Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

BACKGROUND: There are many in vitro selection method of sperm, and swim-up and density gradient centrifugation are commonly used. It remains unclear which method minimizes bad stimulation to the sperm and select sperm with high fertilization potential. OBJECTIVE: To evaluate the effectiveness of swim-up and gradient centrifugation preparation techniques on intrauterine insemination (IUI).METHODS: A computer-based online search of Cochrane Library, PubMed, EMBASE databases was performed, and some related journals were manually searched for related articles published between January 1966 and February 2009. The quality of included randomized controlled trials (RCT) and q-randomized trials (Q-RCT) was evaluated and Meta-analysis was conducted by the Cochrane Collaboration's software RevMan5.0. Experts.RESULTS AND CONCLUSION: A total of 6 studies were included, involving 4 RCTs and 2 Q-RCTs. A total of 486 patients (1 099 IUI cycles) were enrolled. The Meta-analysis indicated that there was no difference between swim-up and gradient centrifugation preparation techniques for the IUI in terms of cycle pregnancy rates [OR = 1.11, 95%CI(0.8,1.55)], miscarriage rates [OR = 0.31, 95%CI(0.09,1.04)], sperm count [the weight mean difference (WMD) =-0.89, 95%CI(-14.17,12.38)], sperm motility [WMD = -2.31, 95%CI(-7.27,2.65)]. There is insufficient evidence to confirm which is the best method in the two specific preparation techniques. The quality of study methods should be improved. And more measure parameters should be included when comparing it before or after treatment, such as sperm motility, sperm count, sperm function.

Albendazole and mebendazole were comparatively evaluated in 22 adult patients for their in vivo effects on hookworm eggs. Both drugs were given 200mg twice daily for three consecutive days. Stool specimens wore collected before treatment and during the following five days. The Stool egg count was carried out by Stolls method and each specimen was also cultured by Hara-da-Mori technique for at least eight days. The mean pre-treatment percentage of incubated hookworm eggs that developed to larvae was 75.3% in albendazole group and 68.8% in mebendazole group respectively. One day following the initiation of treatment the mean percentage was remarkably reduced to 0.25% in albeadaole group and no eggs developed to larval stage beyond day 1. 0ne day and two days following the initiation of treatment the mean percentage was 16.23% and 23.13% respectively in mebendazole group. No eggs developed to larval stage on day 3 and thereafter. Albendazole seems to have better ovicidal effect than mebendazole.Albendazole and mebendazole were also comparatively evaluated in 123 adult patients with single or mixed infections of hookworm, ascarisis, and trichuris. A single dose of 400mg was used for both drugs. 2 and 4 weeks after treatment, their stools were examined by brine flotation technique. The hookworm eggs negative conversion ratss 2 weeks after treatment were 78.8% and 26.4% respectively in albeadazole and mebendazole group; while those 4 weeks after treatment were 74.1% and 25.5% respectivley. For ascariasis, the eggs negative conversion rates were 98.0% and 92.0% respectively. For trichuriasis, the negative conversion rates were only 20.6% and 27.7% respectively