DISCOVERY OF PYRAZOLOPYRIDINE DERIVATIVES DUALLY TARGETING INFLAMMATION AND PROLIFERATION IN COLORECTAL CANCER CELL LINES: IN-SILICO DRUG DESIGN APPROACH

Elimination of inflammation represents a promising strategy for cancer prevention and treatment since cancer and inflammation are related. The combined use of anti-inflammatory agents and cancer therapy is a focal point. In this frame, pyrazolopyridine derivatives DZ-BAU2021-6 and DZ-BAU2021-14, developed in BAU Labs, having promising anti-proliferative activity on colon cancer cells HCT-116 and HT-29 with notable IC50 values and remarkable CDK2 inhibitory effect, were in-silico tested. As an approach to dual anti-inflammatory anticancer potential, their binding modes and energies on the active site of crystalline structure of CDK2 and COX2, (1HCK and 3LN1), respectively were explored. Their physicochemical and pharmacokinetic properties as well as their “drug-likeness” were studied. Computational results declared that DZ-BAU2021-6 and DZ-BAU2021-14 exhibited high binding affinities to CDK2 and COX2 receptors. DZ-BAU2021-14 exhibited lower levels of estimated binding energies with COX2 receptor compared to Celecoxib. It demonstrated high GI absorption, low interference with P-glycoprotein and cytochrome P450 isoforms

DZ-BAU2021-14N AS NOVEL PYRAZOLOPYRIDINE NANOCRYSTALS: APPRAISAL OF ANTICANCER ACTIVITY AGAINST HCT-116 AND HT-29 COLORECTAL CANCER CELL LINES

Mentioning DZ-BAU2021-14 (C19H17N5O2,347.370 g/mol) developed in BAU Labs, its promising preliminary antitumor effect nominated it to be selected as a lead antiproliferative compound against colorectal cancer cell lines owing to its proved Cyclin Dependent Kinase 2 (CDK2) inhibition (Kassem et al., 2021). Solving many problems restricting traditional cancer therapy, nanotechnology is offering safety margins and targeted delivery of poorly soluble drug. The potential effect of this compound was combined with the advantages of nanotechnology, precisely nanocrystals to achieve better antiproliferative and hopeful less cytotoxic patterns. The nanocrystals DZ-BAU2021-14N were prepared by an antisolvent precipitation technique using Poloxamer 407 and Cremophor® RH 40 as stabilizers. The nanocrystals were obtained with a nanometric particle size (89.80 ± 11.2 nm) and a negative zeta potential (-32.6 ± 0.50 mV) and were stable at 4 ± 0.5°C with no significant change in particle size or zeta potential. The anticancer activity of DZ-BAU2021-14 and DZ-BAU2021-14N were assessed. Their antiproliferative effects against colorectal cancer cell lines HCT-116 and HT-29 were studied via viability assay. In addition, their cytotoxic effects on non-tumorigenic cell lines NCM-460D were evaluated and respective IC50 values were determined. Different responses were obtained; DZ-BAU2021-14N provided lower IC50 on HCT-116 compared to the free drug DZ-BAU2021-14 (27 and 22 µM, respectively). The safety profile of the free drug was reflected by its IC50 on NCM-460D of 200µM while that of drug nanocrystals showed relative cytotoxicity with IC50 of 33µM, and this requires further investigation to study this response

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Depressive Symptoms among Plastic Surgery Residents

Background:. A literature review did not reveal any study investigating the prevalence of depression among plastic surgery residents. Methods:. We conducted a cross-sectional mail survey and included all Saudi Plastic Surgery residents in our local program in Saudi Arabia. The Beck Depression Inventory II was used. Results:. The inventory showed that mild, moderate, and severe depressive symptoms were prevalent in 20.6%, 38.2%, and 11.8%, respectively. Junior residents were more prone to depression. Conclusions:. The high prevalence rate of depression among plastic surgery residents is alarming, and further studies are warranted. The problem has received no attention in the plastic surgery literature

Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells

Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds 7a and 7b comprising aminoguanidino or guanidino moiety at position 6 inhibited proliferation of RKO colon cancer cells with IC50 of 8 and 4 μM, respectively. Compounds 7a and 7b induced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds 7a and 7b arrested RKO cells in the G1 phase and the most active compound 7b increased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound 7b also activates release of cytochrome c, which is consistent with activation of caspase-9. Additionally, compound 7b increased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents