Effects of 101BHG-D01, a novel M receptor antagonism, on allergic rhinitis in animal models and its mechanism.

Allergic rhinitis (AR) is a nasal mucosal disease with sneezing and nasal itching as the main symptoms. Although AR treatment continues to improve, there remains a lack of effective drugs. There are still controversies regarding whether anticholinergic drugs can effectively and safely relieve the symptoms of AR and reduce inflammation in the nasal mucosa. Here, we synthesized 101BHG-D01, which is a novel anticholinergic drug that mainly targets the M3 receptor and may reduce the adverse effects of other anticholinergic drugs on the heart. We evaluated the effects of 101BHG-D01 on AR and investigated the potential molecular mechanism of anticholinergic therapy for AR. We found that 101BHG-D01 effectively alleviated AR symptoms, reduced the infiltration of inflammatory cells and attenuated the expression of inflammatory factors (IL-4, IL-5, IL-13, etc.) in various AR animal models. In addition, 101BHG-D01 reduced the activation of mast cells and the release of histamine from rat peritoneal mesothelial cells (RPMCs) challenged by IgE. Moreover, 101BHG-D01 reduced the expression of MUC5AC in IL-13-challenged rat nasal epithelial cells (RNECs) and human nasal epithelial cells (HNEpCs). Furthermore, IL-13 stimulation significantly increased JAK1 and STAT6 phosphorylation, which was suppressed by 101BHG-D01. We demonstrated that 101BHG-D01 reduced mucus secretion and inflammatory cell infiltration in the nasal mucosa, which may occur through a reduction in activation of the JAK1-STAT6 signaling pathway, indicating that 101BHG-D01 is a potent and safe anticholinergic therapy for AR.

A case report of renal pelvis carcinoma.

Urothelial carcinoma (UC) is a common type of carcinoma worldwide, and it is rare to find it metastasize to the brain. Antibody-drug conjugates (ADCs) are an emerging treatment for patients. Our department treated a patient with Urothelial carcinoma (UC) that metastazied to the brain with Disitamab Vedotin. Therefore, the aim of this article is to review and share this rare carcinoma case treated in our department, and to have a deep understanding of Antibody-drug conjugates (ADCs) so that we can improve treatment for Urothelial carcinoma (UC). Informed consent was granted by the patient to share the case information.

Pharmacokinetics and Tissue Distribution of Nasal Spray of a Novel Muscarinic Receptor Blocker, 101BHG-D01, in Dogs and Rats.

BACKGROUND: 101BHG-D01 is a novel selective anti-muscarinic (M) 3 receptor-blocking drug. 101BHG-D01 nasal spray is intended to be used to relieve sneezing and runny nose symptoms caused by allergic rhinitis. METHODS: In this study, we examined the plasma pharmacokinetics, tissue distribution, and major excretion mode of 101BHG-D01 in Beagle dogs and rats following nasal spray and intranasal administration, respectively, using HPLC-MS/MS. RESULTS/DISCUSSION: We found that the pharmacokinetics of 101BHG-D01 was linear in dogs. 101BHG-D01 entered the bloodstream rapidly following nasal spray. Its plasma half-life was approximately 6 h and resided at least 24 h in the body. Moreover, 101BHG-D01 retained a significant amount in the nasal cavity. Finally, we found that 101BHG-D01 was eliminated mainly in the form of stools in rats. CONCLUSION: In conclusion, we provided pertinent reference information regarding the design and optimization of drug delivery regimens for clinical trials.

Corrigendum: Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

[This corrects the article DOI: 10.3389/fphar.2019.00982.].

Association Between Alcohol Consumption and Risk of Bladder Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

BACKGROUND: Controversial results of the association between alcohol consumption and risk of bladder cancer were reported by the previous meta-analyses. OBJECTIVE: To quantitatively investigate the association between alcohol consumption and risk of bladder cancer based on prospective cohort studies, and explore whether there is potential dose-response relation. METHOD: PubMed, EMBASE, the Cochrane Library databases, China Biology Medicine disc (CBM), and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant studies. Categorical meta-analysis was performed for risk estimates of any alcohol consumers versus non-drinkers as well as different drinking degrees (light, moderate, and heavy) versus none. And two-stage generalized least-squares regression and restricted cubic spline, as well as fixed-effects dose-response models, were used for linear and nonlinear dose-response relation exploration. RESULTS: 9 prospective cohort studies including 1,971,396 individuals were finally included. We did not observe a significant association between alcohol intake and the risk of bladder cancer in the entire population. Linear association was detected in those who consumed alcohol from liquor or spirits (P linear=0.02). One drink increment each day of alcohol could elevate the risk of bladder cancer by 9% (RR=1.09; 95%CI: 1.01-1.17). Alcohol was a risk factor of bladder cancer for male drinkers (RR=1.23; 95%CI: 1.13-1.35; I2=3.7%), while none linear or nonlinear relation was found. CONCLUSION: No significant association between alcohol consumption and bladder cancer risk was found in the entire population, but there was a linear dose-response relation in those who consume alcohol from liquor or spirits. Alcohol may elevate the risk of bladder cancer in males in a dose-independent way. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42020216195).

Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

Background: Platinum-based drugs prevail as the main treatment of lung cancer; this is caused by their relative effectiveness despite known side effects, such as neurotoxicity. The risk reward of the treatment and side effects is confronted when dosage is considered and when resistance to treatment develops. Development of new compounds that improve effectiveness and safety profiles addresses this ongoing need in clinical practice. Objectives: The novel water-soluble platinum complex, diplatin, was synthesized, and its antitumor potency and toxicology profile were evaluated in murine xenograft tumor models and in lung cancer cell lines. Methods: The effects of diplatin, cisplatin (DDP), and carboplatin (CBP) on the viability of nine lung tumor cell lines and one normal human lung epithelial cell line were evaluated using the MTT assay. Therapeutic index was calculated as LD50/ED50 to identify and compare the ideal therapeutic windows of the above compounds. Diplatin's antitumor effects were assessed in lung xenograft tumors of nude mice; molecular mechanisms of therapeutic effects were identified. Results: Diplatin had desirable IC50 compared to CBP in a variety of cultured tumor cells, notably lung tumor cells. In the mouse xenograft lung tumor, diplatin led to a substantially improved therapeutic index when compared to the effects of DDP and CBP. Importantly, diplatin inhibited the growth of DDP-resistant lung tumor cells. Diplatin's mode of action was characterized to be through cell cycle arrest in the G2/M phase and induction of lung tumor apoptosis via ROS/JNK/p53-mediated pathways. Conclusion: Diplatin was observed to have antitumor effects in mice with both greater potency and safety compared with DDP and CBP. These observations indicate that diplatin is promising as a potential treatment in future clinical applications.

Preformulation characterization and in vivo absorption in beagle dogs of JFD, a novel anti-obesity drug for oral delivery.

JFD (N-isoleucyl-4-methyl-1,1-cyclopropyl-1-(4-chlorine)phenyl-2-amylamine·HCl) is a novel investigational anti-obesity drug without obvious cardiotoxicity. The objective of this study was to characterize the key physicochemical properties of JFD, including solution-state characterization (ionization constant, partition coefficient, aqueous and pH-solubility profile), solid-state characterization (particle size, thermal analysis, crystallinity and hygroscopicity) and drug-excipient chemical compatibility. A supporting in vivo absorption study was also carried out in beagle dogs. JFD bulk powders are prismatic crystals with a low degree of crystallinity, particle sizes of which are within 2-10 µm. JFD is highly hygroscopic, easily deliquesces to an amorphous glass solid and changes subsequently to another crystal form under an elevated moisture/temperature condition. Similar physical instability was also observed in real-time CheqSol solubility assay. pK(a) (7.49 ± 0.01), log P (5.10 ± 0.02) and intrinsic solubility (S0) (1.75 µg/ml) at 37 °C of JFD were obtained using potentiometric titration method. Based on these solution-state properties, JFD was estimated to be classified as BCS II, thus its dissolution rate may be an absorption-limiting step. Moreover, JFD was more chemically compatible with dibasic calcium phosphate, mannitol, hypromellose and colloidal silicon dioxide than with lactose and magnesium stearate. Further, JFD exhibited an acceptable pharmacokinetic profiling in beagle dogs and the pharmacokinetic parameters T(max), C(max), AUC(0-t) and absolute bioavailability were 1.60 ± 0.81 h, 0.78 ± 0.47 µg/ml, 3.77 ± 1.85 µg·h/ml and 52.30 ± 19.39%, respectively. The preformulation characterization provides valuable information for further development of oral administration of JFD.