This work was performed to study the pharmacokinetics of phenobarbital during renal clearance enhancement, intestinal clearance enhancement, and a combination of both to determine which method is clinically more effective in the management of drug poisoning. Thirty young patients with phenobarbital overdose were enrolled in the study. They were classified according to the method of treatment to enhance the elimination of phenobarbital into three equal groups: those treated with multiple-dose activated charcoal (MDAC) alone; those treated with urinary alkalinization alone; and those treated with a combination of the two methods. All patients received the required supportive care at the same time as the elimination procedures. Plasma phenobarbital levels were determined on admission and at 6, 12, 18, 24, 30, 36, 42, and 48 hours after admission by the enzyme multiplied immunoassay technique. The results showed that the decrease in plasma phenobarbital levels with MDAC was significantly greater than with either urinary alkalinization or the combined use of both. The results also revealed statistically significant greater total body clearance for phenobarbital and consequently a shorter half-life with MDAC treatment versus either urinary alkalinization alone or the combined use of both. Thus, the authors conclude that the management of drug overdose in the case of weak acidic drugs that have small volumes of distribution should include the sole use of MDAC and supportive care, without urinary alkalinization.
Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC50 = 3.105 and 2.15 μM) and 4c (IC50 = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC50 = 0.075 and 4.60 μM, respectively, while 3b showed IC50 = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.
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