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1.
Br J Pharmacol ; 178(3): 582-599, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33119943

RESUMO

BACKGROUND AND PURPOSE: Altered drug pharmacokinetics is a significant concern in non-alcoholic steatohepatitis (NASH) patients. Although high-fat high-cholesterol (HFHC) diet-induced NASH (HFHC-NASH) rats could simulate the typical dysregulation of cholesterol in NASH patients, experimental investigation on the altered drug pharmacokinetics in this model are limited. Thus, the present study comprehensive investigates the nature of such altered pharmacokinetics using simvastatin as the model drug. EXPERIMENTAL APPROACH: Pharmacokinetic profiles of simvastatin and its active metabolite simvastatin acid together with compartmental pharmacokinetic modelling were used to identify the key factors involved in the altered pharmacokinetics of simvastatin in HFHC-NASH rats. Experimental investigations via in situ single-pass intestinal perfusion and intrahepatic injection of simvastatin were carried out. Histology, Ces1 activities and mRNA/protein levels of Oatp1b2/CYP2c11/P-gp in the small intestine/liver of healthy and HFHC-NASH rats were compared. KEY RESULTS: Reduced intestinal absorption and more extensive hepatic elimination in HFHC-NASH rats resulted in less systemic exposures of simvastatin/simvastatin acid. In the small intestine of HFHC-NASH rats, thicker intestinal wall with more collagen fibres, increased Ces1 activity and up-regulated P-gp protein decreased the permeability of simvastatin, accelerated the hydrolysis of simvastatin and promoted the efflux of simvastatin acid respectively. In the liver of HFHC-NASH rats, higher hepatic P-gp expression accelerated the hepatic elimination of simvastatin. CONCLUSION AND IMPLICATIONS: Altered histology, Ces1 activity and P-gp expression in the small intestine/liver were identified to be the major contributing factors leading to less systemic exposure of drugs in HFHC-NASH rats, which may be applicable to NASH patients.

2.
Eur J Clin Pharmacol ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188451

RESUMO

AIMS: Chloroquine (CQ) has been repurposed to treat coronavirus disease 2019 (COVID-19). Understanding the pharmacokinetics (PK) in COVID-19 patients is essential to study its exposure-efficacy/safety relationship and provide a basis for a possible dosing regimen optimization. SUBJECT AND METHODS: In this study, we used a population-based meta-analysis approach to develop a population PK model to characterize the CQ PK in COVID-19 patients. An open-label, single-center study (ethical review approval number: PJ-NBEY-KY-2020-063-01) was conducted to assess the safety, efficacy, and pharmacokinetics of CQ in patients with COVID-19. The sparse PK data from 50 COVID-19 patients, receiving 500 mg CQ phosphate twice daily for 7 days, were combined with additional CQ PK data from 18 publications. RESULTS: A two-compartment model with first-order oral absorption and first-order elimination and an absorption lag best described the data. Absorption rate (ka) was estimated to be 0.559 h-1, and a lag time of absorption (ALAG) was estimated to be 0.149 h. Apparent clearance (CL/F) and apparent central volume of distribution (V2/F) was 33.3 l/h and 3630 l. Apparent distribution clearance (Q/F) and volume of distribution of peripheral compartment (Q3/F) were 58.7 l/h and 5120 l. The simulated CQ concentration under five dosing regimens of CQ phosphate were within the safety margin (400 ng/ml). CONCLUSION: Model-based simulation using PK parameters from the COVID-19 patients shows that the concentrations under the currently recommended dosing regimen are below the safety margin for side-effects, which suggests that these dosing regimens are generally safe. The derived population PK model should allow for the assessment of pharmacokinetics-pharmacodynamics (PK-PD) relationships for CQ when given alone or in combination with other agents to treat COVID-19.

3.
Arthroscopy ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33227322

RESUMO

PURPOSE: To analyze the contribution of a secondary anterolateral structure (ALS) deficiency to knee instability based on anterior cruciate ligament (ACL) deficiency, in the condition of a functional iliotibial band (ITB). METHODS: Nine freshly-frozen cadaveric knees were sectioned sequentially to create ACL-deficiency and ACL-ALS deficiency, using intact knees before sectioning as controls. When ITB was tensioned with 30N, four separate aspects of knee instability were tested as follows: anterior translation in 90N anterior load, isolated internal rotation in 5N·m internal rotational torque from 0° to 90° in 15° increments, and anterolateral translation and internal rotation during a simulated pivot-shift test at 0°, 15°, 30° and 45°. The contribution of ACL deficiency alone and an additional ALS deficiency to knee instability were evaluated. RESULTS: The addition of an ALS lesion produced no significant exacerbation of either anterior translational or pivot shift instability in ACL-deficient knees. Additional ALS deficiency in an ACL deficient knee resulted in a significant increase in isolated internal rotation from 45° to 90°(P=.001 at 45° and P<.001 in other cases). After sequentially sectioning, the contribution to instability of additional ALS deficiency to the entire instability in ACL-ALS deficient knees were significantly smaller than that of ACL deficiency alone during anterior load and pivot-shift test (P<.001 in all cases), but significantly contributed more to isolated internal rotational instability at 60° (P=.011) and 90° (P=.015) CONCLUSIONS: When ITB was tensioned, ALS played a minor role in controlling both anterior or pivot shift stability in ACL-deficient knees while did the major role in restraining isolated internal rotation from 45° to 90°.

4.
Chemistry ; 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33006821

RESUMO

A series of two-coordinate AuI and CuI complexes (3 a, 3 b and 5 a, 5 b) are reported as new organometallic thermally activated delayed fluorescence (TADF) emitters, which are based on the carbene-metal-carbazole model with a pyridine-fused 1,2,3-triazolylidene (PyTz) ligand. PyTz features low steric hindrance and a low-energy LUMO (LUMO=-1.47 eV) located over the π* orbitals of the whole ligand, which facilitates intermolecular charge transfer between a donor (carbazole) and an accepter (PyTz). These compounds exhibit efficient TADF with microsecond lifetimes. Temperature-dependent photoluminescence kinetics of 3 a supports a rather small energy gap between S1 and T1 (ΔE S 1 - T 1 =60 meV). Further experiments reveal that there are dual-emission properties from a monomer-dimer equilibrium in solution, exhibiting single-component multicolor emission from blue to orange, including white-light emission.

5.
J Org Chem ; 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32902273

RESUMO

Mesoionic N-heterocyclic olefins have been developed, which feature high ylidic character. These compounds have been used as efficient catalysts for hydroboration of imines, nitriles, and N-heteroarenes.

6.
Colloids Surf B Biointerfaces ; 196: 111352, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32919244

RESUMO

The use of natural biocompatible drugs is highly desirable in wound dressing compared to synthetic chemicals. Oregano essential oil (OEO) is a promising natural compound with marked antibacterial, antioxidant and anti-inflammatory activities. The topical delivery of OEO may result in lower therapeutic efficacy and irritation to the skin. Moreover, OEO is a volatile compound results in instability as well. To overcome these drawbacks, we successfully encapsulated OEO in Poly (L-lactide-co-caprolactone) (PLCL)/ Silk fibroin (SF) nanofibers membrane (NF) and achieved the encapsulation efficiency (%) up to 59.14 ± 0.58. The fabricated membranes were undergone through physicochemical as well as biological evaluation. SEM characterization revealed that OEO could be successfully encapsulated maintaining a smooth profile of nanofibers. The biocompatibility of the NF membrane was confirmed by cytotoxicity assay. Antibacterial results indicated that OEO containing nanofibrous membranes are highly active against both gram-positive and gram-negative bacteria. The result revealed that 5% is the optimized concentration of OEO capable to completely inhibit bacterial growth. Moreover, the NF membranes were evaluated for their in vivo wound healing potential. The results confirmed that OEO containing NF membrane is not only capable to accelerate the wound contraction but also enhances the quality of wound healing confirmed through histology analysis. H&E and Masson's trichrome staining indicated the neo-epithelialization, granulation tissue formation, angiogenesis, and collagen deposition in a group treated with PLCL/SF/5% OEO. Based on the physicochemical and biological evaluation, PLCL/SF/5% OEO NF membrane can be considered as a potential wound dressing candidate.

7.
Eur J Pharm Sci ; 154: 105515, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32798718

RESUMO

Although EGb 761, the standardized dry extract of Ginkgo biloba leaves, exhibited numerous pharmacological activities and widely used in Asia, European and North America, the quality control of its dosage forms such as tablet mainly relies on monitoring the contents of the active marker components, namely quercetin, kaempferol, isorhamnetin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C. So far, the in vitro dissolution profiles of EGb761 tablet were barely used to monitor its quality and how these dissolution profiles correlate with their in vivo pharmacokinetics was not known. Thus, the present study was proposed aiming to 1) develop the in vitro-in vivo correlations (IVIVCs) for the marker components in EGb 761 tablet; 2) identify the in vivo relevant dissolution media for the marker components in EGb 761 tablet based on the established IVIVCs. The content analyses of the marker components in EGb 761 tablet was first carried out. Then, the dissolution profiles were further obtained using paddle method of United States Pharmacopeia for bilobalide, ginkgolides A, and ginkgolide B, that have previously reported human plasma pharmacokinetics after EGb 761 tablet oral administrations. About seven different media including 0.1 M hydrochloric acid (HCl), acetate buffer, H2O, fasted state simulated gastric fluid (FaSSGF), fasted state simulated intestinal fluid version 2 (FaSSIF-V2), fed state simulated intestinal fluid version 2 (FeSSIF-V2), and sequential medium (0.1 M HCl for 2 h with pH adjusted to 7 for another 2 h) were tested in the current investigation. The obtained in vitro dissolution profiles of bilobalide, ginkgolides A and ginkgolide B from EGb 761 tablet were first fitted with four dissolution models, namely Weibull, Double Weibull, Hill and Makoid-Banakar, to obtain the best-fit model for each component in each medium. The human plasma concentration versus time profiles of the above three components were then inputted into the Phoenix WinNonlin IVIVC Toolkit to obtain their in vivo absorption profiles using numerical deconvolution. The best-fit dissolution profiles of each marker component in the seven studied media were further used to correlate with its obtained in vivo absorption profile by the linear correlation models to establish the corresponding IVIVCs in each studied medium. Finally, the best in vivo correlated medium for each investigated marker component was selected based on their adjusted correlation coefficients, Akaike Information Criterion (AIC) and Schwarz's Bayesian Criterion (SBC) values. As a result, the dissolution profiles of bilobalide, ginkgolide A, ginkgolide B from EGb 761 tablet in 0.1 M HCl, FaSSGF, FaSSIF-V2 demonstrated the best correlation with their in vivo absorption profiles, respectively. Our current studies for the first time applied the concept of IVIVC to EGb 761 tablet and successfully identified the in vivo relevant dissolution media for its three active marker components to improve its quality control.

8.
Life Sci ; 259: 118171, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32738362

RESUMO

Hypoxia, an important feature of the tumor microenvironment, is responsible for the chemo-resistance and metastasis of malignant solid tumors. Recent studies indicated that mitochondria undergo morphological transitions as an adaptive response to maintain self-stability and connectivity under hypoxic conditions. NAD+ may not only provide reducing equivalents for biosynthetic reactions and in determining energy production, but also functions as a signaling molecule in mitochondrial dynamics regulation. In this review, we describe the upregulated KDAC deacetylase expression in the mitochondria and cytoplasm of tumor cells that results from sensing the changes in NAD+ to control mitochondrial dynamics and distribution, which is responsible for survival and metastasis in hypoxia.


Assuntos
Hipóxia/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , NAD/metabolismo , Metástase Neoplásica , Neoplasias/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Microambiente Tumoral
9.
Biomater Sci ; 8(15): 4225-4238, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32578587

RESUMO

Diabetic wounds remain a serious clinical challenge whereas current therapies have limited effects on reducing the high disability and morbidity. Impaired vascularization is closely associated with delayed healing of diabetic wounds and liraglutide (Lira), a GLP-1R receptor agonist, has been reported to promote the angiogenic ability of endothelial cells. However, its application is hindered owing to the unsustainable drug concentration. In this study, we prepared a poly (lactic-co-glycolic acid)/gelatin (PLGA/Gel) nanofibrous mat scaffold to sustain the release of Lira for skin tissue engineering through 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxy sulfosuccinimide (EDC/NHS), a green cross-linking-graft integration method. The incorporation of Lira into PLGA/Gel increased the pore size, hydrophilicity, elasticity and degradation properties of nanofibrous mats, which were advantageous to wound healing. In addition, the effects on diabetic wound healing, vascularization and its underlying mechanism were evaluated. The results revealed that PLGA/Gel/Lira remarkably improved the healing efficiency of diabetic dermal wounds characterized by shortened wound closure time, increased blood vessel density, and elevated collagen deposition and alignment. In vitro, Lira reversed the inhibitory effects on proliferation, migration, tube differentiation, and VEGF secretion of endothelial cells induced by high glucose (HG). As for the underlying mechanism, Lira specifically decreased the level of miR-29b-3p, targeting the AKT/GSK-3ß/ß-catenin pathway to regulate the biological function of endothelial cells. In conclusion, for the first time this study combined PLGA/Gel with Lira to take advantage of their synergistic effects to promote vascularization, a promising strategy to accelerate diabetic wound repair.

10.
Clin Transl Sci ; 13(6): 1345-1354, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32583948

RESUMO

This study aimed to predict long-term progression-free survival (PFS) using early M-protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M-protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M-protein dynamic features from the longitudinal M-protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M-protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M-protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M-protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time-varying receiver operating characteristic curves for the model with the first 2 months of M-protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M-protein data within the first 2 months can provide a prospective and reasonable prediction of future long-term clinical benefit for patients with MM.

11.
J Org Chem ; 2020 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-32408749

RESUMO

Five m-phenylene-embedded cycloparaphenylenes m3[9]CPP 1-5 were synthesized by the platinum-mediated cyclooligomerization strategy with high overall yields. The structures of m3[9]CPP 1-3 were determined by X-ray diffraction analysis. Compared to [9]CPP, m3[9]CPP 1 caused a significant blueshift in the UV-vis absorption and fluorescence spectra. This result shows that the radial π-conjugation is distorted and partially interrupted. The photophysical properties of m3[9]CPP 1 were further tuned by the introduction of various substituents for m3[9]CPP 2-5. Methoxy group substitution at m-phenylene did not change the photophysical properties significantly. Replacement of m-phenylene by tetrafluoro-m-phenylene achieved a significant blueshift. When the carboxyl group was embedded at m-phenylene or the methoxy group was embedded at p-phenylene, significant redshifts were observed with blue color emission. Theoretical calculations revealed that the decrease in the HOMO-LUMO gap in m3[9]CPP 4 and 5 is favorable for the redshift of the fluorescence spectrum.

12.
J Mater Chem B ; 8(18): 4106-4121, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32253395

RESUMO

In the tissue engineering of cartilage, scaffolds with appropriate elasticity and controlled-release properties are essential. Herein, we synthesized a poly(ether-ester-urethane)urea scaffold with a pendant amino group (PEEUUN) through a de-protection process from PEEUU-Boc polymers and grafted kartogenin (KGN) onto the PEEUUN scaffolds (PEEUUN-KGN). Characterization, performance tests, scaffold biocompatibility analysis, and chondrogenesis evaluation both in vitro and in vivo were conducted. The results revealed that the PEEUUN-KGN scaffolds were degradable and three-dimensional (3D) with interconnected pores, and possessed good elasticity, as well as excellent cytocompatibility. Meanwhile, KGN on the PEEUUN-KGN scaffolds underwent stable sustained release for a long time and promoted human umbilical cord mesenchymal stem cells (HUCMSCs) to differentiate into chondrocytes in vitro, thus enhancing cartilage regeneration in vivo. In conclusion, the present PEEUUN-KGN scaffolds would have application potential for cartilage tissue engineering.

13.
J Thromb Thrombolysis ; 50(1): 20-29, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32323192

RESUMO

Rivaroxaban exposure and patient characteristics may affect the rivaroxaban benefit-risk balance. This study aimed to quantify associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation (NVAF), using data from the phase 3 ROCKET AF trial (NCT00403767). In ROCKET AF, 14,264 patients with NVAF were randomized to rivaroxaban (20 mg once daily [OD], or 15 mg OD if creatinine clearance was 30-49 mL/min) or dose-adjusted warfarin (median follow-up: 707 days); rivaroxaban plasma concentration was measured in a subset of 161 patients. In this post hoc exposure-response analysis, a multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event efficacy and safety outcomes in 7061 and 7111 patients, respectively. There was no significant association between model-predicted rivaroxaban trough plasma concentration (Ctrough) and efficacy outcomes. Creatinine clearance and history of stroke were significantly associated with efficacy outcomes. Ctrough was significantly associated with the composite of major or non-major clinically relevant (NMCR) bleeding (hazard ratio [95th percentile vs. median]: 1.26 [95% confidence interval 1.13-1.40]) but not with major bleeding alone. The exposure-response relationship for major or NMCR bleeding was shallow with no clear threshold for an acceleration in risk. History of gastrointestinal bleeding had a greater influence on safety outcomes than Ctrough. These results support fixed rivaroxaban 15 mg and 20 mg OD dosages in NVAF. Therapeutic drug monitoring is unlikely to offer clinical benefits in this indication beyond evaluation of patient characteristics.

14.
Org Lett ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32124613

RESUMO

Mesoionic carbene-iridium complex 1a has been investigated in the hydrogen isotope exchange (HIE) reaction of anilines. By employing 1 mol % of 1a as catalyst, anilines were selectively deuterated at the ortho-position with high deuteration levels. High ortho-selectivity was observed for anilines with various competing directing groups, which is in contrast with catalytic results of Kerr's catalysts.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32180390

RESUMO

Solid oxide fuel cells (SOFCs) offer opportunities for the application as both power sources and chemical reactors. Yet, it remains a grand challenge to simultaneously achieve high efficiency of transforming higher hydrocarbons to value-added products and of generating electricity. To address it, we here present an ingenious approach of nanoengineering the triple-phase boundary of an SOFC anode, featuring abundant Co7W6@WOx core-shell nanoparticles dispersed on the surface of black La0.4Sr0.6TiO3. We also developed a cofeeding strategy, which is centered on concurrently feeding the SOFC anode with H2 and chemical feedstock. Such combined optimizations enable effective (electro)catalytic dehydrogenation of n-butane to butenes and 1,3-butadiene. The C4 alkene yield is higher than 50% while the peak power density of the SOFC reached 212 mW/cm2 at 650 °C. In addition, coke formation is largely suppressed and little CO/CO2 is produced in this process. While this work shows new possibility of chemical-electricity coupling in SOFCs, it might also open bona fide avenues toward the electrocatalytic synthesis of chemicals at higher temperatures.

16.
Bioresour Technol ; 303: 122904, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32028220

RESUMO

The chemical-looping gasification kinetics of corn straw with iron-based oxygen carrier to produce syngas were studied using thermogravimetric analysis. The main reactions of corn straw based on iron-based composite oxygen carrier is divided into three stages: the pyrolysis stage (200-500 °C), the gas-solid reaction stage (500-700 °C), and the solid-solid reaction stage (700-1100 °C). The Coats-Redfern method and the Malek method were used to screen the thirty reactions. The activation energies for the most likely main reactions were estimated to be 81.6 kJ/mol (Mample single-line rule), 117.5 kJ/mol (reaction order function), and 140.9 kJ/mol (Ginstling-Brounshtein equation). The chemical-looping gasification of corn straw with Fe-based oxygen carrier involved multi-step reaction mechanisms.


Assuntos
Oxigênio , Zea mays , Ferro , Cinética , Termogravimetria
17.
Biomed Pharmacother ; 125: 109933, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32036215

RESUMO

Airway remodeling is a key feature of asthma. Extracellular matrix synthesis and vascular remodeling respectively regulated by transforming growth factor (TGF-ß1) and vascular endothelial growth factor (VEGF), are important for the airway remodeling. This study aimed to investigate the effect of Soufeng Yuchuan (SFYC) decoction, a Traditional Chinese Medicine, on airway remodeling and expression of VEGF and TGF-ß1 in asthma model rats. A rat model of asthma was induced by ovalbumin (OVA) treatment. The results showed that SFYC decoction improved general conditions and reduced the damage in lung tissues in asthma model rats. Furthermore, SFYC decoction significantly reduced the OVA-induced levels of VEGF and TGF-ß1 in sera and in bronchoalveolar lavage fluid. Moreover, SFYC decoction decreased the OVA-induced VEGF mRNA and protein levels in lung tissues in asthma model rats. Interestingly, SFYC with high dose was more potent in reducing TGF-ß1 level in rat sera and BALF than dexamethasone (positive control). In summary, SFYC decoction effectively mitigates lung damage in OVA-induced asthma model rats, which was associated with inhibition of VEGF and TGF-ß1.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Líquido da Lavagem Broncoalveolar , Dexametasona/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Ovalbumina , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
AAPS J ; 22(2): 30, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31950308

RESUMO

This study aimed to develop a method for implementing dose correction in a Michaelis-Menten (M-M) approximation of a target-mediated drug disposition (TMDD) model with multiple intravenous (IV) bolus administrations. We derived the formula of a correction factor (Fcorr) for each dose in a multiple IV bolus dosing regimens for M-M model. Fcorr depends on the residual free drug amount prior IV bolus dosing event and dose amount. We conducted a stochastic simulation and estimation (SSE) exercise based on therapeutic antibody PK parameters to evaluate the effect of Fcorr on parameter estimation. Previously published clinical PK data of recombinant human erythropoietin (rHuEPO) from four clinical trials in healthy subjects receiving multiple IV bolus doses were analyzed by both M-M model with and without dose correction (MMC and MMNC) as well as the rapid-binding/quasi-steady-state (RB/QSS) TMDD models. Our results showed that MMNC introduced bias to fixed-effect parameter estimates and overestimated random-effect variables. Compared with MMC, MMNC was not able to adequately characterize the nonlinearity in the PK data of antibody and rHuEPO. The MMC-based simulation demonstrated that thricely weekly 10 IU/kg rHuEPO dosing regimen yielded Fcorr = 0.5. This result suggested that the lower-than-expected exposure for rHuEPO at low dose is due to target binding. An M-M approximation of the TMDD model should include a dose correction to avoid model misfitting and potential bias in the estimated PK parameters.

19.
J Org Chem ; 85(4): 2504-2511, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31910620

RESUMO

A complementary and general strategy for the oxidative generation of iminyl radicals from the readily available α-imino-oxy acids has been established through silver-catalyzed decarboxylation. To demonstrate its synthesis utility, the direct C-H cyanoalkylation of heterocycles and quinones with cyclic α-imino-oxy acids via the iminyl radical-mediated C-C bond cleavage is developed. This cost-effective method takes place under mild reaction conditions and exhibits a broad substrate scope.

20.
Org Lett ; 21(24): 10023-10027, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31797670

RESUMO

Ruthenium-catalyzed aromatic H/D exchange in [D4]acetic acid has been developed. By using N-heteroarenes as directing groups, both ortho and meta positions are selectively deuterated with high levels of D incorporation. Moreover, this strategy provides an alternative way to achieve meta-C-H activation.

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