Effects of tirofiban on large vessel occlusion stroke are modified by etiology and renal function.

OBJECTIVE: Renal function can modify the outcomes of large vessel occlusion (LVO) stroke across stroke etiologies in disparate degrees. The presence of renal function deficit can also impair the pharmacokinetics of tirofiban. Hence, this study aimed to investigate the roles of renal function in determining efficacy and safety of intravenous tirofiban before endovascular treatment (EVT) for acute ischemic stroke patients with large vessel occlusion (LVO). METHODS: This study was a post hoc exploratory analysis of the RESCUE-BT trial. The primary outcome was the proportion of patients achieving functional independence (modified Rankin scale 0-2) at 90 days, and the primary safety outcome was the rate of symptomatic intracranial hemorrhage (sICH). RESULTS: Among 908 individuals with available serum creatinine, decreased estimated glomerular filtration rate (eGFR) status was noted more commonly in patients with cardioembolic stroke (CE), while large artery atherosclerosis (LAA) was predominant in patients with normal renal function. In LAA with normal renal function, tirofiban was associated with higher rates of functional independence at 90 days (41.67% vs 59.80%, p = 0.003). However, for LVO patients with renal dysfunction, tirofiban did not improve functional outcomes for any of the etiologies (LAA, p = 0.876; CE, p = 0.662; others, p = 0.894) and significantly increased the risk of sICH among non-LAA patients (p = 0.020). Mediation analysis showed tirofiban reduced thrombectomy passes (12.27%) and drug/placebo to recanalization time (14.25%) mediated its effects on functional independence. CONCLUSION: This present study demonstrated the importance of evaluating renal function before administering intravenous tirofiban among patients with LVO who are planned to undergo EVT.

Aspartate-modified doxorubicin on its N-terminal increases drug accumulation in LAT1-overexpressing tumors.

L-type amino acid transporter 1 (LAT1), overexpressed on the membrane of various tumor cells, is a potential target for tumor-targeting therapy. This study aimed to develop a LAT1-mediated chemotherapeutic agent. We screened doxorubicin modified by seven different large neutral amino acids. The aspartate-modified doxorubicin (Asp-DOX) showed the highest affinity (Km = 41.423 µmol/L) to LAT1. Aspartate was attached to the N-terminal of DOX by the amide bond with a free carboxyl and a free amino group on the α-carbon atom of the Asp residue. The product Asp-DOX was characterized by HPLC/MS. In vitro, Asp-DOX exerted stronger inhibition on the cancer cells overexpressing LAT1 and the uptake of Asp-DOX was approximately 3.5-fold higher than that of DOX in HepG2 cells. Pharmacokinetic data also showed that Asp-DOX was expressed over a longer circulation time (t1/2 = 49.14 min) in the blood compared to DOX alone (t1/2 = 15.12 min). In HepG2 and HCT116 tumor-bearing mice, Asp-DOX achieved 3.1-fold and 6.4-fold accumulation of drugs in tumor tissue, respectively, than those of the unmodified DOX. More importantly, treatment of tumor-bearing mice with Asp-DOX showed a significantly stronger inhibition of tumor growth than mice treated with free DOX in HepG2 tumor models. Furthermore, after Asp modification, Asp-DOX avoided MDR mediated by P-glycoprotein. These results suggested that the Asp-DOX modified drug may provide a new treatment strategy for tumors that overexpress LAT1 and MDR1.

Potent tumor targeting drug release system comprising MMP-2 specific peptide fragment with self-assembling characteristics.

Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.

Long-acting GLP-1 analogue in V-shaped conformation by terminal polylysine modifications.

Glucagon-like peptide-1 (GLP-1) possesses multiple physiological functions, which make it a potential drug candidate for the treatment of type 2 diabetes. However, its clinical application was limited severely by its short half-life in vivo. Therefore, stabilization of GLP-1 is critical for the use of this peptide in drug development. In this study, a novel GLP-1 derivative, VGLP1K6, processed a significantly prolonged half-life in vivo. Structural analysis using molecular dynamics simulations demonstrated that VGLP1K6 has a rigid V-shaped conformation resulting from the intrapeptide disulfide bond. The C-terminal polylysine residues of VGLP1K6 caused the vulnerable N-terminus of GLP-1 (HA-fragment) to reside within the pocket-like cavity of the peptide due to the intrahydrogen bonds. The structural analysis suggested that this structural alteration contributed to the remarkable prolonged half-life of VGLP1K6, which was approximately 70 h. In addition, VGLP1K6 induced better long-acting glucose tolerance and greater HbA1c reductions than GLP-1 in rodents. Our findings suggest that the GLP-1 derivative VGLP1K6 might be a possible potent antidiabetic drug for the treatment of type 2 diabetes mellitus.

Self-assembling peptides improve the stability of glucagon-like peptide-1 by forming a stable and sustained complex.

The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of T2DM. However, the short half-life of GLP-1 limits its clinical utility. Self-assembling peptides are presumed to wrap GLP-1 peptide, and this helps to prolong the stability of GLP-1 consequently. The aim of this study was to investigate whether self-assembling peptides could be applied to prolong the half-life of GLP-1 as sustained release preparations. In this study, five different self-assembling peptides were employed. The formation of the complexes was monitored using gel filtration and mass spectrometry and was simulated by Molecular Dynamics. Stabilization, insulin secretion stimulation, and glucose tolerance tests were performed to investigate the physiological characteristics retained by GLP-1 following complex formation with self-assembling peptides. Our findings revealed that, among the five different self-assembling peptides tested, complex of Pep-1 and GLP-1 exhibited a remarkable extension in the half-life of GLP-1. In addition, the experimental animals treated with a GLP-1/Pep-1 complex exhibited better blood glucose clearance activity over a greater duration of time than the animals treated with GLP-1 alone. Based on our results, an adjustment of the Pep-1 and GLP-1 ratios is presumed to be able to control the half-life of GLP-1 (e.g., medium-acting and long-acting). Collectively, the findings in this study suggest that the self-assembling peptide Pep-1 could serve as a powerful drug preparation tool to extend the short half-life of therapeutic peptides.

Highly enantioselective hydrogenation of alpha-arylmethylene cycloalkanones catalyzed by iridium complexes of chiral spiro aminophosphine ligands.

The highly efficient asymmetric hydrogenation of alpha-arylmethylene cycloalkanones catalyzed by Ir-complexes of chiral spiro aminophosphine ligands was developed, providing chiral exo-cyclic allylic alcohols at high yields with excellent enantioselectivities (up to 97% ee) and high turnover numbers (S/C up to 10,000). This new reaction provided an efficient method for the synthesis of the key intermediate of the active form of the anti-inflammatory loxoprofen.

Highly enantioselective synthesis of chiral cyclic amino alcohols and conhydrine by ruthenium-catalyzed asymmetric hydrogenation.

A highly efficient enantio- and diastereoselective synthesis of chiral cis-beta-N-alkyl/arylamino cyclic alcohols has been realized by asymmetric hydrogenation of racemic alpha-amino cyclic ketones via DKR catalyzed by [RuCl(2)((S)-Xyl-SDP)((R,R)-DPEN)]. The enantioselectivities of the reaction were up to 99.9% ee with 99:1 cis-selectivities. A practical catalytic asymmetric synthesis of all four isomers of conhydrine was also developed.

Highly enantioselective and diastereoselective synthesis of chiral amino alcohols by ruthenium-catalyzed asymmetric hydrogenation of alpha-amino aliphatic ketones.

A highly efficient asymmetric hydrogenation of racemic acyclic alpha-amino aliphatic ketones via dynamic kinetic resolution has been realized, providing chiral amino alcohols in excellent enantioselectivities and diastereoselectivities. A hydrogen-bonding transition state mode was proposed for explaining the high diastereoselectivity and enantioselectivity of the reaction.

Polyamidoamine dendrimers with a modified Pentaerythritol core having high efficiency and low cytotoxicity as gene carriers.

Polyamidoamine (PAMAM) dendrimers represent one of the most efficient polymeric gene carriers. This study describes a new family of PAMAM dendrimers that can be synthesized using a Pentaerythritol derivative (PD) as a core that possesses 12 branches. This new approach in the synthesis of divergent dendrimers provided a rapid increase in the number of branches, which made it easier to obtain dendrimers with high generation and large enough molecular size. The PD dendrimers of generations 3-5 synthesized in this study could efficiently condense DNA into nanoscale complexes with slightly positive charges. Their transfection efficiency was evaluated in different cell lines. These PD dendrimers were found to show higher transfection efficiency, but much lower cytotoxicity, than the commercial nonviral gene carriers polyethyleneimine (PEI), polylysine (PLL), and PAMAM dendrimers with an ethylenediamine core (generations 5 and 7). The results indicate that, with high transfection efficiency and low cytotoxicity, the PD dendrimers hold promise as novel nonviral gene carriers.

[Study on the microwave extraction and chemical constituents of the essential oil from Amomum tsao-ko in Jinping, Yunnan province].

Essential oil from Amomum tsao-ko collected in Jinping, Yunnan province was obtained by microwave extraction, common solvent extraction and vapor distillation, respectively. Chemical constituents were analyzed by GC-MS and their relative contents were determined by area-normalized method.