Severe cutaneous adverse reactions due to antibiotics therapy: a pharmacovigilance analysis of FDA adverse event reporting system events.

BACKGROUND: The aim of this study was to monitor, identify and evaluate severe cutaneous adverse reactions (SCAR) induced by antibiotics in patients. METHODS: Disproportionality algorithms were performed in data mining to screen suspected SCAR after using nine categories of antibiotics based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to December 2022. The drug information and demographic characteristics of antibiotic-associated SCAR were also investigated. RESULTS: The FAERS database received 12,212 antibiotic-associated SCAR cases. Approximately half of the SCAR patients were females, the majority of them were adults aged 18-65 years (48.35%), and 47.68% of SCAR patients required hospitalization. The highest SCAR signals RORs (95% CI) for antibiotics were: sulfonamides 23.30 (22.05-24.62), glycopeptides 21.27 (20.26-22.33), penicillins 16.00 (15.44-16.59), carbapenems 10.46 (9.57-11.44), and cephalosporins 13.27 (12.57-14.00). Cefotaxime, sulfamethoxazole/trimethoprim, cefixime, vancomycin, piperacillin, ceftriaxone, amoxicillin, and meropenem had stronger associations with the SCAR than the other antibiotics. However, sulfonamides-associated SCAR cases had the lowest fatality rate (6.23%), penicillin-associated SCAR cases had the highest hospitalization rate (54.16%), and carbapenem-associated SCAR cases seemingly resulted in the highest risk of death (19.03%). CONCLUSION: Data mining of FAERS identified 30 antibiotic-associated SCAR signals, and provided a referable evidence of the occurrence, characteristics and prognosis of antibiotic-related SCARs.

Case Report: Severe Diarrhea Caused by Cryptosporidium Diagnosed by Metagenome Next-Generation Sequencing in Blood.

Background: Cryptosporidium is one of the major pathogens causing diarrhea worldwide. At present, cryptosporidiosis is difficult to prevent and control, especially in immunocompromised hosts. It may cause life-threatening diarrhea and malabsorption among children and immunocompromised patients. Therefore, it is very important to explore rapid diagnostic tools and treatment methods for Cryptosporidium infection. Case Presentation: We reported a case of severe diarrhea caused by cryptosporidiosis in a liver transplant recipient, whose condition was finally confirmed by metagenomic next-generation sequencing (mNGS) and fecal microscopy. His illness was resolved with immunosuppression regulation, nitazoxanide administration, and infection control. Conclusion: So far, nitazoxanide is still the first choice for the treatment of cryptosporidiosis. Our institutional experience suggested that nitazoxanide alone may be effective on the basis of adjusting immunosuppressant. In addition, even though diagnosis of Cryptosporidium infection is a challenge, mNGS can serve as a rapid screening tool in low-prevalence setting.

Discovery of 2-Methyl-2-(4-(2-methyl-8-(1H-pyrrolo[2,3-b]pyridin-6-yl)-1H-naphtho[1,2-d]imidazol-1-yl)phenyl)propanenitrile as a Novel PI3K/mTOR Inhibitor with Enhanced Antitumor Efficacy In Vitro and In Vivo.

PI3K/Akt/mTOR signaling pathway is a validated drug target for cancer treatment that plays a critical role in controlling tumor growth, proliferation, and apoptosis. However, no FDA-approved PI3K/mTOR dual inhibitor exists. Thus, a candidate with a better curative effect and lower toxicity is still urgently needed. Herein, we design, synthesize, and evaluate compounds belonging to a novel series of 2-methyl-1H-imidazo[4,5-c]quinoline scaffold derivatives as PI3K/mTOR dual inhibitors. Among them, compound 8o was identified as a novel candidate with excellent kinase selectivity. It manifested remarkable antiproliferative activities against SW620 and HeLa cells. Western blot and immunohistochemical analysis results proved that 8o could regulate the PI3K/AKT/mTOR signaling pathway by inhibiting the phosphorylation of AKT and S6 proteins. Additionally, 8o presented a favorable pharmacokinetic property (oral bioavailability of 76.8%) and significant antitumor efficacy in vivo without obvious toxicity. Collectively, these results indicated that 8o is a promising agent for cancer treatment and merits further development.

Lead optimization to improve the antiviral potency of 2-aminobenzamide derivatives targeting HIV-1 Vif-A3G axis.

The viral infectivity factor (Vif)-apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) axis has been recognized as a valid target for developing novel small-molecule therapies for acquired immune deficiency syndrome (AIDS) or for enhancing innate immunity against viruses. Our previous work reported the novel Vif antagonist 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide (2) with strong antiviral activity. In this work, through optimizations of ring C of 2, we discovered the more potent compound 6m with an EC50 of 0.07 µM in non-permissive H9 cells, reflecting an approximately 5-fold enhancement of antiviral activity compared to that of 2. Western blotting indicated that 6m more strongly suppressed the defensive protein Vif than 2 at the same concentration. Furthermore, 6m suppressed the replication of various clinical drug-resistant HIV strains (FI, NRTI, NNRTI, IN and PI) with relatively high efficacy. These results suggested that compound 6m is a more potent candidate for treating AIDS.

Discovery of a novel covalent CDK4/6 inhibitor based on palbociclib scaffold.

Cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved in dynamic regulation of cell cycle, play an indispensable role in controlling the tumor growth. Here, based on the scaffold of palbociclib, we designed and synthesized a series of covalent CDK4/6 inhibitors that targeted amino acid Thr107. The optimized compound C-13 exhibited potent in vitro anticancer activity against CDK4/6 with high selectivity over CDK4/6. Moreover, C-13 showed significant tumor growth inhibition in MDA-MB-231 tumor xenograft model (TGI of 93.49% at dose of 40 mg/kg) without causing significant weight loss and toxicity during the treatment period.

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design.

Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2'-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors.

Discovery of a PROTAC targeting ALK with in vivo activity.

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.

Discovery of 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline as a novel c-myc inhibitor against colorectal cancer in vitro and in vivo.

Proto-oncogene c-Myc plays an essential role in the development of colorectal cancer (CRC), since downregulation of c-Myc inhibits intestinal polyposis, which is the most cardinal pathological change in the development of CRC. Herein, a series of novel phenoxy-N-phenylaniline derivatives were designed and synthesized. The cytotoxicity activities of all the derivatives were measured by MTT assay in different colon cancer cells, 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline (42) was discovered, the lead compound 42 with excellent cytotoxicity activity of IC50 = 0.32 µM, IC50 = 0.51 µM, in HT29 and HCT 15 cells, respectively. Compound 42 had a good inhibitory activity of c-Myc/MAX dimerization and DNA binding. Besides, compound 42 could effectively induce apoptosis and induced G2/M arrest in low concentration and G0/G1 arrest in high concentration to prevent the proliferation and differentiation in colon cancer cells. Western blot analysis confirmed the 42 strongly down-regulated expression of c-Myc. Furthermore, during 30 days treatment 42 exhibited excellent efficacy in HT29 tumor xenograft model without causing significant weight loss and toxicity. Consequently, 42 could be a promising drug candidate for CRC therapy.

Discovery of 4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and orally active PI3K/mTOR dual inhibitors.

PI3K/Akt/mTOR signaling pathway plays an important role in cancer cell growth and survival. In this study, a new class of molecules with skeleton of 4-phenyl-2H-benzo[b] [1,4]oxazin-3(4H)-one were designed and synthesized targeting this pathway. Bioassays showed that, among all the molecules, 8d-1 was a pan-class I PI3K/mTOR inhibitor with an IC50 of 0.63 nM against PI3Kα. In a wide panel of protein kinases assays, no off-target interactions of 8d-1 were identified. 8d-1 was orally available, and displayed favorable pharmacokinetic parameters in mice (oral bioavailability of 24.1%). In addition, 8d-1 demonstrated significant efficiency in Hela/A549 tumor xenograft models (TGI of 87.7% at dose of 50 mg/kg in Hela model) without causing significant weight loss and toxicity during 30 days treatment. Based on the bioassays, compound 8d-1 could be used as an anti-cancer drug candidate.