECTIOUS PERITONITIS?
Feline coronavirus (FCoV) infection is very common in cats, and it is FCoV infection which can sometimes result in FIP. Infections with FCoV are usually asymptomatic but result in FIP in around 5-10% of cats1. Asymptomatic FCoV infection was previously believed to be confined to the intestinal tract, but we now know that healthy FCoV-infected cats can have systemic FCoV infection, albeit with lower FCoV viral loads than cats with FIP2-4. Why FCoVs result in FIP in some cats and not in the majority of FCoV-infected cats is the subject of much investigation. Viral factors are important. FCoVs have a spike (S) protein that binds to the host (feline) receptor, mediating host cell entry, and S gene mutations can result in amino acid substitutions in the transcribed S protein that influence the tropism of FCoV, and these are believed to be associated with the ability of FCoV replication to occur outside of the intestinal tract (i.e. in monocytes/macrophages) as systemic FCoV infection5, which is a prerequisite to the development of FIP. Other viral factors are also likely to be important for the subsequent development of FIP following systemic FCoV infection6. Host factors are also very likely to play an important part in FIP development; these include the immune response (e.g. T-lymphocyte depletion occurs in cats that develop FIP), the ability of monocytes to sustain FCoV replication, breed and genetics.
Objectives The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for
cats suffering from various forms of naturally acquired feline infectious peritonitis (FIP).
Methods Cats ranged from 3.4–73 months of age (mean 13.6 months); 26 had effusive or dry-to-effusive FIP and five
had non-effusive disease. Cats with severe neurological and ocular FIP were not recruited. The group was started
on GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased when indicated to 4.0 mg/kg
SC q24h.
Results Four of the 31 cats that presented with severe disease died or were euthanized within 2–5 days and a
fifth cat after 26 days. The 26 remaining cats completed the planned 12 weeks or more of treatment. Eighteen of
these 26 cats remain healthy at the time of publication (OnlineFirst, February 2019) after one round of treatment,
while eight others suffered disease relapses within 3–84 days. Six of the relapses were non-neurological and two
neurological. Three of the eight relapsing cats were treated again at the same dosage, while five cats had the
dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a second time at the higher dosage, including
one with neurological disease, responded well and also remain healthy at the time of publication. However, one of
the three cats re-treated at the original lower dosage relapsed with neurological disease and was euthanized, while
the two remaining cats responded favorably but relapsed a second time. These two cats were successfully treated
a third time at the higher dosage, producing 25 long-time survivors. One of the 25 successfully treated cats was
subsequently euthanized due to presumably unrelated heart disease, while 24 remain healthy.
Conclusions and relevance GS-441524 was shown to be a safe and effective treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at least 12 weeks.