Olaparib

Poly ADP ribose polymerase (PARP) inhibitors, such as Olaparib (Lynparza^®), are pivotal in treating certain cancers, particularly those linked to BReast CAncer gene (BRCA) mutations. Despite its established efficacy, Olaparib use is associated with various adverse events (AEs), notably haematologic toxicities, such as anaemia. This retrospective chart review study aimed to examine haematologic outcomes and associated factors in patients treated with Olaparib at a tertiary hospital in the UAE.

We reviewed the medical charts of patients prescribed Olaparib and focused on haematologic indices at a baseline of 1-month, 3-month and 6-month follow-up periods. Data were analysed to determine the AEs frequency, transfusions need and potential associated patients' clinical characteristics.

This study included all patients who received Olaparib (n = 66). Most patients were females (n = 61; 92.4%) and the vast majority were non-smokers (97%) and free of hepatic disease. Themean age of the patients was 57.03-year-old (SD) = 12.06 years), and body mass index (BMI) was 28.16 (SD = 6.40) kg/m². A high rate of anaemia (70.8%) was detected among the patients during their Olaparib therapy. Approximately, one-third of the patients developed neutropenia and thrombocytopenia. Transfusion was needed in almost half of the patients. Glomerular filtration rate (GFR) and neutropenia were significantly correlated with moderate-severe anaemia (OR = 0.097, 95% CI: 0.011-0.88, p value = .038) and (OR = 9.04, 95% CI: 1.024-79.78, p value = .048), respectively.

Our findings highlight the side effects of Olaparib therapy in terms of haematology which could be avoided. Further studies are needed to better understand the therapeutic management of Olaparib and the mitigation of haematologic complications.

Deoxythymidylate kinase (DTYMK) plays a key role in the progression of pancreatic cancer (PC). The computational study began by selecting DTYMK as an anti-cancer target and using a drug library called the FDA-approved anticancer drug library, which contains 1745 compounds. Using molecular docking analysis, MD simulation, and pharmacokinetics profiling, the study identified three novel drug compounds, AZD2281, MDV3100, and carbamazepine with docking scores of -9.8 kcal/mol, -9.7 kcal/mol, and -9.6 kcal/mol, respectively. Additionally, the control compound (E)-1-(4-(hydroxy (phosphonooxy) phosphoryl) but-2-en-1-yl)-5-methyl pyrimidine-1, 3-diium-2, 4-bis (olate) showed a binding affinity of -7.3 kcal/mol. All three compounds met the Lipinski Rule of Five and were considered drug-like. The DTYMK complexes had mean RMSD values of 2.00 Å, 2.07 Å, 1.92 Å, and 2.84 Å for AZD2281, MDV3100, carbamazepine, and the control, respectively. The AZD2281 complex demonstrated the highest stability with no major deviation observed. Salt bridge analysis revealed key interactions such as Glu140-Arg14, Glu26-Arg22, Glu40-Arg37, and Asp103-Lys106. PCA analysis was performed to simplify large datasets, revealing that the eigenvalue patterns of the complexes were quite distinct. MMGB/PBSA calculations showed values of -95.96 kcal/mol and -97.36 kcal/mol for AZD2281, indicating its stability during ligand binding. The most suitable entropy value for AZD2281 suggested the most consistent and ordered binding. This in silico approach identified novel therapeutic compounds for pancreatic cancer, which still require experimental validation and may be modified for targeting DTYMK.