Design and Synthesis of Thiazole Scaffold-Based Small Molecules as Anticancer Agents Targeting the Human Lactate Dehydrogenase A Enzyme.

A new series of thiazole central scaffold-based small molecules of hLDHA inhibitors were designed using an in silico approach. Molecular docking analysis of designed molecules with hLDHA (PDB ID: 1I10) demonstrates that Ala 29, Val 30, Arg 98, Gln 99, Gly 96, and Thr 94 possessed strong interaction with the compounds. Compounds 8a, 8b, and 8d showed good binding affinity (-8.1 to -8.8 kcal/mol), whereas an additional interaction of NO2 at the ortho position in compounds 8c with Gln 99 through hydrogen bonding enhanced the affinity to -9.8 kcal/mol. Selected high-scored compounds were synthesized and screened for hLDHA inhibitory activities and in vitro anticancer activity in six cancer cell lines. Biochemical enzyme inhibition assays showed the highest hLDHA inhibitory activity observed with compounds 8b, 8c, and 8l. Compounds 8b, 8c, 8j, 8l, and 8m depicted significant anticancer activities, exhibiting IC50 values in the range of 1.65-8.60 µM in HeLa and SiHa cervical cancer cell lines. Compounds 8j and 8m exhibited notable anticancer activity with IC50 values of 7.90 and 5.15 µM, respectively, in liver cancer cells (HepG2). Interestingly, compounds 8j and 8m did not induce noticeable toxicity in the human embryonic kidney cells (HEK293). Insilico absorption, distribution, metabolism, and excretion profiling demonstrates that the compounds possess drug-likeness, and results may pave the way for the development of novel thiazole-based biologically active small molecules for therapeutics.

Rational use of antibiotics for major elective gynaecological and obstetrical surgical procedures: quality improvement journey from a tertiary care public facility.

BACKGROUND: Antibiotic resistance is a global problem. Irrational use of antibiotics is rampant. Guidelines recommend administration of single dose of antibiotic for surgical antimicrobial prophylaxis (SSAP) for elective obstetrical and gynaecological surgeries. However, it is not usually adhered to in practice. Majority of women undergoing elective major gynaecological surgeries and caesarean sections in the department of obstetrics and gynaecology of our tertiary level heavy case load public health facility were receiving therapeutic antibiotics (for 7-10 days) instead of recommended SSAP. Our aim was to increase the SSAP in our setting from a baseline 2.1% to more than 60% within 6 months. METHODS: After root cause analysis, we formulated the departmental antimicrobial policy, spread awareness and sensitised doctors and nursing officers regarding antimicrobial resistance and asepsis through lectures, group discussions and workshops. We initiated SSAP policy for elective major surgeries and formed an antimicrobial stewardship team to ensure adherence to policy and follow processes and outcomes. The point of care quality improvement (QI) methodology was used. Percentage of patients receiving SSAP out of all low-risk women undergoing elective surgery was the process indicator and percentage of patients developing surgical site infection (SSI) of all patients receiving SSAP was the outcome indicator. The impact of various interventions on these indicators was followed over time with run charts. RESULTS: SSAP increased from a baseline 2.1%-67.7% within 6 months of initiation of this QI initiative and has since been sustained at 80%-90% for more than 2 years without any increase in SSI rate. CONCLUSION: QI methods can rapidly improve the acceptance and adherence to evidence-based guidelines in a busy public healthcare setting to prevent injudicious use of antibiotics.

Conservative management of cervical pregnancy: a report of two cases.

BACKGROUND: Cervical ectopic pregnancy is a rare form of ectopic pregnancy. Treatment of this clinical condition is controversial. Previously, hysterectomy was the mainstay of treatment, but in the recent past various conservative management approaches have been applied to preserve fertility. We report 2 such cases in which conservative approach was implemented. CASES: Case 1 was an early, nonviable cervical pregnancy in which systemic methotrexate was used with success. Case 2 was a viable, advanced cervical pregnancy (at 11 weeks) in which a combination of uterine artery embolization and systemic methotrexate was used. Ultimately this patient required hysterectomy due to sudden massive hemorrhage on day 22 of intervention. CONCLUSION: On reviewing our results and the literature, we conclude that uterine artery embolization with methotrexate is effective in reducing the ectopic cervical mass. However, there is always a risk of hemorrhage, which can be treated by either repeat uterine artery embolization alone or uterine artery embolization followed by curettage. Hysterectomy should be the last resort if all conservative methods fail.