Clinical outcomes of colistin methanesulfonate sodium in correlation with pharmacokinetic parameters in critically ill patients with multi-drug resistant bacteria-mediated infection: A systematic review and meta-analysis.

BACKGROUND: Colistin is a viable option for multidrug resistant gram-negative bacteria emerged from inappropriate antibiotic use. Nonetheless, suboptimal colistin concentrations and nephrotoxicity risks hinder its clinical use. Thus, the aim of this study is to investigate clinical outcomes in correlation with pharmacokinetic differences and infection types in critically ill patients on intravenous colistin methanesulfornate sodium (CMS). METHODS: A systematic literature search of Embase, Google Scholars, and PubMed was performed to identify clinical trials evaluating pharmacokinetic parameters along with clinical outcomes of CMS treatment from inception to July 2023. The pooled analyses of clinical impact of CMS on nephrotoxicity, mortality, clinical cure, and colistin concentration at steady state (Css,avg) were performed. This study was registered in the PROSPERO (CRD 42023456120). RESULTS: Total of 695 critically ill patients from 17 studies were included. The mortality was substantially lower in clinically cured patients (OR 0.05; 95% CI 0.02 - 0.14), whereas the mortality rate was statistically insignificant between nephrotoxic and non-nephrotoxic patients. Inter-patient variability of pharmacokinetic parameters of CMS and colistin was observed in critically ill patients. The standard mean differences of Css,avg were statistically insignificant between clinically cure and clinically failure groups (standard mean difference (SMD) -0.25; 95% CI -0.69 - 0.19) and between nephrotoxic and non-nephrotoxic groups (SMD 0.67; 95% CI -0.27-1.61). The clinical cure rate is substantially lower in pneumonia patients (OR 0.09; 95% CI 0.01 - 0.56), and pharmacokinetic parameters pertaining to microbiological cure were different among strains. CONCLUSION: The mortality rate was substantially lower in clinically cured patients with CMS. However, no significant differences in Css,avg of colistin were examined to determine the impact of pharmacokinetic differences on clinical outcomes including mortality rate and nephrotoxicity risk. Nevertheless, the clinical cure rate is substantially lower in patients with respiratory infection than patients with urinary tract infection.

DHEC mesylate attenuates pathologies and aberrant bisecting N-glycosylation in Alzheimer's disease models.

Tremendous progress has been made to develop the therapy of Alzheimer's disease (AD). Existing several anti-AD remedies, with certain limitations, are far from adequate. Evidence suggests that dihydroergocristine (DHEC) mesylate, one of the main components of Ergoloid mesylates, can reduce the production of amyloid-ß in vitro. However, the therapeutic effect of DHEC mesylate in AD and its underlying mechanism are still largely unknown. Herein, we characterized the pharmacological effect of DHEC mesylate in AD and found that the spatial memory disorders and Alzheimer-type pathologies were alleviated by DHEC mesylate administration. Moreover, we demonstrated that DHEC mesylate improved aberrant bisecting N-glycosylation, which was identified as a potential biomarker of AD. We further explored the underlying mechanism and confirmed that DHEC mesylate protected against AD via AMPK and ERK signaling, in which, AMPK was the dominant down-stream molecule of DHEC mesylate. In summary, our findings provide foundations for development of DHEC mesylate as a therapeutic approach for AD.

[Clinical Efficacy and Safety of Flumatinib in the Treatment of Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase].

OBJECTIVE: To explore the clinical efficacy and safety of flumatinib mesylate produced in China in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). METHODS: 32 newly diagnosed CML-CP patients admitted to the Hematology Department of the Affiliated Hospital of Southwest Medical University from March 1, 2020 to March 31, 2022, who had never received any tyrosine kinase inhibitor (TKI) were included in the study. The patients were treated by flumatinib mesylate 600mg once daily. The hematologic, cytogenetic and molecular responses were assessed at 3-, 6- and 12-month, and adverse effects of the drug were evaluated. RESULTS: 31 patients were treated with flumatinib for≥3 months, of which 24 patients were treated for ≥6 months and 14 patients were treated for≥12 months. At 3rd month of treatment, 30 out of 31 patients achieved complete hematologic response (CHR); 24 patients underwent cytogenetic testing and 22 cases achieved major cytogenetic response(MCyR), of which 21 cases achieved complete cytogenetic response (CCyR); Among 25 patients who underwent molecular testing, 22 patients had BCR-ABLIS≤10%, including 10 patients with BCR-ABLIS≤0.1%, and 6 patients with BCR-ABLIS≤0.01%. At 6th month of treatment, 23 out of 24 patients achieved CHR; 17 patients underwent cytogenetic testing and all achieved CCyR; Among 23 patients who underwent molecular testing, 20 patients had BCR-ABLIS≤1%, including 16 patients with BCR-ABLIS≤0.1% and 12 patients with BCR-ABLIS≤0.01%. At 12nd month of treatment, all 14 patients achieved CHR and CCyR; Among them, 10 patients had BCR-ABLIS≤0.1%, including 9 patients with BCR-ABLIS≤0.01%. The grade Ⅲ/Ⅳ leukopenia, thrombocytopenia and anemia rates in the patients were 13.3%, 20.0% and 3.3%, respectively. One patient stopped flumatinib therapy due to severe and persistent hematologic toxicity. The major non-hematologic adverse events were abnormal liver function (20%), diarrhea (10%), bone/joint pain (10%), muscle spasm (10%), rash (6.7%), acute kidney injury (6.7%) and nausea(3.3%), most of which were grade I-II. No patient experienced grade Ⅳ non-hematologic adverse events. No drug toxicity-related death occurred. CONCLUSION: Flumatinib mesglate, as the first-line treatment for newly diagnosed CML-CP, can enable the patients to achieve early and deep molecular and cytogenetic responses, and shows good safety.

[Real-World Efficacy and Safety of China-Made Flumatinib Mesylate in the Treatment of Chronic Myeloid Leukemia in Chronic Phase].

OBJECTIVE: To evaluate the efficacy and safty of China-made flumatinib mesylate in the treatment of chronic myeloid leukemia in chronic phase (CML-CP). METHODS: 42 CML-CP patients treated with Chinese produced flumatinib (oral, 600 mg, 1/d) were included in the study, including 14 newly diagnosed patients and 28 patients underwent conversion therapy. The hematological, cytogenetic and molecular response and safety were observed and evaluated after 3, 6 and 12 months of treatment. RESULTS: 35 patients were treated for more than 3 months, among which 31 patients were treated for more than 6 months and 17 patients were treated for more than 12 months. After 3 months of treatment, 33 patients underwent hematological, cytogenetic and molecular examination. Of these, 32 patients achieved complete hematological response (CHR), 13 patients achieved complete cytogenetic response (CCyR), 20 patients showed BCR-ABLIS≤10% and 7 patients reached major molecular response (MMR). After 6 months of treatment, all 30 patients who could evaluate efficacy achieved CHR, of which 17 patients achieved CCyR, 18 patients showed BCR-ABLIS≤1% and 16 patients reached MMR. After 12 months of treatment, all 17 patients were evaluated for efficacy, all achieved CHR, 10 patients obtained CCyR, 7 patients reached MMR. Grade III or IV thrombocytopenia, leukopenia and anemia occurred in 7, 2 and 1 patients, respectively. The non-hematological adverse reactions were diarrhea in 6 cases, renal function damage in 4 cases, rash and pruritus in 3 cases, liver function damage in 3 cases, nausea in 1 case, fever in 1 case, bone/joint or muscle pain in 1 case. CONCLUSION: In the real world, China-made flumatinib mesylate has a positive short-term efficacy and reliable safety in the treatment of CML-CP patients, whether as first-line treatment or second- and third-line conversion therapy.

Analgesic effect of safinamide mesylate in a rat model of neuropathic pain.

Pain is one of the most frequent non-motor symptoms of Parkinson's disease (PD). Neuropathic pain is highly prevalent in PD and negatively affects the quality of life of patients with PD. However, there is currently no evidence-based treatment for its control. Safinamide, a monoamine oxidase (MAO)-B inhibitor with a sodium channel inhibitory effect, showed improvement in PD-related pain in several clinical trials. However, it is unclear for which of the various types of pain in PD safinamide is effective. The aim of the present study was to examine the effect of safinamide on neuropathic pain in a rat model of chronic constriction injury (CCI). Pain was evaluated on postoperative days 14 and 21 using von Frey or weight-bearing tests. Male CCI model rats showed a decreased paw withdrawal threshold and a weight-bearing deficit on postoperative days 14 and 21. Single oral administration of safinamide (15, 30, 45 or 70 mg/kg) dose-dependently improved neuropathic pain in both pain assessments on day 14. Subsequently, the 15 and 45 mg/kg dose groups were administered safinamide orally once daily until day 21. With repeated administration, the effect of safinamide on pain was enhanced. The present findings show that safinamide improves neuropathic pain in male CCI model rats. Further animal model research and pathological and molecular pharmacological investigations are warranted.

Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.

BACKGROUND: Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD). OBJECTIVES: The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY). DESIGN: The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase. SETTING: 76 clinical research sites in North America and Europe. PARTICIPANTS: 545 patients with probable AD or MCI-AD in the final version of the protocol. INTERVENTION: Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose. MEASUREMENTS: Co-primary clinical outcomes are the 11-item Alzheimer's Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography. RESULTS: 446 participants are expected to complete the 12-month placebo-controlled phase in March 2022. CONCLUSIONS: If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.

Delivery of Dihydroergotamine Mesylate to the Upper Nasal Space for the Acute Treatment of Migraine: Technology in Action.

Oral tablets account for the majority of medications used to acutely treat migraine, but relief can be limited by their rates of dissolution and absorption. The nose is an attractive alternative route of drug delivery since it provides patient convenience of at-home use, gastrointestinal (GI) avoidance, and rapid absorption of drugs into systemic circulation because of its large surface area. However, the site of drug deposition within the nasal cavity should be considered since it can influence drug absorption. Traditional nasal devices have been shown to target drug delivery to the lower nasal space where epithelium is not best-suited for drug absorption and where there is an increased likelihood of drug clearance due to nasal drip, swallowing, or mucociliary clearance, potentially resulting in variable absorption and suboptimal efficacy. Alternatively, the upper nasal space (UNS) offers a permeable, richly vascularized epithelium with a decreased likelihood of drug loss or clearance due to the anatomy of this area. Traditional nasal pumps deposit <5% of active drug into the UNS because of the nasal cavity's complex architecture. A new technology, Precision Olfactory Delivery (POD®), is a handheld, manually actuated, propellant-powered, administration device that delivers drug specifically to the UNS. A dihydroergotamine (DHE) mesylate product, INP104, utilizes POD technology to deliver drug to the UNS for the acute treatment of migraine. Results from clinical studies of INP104 demonstrate a favorable pharmacokinetic profile, consistent and predictable dosing, rapid systemic levels known to be effective (similar to other DHE mesylate clinical programs), safety and tolerability on the upper nasal mucosa, and high patient acceptance. POD technology may have the potential to overcome the limitations of traditional nasal delivery systems, while utilizing the nasal delivery benefits of GI tract avoidance, rapid onset, patient convenience, and ease of use.

Efficacy of desferrioxamine mesylate in intracerebral hematoma: a systemic review and meta-analysis.

BACKGROUND: Previous meta-analysis had concluded that desferrioxamine mesylate (DFO) could effectively treat intracerebral hematoma (ICH) in animal models. We hope to confirm that DFO could treat ICH patients effectively through the systemic review and meta-analysis of clinical researches. METHOD: Data extraction included hematoma volume (HV), reduction of National Institute of Health Stroke Scale (NIHSS) scores, and relative perihematomal edema (RPHE). The standard mean difference (SMD) and 95% confidence interval (95%CI) were calculated by fixed effects model. I-square (I2) statistic was used to test the heterogeneity. All p values were two-side with a significant level at 0.05. RESULTS: Five randomized controlled trials were included in the meta-analysis, which included 239 patients. At 7 days after onset, there was significant difference of RPHE development (- 1.87 (- 2.22, - 1.51) (I2 = 0, p = 0.639)) and significant difference of HV absorption (- 0.71 (- 1.06, 0.36) (I2 = 17.5%, p = 0.271)) between DFO and control groups. There was significant difference of reduction of NHISS scores (0.25 (0.05, 0.46) (I2 = 0, p = 0.992)) between DFO and control groups at 30 days after onset. CONCLUSION: DFO reduced HV and perihematomal edema in ICH patients at 7 days after onset and improve neurological function at 30 days after onset efficiently and safely. DFO might be a new route of improving treatment of ICH.

A dose regimen-finding study to evaluate the safety, tolerability, pharmacokinetics, and activity of oratecan in subjects with advanced malignancies.

PURPOSE: Irinotecan is a commonly used chemotherapeutic in solid tumor malignancies. Oratecan is an investigational product comprised of encequidar methanesulfonate, a novel minimally absorbed P-glycoprotein pump inhibitor, and irinotecan. This study sought to determine the maximum tolerated dose (MTD) of oratecan in patients with advanced malignancies. METHODS: Using a "3 + 3″ dose-escalation design, patients were treated with oratecan on day 1 every 21 days. The irinotecan dose was escalated from 20 to 320 mg/m2. The encequidar methanesulfonate dose was fixed at 15 mg (12.9 mg free base). PK sampling for irinotecan, encequidar and its major metabolites was performed following a single dose of oratecan during cycle 1. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. The MTD was determined to be 280 mg/m2 every 21 days. Irinotecan and SN-38 plasma concentration-time profile showed that irinotecan exposure increased with dose and followed biexponential decay. Nine of 17 patients at oratecan dose levels 200 mg/m2 and above had SN-38 exposures comparable to those with intravenous irinotecan at standard dosing. None of the 35 patients achieved a radiologic response, ten patients had SD for > 8 weeks; the median progression-free survival for all treated patients was 9 weeks (95% CI 8.6-13.9). CONCLUSIONS: The MTD of oratecan was encequidar methanesulfonate 15 mg plus irinotecan 280 mg/m2. Exposure for irinotecan and SN-38 increased with increased dose. Potential antitumor activity was observed at the 280 and 320 mg/m2 dose levels. The safety profile of oratecan was comparable to that of intravenous irinotecan.

Pulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and formed colistin following nebulisation of CMS among patients with ventilator-associated pneumonia.

There has been accumulating interest in nebulised colistin methanesulfonate (CMS) for the treatment of ventilator-associated pneumonia (VAP). In this study, pulmonary and systemic pharmacokinetics following nebulisation of CMS at a dose of 3 MIU and 5 MIU, using a vibrating mesh nebuliser, for VAP caused by extensively drug-resistant Gram-negative pathogens was assessed. Blood samples and mini-bronchoalveolar lavage (mini-BAL) was performed post-dose at 1, 4 and 8 h. Concentrations of CMS and formed colistin in mini-BAL and plasma were determined by liquid chromatography-tandem mass spectrometry, and pharmacokinetic analysis was conducted using a population approach. The study population included three groups (n = 10 per group): (A) intravenous CMS and concomitantly nebulised CMS at a dose of 3 MIU (30 min duration); (B) nebulised CMS at a dose of 3 MIU (30 min duration) as monotherapy; and (C) nebulised CMS 5 MIU (45 min duration) as monotherapy. Mean plasma formed colistin concentrations were <1 mg/L following CMS nebulisation as monotherapy (groups B and C). Predicted trough concentrations of formed colistin in the epithelial lining fluid (ELF) following 24-h dosing of 3 MIU and 5 MIU nebulised CMS were 120.4 mg/L and 200.7 mg/L, respectively. The model predicted that concomitant intravenous CMS (group A) had minimal impact on the formed colistin concentration in ELF. This study demonstrated high ELF formed colistin concentrations following nebulised CMS (constantly above colistin MICs), while plasma concentrations were lower than those associated with nephrotoxicity. Our results provide important information for optimisation of nebulised colistin therapy.

[In vitro pharmacodynamic studies of novel class â and â ¡b selective histone deacetylase inhibitor purinostat mesylate in the treatment of diffuse large B-cell lymphoma and its mechanism].

Objective: To investigate the in vitro inhibitory activity of a novel class Ⅰ and Ⅱb selective histone deacetylase (HDAC) inhibitor, purinostat mesylate (PM) , in diffuse large B-cell lymphoma and its mechanism. Methods: The 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide method was used to detect the effect of PM on cell proliferation. The effects of PM on cell cycle and apoptosis were detected by flow cytometry. The acetylation levels of HDAC substrate, cell cycle protein, apoptosis-related protein, and oncogene protein expression were detected by Western blot. Results: PM significantly inhibited the proliferation of lymphoma SUDHL-4 and SUDHL-6 cells and increased the acetylation levels of HDAC substrates H3, H4, and α-tubulin. In cell cycle experiments, PM induced G(0)/G(1) phase arrest in SUDHL-4 and SUDHL-6 cells. Western blot experiment showed that PM could significantly downregulate the expression of cyclin-dependent kinases Cdk2, Cdk4, Cdk6, cyclin D1, and cyclin E and upregulate the expression of CDK inhibitor protein p21. In the apoptosis experiment, PM could induce the apoptosis of SUDHL-4 and SUDHL-6 cells. Western blot experiment demonstrated that PM promoted endogenous apoptosis by activating caspase-3 kinase and affecting antiapoptotic protein Bcl-2. In addition, PM could downregulate the expression of oncogene marker proteins MYC, IKZF1, and IKZF3. Conclusion: PM has an efficient biological activity in vitro for diffuse large B-cell lymphoma, including double-hit lymphoma, and provides valuable experimental evidence for PM in clinical treatment.

Renoprotective effects of the novel prostaglandin EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized chronic kidney disease rats.

Prostaglandins (PGs) are important lipid mediators of numerous physiologic and pathophysiologic processes in the kidney. PGE2, the most abundant renal PG, plays a major role in renal physiology, including renin release and glomerular hemodynamics. We investigated the renoprotective properties of the novel PGE2 EP4 receptor-selective antagonist ASP7657 in 5/6 nephrectomized rats, a chronic kidney disease (CKD) model. Eight weeks of repeated administration of ASP7657 (0.001-0.1 mg/kg) dose-dependently and significantly reduced urinary protein excretion and attenuated the development of glomerulosclerosis and tubulointerstitial damage, including fibrosis and inflammatory cell infiltration, without affecting blood pressure. Additionally, ASP7657 tended to have beneficial effects on renal function, as indicated by the decrease in plasma creatinine and blood urea nitrogen levels and attenuation of the decline in creatinine clearance (Ccr). The angiotensin II receptor blocker losartan (10 mg/kg) also showed these renoprotective effects while significantly reducing blood pressure. ASP7657 dose-dependently and significantly reduced the EP4 receptor agonist-induced increase in plasma renin activity, as assessed by angiotensin I release in normal rats. Additionally, ASP7657 attenuated hyperfiltration assessed by Ccr without changing the renal blood flow or blood pressure in diabetic rats. These results suggest that ASP7657 suppresses the progression of chronic renal failure by modulating renin release and improving renal hemodynamics, and may therefore be a promising therapeutic option for inhibiting the progression of CKD.

Pharmacological properties of ASP7657, a novel, potent, and selective prostaglandin EP4 receptor antagonist.

We determined the pharmacologic profile of ASP7657, trans-4-[({[1-(quinolin-2-ylmethyl)-5-(trifluoromethyl)-1H-indol-7 yl] carbonyl} amino) methyl] cyclohexanecarboxylic acid methanesulfonate (1:1), a newly synthesized selective E-type prostaglandin (EP)4 receptor antagonist using several in vitro and in vivo experiments. ASP7657 exhibited high affinity for rat and human EP4 receptors, with Ki values of 6.02 nM and 2.21 nM, respectively. In addition, ASP7657 potently inhibited the PGE2-induced cyclic adenosine monophosphate (cAMP) increase in Chinese hamster ovary (CHO) cells expressing rat EP4 receptors and human lymphoblastoid T (Jurkat) cells, with IC50 values of 0.86 nM and 0.29 nM, respectively. In contrast, ASP7657 did not inhibit the PGE2-induced intracellular calcium increase in HEK293 cells expressing rat EP1 and EP3 receptors, or cAMP increase in CHO cells expressing rat EP2 receptors. ASP7657 showed good pharmacokinetic properties following oral dosing and dose-dependently antagonized the prostaglandin (PG)E2-mediated inhibition of lipopolysaccharide-induced tumor necrosis factor-α release from rat whole blood culture. In addition, 4 weeks repeated oral administration of ASP7657 dose-dependently attenuated albuminuria in type 2 diabetic mice; these effects were significant at doses of 0.01 mg/kg or higher. These results demonstrate that ASP7657 is a potent and selective EP4 receptor antagonist that may be useful in future studies to help clarify the physiological and pathophysiological roles of PG.

Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone.

Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We found that single, acute administration of MSB dose-dependently reduced alcohol intake and preference in mice after 3-week CED. The effect was specific to alcohol, as shown by the lack of any effect of MSB on sucrose or saccharin intake. We also used the drinking-in-the-dark (DID) model with limited access (4h/day) to evaluate the pharmacological effect of MSB after 3weeks of DID. However, MSB had no effect on alcohol drinking after 3-week DID. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB and naltrexone reduced alcohol intake profoundly after 3-week CED at doses lower than those individual effective doses. Repeated administrations of this combination showed less tolerance development than repeated MSB alone. Our study suggests that the novel KOP-r agonist MSB both alone and in combination with naltrexone shows potential in alcoholism treatment models.

Design, synthesis, cyclooxygenase inhibition and biological evaluation of new 1,3,5-triaryl-4,5-dihydro-1H-pyrazole derivatives possessing amino/methanesulfonyl pharmacophore.

A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole 10a-l was designed and synthesized via cyclization of chalcones 8a-f with 4-amino/methanesulfonylphenylhydrazine hydrochloride 9a-b. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity, ulcerogenic liability and analgesic activity. All compounds were more COX-2 inhibitors than COX-1. While most compounds showed good anti-inflammatory activity, the trimethoxy derivatives (10a, 10b, 10g and 10h) were the most potent derivatives (ED50=55.78, 53.99, 67.65 and 69.20µmol/kg respectively) in comparison with celecoxib (ED50=82.15µmol/kg). Compounds 10a, 10b, 10g and 10h (ulcer index=2.68, 1.20, 2.63 and 2.66 respectively) showed less ulceration effect than celecoxib (ulcer index=2.90). Also, Compounds 10a, 10b, 10g and 10h showed analgesic activity higher than celecoxib and comparable to that of ibuprofen. In addition, molecular docking studies were performed for compounds 10a, 10b, 10g and 10h and the results were in agreement with that obtained from the in vitro COX inhibition assays.

Rational design of an AKR1C3-resistant analog of PR-104 for enzyme-prodrug therapy.

The clinical stage anti-cancer agent PR-104 has potential utility as a cytotoxic prodrug for exogenous bacterial nitroreductases expressed from replicating vector platforms. However substrate selectivity is compromised due to metabolism by the human one- and two-electron oxidoreductases cytochrome P450 oxidoreductase (POR) and aldo-keto reductase 1C3 (AKR1C3). Using rational drug design we developed a novel mono-nitro analog of PR-104A that is essentially free of this off-target activity in vitro and in vivo. Unlike PR-104A, there was no biologically relevant cytotoxicity in cells engineered to express AKR1C3 or POR, under aerobic or anoxic conditions, respectively. We screened this inert prodrug analog, SN34507, against a type I bacterial nitroreductase library and identified E. coli NfsA as an efficient bioactivator using a DNA damage response assay and recombinant enzyme kinetics. Expression of E. coli NfsA in human colorectal cancer cells led to selective cytotoxicity to SN34507 that was associated with cell cycle arrest and generated a robust 'bystander effect' at tissue-like cell densities when only 3% of cells were NfsA positive. Anti-tumor activity of SN35539, the phosphate pre-prodrug of SN34507, was established in 'mixed' tumors harboring a minority of NfsA-positive cells and demonstrated marked tumor control following heterogeneous suicide gene expression. These experiments demonstrate that off-target metabolism of PR-104 can be avoided and identify the suicide gene/prodrug partnership of E. coli NfsA/SN35539 as a promising combination for development in armed vectors.

GPR119: a promising target for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease is associated with metabolic syndrome and has the unique characteristic of excess lipid accumulation in liver. G-protein-coupled receptor 119 (GPR119) is a promising target for type 2 diabetes. However, the role of GPR119 activation in hepatic steatosis and its precise mechanism has not been investigated. In primary cultured hepatocytes from wild-type and GPR119 knockout (KO) mice, expression of lipogenic enzymes was elevated in GPR119 KO hepatocytes. Treatment of hepatocytes and HepG2 cells with GPR119 agonists in phase 2 clinical trials (MBX-2982 [MBX] and GSK1292263) inhibited protein expression of both nuclear and total sterol regulatory element binding protein (SREBP)-1, a key lipogenesis transcription factor. Oral administration of MBX in mice fed a high-fat diet potently inhibited hepatic lipid accumulation and expression levels of SREBP-1 and lipogenesis-related genes, whereas the hepatic antilipogenesis effects of MBX were abolished in GPR119 KO mice. MBX activated AMPK and increased Ser-372 phosphorylation of SREBP-1c, an inhibitory form of SREBP-1c. Moreover, inhibition of AMPK recovered MBX-induced down-regulation of SREBP-1. These findings demonstrate for the first time that the GPR119 ligand alleviates hepatic steatosis by inhibiting SREBP-1-mediated lipogenesis in hepatocytes.

Comparative study of the anti-leukemic effects of imatinib mesylate, Glivec™ tablet and its generic formulation, OHK9511.

Long-term treatment with imatinib mesylate (IM) allows patients with chronic myeloid leukemia (CML) to live a near-normal lifespan. However, the fact that tyrosine kinase inhibitors, including IM, are extremely expensive is a major cause of poor adherence, resulting in disease relapse or drug resistance. Therefore, physicians are encouraged to prescribe generic drugs to reduce the financial burden of medical expenses. In Japan, only generic drugs that have a basic chemical structure and pharmacokinetic data that are the same as those of the original drug are approved. However, it is not mandatory to demonstrate that generic drugs have adequate biological effects. This is one of the reasons why Japanese hematologists do not often use generic IM. The aim of the present study was to compare the anti-leukemic effects of Glivec™ (a commercial IM) and its generic formulation, OHK9511. The IC50 values of OHK9511 and Glivec™ were comparable, and both induced similar levels of apoptosis in several CML cell lines. Furthermore, the overall survival of OHK9511-treated mice transplanted with BCR-ABL-positive cells was similar to that of mice treated with Glivec™. Although the experiments performed herein were basic, the results suggest that physicians should consider using generic IM.