Clinical Pharmacology : Advances and Applications最新文献

{"title":"Modeling and simulation of the endogenous CYP3A induction marker 4β-hydroxycholesterol during enasidenib treatment.","authors":"Yan Li,&nbsp;Jamie N Connarn,&nbsp;Jian Chen,&nbsp;Zeen Tong,&nbsp;Maria Palmisano,&nbsp;Simon Zhou","doi":"10.2147/CPAA.S192687","DOIUrl":"https://doi.org/10.2147/CPAA.S192687","url":null,"abstract":"<p><strong>Background: </strong>Enasidenib (IDHIFA^®, AG-221) is a first-in-class, targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. This was a Phase I/II study evaluating safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of orally administered enasidenib in subjects with advanced hematologic malignancies with an IDH2 mutation.</p><p><strong>Methods: </strong>Blood samples for PK and PD assessment were collected. A semi-mechanistic nonlinear mixed effect PK/PD model was successfully developed to characterize enasidenib plasma PK and to assess enasidenib-induced CYP3A activity.</p><p><strong>Results: </strong>The PK model showed that enasidenib plasma concentrations were adequately described by a one-compartment model with first-order absorption and elimination; the PD model showed a high capacity to induce CYP3A (E_max=7.36) and a high enasidenib plasma concentration to produce half of maximum CYP3A induction (EC₅₀ =31,400 ng/mL). Monte Carlo simulations based on the final PK/PD model showed that at 100 mg once daily dose there was significant drug accumulation and a maximum of three-fold CYP3A induction after multiple doses. Although the EC₅₀ value for CYP3A induction by enasidenib is high, CYP3A induction was observed due to significant drug accumulation.</p><p><strong>Conclusion: </strong>CYP3A induction following enasidenib dosing should be considered when prescribing concomitant medication metabolized via this pathway.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"11 ","pages":"39-50"},"PeriodicalIF":2.0,"publicationDate":"2019-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S192687","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37045039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the effect of omega-3 fatty acid combined with vitamin D3 versus vitamin D3 alone on estradiol levels: a randomized, placebo-controlled trial in females with vitamin D deficiency.","authors":"Amani H Al-Shaer,&nbsp;Mahmoud S Abu-Samak,&nbsp;Luai Z Hasoun,&nbsp;Beisan A Mohammad,&nbsp;Iman A Basheti","doi":"10.2147/CPAA.S182927","DOIUrl":"https://doi.org/10.2147/CPAA.S182927","url":null,"abstract":"<p><strong>Purpose: </strong>Outcomes investigating the effect of vitamin D3 (VD3) and omega-3 fatty acids (Omega-3FA) on serum estradiol (E2) are scarce and conflicting. No previous study has investigated the effect of VD3 combination with Omega-3FA on E2 levels. This study was designed to investigate the effect of VD3, Omega-3FA and VD3 plus Omega-3FA on serum E2 levels in premenopausal females diagnosed with vitamin D deficiency (VDD).</p><p><strong>Subjects and methods: </strong>This randomized, placebo-controlled clinical trial was designed to evaluate the effects of 50,000 IU VD3 taken weekly, 300 mg Omega-3FA taken daily and their combination by the study participants for 8 weeks. The mid-follicular serum levels of E2 and 25-hydroxy vitamin D (25OHD) were assessed at 8 weeks. The study was conducted during winter on a convenience sample of healthy premenopausal Jordanian females with diagnosed VDD. Fasting serum levels for 25OHD and E2 were assessed at baseline and the end of the trial (after 8 weeks). Data were entered into SPSS and analyzed.</p><p><strong>Results: </strong>Healthy premenopausal Jordanian females (N=86) with diagnosed VDD, mean age 32.8±8.9 years, were recruited into the study. Supplementation of VD3 alone resulted in a significant increase in serum 25OHD (13.4±7.9-28.2±7.1 ng/mL, <i>P</i><0.001) and a significant decrease in E2 levels (85.7±16.5-60.3±20.6 pg/mL, <i>P</i>=0.001). Omega-3FA intake led to a significant decrease in serum 25OHD levels (21.2±12.8-13.6±9.2 ng/mL, <i>P</i>=0.001) and a significant increase in E2 levels (56.3±19.2-78.4±23.7 pg/mL, <i>P</i>=0.006). Combination therapy (VD3 plus Omega-3FA) resulted in a significant increase in both 25OHD (12.0±4.7-35.1±9.5 ng/mL, <i>P</i><0.001) and E2 (43.0±23.4-57.3±31.5 pg/mL, <i>P</i>=0.028) levels.</p><p><strong>Conclusion: </strong>Results of this study provide vital insight into the effects of D3, Omega-3FA and a combination of their supplementation on premenopausal Jordanian females with diagnosed VDD. Eight weeks of therapy led to decreased E2 level by VD3 and increased level by Omega-3FA supplementation. With regard to 25OHD, its level was increased by VD3 and decreased by Omega-3FA supplementation. Combination of VD3 plus Omega-3FA increased the levels of both E2 and 25OHD.</p><p><strong>Trial registration: </strong>This trial was registered at clinicaltrials.gov as NCT03333564.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"11 ","pages":"25-37"},"PeriodicalIF":2.0,"publicationDate":"2019-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S182927","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36578090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy.","authors":"William G North,&nbsp;Fuli Liu,&nbsp;Konstantin H Dragnev,&nbsp;Eugene Demidenko","doi":"10.2147/CPAA.S183885","DOIUrl":"https://doi.org/10.2147/CPAA.S183885","url":null,"abstract":"<p><strong>Background: </strong>Small-cell lung cancer (SCLC) has a poor prognosis since there is currently no effective therapy for commonly recurring disease. In our previous study, both primary and recurrent human tumors have been shown to express functional <i>N</i>-methyl-D-aspartate (NMDA) receptors, and blockade of these receptors with GluN1 and GluN2B antagonists decreased tumor cell viability in vitro, and growth of tumor xenografts in nu/nu mice.</p><p><strong>Materials and methods: </strong>In this study, we examine the influence of the GluN2B antagonist ifenprodil and the channel-blocker antagonist memantine, on cell viability and growth of tumor xenografts of recurrent SCLC (rSCLC) in mice.</p><p><strong>Results: </strong>Both antagonists significantly reduced cell viability and levels of components of the ERK1/2 pathway, increased apoptosis, and at very safe levels significantly reduced the growth of tumors in mice. Each antagonist and topotecan had additive effects to reduce cell viability with significant synergy demonstrated for the case of memantine. More significantly, combination treatments of xenografts in mice with ifenprodil and the chemotherapeutic agent topotecan produced clear additive effects that completely stopped tumor growth. Moreover, the ifenprodil and topotecan combination showed excellent supra-addition or synergy of inhibition for tumors ≤300 mm in size (<i>P</i>=4.7E-4). Combination treatment of memantine with topotecan also showed clear addition but, unlike ifenprodil, no synergy for the doses chosen.</p><p><strong>Conclusion: </strong>Since topotecan is a drug of choice for treatment of rSCLC, our findings suggest that combining this agent with NMDA receptor blockade using the GluN2B antagonist, ifenprodil, will significantly improve patient outcomes.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"11 ","pages":"15-23"},"PeriodicalIF":2.0,"publicationDate":"2019-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S183885","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36567882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Method development and validation of ursodiol and its major metabolites in human plasma by HPLC-tandem mass spectrometry.","authors":"Márcio Cardoso Pinto,&nbsp;Danilo Chorfi Berton,&nbsp;Alexandre Cavenatti de Oliveira,&nbsp;Carolina Martins Lazaro,&nbsp;Silvana Aparecida Calafatti Carandina","doi":"10.2147/CPAA.S187519","DOIUrl":"https://doi.org/10.2147/CPAA.S187519","url":null,"abstract":"<p><strong>Background: </strong>Ursodeoxycholic acid (UDCA) and its metabolites tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) have been the subject of several pharmacological studies. The objective of this study was to develop an innovative method of quantification by HPL-tandem mass spectrometry (LC-MS/MS), with a lower cost and suitable, for application in bioequivalence studies.</p><p><strong>Methods: </strong>The procedure involved liquid-liquid extraction for quantification of UDCA/GUDCA and precipitation extraction for TUDCA, using deuterated substances as internal standards (ISs) and Phenomenex Luna 250×4.6 mm 5μ C₁₈ 100A column. The mobile phase used was acetonitrile/ammonium acetate 30 mM (420: 580 v/v pH 7) for UDCA, acetonitrile/ammonium acetate 10 mM/ammonium hydroxide (400:600: 0.5 v/v/v pH 9) for GUDCA, and acetonitrile/ammonium acetate 10 mM (570: 430 v/v pH 7) for TUDCA. Ions were monitored by the electrospray ion source (ESI) mass spectrometer, operating in a negative ionization mode. Compound determination was performed by LC-MS/MS system using a calibration curve of 15-10,000 ng/mL for UDCA/GUDCA and 5-500 ng/mL for TUDCA. The method was developed and validated according to the Brazilian National Health Surveillance Agency (ANVISA) of Brazil norms harmonized with the main international guidelines as a prerequisite for conducting in vivo study in human volunteers.</p><p><strong>Results: </strong>The method did not present matrix effect and residual effect, showing to be selective for studied molecules, with adequate accuracy and precision. In addition, the method was considered sensitive presenting a coefficient of variation less than 20% for the lower limit of quantification of each compound.</p><p><strong>Conclusion: </strong>This method can be applied in bioequivalence studies to determine ursodiol and its metabolites reproducibly, simply, and effectively with the use of readily accessible analytical materials and instrumentation.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"11 ","pages":"1-13"},"PeriodicalIF":2.0,"publicationDate":"2019-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S187519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36917385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation between measured and calculated free phenytoin serum concentration in neurointensive care patients with hypoalbuminemia.","authors":"Seyyede-Sareh Javadi,&nbsp;Reza Mahjub,&nbsp;Abbas Taher,&nbsp;Younes Mohammadi,&nbsp;Maryam Mehrpooya","doi":"10.2147/CPAA.S186322","DOIUrl":"https://doi.org/10.2147/CPAA.S186322","url":null,"abstract":"<p><strong>Purpose: </strong>In critically ill patients, monitoring free phenytoin concentration is a valuable method for phenytoin-dosage adjustment. However, due to technical difficulties and the high cost of these methods, the Sheiner-Tozer equation is routinely used for estimating free phenytoin concentration in clinical practice. There have been conflicting results concerning accuracy and precision of the Sheiner-Tozer equation for prediction of free phenytoin concentration in various patient populations. Therefore, this study was conducted to evaluate the accuracy and correlation of measured and calculated free phenytoin concentrations in neurointensive care patients with hypoalbuminemia.</p><p><strong>Methods: </strong>A total of 65 adult neurointensive care patients with hypoalbuminemia who were receiving phenytoin for prevention or treatment of seizures were recruited in this study. In addition to measuring free phenytoin concentration by HPLC, free phenytoin concentration was calculated using both conventional and revised Sheiner-Tozer equations. Eventually, the correlation and level of agreement between measured and calculated free phenytoin concentrations were evaluated.</p><p><strong>Results: </strong>The mean albumin concentration of studied patients was 2.63±0.57 g/dL. There was a significant but weak-moderate correlation between measured and calculated free phenytoin concentration using conventional and revised Sheiner-Tozer equations (<i>r</i>=0.45 and <i>r</i>=0.43, respectively). Conventional and revised Sheiner-Tozer equations were not able to predict free phenytoin concentrations accurately in 33.85% and 35.4% of patients, respectively. Although the sex of patients did not have a significant impact on the level of agreement, younger patients had a higher level of agreement.</p><p><strong>Conclusion: </strong>Although there was a moderate correlation between calculated and measured free phenytoin concentration, the Sheiner-Tozer equation was not able to predict free phenytoin concentration accurately in all patients, especially in older patients. Therefore, monitoring free phenytoin serum concentration besides clinical outcomes should be considered for phenytoin-dose adjustment in critically ill patients.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"183-190"},"PeriodicalIF":2.0,"publicationDate":"2018-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S186322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36817558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treatment of acne with a combination of propolis, tea tree oil, and <i>Aloe vera</i> compared to erythromycin cream: two double-blind investigations.","authors":"V Mazzarello,&nbsp;M G Donadu,&nbsp;M Ferrari,&nbsp;G Piga,&nbsp;D Usai,&nbsp;S Zanetti,&nbsp;M A Sotgiu","doi":"10.2147/CPAA.S180474","DOIUrl":"https://doi.org/10.2147/CPAA.S180474","url":null,"abstract":"Introduction\u0000Antibiotics that suppress Propionibacterium acnes are the standard treatment for acne but are becoming less effective, due to the appearance of antibiotic-resistant strains. Many plants are known to have innate antimicrobial action and can be used as alternatives to antibiotics; thus, it is necessary to prove their effectiveness in vivo. This study aimed to evaluate the anti-acne efficacy of a new cream based on three natural extracts, comparing it to erythromycin cream and placebo.\u0000\u0000\u0000Patients and methods\u0000Sixty patients with mild to moderate acne vulgaris were randomly divided into three groups: treated with cream containing 20% propolis, 3% \"tea tree oil\", and 10% \"Aloe vera\" (PTAC) (n=20); or with 3 % erythromycin cream (ERC) (n=20); or with placebo (n=20). At baseline, after 15 and 30 days, investigators evaluated response to treatment by counting acne lesions through noninvasive measurements and macrophotography.\u0000\u0000\u0000Results\u0000All the clinical and instrumental values studied were statistically different from placebo except for sebometry, pHmetry, and erythema index values, measured on healthy skin. Unlike in the placebo group, papular and scar lesions showed high erythema reduction after 15 and 30 days of PTAC and ERC application.\u0000\u0000\u0000Conclusion\u0000The PTAC formulation was better than ERC in reducing erythema scars, acne severity index, and total lesion count.","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"175-181"},"PeriodicalIF":2.0,"publicationDate":"2018-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S180474","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36817557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Species difference in paclitaxel disposition correlated with poor pharmacological efficacy translation from mice to humans.","authors":"Ying Fei Li,&nbsp;Chengyue Zhang,&nbsp;Simon Zhou,&nbsp;Miao He,&nbsp;Huixia Zhang,&nbsp;Nianhang Chen,&nbsp;Feng Li,&nbsp;Xin Luan,&nbsp;Manjunath Pai,&nbsp;Hebao Yuan,&nbsp;Duxin Sun,&nbsp;Yan Li","doi":"10.2147/CPAA.S185449","DOIUrl":"https://doi.org/10.2147/CPAA.S185449","url":null,"abstract":"<p><strong>Background: </strong>Paclitaxel (PTX) products currently approved by the Food and Drug Administration include Kolliphor EL-paclitaxel micelles (KoEL-paclitaxel, Taxol) and nanoparticle albumin-bound paclitaxel (<i>nab</i>-paclitaxel, Abraxane). Despite containing the same cytotoxic agent, different PTX formulations have distinct pharmacological responses and indications in patients with cancer. Several novel PTX delivery vehicles that have shown superior efficacy to Taxol in animal models failed to demonstrate efficacy in Phase II/III human clinical trials.</p><p><strong>Materials and methods: </strong>A 10 mg/kg IV dose of KoEL-paclitaxel or <i>nab</i>-paclitaxel was administered to mice, and the pharmacokinetics (PK) profile of PTX in mice was then compared with the human PK profile from clinical studies. Population PK model and simulation was used to delineate the distribution and elimination characteristics in each species. In addition, tumor shrinkage was measured after weekly administration of both formulations in mouse xenograft model.</p><p><strong>Results: </strong>Our pharmacokinetic modeling results suggested that elimination predominates over distribution in driving PTX disposition in mice, hence restricting the PTX tissue accumulation. Moreover, the rapid elimination of PTX in mice minimized the different formulation effects on PTX tissue distribution, which is believed to link to the superior efficacy of <i>nab</i>-paclitaxel over KoEL-paclitaxel seen in human. In contrast to mice, PTX distribution predominates over elimination in human, and the decline in plasma PTX concentration reflected the deeper tissue distribution by <i>nab</i>-paclitaxel.</p><p><strong>Conclusion: </strong>This species difference in PTX distribution and elimination hinders a simple direct extrapolation from animals to humans. Therefore, species difference in drug distribution and elimination should be carefully assessed during translational drug development.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"165-174"},"PeriodicalIF":2.0,"publicationDate":"2018-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S185449","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36799523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.","authors":"Charles Frost,&nbsp;Andrew Shenker,&nbsp;Stanford Jhee,&nbsp;Zhigang Yu,&nbsp;Jessie Wang,&nbsp;Alexander Bragat,&nbsp;Janice Pursley,&nbsp;Frank LaCreta","doi":"10.2147/CPAA.S169505","DOIUrl":"https://doi.org/10.2147/CPAA.S169505","url":null,"abstract":"<p><strong>Purpose: </strong>This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.</p><p><strong>Subjects and methods: </strong>Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration.</p><p><strong>Results: </strong>Ascending single doses of apixaban 2.5-50 mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10 mg. Apixaban reached maximum concentrations (<i>C</i> _max) 3-4 h postdose, with mean <i>C</i> _max ranging from 52.5-485.0 to 44.8-494.3 ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13 h and the renal clearance was 1.1 and 0.8 L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG.</p><p><strong>Conclusion: </strong>Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"153-163"},"PeriodicalIF":2.0,"publicationDate":"2018-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S169505","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36781757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of combined treatment with sodium phenylbutyrate and cisplatin, erlotinib, or gefitinib on resistant NSCLC cells.","authors":"Maha S Al-Keilani,&nbsp;Karem H Alzoubi,&nbsp;Saied A Jaradat","doi":"10.2147/CPAA.S174074","DOIUrl":"https://doi.org/10.2147/CPAA.S174074","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy resistance is the main cause of the marginal clinical benefit of platinum-based chemotherapy and tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC). Thus, the identification of new therapeutic agents that can enhance the sensitivity of these drugs is of clinical importance. Histone deacetylase inhibitors (HDACIs) are emerging as new promising agents with strong antiproliferative effects against different types of cancers. This study investigates the synergistic potential of sodium phenylbutyrate (NaPB) added on top of standard chemotherapy used against NSCLC.</p><p><strong>Objective: </strong>The objective of this study was to evaluate the ability of NaPB to overcome the resistance of NSCLC cell lines to cisplatin, gefitinib, and erlotinib.</p><p><strong>Methods: </strong>MTT cell proliferation assay was used to measure the anticancer effects of cisplatin, erlotinib, or gefitinib alone or combined with various concentrations of NaPB against A549, Calu1, and H1650 NSCLC cell lines. Synergism was estimated by measuring synergy value (R), which is equal to the ratio of IC₅₀ of each primary drug alone divided by combination IC₅₀s. Student's <i>t</i>-test analysis was used to evaluate the potential differences between IC₅₀ values. ANOVA followed by Tukey's post hoc was used to evaluate the potential differences among monotherapy and combination treatment groups. Analyses were performed using R 3.3.2 software. <i>P</i>-value <0.05 was considered to be statistically significant.</p><p><strong>Results: </strong>NaPB was shown to inhibit the growth of A549, Calu1, and H1650 cell lines in a dose-dependent manner (IC₅₀ 10, 8.53, and 4.53 mM, respectively). Furthermore, the addition of NaPB along with cisplatin, erlotinib, or gefitinib to A549, Calu1, and H1650 cell lines resulted in a synergistic antiproliferative effect against the three NSCLC cell lines (<i>R</i>>1.6, <i>P</i>-value <0.05), thus suggesting that NaPB can potentiate the effect of cisplatin, erlotinib, and gefitinib on A549, Calu1, and H1650 cell lines.</p><p><strong>Conclusion: </strong>Current results suggest a potential role of NaPB as a sensitizing agent in NSCLC.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"135-140"},"PeriodicalIF":2.0,"publicationDate":"2018-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CPAA.S174074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36608027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"12-month effects of incretins versus SGLT2-Inhibitors on cognitive performance and metabolic profile. A randomized clinical trial in the elderly with Type-2 diabetes mellitus.","authors":"Simone Perna, Manuela Mainardi, Paolo Astrone, Carlotta Gozzer, Anna Biava, Ruben Bacchio, Daniele Spadaccini, Sebastiano Bruno Solerte, Mariangela Rondanelli","doi":"10.2147/CPAA.S164785","DOIUrl":"10.2147/CPAA.S164785","url":null,"abstract":"<p><strong>Aim: </strong>The aim of the present study is to examine the effects on cognitive performance, anthropometric measures, and metabolic markers in 2 different treatments: Incretins vs sodium-glucose co-transporter-2 inhibitors (SGLT2-I).</p><p><strong>Materials and methods: </strong>A randomized controlled clinical trial was carried out on 39 elderly subjects (23 men and 16 women) with type 2 diabetes mellitus, with a mean age of 77.21±8.07 years. Body mass index (BMI) of 29.92±4.31 kg/m² and a cognitive status measured by a Mini Mental State Examination (scores >27 points). The subjects were on a 3-month treatment with a maximal dose of metformin as a stable regime, with the addition of incretins (liraglutide at doses of up to 1.8 mg/d; vildagliptin at 100 mg/d; sitagliptin 100 mg/d; and linagliptin 5 mg/d), or SGLT2-I (canagliflozin 300 mg/d; empagliflozin 25 mg/d; and dapagliflozin 10 mg/d). Glucose control was monitored by fasting glucose and glycosylated hemoglobin. Cognitive performance (by way of Verbal Fluency Test, Attentive Matrices Test, and Babcock Story Recall Test), anthropometric measures, and plasma lipids were also evaluated.</p><p><strong>Results: </strong>Cognitive status did not change significantly during the 12 months of treatment in either group: Verbal Fluency Test: (SGLT2-I: <i>P</i>=1.00, incretins: <i>P</i>=0.598); Babcock Story Recall Test (SGLT2-I: <i>P</i>=0.391; incretins: <i>P</i>=0.351); and Attentive Matrices Test (SGLT2-I: <i>P</i>=0.679, incretins: <i>P</i>=0.901). SGLT2-I also resulted in a reduction in weight (-1.95 kg; <i>P</i><0.05), in BMI (-0.69 kg/m²; <i>P</i><0.05) and an increase in high-density lipoprotein cholesterol (+5.73 mg/dl; <i>P</i><0.01).</p><p><strong>Conclusion: </strong>Preliminary data show that patients treated with incretins and SGLT2-I have not suffered a reduction in cognitive performance during the 1 year of treatment. Metabolic outcome seemed to benefit, in particular, in patients who were treated with SGLT2-I.</p>","PeriodicalId":10406,"journal":{"name":"Clinical Pharmacology : Advances and Applications","volume":"10 ","pages":"141-151"},"PeriodicalIF":2.0,"publicationDate":"2018-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/52/16/cpaa-10-141.PMC6186903.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36608028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}