Design, Synthesis, and Anti-Cancer Evaluation of Novel Water-Soluble Copper(I) Complexes Bearing Terpyridine and PTA Ligands.

This study presents a simple and energy-efficient self-assembly LAG synthetic method for novel water-soluble copper(I) complexes [Cu(terpy)(PTA)][PF6] (1) and [Cu(terpy)(PTA)2][PF6] (2). They were characterized by FT-IR, 1H, and 31P{1H} NMR spectroscopy, elemental analysis, and single-crystal/powder X-ray diffraction (for 2). The X-ray analysis of compound 2 indicates a bidentate coordination mode of terpyridine to the metal center. Variable-temperature NMR tests indicate dynamic properties for terpyridine in the case of both compounds, as well as for the PTA ligands in the case of 2. Additionally, compounds 1 and 2 exhibit interesting cytotoxic activity, which was tested on normal human dermal fibroblasts (NHDFs), human lung carcinoma (A549), human breast adenocarcinoma (MCF-7), and human cervix carcinoma (HeLa) established cell lines. In comparison to the other tested compounds, complexes 1 and 2 seem to have significantly lower IC50 values against cancer cells (A549, HeLa, MCF-7), indicating their potential as prospective anticancer agents. Moreover, both compounds show no significant toxicity towards normal skin cells (NHDFs), suggesting a certain selectivity in their action on cancer cells. Cisplatin as a reference compound also exhibited considerable cytotoxicity against cancer cells but with a low level of selectivity, which could lead to unwanted effects on normal cells. Remarkably, compounds 1 and 2 exhibit up to 30 times the cytotoxic activity of cisplatin, with a six-fold lower toxicity to normal cells. They also interact strongly with human serum albumin, suggesting potential therapeutic applications. Overall, these compounds hold significant promise as potential chemotherapeutic agents.

Inhibition of ezrin phosphorylation by NSC305787 attenuates procaterol-stimulated ciliary beating in airway cilia.

Ciliary beating in the airway epithelium plays an important role in preventing infection by eliminating small particles and pathogens. Stimulation of ß2 adrenergic receptor (ß2AR) increases [cAMP]i levels and strongly activates this ciliary beating. ß2AR is localized to the apical membrane of the airways by indirectly binding to ezrin, an actin-binding protein. Ezrin takes active phosphorylated and inactive dephosphorylated states at Thr-567. Previously we showed that procaterol-stimulated ciliary beating was impaired in the ezrin-knockdown mice. In this study, we examined the roles of ezrin and its phosphorylation in regulating ciliary beating by using NSC305787, an ezrin inhibitor, in normal human airway epithelial cells (NHBE). We found that NSC305787 inhibits the phosphorylation of ezrin with an IC50 of 50 µM in NHBE. Treatment with NSC305787 for 4 h or more decreased the expression of ß2AR in the cell membrane and induced vesicle- or dot-like expression of ezrin and ß2AR inside the cell. As a result, inhibition of ezrin phosphorylation by NSC305787 attenuated the effect of procaterol-induced activation of ciliary beating in both frequency and distance indices.

The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy.

Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate the development of debilitating fibrosis are in desperate need across a range of conditions. Sphingolipid metabolism is a critical regulator of cell proliferation, apoptosis, autophagy, and pathologic inflammation, processes that are all involved in fibrosis. Opaganib (formerly ABC294640) is the first-in-class investigational drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Opaganib inhibits key enzymes in sphingolipid metabolism, including sphingosine kinase-2 and dihydroceramide desaturase, thereby reducing inflammation and promoting autophagy. Herein, we demonstrate in mouse models of lung damage following exposure to ionizing radiation that opaganib significantly improved long-term survival associated with reduced lung fibrosis, suppression of granulocyte infiltration, and reduced expression of IL-6 and TNFα at 180 days after radiation. These data further demonstrate that sphingolipid metabolism is a critical regulator of fibrogenesis, and specifically show that opaganib suppresses radiation-induced pulmonary inflammation and fibrosis. Because opaganib has demonstrated an excellent safety profile during clinical testing in other diseases (cancer and COVID-19), the present studies support additional clinical trials with this drug in patients at risk for pulmonary fibrosis.

Saxagliptin/dapagliflozin is non-inferior to insulin glargine in terms of ß-cell function in subjects with latent autoimmune diabetes in adults: A 12-month, randomized, comparator-controlled pilot study.

AIM: To compare the efficacy and safety of saxagliptin/dapagliflozin and insulin glargine in people with latent autoimmune diabetes in adults (LADA). METHODS: In this phase 2b multicentre, open-label, comparator-controlled, parallel-group, non-inferiority study, we randomly assigned 33 people with LADA who had a fasting C-peptide concentration ≥0.2 nmol/L (0.6 ng/mL) to receive 1-year daily treatment with either the combination of saxagliptin (5 mg) plus dapagliflozin (10 mg) or insulin glargine (starting dose: 10 IU), both on top of metformin. The primary outcome was the 2-h mixed meal-stimulated C-peptide area under the curve (AUC), measured 12 months after randomization. Secondary outcomes were glycated haemoglobin (HbA1c) levels, change in body mass index (BMI), and hypoglycaemic events. RESULTS: In the modified intention-to-treat analysis, the primary outcome was similar in participants assigned to saxagliptin/dapagliflozin or to insulin glargine (median C-peptide AUC: 152.0 ng*min/mL [95% confidence interval {CI} 68.2; 357.4] vs. 122.2 ng*min/mL [95% CI 84.3; 255.8]; p for noninferiority = 0.0087). Participants randomized to saxagliptin/dapagliflozin lost more weight than those randomized to insulin glargine (median BMI change at the end of the study: -0.4 kg/m2 [95% CI -1.6; -0.3] vs. +0.4 kg/m2 [95% CI -0.3; +1.1]; p = 0.0076). No differences in HbA1c or in the number of participants experiencing hypoglycaemic events were found. CONCLUSIONS: Saxagliptin/dapagliflozin was non-inferior to glargine in terms of ß-cell function in this 12-month, small, phase 2b study, enrolling people with LADA with still viable endogenous insulin production. Weight loss was greater with saxagliptin/dapagliflozin, with no differences in glycaemic control or hypoglycaemic risk.

S288T mutation altering MmpL3 periplasmic domain channel and H-bond network: a novel dual drug resistance mechanism.

CONTEXT: Mycobacterial membrane proteins Large 3 (MmpL3) is responsible for the transport of mycobacterial acids out of cell membrane to form cell wall, which is essential for the survival of Mycobacterium tuberculosis (Mtb) and has become a potent anti-tuberculosis target. SQ109 is an ethambutol (EMB) analogue, as a novel anti-tuberculosis drug, can effectively inhibit MmpL3, and has completed phase 2b-3 clinical trials. Drug resistance has always been the bottleneck problem in clinical treatment of tuberculosis. The S288T mutant of MmpL3 shows significant resistance to the inhibitor SQ109, while the specific action mechanism remains unclear. The results show that MmpL3 S288T mutation causes local conformational change with little effect on the global structure. With MmpL3 bound by SQ109 inhibitor, the distance between D710 and R715 increases resulting in H-bond destruction, but their interactions and proton transfer function are still restored. In addition, the rotation of Y44 in the S288T mutant leads to an obvious bend in the periplasmic domain channel and an increased number of contact residues, reducing substrate transport efficiency. This work not only provides a possible dual drug resistance mechanism of MmpL3 S288T mutant but also aids the development of novel anti-tuberculosis inhibitors. METHODS: In this work, molecular dynamics (MD) and quantum mechanics (QM) simulations both were performed to compare inhibitor (i.e., SQ109) recognition, motion characteristics, and H-bond energy change of MmpL3 after S288T mutation. In addition, the WT_SQ109 complex structure was obtained by molecular docking program (Autodock 4.2); Molecular Mechanics/ Poisson Boltzmann Surface Area (MM-PBSA) and Solvated Interaction Energy (SIE) methods were used to calculate the binding free energies (∆Gbind); Geometric criteria were used to analyze the changes of hydrogen bond networks.

Reversible synaptic adaptations in a subpopulation of murine hippocampal neurons following early-life seizures.

Early-life seizures (ELSs) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELSs induce persistent changes in specific neuronal populations and whether these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELSs in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated (AMPAR-mediated) excitatory synaptic transmission and inward rectification. ELS-TRAPed neurons, but not non-TRAPed surrounding neurons, exhibited enduring decreases in Gria2 mRNA, responsible for encoding the GluA2 subunit of the AMPARs. This was paralleled by decreased synaptic GluA2 protein expression and heightened phosphorylated GluA2 at Ser880 in dendrites, indicative of GluA2 internalization. Consistent with increased GluA2-lacking AMPARs, ELS-TRAPed neurons showed premature silent synapse depletion, impaired long-term potentiation, and impaired long-term depression. In vivo postseizure treatment with IEM-1460, an inhibitor of GluA2-lacking AMPARs, markedly mitigated ELS-induced changes in TRAPed neurons. These findings show that enduring modifications of AMPARs occur in a subpopulation of ELS-activated neurons, contributing to synaptic dysplasticity and network hyperexcitability, but are reversible with early IEM-1460 intervention.

Relationship between saxagliptin use and left ventricular diastolic function assessed by cardiac MRI.

AIMS: Type 2 diabetes mellitus (T2DM) increases the risk of major cardiovascular events. In SAVOR-TIMI53 trial, the excess heart failure (HF) hospitalization among patients with T2DM in the saxagliptin group remains poorly understood. Our aim was to evaluate left ventricular (LV) diastolic function after 6 months of saxagliptin treatment using cardiac magnetic resonance imaging (CMR) in patients with T2DM. METHODS: In this prospective study, 16 T2DM patients without HF were prescribed saxagliptin as part of routine guideline-directed management. CMR performed at baseline and 6 months after initiation of saxagliptin treatment were evaluated in a blinded fashion. We assessed LV diastolic function by measuring LV peak filling rate with correction for end-diastolic volume (PFR/LVEDV), time to peak filling rate with correction for cardiac cycle (TPF/RR), and early diastolic strain rate parameters [global longitudinal diastolic strain rate (GLSR-E), global circumferential diastolic strain rate (GCSR-E)] by feature tracking (FT-CMR). RESULTS: Among the 16 patients (mean age of 59.9, 69% males, mean hemoglobin A1c 8.3%, mean left ventricular ejection fraction 57%), mean PFR was 314 ± 108 ml/s at baseline and did not change over 6 months (- 2.7, 95% CI - 35.6, 30.2, p = 0.86). There were also no significant changes in other diastolic parameters including PFR/EDV, TPF, TPF/RR, and GLSR-E and GCSR-E (all p > 0.50). CONCLUSION: In T2DM patients without HF receiving saxagliptin over 6 months, there were no significant subclinical changes in LV diastolic function as assessed by CMR.

P2X7 receptor antagonism by AZ10606120 significantly reduced in vitro tumour growth in human glioblastoma.

Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14-18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas.

Dapagliflozin or Saxagliptin in Pediatric Type 2 Diabetes.

Dapagliflozin or Saxagliptin in Pediatric Type 2 DiabetesDapagliflozin (a sodium-glucose co-transporter-2 inhibitor) and saxagliptin (a dipeptidyl peptidase-4 inhibitor) have both been approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in adults but not in children. In this randomized trial of 245 pediatric patients (10 to 17 years of age) with uncontrolled type 2 diabetes, dapagliflozin but not saxagliptin significantly reduced A1C compared with placebo.

Comparative Therapeutic Effect of Single/Combined Administration of Saxagliptin, Metformin and Intranasal Insulin on Dexamethasone Induced Insulin Resistance in Albino Wistar Rat Model.

Glucocorticoids have therapeutic benefits in the management of several inflammatory and immunological disorders. Despite these medicinal effects, they have the drawback of causing metabolic disorders such as hyperglycemia, insulin resistance etc., which is known to be a key indicator of metabolic syndrome. Metabolic syndrome is a major predisposing factor to type 2 diabetes mellitus and cardiomyopathy. This study was designed to compare and evaluate the effects of saxagliptin, metformin and intranasal insulin (when used singly or in combination) on dexamethasone induced insulin resistance. Fifty-six female rats were randomly assigned into eight groups. Group 1 represented the control; Group 2 was administered with dexamethasone (1mg/kg) (untreated); Group 3 received dexamethasone + intranasal insulin (2IU); Group 4 received dexamethasone + intranasal insulin + metformin (40mg/kg); Group 5; received dexamethasone + intranasal + saxagliptin (8mg/kg); Group 6 received dexamethasone + metformin (40mg/kg); Group 7 received dexamethasone + saxagliptin (8mg/kg); Group 8 received dexamethasone + saxagliptin(8mg/kg) + metformin(40mg/kg). Treatments were given for one week. At the end of the study, blood samples were collected for biochemical assays and pancreas excised for histological examination. Dexamethasone (1mg/kg) induced hyperglycemia, hyperinsulinemia, dyslipidemia, impaired glucose tolerance and disrupted the structural integrity of the pancreas. Treatment with saxagliptin, metformin and their combination significantly decreased blood glucose level, decreased LDL Level and improved glucose tolerance. The selected hypoglycemic agents used in present study ameliorate the dexamethasone induced hyperglycemia and insulin resistance of which the combination of metformin with saxagliptin showed greater efficacy.

Neuropeptides, substrates and inhibitors of human dipeptidyl peptidase III, experimental and computational study - A new substrate identified.

Dipeptidyl peptidase III (DPP III) is a cytosolic, two-domain zinc-exopeptidase. It is widely distributed in mammalian tissues, where it's involved in the final steps of normal intracellular protein degradation. However, its pronounced affinity for some bioactive peptides (angiotensins, enkephalins, and endomorphins) suggests more specific functions such as blood pressure regulation and involvement in pain regulation. We have investigated several different neuropeptides as potential substrates and inhibitors of human DPP III. The binding affinities and kinetic data determined by isothermal titration calorimetry, in combination with measurements of enzyme inhibition identified the hemorphin-related valorphin, tynorphin, S-tynorphin, and I-tynorphin as the most potent inhibitors of DPP III (actually slow substrates), whereas hemorphin-4 proved to be the best substrate of all neuropeptides examined. In addition, we have shown that the neuropeptides valorphin, Leu-valorphin-Arg, and the opioid peptide ß-casomorphin, are DPP III substrates. The molecular modelling of selected peptides shows uniform binding to the lower domain ß-strand residues of DPP III via peptide backbone atoms, but also previously unrecognized stabilizing interactions with conserved residues of the metal-binding site and catalytic machinery in the upper domain. The computational data helped explain the differences between substrates that are hydrolyzed effectively and those hydrolysed slowly by DPP III.

Peficitinib inhibits fibroblast-like synoviocyte activation and angiogenic vascular endothelial tube formation via inhibitory effects on PDGF and VEGF signaling in addition to JAK.

PURPOSE: Peficitinib and tofacitinib are known to suppress inflammation in rheumatoid arthritis (RA) by inhibiting Janus kinases (JAKs). However, these effects on tyrosine kinases other than JAKs have not yet been well investigated. We evaluated the effects of peficitinib and tofacitinib on platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) and on the activation of fibroblast-like synoviocytes (FLSs) and endothelial cells, main pathological causes of RA. METHODS: Peficitinib and tofacitinib were tested in PDGF and VEGF RTK assays. We then used FLSs derived from RA patient (RA-FLSs) and human umbilical vein endothelial cells (HUVECs) to study the effects of peficitinib and tofacitinib on PDGF- and VEGF-induced signal transduction and on the activation of RA-FLSs and endothelial cell tube formation. FINDINGS: Peficitinib, not tofacitinib, inhibited both PDGF and VEGF RTKs in addition to JAKs in cell-free assay system. Peficitinib and tofacitinib attenuated PDGF- and VEGF-induced intracellular signal transduction pathways in RA-FLSs and HUVECs to varying degrees. Only peficitinib potently inhibited PDGF-induced secretion of interleukin-6, VEGF, and matrix metalloproteinase-3 in RA-FLSs, and endothelial cell tube formation by HUVECs. CONCLUSION: Peficitinib may improve RA through inhibition of PDGF and VEGF signal transduction, in addition to JAK inhibition.

[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-ß and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-ß and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-ß, tau, and class I histone deacetylase (HDAC I isoforms 1-3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-ß PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-ß and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-ß plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology.

Recent Progress in the Development of Opaganib for the Treatment of Covid-19.

The Covid-19 pandemic driven by the SARS-CoV-2 virus continues to exert extensive humanitarian and economic stress across the world. Although antivirals active against mild disease have been identified recently, new drugs to treat moderate and severe Covid-19 patients are needed. Sphingolipids regulate key pathologic processes, including viral proliferation and pathologic host inflammation. Opaganib (aka ABC294640) is a first-in-class clinical drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Recent work demonstrates that opaganib also has antiviral activity against several viruses including SARS-CoV-2. A recently completed multinational Phase 2/3 clinical trial of opaganib in patients hospitalized with Covid-19 demonstrated that opaganib can be safely administered to these patients, and more importantly, resulted in a 62% decrease in mortality in a large subpopulation of patients with moderately severe Covid-19. Furthermore, acceleration of the clearance of the virus was observed in opaganib-treated patients. Understanding the biochemical mechanism for the anti-SARS-CoV-2 activity of opaganib is essential for optimizing Covid-19 treatment protocols. Opaganib inhibits three key enzymes in sphingolipid metabolism: sphingosine kinase-2 (SK2); dihydroceramide desaturase (DES1); and glucosylceramide synthase (GCS). Herein, we describe a tripartite model by which opaganib suppresses infection and replication of SARS-CoV-2 by inhibiting SK2, DES1 and GCS. The potential impact of modulation of sphingolipid signaling on multi-organ dysfunction in Covid-19 patients is also discussed.

Sampsonione F suppresses adipogenesis via activating p53 pathway during the mitotic clonal expansion progression of adipocyte differentiation.

The abnormal proliferation and hypertrophy of adipocytes mediate the expansion of adipose tissue and then cause obesity-related diseases. Theoretically, an approach for preventing and curing obesity is to inhibit cell proliferation during the mitotic clonal expansion (MCE) progression of adipocyte differentiation. Polycyclic polyprenylated acylphloroglucinols (PPAPs) are mainly found from Hypericum and Garcinia genus, which have been reported to have various biological activities such as anti-depressant, anti-oxidant, and anti-tumor. Previously, our group has reported that adamantane-type PPAPs exhibited blunting activity in adipogenesis. In this study, another six adamantane PPAPs were screened to investigate their anti-adipogenesis activities and then discussed the structure-activity relationship. Particularly, sampsonione F, one of the PPAPs dramatically suppressed adipogenesis dose-dependently in vitro, along with decreased expressions of C/EBPß, C/EBPα, PPARγ, FABP4, and FAS. Moreover, sampsonione F upregulated the expression of p27 by activating p53 pathway and then downregulated the expressions of key regulators during G1/S phase arrest. Our data support that sampsonione F suppressed adipogenesis by activating p53 pathway, regulating cyclins, and resulting in G1/S phase arrest during the MCE progression of adipogenesis. This work provides a new adamantane-type PPAPs in the regulation of adipogenesis and extends our knowledges on the mechanism of the type PPAPs in regulation of adipogenesis.

The efficacy and safety of tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib in plaque psoriasis - A network meta-analysis.

Janus kinase (JAK) inhibitors are novel treatment approaches for psoriasis. However, there is no direct comparison of JAK inhibitors in plaque psoriasis. In order to compare the efficacy and safety of JAK inhibitors in psoriasis, we conducted a network meta-analysis using eligible randomized clinical trials (RCTs). The efficacy of JAK inhibitors was evaluated using a 75% improvement in Psoriasis Area and Severity Index (PASI75) from baseline, and the proportion of patients achieving the Physician's Global Assessment (PGA) response. The incidence of treatment-related adverse events (AEs) was also assessed. A total of eight RCTs with tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib were included. A total of 3612 participants who were diagnosed with moderate-to-severe plaque psoriasis were analysed. Overall, JAK inhibitors showed superior PASI75 response over placebo at both 8 and 12 weeks. Among all included JAK inhibitors, tofacitinib 15 mg twice a day (BID) had the highest probability of achieving PASI75 at both 8 and 12 weeks (SUCRA = 0.938 and 0.937, separately), followed by tofacitinib 10 mg BID (SUCRA = 0.905 and 0.908, separately) and deucravacitinib 12 mg once daily (QD) (SUCRA = 0.874 and 0.837, separately). A similar finding was observed for PGA response. Safety assessment showed that all JAK inhibitors had non-inferior safety compared with placebo, except for deucravacitinib 6 mg BID and 12 mg QD. Tofacitinib 2 mg BID was the first-ranked drug for safety profile followed by deucravacitinib 3 mg QD, and tofacitinib 5 mg BID. When comprehensively evaluated the efficacy and safety, tofacitinib (2 mg, 5 mg, 10 mg, 15 mg BID) was superior to other included JAK inhibitors with satisfying PASI75 and PGA response, as well as relatively low incidence of AEs. Our study confirmed that JAK inhibitors had promising treatment efficacy for moderate-to-severe plaque psoriasis. Tofacitinib showed superior efficacy and safety over peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib.

Pharmacokinetics and Safety of Single and Multiple Doses of Peficitinib (ASP015K) in Healthy Chinese Subjects.

Objective: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses. Methods: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated. Results: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0-1.5h and mean t1/2 was 7.4-13.0h for all doses. In the multiple-dose period, median tmax was 1.5-2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of >150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death. Conclusion: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses. Clinicaltrialsgov Identifier: NCT04143477.

[Saxagliptin alleviates kidney injury in diabetic rats by down-regulating the expression of mammalian target of rapamycin (mTOR)].

Objective To investigate the effect of saxagliptin (Sax) against kidney injury in diabetic rats and its mechanisms. Methods SD male rats were fed for 2 weeks, among which 14 rats were selected randomly and given intraperitoneal injection of streptozotocin (STZ) to establish the type 2 diabetes mellitus (T2DM) model, and then were randomly divided into T2DM group and Sax group after the model was successfully established; 6 rats were selected as normal control (NC) group randomly. The rats of Sax group were given the saxagliptin solution. The rats of NC and T2DM groups were injected with the same amount of sodium carboxymethyl cellulose solution. After 8 weeks of continuous gastric administration, the rats were sacrificed and their blood and kidney tissues were collected. Glucose (G1u), albumin (ALB), aspartate transaminase (AST), alanine transaminase (ALT), serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), serum total cholesterol (TC), triglycerides (TG) were detected by automatic biochemical analyzer. HE, PAS, Masson staining and transmission electron microscopy were performed to observe the morphological changes of renal. Immunohistochemical staining was used to detect the protein expression level of mammalian target of rapamycin (mTOR), interleukin 1 (IL-1), IL-6, tumor necrosis factor α (TNF-α) in renal tissues. Results Compared with the NC group, the levels of biochemical indicators such as G1u, ALB, AST, ALT, Scr, BUN, UA, TC, and TG showed significant increase; the number of glomerular mesangial cells also increased, and the mesangial matrix hyperplasia, mTOR, IL-1, IL-6, TNF-α protein expression levels exhibited significant increase in T2DM group. Compared with T2DM group, Sax group showed decreased levels of biochemical indicators such as G1u, ALB, AST, ALT, Scr, BUN, UA, TC, and TG and improved renal pathological damage performance, together with a profound reduction in mTOR, IL-1, IL-6, TNF-α protein expression level. Conclusion Sax may suppress inflammatory response and reduce renal injury in diabetic rats by down-regulating mTOR expression.

Stability-indicating HPLC method development and validation for simultaneous estimation of metformin, dapagliflozin, and saxagliptin in bulk drug and pharmaceutical dosage form.

A simple, precise, and rapid stability-indicating reversed-phase-HPLC method was developed and validated for the estimation of metformin (MET), dapagliflozin (DAP), and saxagliptin (SAX) combination in bulk and tablet dosage forms. The proposed method uses a Kromasil C18 column (150 × 4.6 mm, 5 µm) with column oven temperature of 30°C and mobile phase containing a mixture of 60% phosphate buffer (pH = 3) and 40% acetonitrile. The flow rate was set at 1.0 mL/min, and the injection volume was 10 µL. The detection was carried out at 230 nm using a photodiode array detector, and the total run time was 4 min. The proposed method was validated according to International Council for Harmonisation (ICH) guidelines for specificity, linearity, precision, accuracy, robustness, and solution stability. The method is linear over the range of 125-750 µg/mL for MET, 1.25-7.5 µg/mL for DAP, and 0.625-3.75 µg/mL for SAX. The observed correlation coefficients (R2 ) for MET, DAP, and SAX are >0.999. The proposed method is precise, and the percentage relative standard deviation was found to be between 0.4 and 0.8. The observed percentage recoveries were between 98.51 and 100.80 for all three compounds. The product was subjected to stress conditions of acid, base, oxidative, thermal, and photolytic degradation. The product was found to degrade significantly in oxidative, acid, and base hydrolysis degradation conditions, and the degradation products were well determined from the active peaks, thus proving the stability-indicating power of the method. The developed and validated stability-indicating reversed-phase-HPLC method was appropriate for quantitative determination of these drugs in pharmaceutical preparations and also for quality control in bulk manufacturing.

Hydrogen Bonding in the Dimer and Monohydrate of 2-Adamantanol: A Test Case for Dispersion-Corrected Density Functional Methods.

Weakly-bound intermolecular clusters constitute reductionist physical models for non-covalent interactions. Here we report the observation of the monomer, the dimer and the monohydrate of 2-adamantanol, a secondary alcohol with a bulky ten-carbon aliphatic skeleton. The molecular species were generated in a supersonic jet expansion and characterized using broadband chirped-pulse microwave spectroscopy in the 2-8 GHz frequency region. Two different gauche-gauche O-H···O hydrogen-bonded isomers were observed for the dimer of 2-adamantanol, while a single isomer was observed for the monomer and the monohydrate. The experimental rotational parameters were compared with molecular orbital calculations using density functional theory (B3LYP-D3(BJ), B2PLYP-D3(BJ), CAM-B3LYP-D3(BJ), ωB97XD), additionally providing energetic and electron density characterization. The shallow potential energy surface makes the dimer an interesting case study to benchmark dispersion-corrected computational methods and conformational search procedures.