Bioequivalence Assessment of Two Dapoxetine Hydrochloride Formulations in Healthy Chinese Males Under Fasted and Fed Conditions.

This study evaluated the bioequivalence of the newly developed dapoxetine hydrochloride tablet relative to the marketed reference product by comparing their pharmacokinetic profiles under fasted and fed conditions. A total of 60 healthy Chinese male subjects participated in a single-center, 2-period, 2-sequence, randomized, open-label, self-crossover study with a washout period of 14 days, 30 in the fasted group and 30 in the fed group. Following a single 30-mg oral dose of the test or reference dapoxetine formulation, blood samples were collected before dosing to 72 hours after dosing. Liquid chromatography-tandem mass spectrometry was performed to measure plasma concentration of dapoxetine and determine pharmacokinetic parameters through noncompartmental analysis. The vital signs and adverse events were also monitored during the study. The 90% confidence intervals of the geometric mean ratios for maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last concentration time, and area under the plasma concentration-time curve from time 0 extrapolated to infinity of the 2 dapoxetine formulations completely fell within the regulatory criteria for bioequivalence of 80%-125%. In addition, both dapoxetine hydrochloride formulations were generally well tolerated. The generic dapoxetine hydrochloride tablet was bioequivalent to the marketed reference product in healthy Chinese men with no discernible safety differences.

Cardioprotective Effects of Tetrahydropalmatine on Acute Myocardial Infarction in Rats.

Tetrahydropalmatine (THP) is an active component of Corydalis yanhusuo W. T. Wang. The current study investigates the possible cardioprotective effects of tetrahydropalmatine in acute myocardial ischemia (AMI) rats. The anterior descending coronary artery of SD rats was ligated to establish an AMI model. After two weeks of gavage of THP, cardiac function was determined by echocardiography. The organ index and the infarct size were assessed after the experiment, and the histopathological myocardial tissue changes were observed. In addition, the apoptosis index of myocardial cells was detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The levels of SOD, MDA, CAT, GSH-Px, BNP, and cTn-I were measured by enzyme-linked immunosorbent assay. To determine relevant proteins, the Western blot and molecular docking were applied. Compared with the model group, THP could enhance rat cardiac ejection function to improve cardiac function, drastically lessen the infarct size, reduce myocardial cell damage and inflammatory cell infiltration. THP might also prevent ischemic myocardial damage by inhibiting myocardial cell apoptosis and efficiently reducing oxidative stress. Specifically, THP could decrease MDA, BNP, c-TnI activities, as well as the expression of Bax and Caspase-3 protein, while increasing SOD, GSH-Px, CAT activities, and Bcl-2 level. Furthermore, THP could significantly promote the phosphorylation of PI3K and Akt proteins. The involved pathways and proteins have also been verified through molecular docking. According to these findings, THP may preserve the myocardium due to its anti-oxidant and anti-apoptotic properties.

Cascade targeting codelivery of ingenol-3-angelate and doxorubicin for enhancing cancer chemoimmunotherapy through synergistic effects in prostate cancer.

Immunotherapy has led to an expansion of the treatment of malignancies, but its effect in prostate cancer (PCa) patients is modest. Chemoimmunotherapy is a promising approach that has attracted substantial attention. Although the widely used clinical chemotherapeutic drug doxorubicin (DOX) elicits immunogenic cell death (ICD), its weak ICD effect and the abnormal vasculature of tumors severely limit its efficacy in chemoimmunotherapy. Ingenol-3-angelate (I3A), an emerging antitumor drug with dual chemotherapeutic and immune response-eliciting effects, is expected to exert synergistic effects when administered in combination with DOX. I3A induces the ICD of PCa cells by triggering mitophagy and apoptosis and promotes the normalization of tumor vessels, resulting in sufficient infiltration of immune cells into tumors. A synergistic effect of I3A and DOX was observed in vitro at a molar ratio of 1:4. To codeliver this ratio of I3A and DOX to tumor and ensure their uptake, we designed a dual-targeting delivery system, polylactide-poly(ethylene) glycol-2-(3-((S)-5-amino-1-carboxypentyl)-ureido) pentanedioate/triphenylphosphonium (PLA-PEG-ACUPA/TPP), which targets prostate-specific membrane antigen (PSMA) and mitochondria. Delivery of these nanomedicines led to inhibited tumor growth and a strong antitumor immune response. This study sheds light on the mitophagic and antiangiogenic mechanisms underlying I3A treatment of PCa and provides a strategy for combining vascular normalization and chemoimmunotherapy for PCa treatment.

Acetyl-11-keto-ß-boswellic acid (AKBA) inhibits human gastric carcinoma growth through modulation of the Wnt/ß-catenin signaling pathway.

BACKGROUND: Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, an active component of Boswellia serrata gum resin. We examined the effect of AKBA on human gastric carcinoma growth and explored the underlying molecular mechanisms. METHODS: Inhibition of cancer cell growth was estimated by colorimetric and clonogenic assays. Cell cycle distribution was analyzed by flow cytometry and apoptosis determined using Annexin V-FITC/PI staining and DNA ladder quantification. After three weeks of oral AKBA administration in nude mice bearing cancer xenografts, animals were sacrificed and xenografts removed for TUNEL staining and western blot analysis. RESULTS: AKBA exhibited anti-cancer activity in vitro and in vivo. With oral application in mice, AKBA significantly inhibited SGC-7901 and MKN-45 xenografts without toxicity. This effect might be associated with its roles in cell cycle arrest and apoptosis induction. The results also showed activation of p21(Waf1/Cip1) and p53 in mitochondria and increased cleaved caspase-9, caspase-3, and PARP and Bax/Bcl-2 ratio after AKBA treatment. Further analysis suggested that these effects might arise from AKBA's modulation of the aberrant Wnt/ß-catenin signaling pathway. Upon AKBA treatment, ß-catenin expression in nuclei was inhibited, and membrane ß-catenin was activated. In the same sample, active GSK3ß was increased and its non-active form decreased. Levels of cyclin D1, PCNA, survivin, c-Myc, MMP-2, and MMP-7, downstream targets of Wnt/ß-catenin, were inhibited. CONCLUSIONS: AKBA effects on human gastric carcinoma growth were associated with its activity in modulating the Wnt/ß-catenin signaling pathway. GENERAL SIGNIFICANCE: AKBA could be useful in the treatment of gastric cancers.