Interactions of the potent synthetic AT1 antagonist analog BV6 with membrane bilayers and mesoporous silicate matrices

The present work describes the drug:membrane interactions and a drug delivery system of the novel potent AT1 blocker BV6. This designed analog has most of the pharmacological segments of losartan and an additional biphenyltetrazole moiety resulting in increased lipophilicity. We found that BV6:membrane interactions lead to compact bilayers that may in part explain its higher in vitro activity compared to losartan since such environment may facilitate its approach to AT1 receptor. Its high docking score to AT1 receptor stems from more hydrophobic interactions compared to losartan. X-ray powder diffraction (XRPD) and thermogravimetric analysis (TGA) have shown that BV6 has a crystalline form that is not decomposed completely up to 600 °C. These properties are desirable for a drug molecule. BV6 can also be incorporated into a mesoporous silicate drug-delivery matrix SBA-15. The properties of the obtained drug-delivery system have been inspected by XRD, 13C CP/MAS, TGA and nitrogen sorption experiments

Aspiration thrombectomy of M2 middle cerebral artery occlusion to treat acute ischemic stroke: A core lab–adjudicated subset analysis from the COMPLETE registry and literature review

Background Although the benefits of aspiration thrombectomy for treating acute ischemic stroke caused by proximal large vessel occlusion have been established, fewer data are available for evaluating aspiration thrombectomy of distal occlusion. The objective of this study was to evaluate, by means of prospectively collected data, the safety and efficacy of aspiration thrombectomy in patients with M2 middle cerebral artery (MCA) occlusion. Methods This study is a subset analysis of a global prospective multicenter observational registry that included patients who presented with either anterior or posterior large vessel occlusion and were eligible for mechanical thrombectomy using the Penumbra System including the Penumbra 3D Revascularization Device. For this analysis, all patients in the registry with M2 MCA occlusion were included. Results Of the 650 patients in the registry, 113 (17.4%) had M2 MCA occlusion. The rate of a modified treatment in cerebral infarction score of 2b to 3 after the procedure was 79.6% (90/113), the rate of a modified Rankin Scale score of 0–2 at 90 days was 72.5% (79/109), and the all-cause mortality rate at 90 days was 8.8% (10/113). Device-related serious adverse events occurred in one patient (0.9%) within 24 h and in two patients (1.8%) overall. Procedure-related serious adverse events occurred in four patients (3.5%) within 24 h and in six patients (5.3%) overall (nine events). Conclusion For appropriately selected patients, aspiration thrombectomy for acute ischemic stroke due to M2 MCA occlusion was safe and effective, with high rates of technical success and good functional outcome

Halogenated triazinediones behave as antagonists of PKR1: in vitro and in vivo pharmacological characterization

Different prokineticin receptor antagonists, based on the triazinedione scaffold, were synthesized by a new efficient method. Here we demonstrated that 5-benzyltriazinedionessubstituted in position para of the benzyl group with halogens provide compounds endowed with interesting selectivity for the Prokineticin receptor 1 (PKR1). BRET technology indicates that such substitutionresults in increased affinity for thePKR1.The affinity for PKR2, always in M range, was never significantly affected by the para-halogen-benzyl pharmacophores. The analog bearing a para-bromobenzyl pharmacophore (PC-25) displayed the highest affinity for PKR1 (~18 times higher than the reference PC-1 that bears apara-ethyl benzyl group) and the highest selectivity (~300 times). The other halogen substitutedanalogs (PC-7, PC-18 and PC-35), showed selectivity for PKR1 more than 100 times higher than for PKR2. Using transgenic mice lacking one of the two PKRs we demonstrated that all these compounds were able to abolish the Bv8-induced hyperalgesia in mice still expressing the PKR1 at doses lower than those necessary to abolish hyperalgesia in mice expressing only the PKR2. The dose ratio reflected the in- vitro evaluated receptor selectivity

Molecular epidemiology of SARS-CoV-2: the dominant role of arginine in mutations and infectivity

Background, Aims, Methods, Results, Conclusions: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CLpro) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants’ distribution data for SARS-CoV-2 across EU/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1/S2 (681-PRRARS-686) S2′ (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19

The association between clinician-based common terminology criteria for adverse events (CTCAE) and patient-reported outcomes (PRO): a systematic review

Symptomatic adverse events (AEs) are monitored by clinicians as part of all US-based clinical trials in cancer via the U.S. National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) for the purposes of ensuring patient safety. Recently there has been a charge toward capturing the patient perspective for those AEs amenable to patient self-reporting via patient-reported outcomes (PRO). The aim of this review was to summarize the empirically reported association between analogous CTCAE and PRO ratings

Influence of the initial chemical conditions on the rational design of silica particles

The influence of the water content in the initial composition on the size of silica particles produced using the Stöber process is well known. We have shown that there are three morphological regimes defined by compositional boundaries. At low water levels (below stoichiometric ratio of water:tetraethoxysilane), very high surface area and aggregated structures are formed; at high water content (>40 wt%) similar structures are also seen. Between these two boundary conditions, discrete particles are formed whose size are dictated by the water content. Within the compositional regime that enables the classical Stöber silica, the structural evolution shows a more rapid attainment of final particle size than the rate of formation of silica supporting the monomer addition hypothesis. The clearer understanding of the role of the initial composition on the output of this synthesis method will be of considerable use for the establishment of reliable reproducible silica production for future industrial adoption

Evaluation of a stable Gonadotropin-Releasing Hormone analog in mice for the treatment of endocrine disorders and prostate cancer

Gonadotropin-releasing hormone (GnRH) receptor agonists have wide clinical applications including the treatment of prostate cancer and endocrine disorders. However, such agonists are characterized by poor pharmacokinetic properties, often requiring repeated administration or special formulations. Therefore, the development of novel peptide analogs with enhanced in vivo stability could potentially provide therapeutic alternatives. The pharmacological evaluation of a bioactive peptide [Des-Gly10,Tyr5(OMe),D-Leu 6,Aze-NHEt9]GnRH, analog 1, is presented herein and compared with leuprolide. Peptide stability was evaluated using mouse kidney membrane preparations, followed by a liquid chromatography-tandem mass spectrometry-based approach that afforded identification and quantification of its major metabolites. The analog was significantly more stable in vitro in comparison with leuprolide. In vitro and in vivo stability results correlated well, encouraging us to develop a clinically relevant pharmacokinetic mouse model, which facilitated efficacy measurements using testosterone as a biomarker. Analog 1, an agonist of the GnRH receptor with a binding affinity in the nanomolar range, caused testosterone release in mice that was acutely dose-dependent, an effect blocked by the GnRH receptor antagonist cetrorelix. Repeated dosing studies in mice demonstrated that analog 1 was well tolerated and had potency similar to that of leuprolide, based on plasma and testis testosterone reduction and histopathological findings. Analog 1 also shared with leuprolide similar significant antiproliferative activity on androgen-dependent prostate cancer (LNCaP) cells. On the basis of pharmacokinetic advantages, we expect that analog 1 or analogs based on this new design will be therapeutically advantageous for the treatment of cancer and endocrine disorders. Copyrigh