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BACKGROUND: Although imatinib is a well-established first-line drug for treating a vast majority of gastrointestinal stromal tumours (GIST), GISTs acquire secondary resistance during therapy. Multi-omics approaches provide an integrated perspective to empower the development of personalised therapies through a better understanding of functional biology underlying the disease and molecular-driven selection of the best-targeted individualised therapy. In this study, we applied integrative metabolomic and transcriptomic analyses to elucidate tumour biochemical processes affected by imatinib treatment. MATERIALS AND METHODS: A GIST xenograft mouse model was used in the study, including 10 mice treated with imatinib and 10 non-treated controls. Metabolites in tumour extracts were analysed using gas chromatography coupled with mass spectrometry (GC-MS). RNA sequencing was also performed on the samples subset (n=6). RESULTS: Metabolomic analysis revealed 21 differentiating metabolites, whereas next-generation RNA sequencing data analysis resulted in 531 differentially expressed genes. Imatinib significantly changed the profile of metabolites associated mainly with purine and pyrimidine metabolism, butanoate metabolism, as well as alanine, aspartate, and glutamate metabolism. The related changes in transcriptomic profiles included genes involved in kinase activity and immune responses, as well as supported its impact on the purine biosynthesis pathway. CONCLUSIONS: Our multi-omics study confirmed previously known pathways involved in imatinib anticancer activity as well as correlated imatinib-relevant downregulation of expression of purine biosynthesis pathway genes with the reduction of respectful metabolites. Furthermore, considering the importance of the purine biosynthesis pathway for cancer proliferation, we identified a potentially novel mechanism for the anti-tumour activity of imatinib. Based on the results, we hypothesise metabolic modulations aiming at the reduction in purine and pyrimidine pool may ensure higher imatinib efficacy or re-sensitise imatinib-resistant tumours. ispartof: Transl Oncol vol:30 pages:101632- ispartof: location:United States status: published

Purpose Treatment with the tyrosine kinase inhibitor (TKI) imatinib in patients with gastrointestinal stromal tumours (GIST) causes symptoms that could negatively impact health-related quality of life (HRQoL). Treatment-related symptoms are usually clinician-reported and little is known about patient reports. We used survey and online patient forum data to investigate (1) prevalence of patient-reported symptoms; (2) coverage of symptoms mentioned on the forum by existing HRQoL questionnaires; and (3) priorities of prevalent symptoms in HRQoL assessment. Methods In the cross-sectional population-based survey study, Dutch GIST patients completed items from the EORTC QLQ-C30 and Symptom-Based Questionnaire (SBQ). In the forum study, machine learning algorithms were used to extract TKI side-effects from English messages on an international online forum for GIST patients. Prevalence of symptoms related to imatinib treatment in both sources was calculated and exploratively compared. Results Fatigue and muscle pain or cramps were reported most frequently. Seven out of 10 most reported symptoms (i.e. fatigue, muscle pain or cramps, facial swelling, joint pain, skin problems, diarrhoea, and oedema) overlapped between the two sources. Alopecia was frequently mentioned on the forum, but not in the survey. Four out of 10 most reported symptoms on the online forum are covered by the EORTC QLQ-C30. The EORTC-SBQ and EORTC Item Library cover 9 and 10 symptoms, respectively. Conclusion This first overview of patient-reported imatinib-related symptoms from two data sources helps to determine coverage of items in existing questionnaires, and prioritize HRQoL issues. Combining cancer-generic instruments with treatment-specific item lists will improve future HRQoL assessment in care and research in GIST patients using TKI.

This paper describes a stereoselective synthesis of (–)-heliannuol E through intramolecular cyclization of a phenol mesylate. The introduction of the aromatic group was achieved by α-selective propargyl substitution of a propargylic phosphate.

Furmonertinib mesylate (hereafter furmonertinib) [Ivesa®] is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) being developed by Allist Pharmaceuticals for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In March 2021, furmonertinib received its first approval in China for the treatment of patients with locally advanced or metastatic NSCLC with confirmed EGFR T790M mutation whose disease has progressed during or after EGFR TKI therapy. Furmonertinib (as monotherapy and/or combination therapy) continues to be assessed in phase I/II and phase III trials for NSCLC with EGFR mutation in China, and its clinical development is also underway/planned in China and elsewhere for NSCLC with various EGFR mutations. This article summarizes the milestones in the development of furmonertinib leading to this first approval for EGFR T790M-positive NSCLC.

Eribulin treatment improved overall survival with predictable toxicities in phase 3 trials of patients with previously treated, locally advanced/metastatic breast cancer. This study (NCT02443428) prospectively observed eribulin-treated patients in real-world clinical practice.This observational multicentre registry study enrolled 76 patients with locally advanced/metastatic breast cancer who had ≤2 prior chemotherapeutic regimens for advanced disease. Eribulin was administered at a 1.23 mg/mAEs occurred in 98.7% of patients; 88.2% had eribulin-related AEs. The most common AEs were fatigue (64.5%), alopecia (36.8%), nausea (35.5%) and constipation (30.3%). Serious AEs occurred in 42.1% of patients. The most common grade 3/4 AEs were neutropenia (9.2%), febrile neutropenia (9.2%), dyspnoea (5.3%) and pleural effusion (5.3%). No fatal AEs occurred. Dose reductions occurred in 31.6% of patients, 42.1% experienced dose delays and 9.2% discontinued due to worsening condition. There were complete responses in 2.6% and partial responses in 15.8% of patients. Median time to progression and overall survival were 4.0 and 8.3 months, respectively.Eribulin was well tolerated in real-world clinical practice, comparable to safety and effectiveness reported in other clinical trials.

Objective To report the safety, tolerability, exploratory efficacy, and patient acceptability of INP104 for the acute treatment of migraine from the Phase 3 STOP 301 trial. Background Dihydroergotamine (DHE) has long been used to treat migraine, but intravenous administration is invasive, frequently associated with adverse events (AEs), and not suitable for at-home administration. INP104 is an investigational drug device that delivers DHE mesylate to the upper nasal space using a Precision Olfactory Delivery technology and was developed to overcome the shortcomings of available DHE products. Methods STOP 301 was an open-label, 24-week safety study, with a 28-week extension period. After a 28-day screening period where patients used their "best usual care" to treat migraine attacks, patients were given INP104 (1.45 mg) to self-administer nasally with self-recognized attacks. The primary objective of this study was to assess safety and tolerability, with a specific focus on nasal mucosa and olfactory function. Exploratory objectives included efficacy assessments of migraine measures and a patient acceptability questionnaire. Results A total of 360 patients entered the 24-week treatment period, with 354 patients dosing at least once. INP104-related treatment-emergent AEs were reported by 36.7% (130/354) of patients, and 6.8% (24/354) discontinued treatment due to AEs over 24 weeks. No new safety signals were observed following delivery to the upper nasal space. Pain freedom, the most bothersome symptom freedom, and pain relief at 2 h post-INP104 were self-reported by 38.0% (126/332), 52.1% (173/332), and 66.3% (167/252) of patients, respectively. A low recurrence rate at 24 and 48 h was observed (7.1% [9/126] and 14.3% [18/126], respectively). Most patients found INP104 easy to use and preferred it over their current therapy. Conclusions INP104 has the potential to deliver rapid symptom relief, without injection, that is well tolerated and suitable for outpatient use. Results suggest INP104 may be a promising treatment for patients with migraine.

Sepsis-induced diaphragm dysfunction is a major contributor to respiratory failure in mechanically ventilated patients. There are no pharmacological treatments for this syndrome, but studies suggest that diaphragm weakness is linked to mitochondrial free radical generation. We hypothesized that administration of mitoquinone mesylate (MitoQ), a mitochondrially targeted free radical scavenger, would prevent sepsis-induced diaphragm dysfunction. We compared diaphragm function in 4 groups of male mice: 1) sham-operated controls treated with saline (0.3 mL ip), 2) sham-operated treated with MitoQ (3.5 mg/kg/day given intraperitoneally in saline), 3) cecal ligation puncture (CLP) mice treated with saline, and 4) CLP mice treated with MitoQ. Forty-eight hours after surgery, we assessed diaphragm force generation, myosin heavy chain content, state 3 mitochondrial oxygen consumption (OCR), and aconitase activity. We also determined effects of MitoQ in female mice with CLP sepsis and in mice with endotoxin-induced sepsis. CLP decreased diaphragm specific force generation and MitoQ prevented these decrements (e.g. maximal force averaged 30.2 ± 1.3, 28.0 ± 1.3, 12.8 ± 1.9, and 30.0 ± 1.0 N/cm(2) for sham, sham + MitoQ, CLP, and CLP + MitoQ groups, respectively, P < 0.001). CLP also reduced diaphragm mitochondrial OCR and aconitase activity; MitoQ blocked both effects. Similar responses were observed in female mice and in endotoxin-induced sepsis. Moreover, delayed MitoQ treatment (by 6 h) was as effective as immediate treatment. These data indicate that MitoQ prevents sepsis-induced diaphragm dysfunction, preserving force generation. MitoQ may be a useful therapeutic agent to preserve diaphragm function in critically ill patients with sepsis. NEW & NOTEWORTHY This is the first study to show that mitoquinone mesylate (MitoQ), a mitochondrially targeted antioxidant, treats sepsis-induced skeletal muscle dysfunction. This biopharmaceutical agent is without known side effects and is currently being used by healthy individuals and in clinical trials in patients with various diseases. When taken together, our results suggest that MitoQ has the potential to be immediately translated into treatment for sepsis-induced skeletal muscle dysfunction.

The pharmacokinetics of levofloxacin mesylate in healthy adult giant panda is unknown. In this study, the pharmacokinetics of levofloxacin after intramuscular administration at a dose of 2 mg/kg and oral administration at a dose of 3 mg/kg in healthy adult giant pandas was determined. Levofloxacin concentrations in plasma were determined using liquid chromatography. In the levofloxacin intramuscular administration group, the absorption and elimination half-lives of the drug were determined to be 0.123 (range: 0.02) hr and 5.402 (range: 0.70) hr, respectively. In the levofloxacin oral administration group, the absorption and elimination half-lives were determined to be 0.325 (range: 0.02) hr and 7.143 (range: 0.63) hr, respectively. Furthermore, the blood-drug concentration of levofloxacin was found to be above 1 μg/ml after 8 hr of intramuscular administration and above 0.5 μg/ml after 12 hr of oral administration. In this study, HPLC conditions and pretreatment methods of plasma samples were optimized and a detection method was established. Our results indicated that in healthy adult giant pandas, levofloxacin was rapidly absorbed and slowly eliminated. This study will therefore provide to be a guide in veterinary research and will be helpful in the rational use of levofloxacin in giant panda.

We successfully radiolabelled a novel prospective cannabinoid type 2 receptor ligand with 18F and tested its biodistribution in animal models by positron emission tomography (PET)/computed tomography (CT) imaging. The radiolabelling process was conducted on an alkyl mesylate fragment of the main naphthyridine core, using highly efficient microfluidic technology. No preliminary protection was needed, and the product was purified by semi-prep HPLC and SPE formulation, allowing the desired diastereomeric mixture to be obtained in 29 % radiochemical yield and > 95 % radiochemically pure. SOD1G93A mice were used as model of overexpression of CB2 receptors; PET imaging revealed a significant increase of the tracer distribution volume in the brain of symptomatic subjects compared with the asymptomatic ones.

This study was planned to increase the intestinal permeability and thereby bioavailability of eprosartan mesylate (EPM) by designing a self-microemulsifying drug delivery system (SMEDDS) by the use of vegetable oils. Various SMEDDS-based formulations were prepared with oleic acid and peppermint oil. Tween 80 was used as surfactant and PEG 400 as co-surfactant. Pseudo ternary phase diagrams were constructed for identifying emulsification region between 1:1, 1:2, 2:1, 3:1 ratio of SCOS mix. Eight batches of SMEDDS were found to be thermodynamically stable and from which SMEDDSOF9 and PF5 were best formulations due to their highest drug content, minimum particle size. They have shown highest release of drug in vitro and higher in vitro drug diffusion and ex vivo permeation analysis than pure drug. FTIR study ascertained no incompatibility between drug and excipients present in formulation. From the accelerated stability study, slight effect on particle size and zeta potential, assay content along with cumulative % of drug release was found. The results demonstrated the SMEDDS of EPM are potent drug delivery system to increase dissolution rate and bioavailability of drug via increased intestinal permeability and consequently improving the therapeutic efficacy of eprosartan mesylate.

S-(-)-trans-Verbenol (1) and its antipode, R-(+)-trans-verbenol (1') have been confirmed as the critical pheromone components of bark beetles. Synthesis of these two active secondary alcohols (1 and 1') from commercially available starting materials S-α-pinene and R-α-pinene was reported. The key steps were mainly depended on the effective SN2 stereo-inversion of the hydroxy group of sterically hindered alcohols (3 and 3'), using Mitsunobu reaction or hydrolysis of mesylate ester, alternatively. Our results provide a new and stereo-selectivity way to obtain optically active insect pheromones.

Rivoceranib (known in China as apatinib) is a selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor which inhibits angiogenesis in solid tumors. The aim of study was to evaluate potential pharmacokinetic (PK) differences between the Caucasian, Japanese, and Chinese populations. An open-label, single-dose, parallel-design PK study of rivoceranib was conducted in Caucasian, Japanese, and Chinese subjects. A total of 18 healthy males were recruited to each group (54 total), and 201 mg rivoceranib tablets (as 250 mg rivoceranib mesylate) were administered orally to subjects. Plasma samples were collected, and rivoceranib plasma concentration was determined using LC-MS/MS. For PK analysis, non-compartmental and compartmental analyses were performed. Intrinsic factors (CYP2C19 and CYP3A4 genotype) were also examined. Non-compartmental analysis showed no significant difference in AUC0-t , AUC0-∞ , Cmax , tmax , and t1⁄2 . Apparent clearance and volume of distribution were different across the three populations; however, the extent of this difference does not require dose modification. For compartmental modeling, a two-compartment model was used to fit the plasma concentrations. No significant difference was observed in absorption, elimination, and intercompartmental transfer rate constants among the three groups. The present study shows no major ethnic PK differences between Caucasian, Japanese, and Chinese populations.

Objective： To explore pharmaceutical care methods for hand-foot skin reactions induced by apatinib mesylate tablets，so as to provide reference for rational use of drugs clinically.Methods： A case of severe hand-foot skin reactions induced by apatinib mesylate tablets in the treatment of advanced gastric cancer was reported.The clinical manifestations，treatment principles and possible mechanism of the disease were reviewed in combination with literature.Results： Most of the hand-foot skin reactions caused by oral administration of apatinib mesylate tablets occurred 2-3 weeks after medication，mostly with clinical manifestations of erythema in palms，fingers，joints and toes accompanied with swelling and pain，as well as hyperkeratosis of the skin with paresthesia.The occurrence of hand-foot skin reactions caused by apatinib mesylate tablets were associated with such factors as inhibition of vascular endothelial growth factor and decreased capillary repair capacity and other factors.To prevent its occurrence，daily life care，adjustment of the dosage of apatinib mesylate，external application of topical emollients containing urea，analgesics and external use of super-potent topical corticosteroids could obviously reduce the severity of hand-foot skin reactions.If hand-foot skin reactions were recurrent and difficult to control，replacement with other targeted drugs could be considered.Conclusion： In the application of apatinib mesylate tablets，hand-foot skin reactions were not rare.Close attention should be paid to drug monitoring on the part of clinicians and clinical pharmacists，so that the occurrence of adverse drug reactions could be reduced.In case there were hand-foot skin reactions，timely symptomatic treatment and close observation should be given，so as to improve the safety and efficacy of drug therapy.

Apatinib mesylate (APM), a novel tyrosine kinase inhibitor, has been applied in treating various cancers. In the present study, the binding mechanism of APM with bovine serum albumin (BSA) was studied by making use of various spectroscopic and theoretical calculation approaches to provide theoretical support for further studying its pharmacokinetics and metabolism. The results from fluorescence experiments showed that the quenching mechanism of BSA induced by APM was static quenching and the APM-BSA complex with the stoichiometry of 1:1 was formed during binding reaction. Moreover, the findings also showed that the binding process of APM to BSA was spontaneous and enthalpy-driven, and the mainly driving forces were hydrogen bonding, van der Waals as well as hydrophobic interactions. From the outcomes of the competitive experiments, it can be found that the binding site was primarily nestled in sub-domain IIIA of BSA (site II) which was in line with the results of molecular docking. An appreciable decline in α-helix content of BSA can be observed from the FT-IR data, meaning that the conformational change of BSA occurred after binding with APM, this phenomenon can be corroborated by the results of UV-vis, synchronous fluorescence and 3D fluorescence studies. Furthermore, the effect of some metal ions (e.g. K

Alalevonadifloxacin mesylate (ALA), pro-drug of levonadifloxacin is a new antibiotic approved in India to treat infections caused by Gram-positive bacteria. Alkyl mesylates (AMs) are known genotoxic impurities (GTI’s) formed in drug substances isolated as mesylate salts. Time-dependent selected reaction monitoring (t-SRM)-based gas chromatography tandem mass spectrometry (GC-MS/MS) method has been developed for trace estimation of AMs, namely, methyl methane sulfonate (MMS), ethyl methane sulfonate (EMS) and isopropyl methane sulfonate (IMS) in ALA. Liquid-liquid extraction (LLE) procedure using dichloromethane (DCM) as an extracting solvent was employed to extract AMs from the drug substance. Automatic selective reaction monitoring (auto-SRM) tool was applied to identify the most intense SRM pair of the ions to achieve the highest sensitivity. The method was validated in terms of specificity, linearity, sensitivity, precision, and accuracy. The limit of quantitation (LOQ) for the MMS, EMS and IMS were 5, 10, and 20 ng/g of ALA, respectively. For all analytes, the correlation coefficient (R) were greater than 0.9975 in the concentration range of 3.0–260 ng/mL. Mean recovery of all analytes was in the range of 91.77 to 97.65%.

N,N,N',N'-tetramethyl-N,N'-bis(sulfo)ethane-1,2-diaminium mesylate ‎‎([TMBSED][Oms]2) is ‎used as a highly efficient and dual-functional catalyst for the one-pot multi-component ‎condensation of 2-naphthol with arylaldehydes and thioacetamide under green, mild (70 °C), ‎and solvent-free conditions. In this reaction, 1-thioamidoalkyl-2-naphthols are produced in ‎high to excellent yields and in relatively short reaction times. In this reaction, products ‎are identified by analysis of its 1H NMR, 13C NMR, and FT-IR data.‎ Moreover, a plausible mechanism based on dual-functionality of the catalyst was proposed.

BACKGROUND: Apatinib is a small-molecule multitargeted tyrosine kinase inhibitor. Apatinib has demonstrated encouraging antitumor activities. This study aimed to observe the efficacy and safety of apatinib for the treatment of multiple brain micrometastases. CASE SUMMARY: We report two patients with multiple brain micrometastases after failure of second-line treatment. Both patients had extracerebral metastases. When the patients took 250 mg/d apatinib orally, the intracerebral lesions disappeared. The extracerebral lesions were partially alleviated. Both patients had a progression-free survival of more than 12 mo and were still stable. The safety was good. The main adverse events (AEs) were mild hypertension and proteinuria, which could be controlled. CONCLUSION: Apatinib has clear efficacy and good tolerance in patients with multiple brain micrometastases after failure of second-line treatment.

Objective To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal® ), and intramuscular (IM) DHE injection in healthy subjects. Methods This was a 2-part, active-controlled, 3-period crossover study over 3 weeks, separated by 1-week washout periods. In part 1, 3 ascending dosage strengths of STS101 (1.3, 2.6, and 5.2 mg) were administered to 15 healthy subjects with no history of migraine. In part 2, 27 healthy subjects were administered 1 dose each of STS101 5.2 mg, Migranal DHE Mesylate Liquid Nasal Spray 2.0 mg, and IM DHE Mesylate 1.0 mg in a randomized order. Liquid chromatography, tandem mass spectrometry was used to determine plasma levels of DHE and its major metabolite, 8'OH-DHE. Pharmacokinetic parameters (Cmax , Tmax , AUC0-2 h , AUC0-48 h , AUC0-inf , and t1/2 ) for DHE and metabolite were calculated. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared. Safety was evaluated by monitoring adverse events, vital signs, electrocardiograms, subjective and objective assessments of nasal signs and symptoms, and changes in laboratory parameters. The study is registered as NCT03874832. Results Forty-three subjects were enrolled and received study medication. Forty completed all study activities, 14 in part 1 and 26 in part 2. In part 1, DHE plasma levels showed a dose-dependent increase, with STS101 5.2 mg reaching a mean Cmax of 1870 pg/mL with a Tmax of 23 minutes. In part 2, STS101 5.2 mg showed rapid absorption, achieving mean DHE plasma concentrations of 1230 and 1850 pg/mL at 10 and 15 minutes after administration, respectively. In comparison to Migranal, STS101 5.2 mg showed approximately 2-fold higher Cmax (2175 vs 961 pg/mL), AUC0-2 h (2979 vs 1316 h × pg/mL), and AUC0-inf (12,030 vs 6498 h × pg/mL), respectively. The mean AUC0-inf of STS101 5.2 mg was comparable to IM DHE (12,030 vs 13,650 h × pg/mL). STS101 5.2 mg showed substantially lower variability compared to Migranal for Cmax (41% vs 76%), AUC0-2 h (39% vs 75%), and AUC0-inf (39% vs 55%). The incidence of treatment emergent AEs (TEAEs), all mild and transient, reported in parts 1 and 2 combined was 9/15 (60%), 5/15 (33%), and 16/41 (39%) of the subjects after 1.3, 2.6, and 5.2 mg STS101, respectively, and 4/26 (15%) and 5/27 (19%) of the subjects after IM DHE and Migranal, respectively. Conclusion STS101 showed rapid absorption, achieving effective DHE plasma concentrations within 10 minutes. It achieved substantially higher Cmax , AUC0-2 h and AUC0-inf , compared to Migranal suggesting potentially better efficacy than Migranal. Its variability was better than Migranal, thus offering improved consistency of response. AUC0-inf was comparable to IM DHE, suggesting prolonged action and low recurrence. Additionally, the Cmax was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non-injected, acute treatment for migraine, with a favorable tolerability profile and is expected to provide rapid and consistent freedom from pain and associated migraine symptoms without recurrence.

The aim of this study was to investigate the efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis.Designed as a retrospective study, a total of 105 metastatic osteosarcoma patients who progressed after standard therapy were included in this study. The metastatic osteosarcoma patients received 500-750 mg Apatinib mesylate according to body surface area until disease progression or unacceptable toxicity with 28 days one cycle. Overall response was evaluated after two cycles Apatinib treatment, then progression-free survival (PFS) and overall survival (OS) were evaluated, and safety data were recorded. Additionally. peripheral blood and peripheral blood mononuclear cell (PBMC) specimens in the osteosarcoma patients were collected for the genotyping of VEGFR2 genetic variation and mRNA expression, respectively. Analysis on the association between genotype and baseline characteristics and VEGFR2 gene mRNA expression was analyzed. The univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, and multivariate analysis was adjusted by Cox regression analysis.The objective response rate (ORR) of the 105 metastatic osteosarcoma patients was 37.14%, disease control rate (DCR) was 77.14%, median PFS was 4.1 months, and median OS was 9.0 months. Regarding the VEGFR2 gene polymorphisms analysis, only - 906 T C was of clinical significance. The prevalence of - 906 T C in VEGFR2 among the study population was as follows: TT genotype 62 cases (59.05%), TC genotype 36 cases (34.29%) and CC genotype 7 cases (6.66%), minor allele frequency of - 906 T C was 0.24. Compared with patients with TC/CC genotype, patients with TT genotype showed longer median PFS (5.0 versus 3.1 months, P = 0.011) and median OS (9.8 versus 7.6 months, P = 0.032). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression in 69 randomly selected sample indicated that the mRNA expression of VEGFR2 of the patients with CC/TC genotypes were significantly higher than those of the TT genotype patients (P 0.001).Apatinib was safe and effective in the treatment of metastatic osteosarcoma patients who progressed after standard therapy. The clinical outcomes of Apatinib may be influenced by the polymorphism - 906 T C of VEGFR2 through mediating the mRNA expression of VEGFR2.

Introduction Enrofloxacin is used in the treatment of a wide variety of bacterial infections in mammals. However, its poor solubility limits the clinical use. Methods In order to improve the solubility of enrofloxacin, the enrofloxacin mesylate (EM) were obtained by a chemical synthesis method. The characterization of EM was carried out using ultraviolet scan (UV), synchronous thermal analysis (SDT), fourier transform infrared spectrometer (FTIR) and mass spectrometry (MS), nuclear magnetic resonance (NMR) and X-ray powder diffraction analysis (XRPD). Acute toxicity of EM in Kunming mice was studied. Besides, pharmacokinetic studies were performed in New Zealand rabbits at a single oral dose of 10 mg/kg, and the antibacterial activity of EM was also evaluated. Results EM was successfully synthesized and purified. The stoichiometric ratio of mesylate to enrofloxacin was 1:1 and the aqueous solubility of EM was 483.01±4.06 mg/mL, the solubility of EM was about 2000 times higher than enrofloxacin. The oral lethal dose (LD50) of EM was 1168.364 mg/kg, and the pharmacokinetics indicated that the oral relative bioavailability of EM was about 1.79 times and 1.48 times higher than that of enrofloxacin and enrofloxacin hydrochloride, respectively. In addition, the in vitro antibacterial activity of EM was not significantly changed compared with enrofloxacin and enrofloxacin hydrochloride. Conclusion EM has higher solubility, low toxicity for oral use, and increases the oral bioavailability in rabbit. This study may be of benefit for the development of new enrofloxacin drugs.

Purpose This study investigated the clinical outcomes and safety of apatinib mesylate in the treatment of advanced non-squamous non-small cell lung cancer (NSCLC) in patients who progressed after standard therapy, and analyzed the kinase insert domain receptor (KDR) gene polymorphism. Methods A total of 135 patients with advanced non-squamous NSCLC who received apatinib mesylate were included. Objective response rates were evaluated. Subsequently, progression-free survival (PFS) and overall survival (OS) were assessed and safety data were recorded. Additionally, peripheral blood and biopsy cancer tissue specimens were collected from the patients with NSCLC for the genotyping of the genetic polymorphism and mRNA expression of the KDR gene, respectively. Analysis on the association between genotypes and prognosis was conducted. Results The objective response rate of the 135 patients with NSCLC was 18.52%, disease control rate was 65.19%, median PFS was 3.95 months, and median OS was 10.05 months. Regarding the KDR gene polymorphism analysis, the distribution of the 4397T>C polymorphism genotypes was in accordance with the Hardy-Weinberg Equilibrium (P=0.868). Moreover, the prognosis analysis indicated that the median PFS of patients with the CC/TC and TT genotypes was 2.80 and 4.80 months, respectively (P=0.002). Furthermore, the median OS of patients with the two genotypes was 9.10 and 10.56 months, respectively (P=0.041). The multivariate Cox regression analysis showed that the TC/CC genotypes were an independent factor for PFS (odds ratio: 1.72, P=0.009). There was no correlation between the polymorphism and adverse reactions. Additionally, the mRNA expression analysis suggested that the mRNA levels of KDR in cancer tissues were significantly different between the TT and TC/CC genotypes (P Conclusion The clinical outcomes of treatment with apatinib mesylate for advanced non-squamous NSCLC in patients who progressed after standard therapy may be influenced by the KDR 4397T>C polymorphism through mediation of the mRNA expression of KDR.

Apatinib mesylate is an oral antiangiogenic agent that can inhibit activation of vascular endothelial growth factor receptor-2 tyrosine kinase. However, its therapeutic use in liver cancer is restricted due to severe systemic toxicity. Our work aimed to construct apatinib-loaded CalliSpheres Beads (CBAPA) and investigate its application in transarterial chemoembolization (TACE) of liver cancer. The established stock solution containing 20, 40 or 60 mg apatinib were fully mixed with 100–300 μm CalliSpheres Beads (CB) for 2 hours, respectively. The highest loading efficiency at 30 min after combination in 20 mg group (maximum 70.7%). Further, apatinib can be steadily released from CBAPA in vitro release test. For pharmacokinetics and tumor response in vivo, sixty New Zealand white rabbits with VX2 liver tumor were assigned into four groups: sham (NS) group, apatinib solution alone (APA) group, CB group and CBAPA group. Apatinib was measured in plasma and liver tissue by high performance liquid chromatography–tandem mass spectrometry. Compared to APA group, the administration of apatinib by TACE with CBAPA resulted in low systemic concentration. In addition, intratumoural apatinib concentration was higher than adjacent hepatic parenchyma in the CBAPA group. Compared to other three groups, CBAPA group achieved lower tumor growth rate and improved survival time. In conclusion, these findings provide a basis for the potential application of apatinib-loaded CalliSpheres Beads in liver cancer.

Purpose: This study was to perform preclinical evaluation of a novel class I and IIb HDAC-selective inhibitor, purinostat mesylate, for the treatment of Ph+ B-cell acute lymphoblastic leukemia (B-ALL). Experimental Design: Biochemical assays were used to test enzymatic activity inhibition of purinostat mesylate. Ph+ leukemic cell lines and patient cells were used to evaluate purinostat mesylate activity in vitro. BL-2 secondary transplantation Ph+ B-ALL mouse model was used to validate its efficacy, mechanism, and pharmacokinetics properties in vivo. BCR-ABL(T315I)–induced primary B-ALL mouse model and PDX mouse model derived from relapsed Ph+ B-ALL patient post TKI treatment were used to determine the antitumor effect of purinostat mesylate for refractory or relapsed Ph+ B-ALL. Long-term toxicity and hERG blockade assays were used to safety evaluation of purinostat mesylate. Results: Purinostat mesylate, a class I and IIb HDAC highly selective inhibitor, exhibited robust antitumor activity in hematologic cancers. Purinostat mesylate at low nanomolar concentration induced apoptosis, and downregulated BCR-ABL and c-MYC expression in Ph+ leukemia cell lines and primary Ph+ B-ALL cells from relapsed patients. Purinostat mesylate efficiently attenuated Ph+ B-ALL progression and significantly prolonged the survival both in BL-2 secondary transplantation model with clinical patient symptoms of Ph+ B-ALL, BCR-ABL(T315I)–induced primary B-ALL mouse model, and PDX model derived from patients with relapsed Ph+ B-ALL post TKI treatment. In addition, purinostat mesylate possesses favorable pharmacokinetics and low toxicity properties. Conclusions: Purinostat mesylate provides a new therapeutic strategy for patients with Ph+ B-ALL, including those who relapse after TKI treatment.

Several additives were screened for the stereoselective reduction of a 4-substituted cyclohexanone en route to linrodostat mesylate. It was found that the addition of sub-stoichiometric cerium(III)...

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented: a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free-base roller-compacted (RC) tablets, free-base high-shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.80-to-1.25 confidence bounds; however, the HSWG tablet maximum observed concentration (Cmax) was higher than the reference (ratio, 1.15; 90% CI, 1.0113, 1.3047). In the healthy adult (n = 16) and adolescent (n = 17) study, a gepotidacin mesylate salt tablet was evaluated as a 1,500-mg single dose or 2 doses administered 6 or 12 h apart (6,000 mg total), or placebo was administered. The single-dose mean Cmax was ∼27% higher in adolescents than in adults, and area under the concentration-time curve (AUC) values were comparable in both populations. After 2 doses were administered, the mean Cmax values were similar for both age groups, and the mean AUC was ∼35% higher in adolescents than in adults. Concentrations increased proportionally with dose. Safety-risk profiles were similar for both age groups. Across studies, the most common adverse events were gastrointestinal. Overall, the pharmacokinetics of the final gepotidacin mesylate salt tablet have been well characterized, enrollment of adolescents into the pivotal trials is supported, and dosing intervals were determined that should provide adequate exposures for microbiological efficacy. (This study has been registered at ClinicalTrials.gov under identifiers NCT02853435 and NCT04079790.)

Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon’s two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm−5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm−5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm−5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.

Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Background Vascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro. Methods C57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions. Results Imatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake. Conclusion Imatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib.

N,N,N’, N’-tetramethyl- N,N’-bis(sulfo)ethane-1,2-diaminium mesylate ([TMBSED][OMs]2) was employed for the synthesis of piperidines and dihydropyrrol-2-ones via one-pot multi-component reactions in simple and green processes. This pseudo five-component reaction of aromatic aldehydes, anilines and alkyl acetoacetates was carried out under reflux conditions in ethanol to afford substituted piperidines. Also, dihydropyrrol-2-one derivatives were synthesized by means of four-component reactions of various amines, dialkyl acetylenedicarboxylates and formaldehyde in ethanol at room temperature. The present approaches have several advantages such as good yields, easy work-ups, short reaction times, and utilize mild and clean reaction conditions.

Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.

Few pieces of evidence have been published on the use of Apatinib Mesylate (AM) against EGFR-TKI resistance in lung adenocarcinoma (LA) patients. Here, we investigate the clinical efficacy and safety of AM in the treatment of advanced progressed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) resistant LA patients. We conducted a double-blind, randomized controlled trial in 68 patients admitted to 18 hospitals of Anhui province in China. The efficacy and safety of AM treatment were evaluated in terms of progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), as well as related adverse events (AE). A literature knowledge database analysis and a pathway model reconstruction were performed to decipher the relevant mechanism may be involved. Our results showed that, compared to the control group, AM presented improved efficacy in PFS (P = 0.033), ORR (P

Background Apatinib is a new oral micromolecular tyrosine kinase inhibitor, which is mainly used as a third-line treatment for chemotherapy-refractory advanced metastatic gastric cancer patients. However, apatinib has shown dose titration and severe adverse reactions in clinical practice. Quantification of plasma concentrations of apatinib may be an effective method to balance the clinical efficacy and adverse reactions. The purpose of this study was to develop and validate a 2-dimensional liquid chromatography method for the measurement of apatinib in plasma. Methods The analysis of apatinib was performed using a 2-dimensional high-performance liquid chromatography system. We precipitated the proteins with acetonitrile. The mobile phases consisted of a first-dimensional mobile phase (acetonitrile:methanol:25 mmol·L ammonium phosphate = 25:25:50, V/V/V, pH adjusted to 7.2 using phosphoric acid) and a second-dimensional mobile phase (acetonitrile:10 mmol·L ammonium phosphate = 28:72, vol/vol, pH adjusted to 3.7 using phosphoric acid). The ultraviolet detection wavelength was set at 340 nm. The temperature of the detector cell was 40°C, and the injection volume was 500 μL. Results The range of calibration curve was 15.27-1491.48 ng/mL. The accuracy and imprecision were within ±2.23% and less than 10.22%, respectively (intraday and interday). The range of recovery was 97.45%-108.92%. The intraday and interday relative SDs (reproducibility) of high-performance liquid chromatography retention times were less than 0.18% and 0.46%, respectively. In the clinical assessment, the dose range of apatinib mesylate for patients with gastric cancer was 250-500 mg every day (2-60 days), resulting in trough plasma concentrations between 272.7 and 727.8 ng/mL. Conclusions A simple, convenient, accurate, and robust 2-dimensional liquid chromatography method was developed and verified, which successfully determined the plasma concentrations of apatinib in patients with gastric cancer.

The title salt crystallizes with three independent ionic pairs in the asymmetric unit. In the crystal, (3,5-di­methyl­adamantan-1-yl)ammonium cations and methane­sulfonate anions associate via N—H⋯O hydrogen bonds into layers that extend parallel to (001) and comprise large supra­molecular hydrogen-bonded rings., The asymmetric unit of the title compound, C12H22N+·CH3O3S−, consists of three (3,5-di­methyl­adamantan-1-yl)ammonium cations, C12H22N+, and three methane­sulfonate anions, CH3O3S−. In the crystal, the cations and anions associate via N—H⋯O hydrogen bonds into layers, parallel to the (001) plane, which include large supra­molecular hydrogen-bonded rings.

Dongseong Shin,1–3 Sang-In Park,4,5Hong-Sub Lee,6 Kyung-Mi An,6 Juyoung Jung,6 MyongJae Lee,6 Kyung-Sang Yu31Department of Pharmacology, Gachon University College of Medicine, Incheon, Korea; 2Clinical Trials Center, Gachon University Gil Medical Center, Incheon, Korea; 3Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea; 4Department of Clinical Pharmacology and Therapeutics, Kyung Hee University Hospital, Seoul, Korea; 5East-West Medical Research Institute, Kyung Hee University, Seoul, Korea; 6Research Laboratories ILDONG Pharmaceutical Co. Ltd, Hwaseong, KoreaBackground and objective: IDP-73152 mesylate is a peptide deformylase inhibitor under investigation for the treatment of complicated skin and respiratory tract infections. The objective of this study was to investigate the pharmacokinetic (PK) profile and tolerability of IDP-73152 and the effect of food after a single oral administration.Methods: A dose block-randomized, double-blind, placebo-controlled, dose-escalation study was conducted. A total of 56 healthy volunteers received IDP-73152 mesylate in a single oral dose of 40, 80, 160, 320, 640, or 1280 mg in the fasted and fed (640 mg only) states. Blood and urine samples for PK analysis were collected up to 48 h post dose.Results: The area under the plasma concentration-time curve (AUC0-t) of IDP-73152 increased in a dose-proportional manner in the range of 40–320 mg. The mean terminal half-life decreased from 10.7 to 6.2 hrs as the dose increased. The fraction excreted unchanged in the urine ranged from 0.05 to 0.12. In the 640-mg dose group, food delayed the median time to peak concentration (tmax) from 0.9 to 3.5 hrs. Furthermore, the maximum plasma concentration (Cmax) were decreased by 36.2%; however, AUC0-t was not generally affected. No serious adverse event or clinically significant findings were observed.Conclusions: The systemic exposure of IDP-73152 proportionally increased as the dose increased up to 320 mg. The rate of absorption and extent of exposure were reduced by food intake. IDP-73152 was well tolerated without clinically significant adverse effects after a single oral administration.Keywords: phase I, pharmacokinetics, antibiotics, peptide deformylase inhibitor

Two series of cholestane-based diamines (1,2 and 1,3) were synthesized using simple and efficient procedures. The convenient substrates for these syntheses were cholesteryl mesylate and tosylate, which were converted to appropriate amines via easily obtained azides. The final diamines were prepared using a substitution reaction with bromoacetonitrile (in the case of 1,2-diamines) or condensation with acrylonitrile (in the case of 1,3-diamines), followed by the reduction of intermediate aminonitriles. Furthermore, the other two amines were synthesized from 16-dehydropregnenolone acetate using aza-Michael addition as a key step. Some of the diamines were subjected to complexation reactions with K2PtCl4 to form steroidal analogs of cisplatin. The synthetic methods tested in this work will allow us to prepare other cisplatin derivatives based on steroids showing anticancer properties themselves.

© 2019 Elsevier B.V. Sulfonates express a variety of biological and pharmacological activities, which indicates them as compounds of interest, in both synthetic and biological research areas. Among sulfonates, mesylates (methanesulfonyloxy compounds) draw attention by their physicochemical and biological properties, as well as by their reactivity. Here we present X-ray and computational study of 3β-acetoxy-17-methanesulfonyloxy-16,17-secoandrost-5-ene-16-nitrile (1) and its anti-proliferative activity against five common human cancer cell lines. Computational study includes geometry optimization, frontier molecular orbital analysis and molecular electrostatic potential mapping at the PW6B95-D3BJ/Def2-TZVP level of theory. Studied mesylate compound 1 expressed quite strong selective anti-proliferative effect against human breast and prostate cancer cell lines. Anticancer activity of this compound was compared to its 17-methyl analogs (compounds 2 and 3). Computational study of D-secoandrostane compounds 1–3 allowed us to presume the structural features, important for their chemical reactivity. The differences between the antiproliferative activity of D-secomesylate compound 1 and its 17-methyl analogs 2 and 3 could be explained by possible mechanism in the cancer cells.

Objective: Control the release and enhance the bioavailability of chitosan-doxazosin mesylate nanoparticles (DM-NPs). Significance: Improve DM bioavailability for the treatment of benign prostatic hyperplasia and hypertension. Methods: Plackett-Burman design was utilized to screen the variables affecting the quality of DM-NPs prepared by ionic gelation method. The investigated variables were initial drug load (X1), chitosan percentage (X2), tripolyphosphate sodium (TPP) percentage (X3), poloxamer percentage (X4), homogenization speed (X5), homogenization time (X6) and TPP addition rate (X7). The prepared DM-loaded NPs have been fully evaluated for particle size (Y1), Zeta potential (Y2), production yield (Y3), entrapment efficiency (Y4), loading capacity (Y5), initial burst (Y6), and cumulative drug release (Y7). Finally, DM pharmacokinetic has been investigated on healthy albino male rabbits by means of non-compartmental analysis. Results: The combination of variables showed variability of Y1, Y2, and Y3 equal to 122-710 nm, 3.49-23.63 mV, and 47.31-92.96%, respectively. While Y4 and Y5, reached 99.87%, and 8.53%, respectively. The prepared NPs revealed that X2, X3, and X4 are the variables that play the important role in controlling the release behavior of DM from the NPs. The in vivo pharmacokinetic results indicated the enhancement in bioavailability of DM by 7 folds compared to drug suspension and the mean residence time prolonged to 23.72 h compared to 4.7 h of drug suspension. Conclusion: The study proved that controlling the release of DM from NPs enhance its bioavailability and improve the compliance of patients with hypertension or benign prostatic hyperplasia.

Introduction: About 40% of patients with epilepsy are associated with drug-resistant seizures, therefore there has been a continuous search for novel treatment approaches. In experimental studies, natural and synthetic cannabimimetic compounds alone or combined with antiepileptic drugs (AEDs) have been extensively studied and cannabidiol, a naturally occurring compound, has been involved in a number of clinical trials.Areas covered: The authors have performed a literature search (PubMed database up to December 2018) for studies evaluating interactions between AEDs and cannabinoid receptor ligands in experimental models of seizures. Clinical data relate to the add-on treatment with cannabidiol.Expert opinion: WIN55,212–2 mesylate (WIN, a non-selective agonist of CB1 and CB2 receptors) significantly potentiated the anticonvulsant activity of various AEDs in mice. Profound neurotoxic effects accompanied combinations of WIN with conventional AEDs. Among conventional and newer AEDs, ACEA (a selective ...

Apatinib (APA) is a targeted anti-neoplastic drug by inhibiting the vascular endothelial cell growth factor receptor of tyrosine kinase. Its therapeutic solid form, apatinib mesylate (ATM), is diss...

Through systematical comparison of various N4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta-stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N4-Bz cytosine and anomeric mixture of 2,2‘-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) – a selective, potent, oral IDO1 inhibitor – combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320

A novel synthetic route of producing ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) was developed through multiple reactions from cheap and readily-available cholic acid. The reaction conditions of the key elimination reaction of mesylate ester group were also investigated and optimized, including solvent, base and reaction temperature. In the straightforward synthetic route for preparation of UDCA and OCA, most of the reaction steps have high conversions with average yields of 94% and 92%, and overall yield up to 65% (7 steps) and 36% (11 steps) from cholic acid, respectively. This promising route offers economical and efficient strategies for potential large-scale production of UDCA and OCA.

Background Nanotechnology is now considered a promising drug delivery method for orally administered hydrophobic drugs to their sites of action. The effect of nanodispersion on cellular transport and accumulation of saquinavir (SQV) was investigated. Methods The transport of five solid drug nanoparticle (SDN) SQV formulations along Caco-2 cell monolayers (CCM) was compared to that of standard SQV. The SDNs were prepared using SQV mesylate (20%), Pluronic F127 (10%) plus five other excipients (HPMC, PVP, PVA, Lecithin S75 and Span 80) in different proportions. Cellular accumulation in CEM parental and CEMVBL (P-gp overexpressing) cells was conducted to ascertain the effect of nanodispersion on P-gp mediated efflux of SQV. All SDN formulations were dissolved in water, whereas SQV in DMSO to improve solubility. Quantification was via HPLC. Results From transport results, an SDN sample composed of SQV mesylate/Pluronic F127 plus HPMC (70%) and had a 24% increase in apparent absorption compared to standard SQV, largely driven by a 38% reduction in basolateral to apical permeation. Additionally, the formulation and two others (SQV mesylate/Pluronic F127 alone; and + HPMC (65%)/Lecithin [5%]) accumulated more significantly in CEM cells, suggesting enhanced delivery to these cells. Moreover, accumulation and transport of the three SDNs compared well to that of SQV despite being dissolved in water, suggestive of improved dissolution. The inclusion of PVA resulted in increased efflux. Conclusion The use of HPMC and Pluronic F127 produced SQV SDNs with improved permeation in Caco-2 cells and improved accumulation in CEM cells, but negative effects with PVA.

Bedaquiline is used to treat multi-resistant tuberculosis in adults. The fumarate salt is commercially available and used in the product Sirturo. To provide open access to bedaquiline molecule once the patent on the chemical substance expires, new salts were screened. This work offers additional information on the bedaquiline system, as new salts may present better pharmacokinetic properties. The current studies focus on the attempted isolation of the acetate, benzoate, benzenesulfonate, hydrobromide, succinate, hydrochloride, tartrate, lactate, maleate, malate, and mesylate salts of bedaquiline. Potential salts were screened using a unique combination of conventional screening, and small-scale experiments supplemented by crystallographic analysis and infrared microspectroscopy. Salts were prepared on a larger scale by dissolving 1:1 ratios of the individual salt formers and bedaquiline base (30 mg, 0.055 mmol) in different solvents and allowing the solutions to evaporate or crystallize. X-ray diffraction (XRD) techniques and spectroscopic and thermal analyses were employed to characterize the salts. The benzoate and maleate salts were selected as lead candidates after reviewing preliminary characterization data. To determine the most stable forms for the leads, a polymorph screen was conducted using solvents of various polarities. These salt screens successfully generated five new salts of bedaquiline, namely, benzoate, maleate, hydrochloride, besylate, and mesylate. The existence of these salts was confirmed by powder XRD, proton NMR, and IR spectroscopies. TGA and DSC thermal analysis along with hot-stage optical microscopy were further used to characterize the salts. The polymorph screen conducted on the salts suggested the absence of additional polymorphs at 1 g scale. Supplementary Information The online version contains supplementary material available at 10.1208/s12249-021-02106-7.

Objectives: To evaluate the clinical effect of apatinib combined with chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). Methods: Eighty patients with advanced NSCLC treated in Hebei General Hospital from January 2017 to July 2020 were randomly divided into two groups: the experimental group and the control group, each with 40 cases. Patients in the control group were treated with conventional paclitaxel combined with cisplatin chemotherapy, while patients in the experimental group were treated with apatinib mesylate tablets based on the treatment of the control group. After treatment, tumor efficacy evaluation was conducted on all patients every two cycles, and the therapeutic effect, adverse drug reactions, improvement of quality-of-life scores prior to and after treatment, and changes of indicators such as tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 153(CA153) were compared and analyzed between the two groups. Results: The total effective rate of the experimental group was 67.5%, which was significantly better than the 45% of the control group (p=0.04); The incidence of adverse drug reactions in the experimental group was 25%, while that in the control group was 37.5%, with no significant difference (p=0.23); Moreover, the improvement rate of quality of life scores in the experimental group was significantly higher than that in the control group (p=0.03), and the levels of CEA and CA153 in the experimental group were significantly lower after treatment than those in the control group, with a statistically significant difference (p=0.01). Conclusion: Apatinib combined with conventional chemotherapy is effective in the treatment of advanced non-small cell lung cancer, the quality of life can be significantly improved, tumor markers can be significantly reduced, and adverse reactions will not be significantly increased. doi: https://doi.org/10.12669/pjms.37.4.4066 How to cite this:Cui Y, Liu J, Liu M, Zhang H. Observation on the Clinical Effect of Apatinib Combined with Chemotherapy in the Treatment of Advanced Non-Small Cell Lung Cancer. Pak J Med Sci. 2021;37(4):1036-1041. doi: https://doi.org/10.12669/pjms.37.4.4066 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background [18F]MC225 is a radiotracer for imaging P-glycoprotein (P-gp) function at the blood-brain barrier. The P-gp function can be altered due to different factors, for instance, decreased P-gp function has been described in patients with Alzheimer’s or Parkinson’s Disease. The current applied radiosynthesis of [18F]MC225 involves 2 steps, including the distillation of the [18F] fluoroethylbromide intermediate. To develop a more robust synthetic procedure, it is of interest to produce the radiotracer via a 1-step synthesis. The present study describes a new synthetic approach to produce [18F]MC225 via direct 18F-fluorination. Moreover, we also provide the appropriate conditions for the automation of the synthesis. A mesylate precursor was synthesized via a multi-step synthetic route and used for the radiolabeling. The nucleophilic substitution of the mesylate group by [18F] Fluoride was automated in two different synthesis modules: IBA Synthera and Eckert and Ziegler PharmTracer (E&Z). Results The mesylate precursor was synthesized in 7 steps starting with 5-hydroxy-1-tetralone (commercially available) in practical yields. The stability of the precursor was improved via mesylate salt formation method. The radiolabeling was done by adding the mesylate precursor dissolved in DMF to the dried [18F]KF/K2.2.2 complex and heating at 140 °C for 30 min. Quality control by UPLC confirmed the production of [18F]MC225 with a molar activity (Am) higher than 100 GBq/micromole. The synthesis time in Synthera was 106 min and the product was obtained with a radiochemical purity higher than 95% and RCY of 6.5%, while the production in E&Z lasted 120 min and the product had a lower radiochemical purity (91%) and RCY (3.8%). Conclusions [18F]MC225 was successfully produced via a 1-step reaction. The procedure is suitable for automation using commercially available synthesis modules. The automation of the radiosynthesis in the Synthera module allows the production of the [18F]MC225 by a reliable and simple method.