Search

Purpose: Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury., Methods: We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury., Results: In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size., Conclusion: This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury., Competing Interests: The authors declared no conflicts of interest in this work., (© 2024 Wang et al.)

The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with β-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

What Is Known and Objectives: Poor image quality was randomly seen in [ 99m Tc]Tc-tetrofosmin myocardial perfusion scintigraphic imaging. The interference hampered or even precluded medical interpretation. Our objective was to identify the cause of the random interferences., Methods: Out of 40 patients planned for [ 99m Tc]Tc-tetrofosmin MPS, 36 presented normal tracer uptake and 4 exhibited subdiaphragmatic artefacts. Pharmaceutical interviews (P.I.) were set up to formally identify aetiologies of subdiaphragmatic uptake of [ 99m Tc]Tc-tetrofosmin. Patients were questioned about their diet and current drug treatments., Results and Discussion: P.I. led to identification of dipyridamole as the cause of the artefacts. The systematic ingestion of a solid 25-gram high-fat snack bar and a glass of fresh water was introduced immediately after the injection of dipyridamole in 12 other patients undergoing [ 99m Tc]Tc-tetrofosmin MPS. None of the 12 patients presented subdiaphragmatic artefacts., What Is New and Conclusion: P.I. identified the cause of poor scintigraphic images to allow improved diagnoses., (© 2021 John Wiley & Sons Ltd.)

Background Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non-small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m 2 ; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m 2 ; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable., (© 2021. The Author(s).)

Purpose: Inflammation of the ocular surface is central to dry eye disease (DED). The anti-inflammatory agent phospho-sulindac (PS) at a high dose was efficacious against DED in a rabbit model. We assessed the dose, formulation and structure dependence of PS's effect. Methods: In rabbits with concanavalin A-induced DED we evaluated a range of PS concentrations (0.05%-1.6%) and dosing frequencies, assessed the duration of its effect with PS in 2 solution formulations and one emulsion formulation, and compared the efficacy of PS to that of sulindac, and of the structurally similar phospho-ibuprofen amide. We determined tear breakup time (TBUT) (tear stability), Schirmer's tear test (tear production), and by esthesiometry corneal sensitivity (symptoms). We also determined the biodistribution in the eye of topically applied PS. Results: PS in a solution formulation, given as eye drops q.i.d. was efficacious starting at a dose of 0.1%. The effect was apparent after 2 days of treatment and lasted at least 8 days after the last dose. Both signs (evidenced by TBUT and Schirmer's test) and symptoms (measured by corneal sensitivity) improved significantly. The best formulation was the solution formulation; a cyclodextrin-based formulation was also successful but the emulsion formulation was not. PS and its metabolites were essentially restricted to the anterior chamber of the eye. Sulindac and phospho-ibuprofen amide had no efficacy on DED. Conclusions: PS is efficacious against DED. Its effect, encompassing signs, and symptoms, are dose, formulation, and structure dependent. PS has therapeutic promise and merits further development.

The positive-charged lipophilic triphenylphosphonium cations (TPPs + ) have been served as mitochondrial targeting vehicles for the delivery of various probes. In this study, we developed a new method for the preparation of radioiodine-labeled TPPs + . Four 125 I-labeled TPPs + , [ 125 I] 9-[ 125 I] 12, were prepared from the corresponding triphenylphosphine phenylborate precursors of B 5-B 8 via an optimized copper-catalyzed one-step procedure in high radiochemical yield (>95%). After radio-HPLC purification, the final products could be obtained with high specific activity. Their physicochemical properties, in vitro cellular uptake, and ex vivo mice biodistribution were investigated. The results suggested the 125 I-labeled TPPs + were lipophilic and could specifically accumulate in the mitochondrial-rich myocardial cells through the mitochondrial membrane potential., (© 2021 John Wiley & Sons, Ltd.)

Acute organophosphorus pesticide poisoning (AOPP) is a worldwide health concern that has threatened human lives for decades, which attacks acetylcholinesterase (AChE) and causes nervous system disorders. Classical treatment options are associated with short in vivo half-life and side effects. As a potential alternative, delivery of mammalian-derived butyrylcholinesterase (BChE) offers a cost-effective way to block organophosphorus attack on acetylcholinesterase, a key enzyme in the neurotransmitter cycle. Yet the use of exotic BChE as a prophylactic or therapeutic agent is compromised by short plasma residence, immune response and unfavorable biodistribution. To overcome these obstacles, BChE nanodepots (nBChE) composed of a BChE core/polymorpholine shell structure were prepared via in situ polymerization, which showed enhanced stability, prolonged plasma circulation, attenuated antigenicity and reduced accumulation in non-targeted tissues. In vivo administration of nBChE pre- or post-organophosphorus exposure in a BALB/C mouse model resulted in potent prophylactic and therapeutic efficiency. To our knowledge, this is the first systematic delivery of non-human BChE to tackle AOPP. In addition, this work also opens up a new avenue for real applications in both research and clinical settings to cope with acute intoxication-related diseases.

Background and Objectives: Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib., Methods: Plasma concentration-time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3)., Results: Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates., Conclusions: Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.

The synthesis of a new series of Gd(III)-arylphosphonium complexes is described and the solution stability of selected compounds is reported. Their lipophilicity and uptake in human glial (SVG p12) and human glioblastoma multiforme (T98G) cell lines are presented. The in vitro cytotoxicity of all complexes was determined to be low at therapeutically-relevant concentrations. Selected Gd(III) complexes are potential candidates for further investigation as theranostic agents.

The mitochondrion can be considered as the metabolic powerhouse of the cell, having a key impact on energy production, cell respiration, and intrinsic cell death. Mitochondria are also the main source of endogenous reactive oxygen species , including free radicals (FR), which are physiologically involved in signaling pathways but may promote cell damage when unregulated or excessively formed in inappropriate locations. A variety of chronic pathologies have been associated with FR-induced mitochondrial dysfunctions , such as cancer, age-related neurodegenerative diseases, and metabolic syndrome.In recent years drug design based on specific mitochondria-targeted antioxidants has become a very attractive therapeutic strategy and, among target compounds, nitrones have received growing attention because of their specific affinity toward FR. Here, we describe protocols dealing with the preparation, mitochondria permeation assessment, electron paramagnetic resonance (EPR) spin trapping setting, and antiapoptotic properties evaluation of a series of new linear nitrones vectorized by a triphenylphosphonium cation and labeled with a diethoxyphosphoryl moiety as 31 P nuclear magnetic resonance (NMR) reporter with antioxidant property.

We have previously reported that radiolabeled phosphonium cations accumulate in the mitochondria down a transmembrane potential gradient. We present an optimized procedure for synthesis of three [ 18 F]-labeled fluoroalkyl triphenylphosphonium salts ([ 18 F]FATPs) via two-step simple nucleophilic substitution reactions to develop new myocardial imaging agents for positron emission tomography (PET) . The total reaction time of [ 18 F]FATPs was within 60 min, and the overall decay-corrected radiochemical yield was approximately 15-30% (decay corrected). Radiochemical purity was >98% according to analytical high-performance liquid chromatography (HPLC) . The specific activity of [ 18 F]FATPs was >6.1 TBq/μmol. The [ 18 F]FATPs exhibited higher first-pass extraction fraction values in isolated heart, higher uptake in the myocardium, and a more rapid clearance from the liver and lung than [ 13 N]NH 3 in normal rats. The images from rats with an occluded left coronary artery demonstrated sharply defined myocardial defects in the corresponding area of the myocardium. This imaging technology may enable high-throughput, multiple studies daily and wide distribution of PET myocardial studies in clinic.

Reactive oxygen species (ROS)-induced neuronal mitochondrial dysfunction is a key pathologic factor in sporadic Alzheimer's disease (AD). Neuronal mitochondria have been proposed to be a promising therapeutic target for AD, especially for the failures of phase III clinical trials on conventional amyloid-β (Aβ) targeted therapy. However, the efficient intravenous delivery of therapeutic agents to neuronal mitochondria in the brain remains a major challenge due to the complicated physiological environment. Recently, biomaterials-based nanomedicine has been widely investigated for the treatment of AD. Herein, we devised a strategy for functional antioxidant delivery to neuronal mitochondria by loading antioxidants into red blood cell (RBC) membrane-coated nanostructured lipid carriers (NLC) bearing rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules attached to the RBC membrane surface (RVG/TPP NPs@RBCm). With the advantage of suitable physicochemical properties of NLC and unique biological functions of the RBC membrane, RVG/TPP NPs@RBCm are stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. Under the synergistic effects of RVG29 and TPP, RVG/TPP NPs@RBCm can not only penetrate the blood-brain barrier (BBB) but also target neuron cells and further localize in the mitochondria. After encapsulating Resveratrol (RSV) as the model antioxidant, the data demonstrated that RVG/TPP-RSV NPs@RBCm can relieve AD symptoms by mitigating Aβ-related mitochondrial oxidative stress both in vitro and in vivo . The memory impairment in APP/PS1 mice is significantly improved following the systemic administration of RVG/TPP-RSV NPs@RBCm. In conclusion, intravenous neuronal mitochondria-targeted dual-modified novel biomimetic nanosystems are a promising therapeutic candidate for ROS-induced mitochondrial dysfunction in AD.

Phosphonates-based agents are well-known bone-seeking radiopharmaceuticals with application in detection and therapy. With higher sensitivity and resolution offered by Positron Emission Tomography (PET), tracers based on this technique are gaining huge attention. 68 Ga-based generator and radiotracers render independence from the on-site cyclotron. We report the development of 68 Ga-labeled DOTA-based bismacrocyclic phosphonate derivative, for bone PET imaging. The synthesis and characterization of 68 Ga- DO3P-AME-DO3P was carried out in > 95% purity. The radiotracer displayed high stability and low binding affinity (<3%) to blood serum. High in vitro binding affinity were observed for synthetic hydroxyapatite, SAOS-2, osteoclast and osteoblast cells. In vivo pharmacokinetics revealed fast washout with biphasic release pattern. The deposition of radiotracer in osseous tissues was high (Bone/Muscle ratio:18), as studied from the biodistribution studies. In vivo PET/CT and biodistribution analyses revealed the ability of 68 Ga-DO3P-AME-DO3P to target and accumulate in bone, thus displaying its potential as a PET bone imaging agent., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events)., Methods: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected., Results: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69)., Conclusion: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.

We present a simple method for chiral separation and analysis of organophosphorus nerve agents and apply it to monitor the enantioselective blood elimination kinetics of sarin in-vitro. The method is implemented in standard reverse phase LC-MS operating conditions, relieving the user of the dedicated operating conditions frequently demanded in chiral LC-MS analysis. The method consists of formation of diastereomers by a rapid derivatization with (R)-2-(1 aminoethyl) phenol, followed by LC-MS/MS analysis. Derivatization enantioselectivity was studied by comparing the reaction of optically pure sarin and racemic sarin, proving no substantial enantiomeric preference in the reaction and demonstrating the enantiomeric discrimination abilities of the technique. Enantioselective sarin elimination pathways were probed in-vitro by following the fast elimination kinetics of the two sarin enantiomers as well as its hydrolysis metabolite (isopropyl methyl-phosphonic acid, IMPA) in whole blood and plasma compared to water. Sarin enantiomers showed the known marked differences in elimination kinetics with rapid elimination of the (+) enantiomer and slower elimination of the (-) enantiomer in whole blood and plasma as well as dose-dependent kinetics (faster elimination at lower concentrations). We found that small amounts of acetonitrile in plasma prevent the rapid elimination of the (+) enantiomer, resulting in similar, slower elimination kinetics for both enantiomers.

The strategy of using radioligands for targeting the prostate-specific membrane antigen (PSMA) revealed to be promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently developed albumin-binding PSMA radioligands showed a remarkably increased tumor uptake because of the enhanced blood circulation, but higher accumulation of activity was also observed in off-target organs and tissues. The aim of this study was to investigate the option of using fast-cleared, small-molecular-weight PSMA inhibitors (PSMA-11, 2-PMPA, and ZJ-43) to reduce the kidney uptake of [ 177 Lu]Lu-PSMA-ALB-56, a previously developed albumin-binding PSMA radioligand. Dual-isotope SPECT/CT imaging was performed with tumor-bearing mice coinjected with [ 177 Lu]Lu-PSMA-ALB-56 and a 2.5-fold molar excess of [ 67 Ga]Ga-PSMA-11. At early timepoints after injection, the high renal uptake of [ 67 Ga]Ga-PSMA-11 reduced the accumulation of [ 177 Lu]Lu-PSMA-ALB-56 in the kidneys substantially, whereas the tumor uptake of [ 177 Lu]Lu-PSMA-ALB-56 was only slightly affected. These findings were confirmed in biodistribution studies, which revealed reduced uptake of [ 177 Lu]Lu-PSMA-ALB-56 in the kidneys due to coadministered unlabeled PSMA-11 (9.1 ± 0.8% IA/g vs 46 ± 11% IA/g; 1 h p.i.). The tumor uptake of [ 177 Lu]Lu-PSMA-ALB-56 was almost the same at 1 h p.i., irrespective of whether or not PSMA-11 was coinjected (24 ± 6% IA/g vs 27 ± 7% IA/g). The application of [ 177 Lu]Lu-PSMA-ALB-56 with 2-PMPA or ZJ-43, respectively, showed similar results in biodistribution studies. Among all three tested PSMA inhibitors, 2-PMPA, applied at a 2.5-fold molar excess relative to [ 177 Lu]Lu-PSMA-ALB-56, was most effective to improve the tumor-to-kidney ratios over the first hours after injection of [ 177 Lu]Lu-PSMA-ALB-56. The concept of using a PSMA inhibitor together with [ 177 Lu]Lu-PSMA-ALB-56 appears promising in view of a clinical translation of this and possibly other long-circulating PSMA radioligands.

The aim of this present study was to investigate the ability of different dissolution methods to predict the in vivo performance of efonidipine hydrochloride (EFH). The solid dispersions of EFH were prepared by solvent evaporation method with HPMC-AS as matrix and urea as a pH adjusting agent. The paddle method, the open-loop, and the closed-loop flow-through cell methods were studied. In the study, Weibull's model was the best fit to explain release profiles. The pharmacokinetics behaviors of two kinds of solid dispersions with different release rate were investigated in comparison to the EFH after oral administration in rats. In vivo absorption was calculated by a numerical deconvolution method. In the study, the level A in vivo and in vitro correlation (IVIVC) was utilized. The correlation coefficient was calculated and interpreted by means of linear regression analysis (Origin.Pro.8.5 software). As a result, excellent IVIVC for solid dispersions and crude drug (r 2  = 0.9352-0.9916) was obtained for the dissolution rate determined with flow-through cell open-loop system in phosphate buffer solution with 0.1% (w/v) polysorbate 80 at pH 6.5, the flow-rate of 4 mL/min. In addition, the self-assembled flow cell system had good repeatability and accuracy. The dissolution rate of the solid dispersion could be slowed down by the flow-through method, and the difference caused by preparation was significantly distinguished. The study demonstrated that flow-through cell method of the open-loop, compared with paddle method, was suitable for predicting in vivo performance of EFH solid dispersions.

Our HCV research program investigated novel 2'-dihalogenated nucleoside HCV polymerase inhibitors and identified compound 1, a 5'-phosphoramidate prodrug of 2'-deoxy-2'-α-bromo-β-chloro uridine. Although 1 had a favorable in vitro activity profile in HCV replicons, oral dosing in dog resulted in low levels of the active 5'-triphosphate (TP) in liver. Metabolism studies using human hepatocytes provided a simple assay for screening alternative phosphoramidate prodrug analogs. Compounds that produced high TP concentrations in hepatocytes were tested in dog liver biopsy studies. This method identified 2-aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrug 14, which provided 100-fold higher TP concentrations in dog liver in comparison to 1 (4 and 24 h after 5 mg/kg oral dose)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JTR, TL, ACK, HRH, HJC, DAJB, CVH, VP, RAC, DS, TD, PK, RW, and DAD are employees of AbbVie. MI was an employee of AbbVie at the time of the study. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background & Aims: Pradefovir is a liver targeted novel prodrug of adefovir (PMEA) developed to provide higher antiviral activity with reduced systemic toxicities. This study evaluated the tolerability, pharmacokinetics, and antiviral activity of pradefovir in patients with chronic hepatitis B (CHB) virus infection., Methods: Non-cirrhotic, treatment-naïve subjects with CHB were divided into five groups (10 patients each) and randomized within each group in a ratio of 6:2:2 to receive an ascending dose of 30, 60, 75, 90, or 120 mg pradefovir, 10 mg adefovir dipivoxil (ADV), or 300 mg tenofovir disoproxil fumarate (TDF) once a day for 28 days., Results: A total of 51 subjects were randomized and 49 subjects completed the study. The groups were well matched and included 39 males, of whom 71% were hepatitis B e-antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.4-7.16 log10 IU/mL. No subject experienced a serious adverse event or nephrotoxicity. The most frequently reported adverse event was asymptomatic reduction in blood cholinesterase levels in the pradefovir group which recovered without any treatment about 13 ± 7 days after drug discontinuation. This adverse event was not observed in the ADV and TDF groups. The mean changes in serum HBV DNA were -2.78, -2.77, -3.08, -3.18, -3.44, -2.34, and -3.07 log10 IU/mL at 30, 60, 75, 90, and 120 mg pradefovir, 10 mg ADV and 300 mg TDF, respectively, with plateau levels reached with 60 mg pradefovir. Pradefovir and its metabolite PMEA showed linear pharmacokinetics proportional to the dose. The half-life of PMEA in the pradefovir group was 11.47-17.63 h., Conclusions: Short-term use of pradefovir was well tolerated. A decline in HBV DNA levels was superior to TDF at higher doses of pradefovir. 30-60 mg pradefovir is recommended for CHB treatment., Clinical Trial Number: CTR20150224., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interests. Compliance with ethical standards., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In vitro data support involvement of cytochrome P450 (CYP)2C8 and CYP3A4 in the metabolism of the anaplastic lymphoma kinase inhibitor brigatinib. A 3-arm, open-label, randomized, single-dose, fixed-sequence crossover study was conducted to characterize the effects of the strong inhibitors gemfibrozil (of CYP2C8) and itraconazole (of CYP3A) and the strong inducer rifampin (of CYP3A) on the single-dose pharmacokinetics of brigatinib. Healthy subjects (n = 20 per arm) were administered a single dose of brigatinib (90 mg, arms 1 and 2; 180 mg, arm 3) alone in treatment period 1 and coadministered with multiple doses of gemfibrozil 600 mg twice daily (BID; arm 1), itraconazole 200 mg BID (arm 2), or rifampin 600 mg daily (QD; arm 3) in period 2. Compared with brigatinib alone, coadministration of gemfibrozil with brigatinib did not meaningfully affect brigatinib area under the plasma concentration-time curve (AUC 0-inf ; geometric least-squares mean [LSM] ratio [90%CI], 0.88 [0.83-0.94]). Coadministration of itraconazole with brigatinib increased AUC 0-inf (geometric LSM ratio [90%CI], 2.01 [1.84-2.20]). Coadministration of rifampin with brigatinib substantially reduced AUC 0-inf (geometric LSM ratio [90%CI], 0.20 [0.18-0.21]) compared with brigatinib alone. The treatments were generally tolerated. Based on these results, strong CYP3A inhibitors and inducers should be avoided during brigatinib treatment. If concomitant use of a strong CYP3A inhibitor is unavoidable, the results of this study support a dose reduction of brigatinib by approximately 50%. Furthermore, CYP2C8 is not a meaningful determinant of brigatinib clearance, and no dose modifications are needed during coadministration of brigatinib with CYP2C8 inhibitors., (© 2019 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

The dynamics of mitochondria in live cells play a pivotal role in biological events such as cell metabolism, early stage apoptosis, and cell differentiation. Triphenylphosphonium (TPP) is a commonly used mitochondria-targeting agent for mitochondrial studies. However, there has been a lack of understanding in intracellular behaviors of TPP in the course of targeting mitochondria due to the difficulty in tracking and quantifying small molecules in a biological environment. Here, we report the utility of hyperspectral stimulated Raman scattering (SRS) microscopy associated with a Raman tag synthesized for real-time visualization and quantitation of TPP dynamics within live cells at the subcellular level. With the myriad of merits offered by a synthesized aryl-diyne-based Raman tag such as excellent photostability, negligible background interferences, and a linear dependence of the SRS signal on the TPP concentration, we successfully establish a quantitative model to associate the mitochondrial membrane potential with the key pharmacokinetic parameters of TPP inside the live cells. The model reveals that reduction in the mitochondrial membrane potential leads to significant decreases in both the uptake rate and intracellular concentrations of TPP. Further, on the basis of the multiplexed SRS images concurrently highlighting the cellular proteins and lipids without further labeling, we find that the TPP uptake causes little cytotoxicity to the host cells. The bioorthogonal hyperspectral SRS microscopy imaging reveals that TPP can maintain stable affinity to mitochondria during the restructuring of mitochondrial networking, demonstrating its great potential for real-time monitoring of pharmacokinetics of small molecules associated with live biological hosts, thereby promoting the development of mitochondria-targeting imaging probes and therapies in the near future.

There is a unique in vivo interplay involving the mechanism of inactivation of acetylcholinesterase (AChE) by toxic organophosphorus (OP) compounds and the restoration of AChE activity by oxime antidotes. OP compounds form covalent adducts to this critical enzyme target and oximes are introduced to directly displace the OP from AChE. For the most part, the in vivo inactivation of AChE leading to neurotoxicity and antidote-based therapeutic reversal of this mechanism are well understood, however, these molecular-level events have not been evaluated by dynamic imaging in living systems at millimeter resolution. A deeper understanding of these critically, time-dependent mechanisms is needed to develop new countermeasures. To address this void and to help accelerate the development of new countermeasures, positron-emission tomography (PET) has been investigated as a unique opportunity to create platform technologies to directly examine the interdependent toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic features of OPs and oximes in real time within live animals. This review will cover two first-in-class PET tracers representing an OP and an oxime antidote, including their preparation, requisite pharmacologic investigations, mechanistic interpretations, biodistribution and imaging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation PET tracers may be suitable for early detection of cardiotoxicity. This study aimed to evaluate an 18 F-labeled lipophilic phosphonium cation, [1-(2- 18 F-fluoroethyl),1 H [1,2,3]triazole-4-ethylene]triphenylphosphonium bromide ( 18 F-MitoPhos), as a cardiac imaging agent, comparing it with leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin model. Methods: Cardiac uptake and response to decreased mitochondrial membrane potential of 18 F-MitoPhos and 99m Tc-sestamibi were tested in isolated perfused rat hearts. Baseline pharmacokinetic profiles of 18 F-MitoPhos and 18 F-fluorobenzyltriphenylphosphonium and their response to acute doxorubicin-induced cardiotoxicity were assessed in rats in vivo (10, 15, or 20 mg of doxorubicin per kilogram, intravenously, 48 h beforehand). Results: Cardiac retention of 18 F-MitoPhos was more than double that of 99m Tc-sestamibi in isolated perfused rat hearts. A favorable biodistribution of 18 F-MitoPhos in vivo was observed, with heart-to-tissue ratios of 304 ± 186, 11.2 ± 1.2, and 3.8 ± 0.6 for plasma, liver, and lung, respectively (60 min). A significant dose-dependent loss of cardiac retention of 18 F-MitoPhos was observed on doxorubicin treatment, with average cardiac SUV from 30 to 60 min (mean ± SD) decreasing from 3.5 ± 0.5 (control) to 1.8 ± 0.1 (doxorubicin, 20 mg/kg). Other assessed biomarkers showed no alterations. Conclusion: 18 F-MitoPhos showed pharmacokinetic parameters suitable for cardiac imaging. A significant dose response of cardiac uptake to doxorubicin treatment was observed before detectable biomarker alterations. 18 F-MitoPhos is therefore a promising tracer for imaging chemotherapy-induced cardiotoxicity. To our knowledge, this is the first demonstration of radiolabeled lipophilic cations being used for the PET imaging of chemotherapy-induced cardiotoxicity and indicates the potential application of these compounds in this area., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

An investigation of the yeast cell resealing process was performed by studying the absorption of the tetraphenylphosphonium (TPP + ) ion by the yeast Saccharomyces cerevisiae. It was shown that the main barrier for the uptake of such TPP + ions is the cell wall. An increased rate of TPP + absorption after treatment of such cells with a pulsed electric field (PEF) was observed only in intact cells, but not in spheroplasts. The investigation of the uptake of TPP + in PEF treated cells exposed to TPP + for different time intervals also showed the dependence of the absorption rate on the PEF strength. The modelling of the TPP + uptake recovery has also shown that the characteristic decay time of the non-equilibrium (PEF induced) pores was approximately a few tens of seconds and this did not depend on the PEF strength. A further investigation of such cell membrane recovery process using a florescent SYTOX Green nucleic acid stain dye also showed that such membrane resealing takes place over a time that is like that occurring in the cell wall. It was thus concluded that the similar characteristic lifetimes of the non-equilibrium pores in the cell wall and membrane after exposure  to  PEF indicate a strong coupling between these parts of the cell.

2-(Phosphonomethyl)-pentanedioic acid (2-PMPA) is a potent (IC 50 = 300 pM) and selective inhibitor of glutamate carboxypeptidase II (GCPII) with efficacy in multiple neurological and psychiatric disease preclinical models and more recently in models of inflammatory bowel disease (IBD) and cancer. 2-PMPA ( 1 ), however, has not been clinically developed due to its poor oral bioavailability (<1%) imparted by its four acidic functionalities ( c  Log  P = -1.14). In an attempt to improve the oral bioavailability of 2-PMPA, we explored a prodrug approach using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (ODOL), an FDA-approved promoiety, and systematically masked two ( 2 ), three ( 3 ), or all four ( 4 ) of its acidic groups. The prodrugs were evaluated for in vitro stability and in vivo pharmacokinetics in mice and dog. Prodrugs 2 , 3 , and 4 were found to be moderately stable at pH 7.4 in phosphate-buffered saline (57, 63, and 54% remaining at 1 h, respectively), but rapidly hydrolyzed in plasma and liver microsomes, across species. In vivo, in a single time-point screening study in mice, 10 mg/kg 2-PMPA equivalent doses of 2 , 3 , and 4 delivered significantly higher 2-PMPA plasma concentrations (3.65 ± 0.37, 3.56 ± 0.46, and 17.3 ± 5.03 nmol/mL, respectively) versus 2-PMPA (0.25 ± 0.02 nmol/mL). Given that prodrug 4 delivered the highest 2-PMPA levels, we next evaluated it in an extended time-course pharmacokinetic study in mice. 4 demonstrated an 80-fold enhancement in exposure versus oral 2-PMPA (AUC 0- t : 52.1 ± 5.9 versus 0.65 ± 0.13 h*nmol/mL) with a calculated absolute oral bioavailability of 50%. In mouse brain, 4 showed similar exposures to that achieved with the IV route (1.2 ± 0.2 versus 1.6 ± 0.2 h*nmol/g). Further, in dogs, relative to orally administered 2-PMPA, 4 delivered a 44-fold enhanced 2-PMPA plasma exposure (AUC 0- t for 4 : 62.6 h*nmol/mL versus AUC 0- t for 2-PMPA: 1.44 h*nmol/mL). These results suggest that ODOL promoieties can serve as a promising strategy for enhancing the oral bioavailability of multiply charged compounds, such as 2-PMPA, and enable its clinical translation.

Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK + non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment-emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high-fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Understanding the bioaccumulation and biotransformation of xenobiotic compounds is critical for evaluating their fate and potential toxicity in vivo. In the present study, the tissue specific accumulation and depuration of seven organophosphorus flame retardants (PFRs) in common carp (Cyprinus carpio) were investigated after exposing the fish to an environmental relevant level of PFRs. The log K ow of PFRs was significantly negatively correlated to the percentages of individual PFRs to the total PFRs in serum (p < 0.04), whereas significantly positive correlations were observed in all other tissues (p < 0.02). Significant correlations (p < 0.01) between the log K ow of PFRs and their log bioconcentration factor (BCF ww ) were also found in all investigated tissues except for serum. This suggests that the hydrophobicity of PFRs played a significant role in the distribution and body compartment accumulation of PFRs in common carp. The bioaccumulation potential of PFRs in serum was different from the other tissues, probably due to its specific properties. Dialkyl and/or diaryl phosphate esters (DAP) and hydroxylated PFRs (HO-PFRs) were quantified as the major metabolites. Their levels in liver and intestine were significantly higher than in other tissues. Biotransformation processes also played a crucial role in the accumulation of PFRs in fish. Our results provide critical information for further understanding the bioconcentration, tissue distribution and metabolism of PFRs in fish., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mitochondrial dysfunctions induced by oxidative stress could play a pivotal role in the development of testicular damage and degeneration, leading to impaired fertility in adulthood. MitoQ as mitochondria-targeted antioxidant has been used in many diseases for a long time, but its therapeutic effects on testicular injury 'have not been reported yet. Here, we examined the protective action mechanism of MitoQ on testicular injury from oxidative stress induced by triptolide (TP). Mice were orally administrated with MitoQ (1.3, 2.6 and 5 .2mg/kg, respectively) in a TP-induced model of testicular damage for 14 days. And then testis injuries were comprehensively evaluated in terms of morphological changes, spermatogenesis assessment, blood-testis barrier (BTB) integrity, and apoptosis. The results demonstrated MitoQ effectively increased testicular weight, maintained the integrity of BTB, protected microstructure of testicular tissue and sperm morphology by inhibition of oxidative stress. Further mechanism studies revealed that MitoQ markedly activates the Keap1-Nrf2 antioxidative defense system characterized by increasing the expression of Nrf2 and its target genes HO-1 and NQO1. Meanwhile, MitoQ upregulated the expression of mitochondrial dynamics proteins Mfn2 and Drp-1and exerted a protective effect on mitochondria. On this basis, the results from pharmacokinetic study indicated that the MitoQ could enter into testis tissues after oral administration in despite of the low absolute bioavailability, which provided the material basis for MitoQ in the treatment of testicular damage. More importantly, MitoQ reached mitochondria quickly and had an outstanding feature of mitochondria targeting in Sertoli cells. Therefore, these results provide information for the application of MitoQ against testicular injury diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The identification of anaplastic lymphoma kinase rearrangements in 2-5% of patients with non-small-cell lung cancer led to rapid advances in the clinical development of oral tyrosine kinase inhibitors. Anaplastic lymphoma kinase inhibitors are an effective treatment in preclinical models and patients with anaplastic lymphoma kinase-translocated cancers. Four anaplastic lymphoma kinase inhibitors (crizotinib, ceritinib, alectinib, and brigatinib) have recently been approved. Post-marketing studies provided additional pharmacokinetic information on their pharmacokinetic parameters. The pharmacokinetic properties of approved anaplastic lymphoma kinase inhibitors have been reviewed herein. Findings from additional studies on the effects of drug-metabolizing enzymes, drug transporters, and drug-drug interactions have been incorporated. Crizotinib, ceritinib, and alectinib reach their maximum plasma concentrations after approximately 6 h and brigatinib after 1-4 h. These drugs are primarily metabolized by cytochrome P450 3A with other cytochrome P450 enzymes. They are mainly excreted in the feces, with only a minor fraction being eliminated in urine. Crizotinib, ceritinib, and brigatinib are substrates for the adenosine triphosphate binding-cassette transporter B1, whereas alectinib is not. The different substrate specificities of the transporters play a key role in superior blood-brain barrier penetration by alectinib than by crizotinib and ceritinib. Although the absorption, distribution, and excretion of anaplastic lymphoma kinase inhibitors are regulated by drug transporters, their transporter-mediated pharmacokinetics have not yet been elucidated in detail in patients with non-small-cell lung cancer. Further research to analyze the contribution of drug transporters to the pharmacokinetics of anaplastic lymphoma kinase inhibitors in patients with non-small-cell lung cancer will be helpful for understanding the mechanisms of the inter-individual differences in the pharmacokinetics of anaplastic lymphoma kinase inhibitors.

Owing to its favorable radioactive decay characteristics (T 1/2  = 32.51 d, E β [max] = 434.6 keV [70.5%] and 580.0 keV [29.5%], E γ  = 145.4 keV [48.5%]), 141 Ce could be envisaged as a theranostic radionuclide for use in nuclear medicine. The present article reports synthesis and evaluation of 141 Ce complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (DOTMP) as a potent theranostic agent targeting metastatic skeletal lesions. Ce-141 was produced with 314 ± 29 MBq/mg (n = 6) specific activity and >99.9% radionuclidic purity (n = 6). Around 185 MBq dose of [ 141 Ce]Ce-DOTMP was synthesized with 98.6 ± 0.5% (n = 4) radiochemical yield under optimized conditions of reaction, and the preparation showed adequately high in vitro stability. Biodistribution studies in normal Wistar rats demonstrated significant skeletal localization and retention of injected activity (2.73 ± 0.28% and 2.63 ± 0.22% of injected activity per gram in femur at 3 hours and 14 days post-injection, respectively) with rapid clearance from non-target organs. The results of biodistribution studies were corroborated by serial scintigraphic imaging studies. These results demonstrate the potential utility of 141 Ce-DOTMP as a theranostic molecule for personalized patient care of cancer patients suffering from painful metastatic skeletal lesions., (© 2019 John Wiley & Sons, Ltd.)

The heart failure epidemic continues to rise with coronary artery disease as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 s), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18 F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18 F-labeled perfusion radiotracers will be discussed.

Hydrogels are widely studied as drug delivery system. In this work we propose the employment of tetrakis(hydroxymethyl)phosphonium chloride as crosslinking agent to obtain covalent hydrogels based on chitosan. These hydrogels are obtained by Mannich reaction between the amino groups of chitosan with the hydroxymethyl groups of the crosslinker molecule. They show a pH sensitive second order swelling kinetic, have low toxicity, are biocompatible, mucoadhesive and allow a modified release of the encapsulated drug, camptothecin, for 48 h. This antitumor drug has been studied as a drug of interest to develop oral chemotherapy administration strategies. According to the obtained results, oral administration of camptothecin through hydrogels would provide low concentrations of drug at the absorption site, avoiding carrier saturation and reducing its intestinal toxicity., (Copyright © 2019. Published by Elsevier B.V.)

We studied the pharmacokinetics, biodistribution and metabolism of phospho-sulindac (PS), a novel agent efficacious in the treatment of dry eye, formulated in nanoparticles (PS-NPs) following its topical administration to the eye of New Zealand White rabbits. The nanoparticles were spherical with effective diameter = 108.9 ± 41.7 nm, zeta potential = -21.70 ± 3.78 mV, drug loading = 7%, and entrapment efficiency = 46.4%. Of the total PS delivered topically to the eye, >95% was retained in the anterior segment, predominantly in the cornea (C max  = 101.3 μM; T max  = 1 h; T 1/2  = 2.6 h; area AUC 0-16h  = 164.4 µM·h) and conjunctiva (C max  = 89.4 μM; T max  = 0.25 h; T 1/2  = 3.1 h; AUC 0-16h  = 63.5 µM·h), the tissues most affected by dry eye disease. No PS or its metabolites were detected in the systemic circulation. PS was metabolized to PS sulfide and PS sulfone; all three molecules were hydrolyzed to sulindac, which was converted to sulindac sulfide and sulindac sulfone. A solution formulation of PS provided lower PS levels in ocular tissues but higher levels of PS metabolites, compared to PS-NPs. Therefore, NPs represent an effective formulation for the topical ocular administration of PS for anterior segment diseases, such as dry eye disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Targeting of drugs to the subcellular compartments represents one of the modern trends in molecular pharmacology. The approach for targeting mitochondria was developed nearly 50 years ago, but only in the last decade has it started to become widely used for delivering drugs. A number of pathologies are associated with mitochondrial dysfunction, including cardiovascular, neurological, inflammatory and metabolic conditions., Objective: This mini-review aims to highlight the role of mitochondria in pathophysiological conditions and diseases, to classify and summarize our knowledge about targeting mitochondria and to review the most important preclinical and clinical data relating to the antioxidant lipophilic cations MitoQ and SkQ1., Methods: This is a review of available information in the PubMed and Clinical Trials databases (US National Library of Medicine) with no limiting period., Results and Conclusion: Mitochondria play an important role in the pathogenesis of many diseases and possibly in aging. Both MitoQ and SkQ1 have shown many beneficial features in animal models and in a few completed clinical trials. More clinical trials and research efforts are needed to understand the signaling pathways influenced by these compounds. The antioxidant lipophilic cations have great potential for the treatment of a wide range of pathologies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study compared the efficiency for in vitro human skin decontamination using DDGel and RSDL when applied at different timepoints (5 min and 90 min). Experiments were performed using in vitro human skin models, in which skin was mounted onto Flow-Through diffusion cells. The mass of 14 -C DIMP removed from skin surface after decontamination was quantitated by measuring radioactivity with a liquid scintillation spectrometer. Both decontaminants removed more than 90% recovery dose of DIMP from skin compared to control group (p < 0.05). DDGel skin decontamination reduced more toxicant amount when compared to RSDL. DDGel showed slight higher decontamination ability of DIMP than RSDL and efficiently removed chemicals from the skin surface, also reduced the amount of DIMP in receptor fluid. A similar decontamination regimen with RSDL and DDGel at 90 min showed that both were still might effectively increase the time window of opportunity for treatment. Thus, DDGel can offer a potential as a next generation skin decontamination platform technology for military and civilian applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several second and third generation ALK inhibitors have been introduced in recent years. A bioanalytical assay for simultaneous quantification of alectinib, brigatinib, and lorlatinib was developed and validated for human plasma. The method was also partially validated for diluted mouse plasma and tissue homogenates of brain, liver, kidney, and spleen. Samples (40 μl) were pretreated in a 96-well plate by protein precipitation with acetonitrile containing the internal standard [ 2 H 8 ]-alectinib. After chromatographic separation on an ethylene bridged octadecyl silica column by gradient elution at 600 μl/min using 1% (v/v) formic acid (in water) and acetonitrile, compounds were ionized by a turbo electrospray and monitored by selected reaction monitoring on a triple quadrupole mass spectrometer. Validation was performed in a 2-2000 ng/ml concentration range for alectinib and lorlatinib and a 4-4000 ng/ml range for brigatinib. Precisions (within-day and between-day) were in the range 2.2-15.0% and accuracies were in between 87.2 and 110.2% for all matrices and levels. Compounds were sufficiently stable under most investigated conditions. Results of a pilot pharmacokinetic and tissue distribution study for brigatinib in mice are reported. Finally, successful incurred samples reanalysis of tissue homogenate samples containing brigatinib and lorlatinib is presented. Lorlatinib homogenate samples were also successfully reanalyzed using a second independent assay (cross-validation)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bone pain is the major manifestation of skeletal metastases. Although various treatment modalities are available for bone pain palliation, use of radiolabeled phosphonates is documented to be more effective. Among radionuclides available for this purpose, lutetium-177 is gaining popularity due to its moderate beta energy, theranostic capability, favorable half-life and convenient production logistics. 177 Lu-DOTMP has shown considerable promise as a metastatic bone pain palliating agent in preliminary evaluations and recent clinical studies. Therefore, an attempt was made to elucidate the possible mechanism of in vitro cell death induced by 177 Lu-DOTMP in MG63 cells. 177 Lu-DOTMP binding studies were carried out in mineralized bone of MG63 cells and around 50% binding was observed. Skeletons of Wistar rats showed 1.78 ± 0.5% IA/g at a 3 h time period which was almost constant up to 7 days. MG63 cells were incubated with 3.7 and 37 MBq of 177 Lu-DOTMP for 48 h prior to perform assays. An increase in the magnitude of cell toxicity and apoptotic DNA fragmentation was observed. Enhancement of G2/M phase cell cycle arrest and apoptosis were documented which were dose-dependent. Thus, 177 Lu-DOTMP induced apoptotic cell death in MG63 cells, which might be one of the primary causes of pain relief in osseous metastases., (© 2018 John Wiley & Sons, Ltd.)

The aim of this study was to improve the oral bioavailability of a practically insoluble drug, efonidipine hydrochloride (EFH), by agglomeration in acid solution/gastric fluid. The EFH nanosuspension was prepared by the wet-milling method with F68 as a dispersing agent, SDS as an auxiliary stabilizer and l-arginine as a pH adjusting agent. The EFH nanosuspension have been prepared in industrial scale-up. The dissolution rate of the EFH nanosuspension was greater than that of bulk EFH. An in vitro intestinal permeability study showed a clear increase in the apparent permeability of different intestinal segments compared with bulk EFH. Also, a pharmacokinetic study showed that the C max and AUC 0-24h of the nanosuspensions were approximately 1.76-fold and 2.2-fold greater than that of bulk EFH, respectively, and there was no significant difference compared with commercial tablets. It appears that wet-milling offers an effective approach to improve the dissolution rate and oral absorption of this practically insoluble drug., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Single photon emission computed tomography (SPECT)/computed tomography (CT) imaging allows for assessment of skeletal muscle microvascular perfusion but has not been quantitatively assessed in angiosomes, or 3-dimensional vascular territories, of the foot. This study assessed and compared resting angiosome foot perfusion between healthy subjects and diabetic patients with critical limb ischemia (CLI). Additionally, the relationship between SPECT/CT imaging and the ankle-brachial index-a standard tool for evaluating peripheral artery disease-was assessed., Methods and Results: Healthy subjects (n=9) and diabetic patients with CLI and nonhealing ulcers (n=42) underwent SPECT/CT perfusion imaging of the feet. CT images were segmented into angiosomes for quantification of relative radiotracer uptake, expressed as standardized uptake values. Standardized uptake values were assessed in ulcerated angiosomes of patients with CLI and compared with whole-foot standardized uptake values in healthy subjects. Serial SPECT/CT imaging was performed to assess uptake kinetics of technetium-99m-tetrofosmin. The relationship between angiosome perfusion and ankle-brachial index was assessed via correlational analysis. Resting perfusion was significantly lower in CLI versus healthy subjects ( P =0.0007). Intraclass correlation coefficients of 0.95 (healthy) and 0.93 (CLI) demonstrated excellent agreement between serial perfusion measurements. Correlational analysis, including healthy and CLI subjects, demonstrated a significant relationship between ankle-brachial index and SPECT/CT ( P =0.01); however, this relationship was not significant for diabetic CLI patients only ( P =0.2)., Conclusions: SPECT/CT imaging assesses regional foot perfusion and detects abnormalities in microvascular perfusion that may be undetectable by conventional ankle-brachial index in patients with diabetes mellitus. SPECT/CT may provide a novel approach for evaluating responses to targeted therapies., (© 2018 The Authors.)

The full understanding of the single and joint toxicity of a variety of organophosphorus (OP) pesticides is still unavailable, because of the extreme complex mechanism of action. This study established a systems-level approach based on systems toxicology to investigate OP pesticide toxicity by incorporating ADME/T properties, protein prediction, and network and pathway analysis. The results showed that most OP pesticides are highly toxic according to the ADME/T parameters, and can interact with significant receptor proteins to cooperatively lead to various diseases by the established OP pesticide -protein and protein-disease networks. Furthermore, the studies that multiple OP pesticides potentially act on the same receptor proteins and/or the functionally diverse proteins explained that multiple OP pesticides could mutually enhance toxicological synergy or additive on a molecular/systematic level. To the end, the integrated pathways revealed the mechanism of toxicity of the interaction of OP pesticides and elucidated the pathogenesis induced by OP pesticides. This study demonstrates a systems-level approach for investigating OP pesticide toxicity that can be further applied to risk assessments of various toxins, which is of significant interest to food security and environmental protection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Lipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development of 99m Tc tumor-targeted imaging agents., Methods: Two tridentate ligands containing the triphenylphosphonium cation, L1 (S-cysteinyl) and L2 (N-iminodiacetate) as well as the respective 99m Tc/ReL1 and 99m Tc/ReL2 tricarbonyl complexes were synthesized. The effect of the ligands and the Re complexes on cell growth in U-87 MG glioblastoma cells was assessed. In vitro stability studies and measurement of logP of the 99m Tc tracers was performed. The cellular and mitochondrial uptake of the 99m Tc tracers in U-87 MG cells was evaluated. Biodistribution of 99m TcL1 and 99m TcL2 were performed on SCID mice bearing U-87 MG tumors., Results: The ligands L1, L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single products 99m TcL1 and 99m TcL2, >90% stable in rat serum, were obtained. LogP was 0.40±0.14 for 99m TcL1 and -0.02±0.07 for 99m TcL2. L1, ReL1 and ReL2 caused no notable cytotoxicity and L2 was found to infer 40% inhibition of cellular growth at 10 -5 M as well as 80% cell death in culture at 10 -4 M. The cell uptake of 99m TcL1 and 99m TcL2 over 4h was 1.26±0.08% and 0.06±0.01% respectively, of which 13.41±3.63% and 18.61±6.19% was distributed in the mitochondria respectively. The initial tumor uptake in mice was found to be >1% ID/g for both 99m Tc tracers., Conclusions: In vitro mitochondrial and in vivo tumor targeting was observed, better in 99m TcL1, however these properties should be optimized in future studies. Advances in Knowledge and Implications for Patient Care: Continuous efforts in this direction may lead to a suitable mitochondrial-targeted 99m Tc imaging agent for tumor detection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background and Objective: Skeletal uptake of 90Y-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetramethylene-phosphonate (DOTMP) is used to deliver high doses of this radiopharmaceutical to the bone marrow., Methods: In this research, carrier-free (c.f.) 90Y was obtained from an electrochemical 90Sr/90Y generator. The c.f. 90Y was mixed with 300 µL of DOTMP (20 mg/mL) and incubated under stirring conditions at room temperature for 45 min., Results: The [90Y]Y-DOTMP that was obtained under optimized reaction conditions had high radiochemical purities (>98%). Moreover, the radiolabeled complex exhibited excellent stability at room temperature, as well as in human serum. The biodistribution studies in rats showed the favorable selective skeletal uptake with rapid clearance from the blood, albeit with insignificant accumulation of activity in other non-target organs for the radiolabeled complex. Also, the present work has utilized the Monte Carlo codes MCNP-4C to simulate the depth dose profile for 90Y in a mice femur bone and compared with that produced by 153Sm and 177Lu., Conclusion: The results show that the absorbed dose produced by 90Y in the bone marrow is higher than 153Sm and 177Lu per 1MBq of the injected activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Brigatinib is the second-generation anaplastic lymphoma kinase - inhibitor in non-small cell lung cancer and it can overcome the crizotinib-resistance. Chromatographic separation was carried out on an Acquity Ultra Performance Liquid Chromatography (UPLC) unit with a BEH C18 column (2.1mm×50mm, 1.7μm). The mobile phase was composed of acetonitrile and 0.1% formic acid in water. No endogenous interfering compounds was discovered at retention time of brigatinib (0.56min) and imatinib (IS, 1.41min). MS/MS detection was performed in positive mode. And the MRM transitions were m/z 584.09→484.08 and m/z 494.3→394.2 for brigatinib and IS, respectively. This method was assessed to be stable, specificity, and no matrix effect in three concentrations (0.004, 0.4, 4μg/mL). The intra-day and inter-day precisions were less than 11.09% and 6.43%. And intra-day and inter-day accuracies were ranged from -3.88% to 5.44%. The recovery of brigatinib was from 85.26% to 96.05%. Additionally, the method had a good linearity in the range of 0.002-5μg/mL. The presented method was effectively implemented to determine the concentration of brigatinib in rat plasma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Photoimmunotherapy (PIT) is an emerging low side effect cancer therapy based on a monoclonal antibody (mAb) conjugated with a near-infrared (NIR) phthalocyanine dye IRDye 700DX. IR700 is fluorescent, can be used as an imaging agent, and also is phototoxic. It induces rapid cell death after exposure to NIR light. PIT induces highly selective cancer cell death, while leaving most of tumor blood vessels unharmed, leading to an effect called super-enhanced permeability and retention (SUPR). SUPR significantly improves the effectiveness of the anticancer drug. Currently, the therapeutic effects of PIT are monitored using the IR700 fluorescent signal based on macroscopic fluorescence reflectance imagery. This technique, however, lacks the resolution and depth information to reveal the intratumor heterogeneity of mAb-IR700 distribution. We applied a minimally invasive two-channel fluorescence fiber imaging system by combining the traditional fluorescence imaging microscope with two imaging fiber bundles (~0.85mm). This method monitored mAb-IR700 distribution and therapeutic effects during PIT at different intratumor locations (e.g., tumor surface vs. deep tumor) in situ and in real time simultaneously. This enabled evaluation of the therapeutic effects in vivo and treatment regimens. The average IR700 fluorescence intensity recovery after PIT to the tumor surface is 91.50%, while it is 100.63% in deep tumors. To verify the results, two-photon microscopy combined with a microprism was also used to record the mAb-IR700 distribution and fluorescence intensity of green fluorescent protein (GFP) at different tumor depths during PIT. After PIT treatment, there was significantly higher IR700 fluorescence recovery in deep tumor than in the tumor surface. This phenomenon can be explained by increased vascular permeability immediately after NIR-PIT. Fluorescence intensity of GFP at the tumor surface decreased significantly more compared to that of deep tumor and in controls (no PIT)., (Copyright © 2017. Published by Elsevier B.V.)

Use of bone-seeking radiopharmaceuticals is an established modality in the palliative care of pain due to skeletal metastases. 177 Lu-DOTMP is a promising radiopharmaceutical for this application owing to the ideally suited decay properties of 177 Lu and excellent thermodynamic stability and kinetic rigidity of the macrocyclic complex. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of clinical doses of 177 Lu-DOTMP at hospital radiopharmacy. After extensive radiochemical studies, an optimized strategy for formulation of clinical doses of 177 Lu-DOTMP was developed, which involves simple mixing of approximately 3.7 GBq of 177 Lu activity as 177 LuCl 3 solution to an aqueous solution containing 5 mg of DOTMP and 8 mg of NaHCO 3 . The proposed protocol yielded 177 Lu-DOTMP with >98% radiochemical purity, and the resultant formulation showed excellent in vitro stability and desired pharmacokinetic properties in animal model. Preliminary clinical investigations in 5 patients showed specific skeletal accumulation with preferential localization in the osteoblastic lesion sites and almost no uptake in soft tissue or any other major nontarget organ. The developed "mix-and-use" strategy would be useful for large number of nuclear medicine centers having access to 177 Lu activity and would thereby accelerate the clinical translation of 177 Lu-DOTMP., (Copyright © 2017 John Wiley & Sons, Ltd.)

Brigatinib (ALUNBRIG™) is a small molecule antineoplastic anaplastic lymphoma kinase (ALK) inhibitor being developed by ARIAD Pharmaceuticals (a wholly-owned subsidiary of Takeda Pharmaceutical Company). In April 2017 brigatinib received accelerated approval in the USA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The development of resistance to crizotinib is a therapeutic challenge that has led to the development of second-generation ALK-inhibitors such as brigatinib, which have activity against treatment-resistant ALK mutants. This article summarizes the milestones in the development of brigatinib leading to this first global approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Background: Pradefovir is efficiently converted to adefovir [9-(2-phosphonylmethoxyethyl) adenine (PMEA)], producing high hepatic PMEA concentration but low levels in the systemic circulation and kidney. The aim of this study is to evaluate the tolerability, adverse effect (AEs), pharmacokinetics and pharmacogenetics of a single ascending dose of pradefovir., Methods: Fifty healthy subjects were divided into five groups and randomized within each group at a ratio of 3:1:1 to receive a single ascending dose of pradefovir (10, 30, 60, 90, or 120 mg), and 10 mg adefovir dipivoxil (ADP) or placebo. Blood and urine samples were collected and analyzed. A total of 1930 polymorphic loci were analyzed in 6 blood samples collected from the 90 mg pradefovir group., Results: The single oral dose of pradefovir up to 120 mg was well tolerated. A total of 29 dose-limited mild AEs were reported in 17 subjects. The peak plasma concentration (C max ) and area under the curve (AUC) 0-48 of serum pradefovir ranged from (21.41 ± 12.98) to (447.33 ± 79.34) ng/mL and (46.10 ± 29.45) to (748.18 ± 134.15) ng h/mL across the dose range, respectively. The C max and AUC 0-48 of serum PMEA ranged from 18.10 ± 4.96 to 312.33 ± 114.19 ng/mL and 72.65 ± 28.25 to 1095.48 ± 248.47 ng h/mL. Generally, no kidney impairment was observed. Pharmacogenetic analysis identified three metabolism-related single nucleotide polymorphism (SNP) locis, P450 (cytochrome) oxidoreductase [POR (rs6965343)], arylamine N-acetyltransferases [NAT1 (rs4986993)] and CYP2F1 (rs305968)], and one distribution-related loci, orosomucoid 2 [ORM2 (rs12685968)]., Conclusions: The single oral dose of pradefovir 10-120 mg was well tolerated. SNPs may be associated with variable rates of adverse events., Trial Registration Number: CTR20140341.

The potential for prenatal exposure has recently raised concerns over the health risks of endocrine disruptors; however, knowledge about human prenatal exposure to organophosphorus flame retardants (OPFRs) is lacking. In this study, 2-ethylhexyl diphenyl phosphate (EHDPP), tributyl phosphate (TBP), triphenyl phosphate (TPHP), and tris(2-chloroethyl) phosphate (TCEP) were detected in the majority of chorionic villus samples, with median concentrations of 13.6, 18.8, 11.1, and 0.51 ng/g of dry weight (dw), respectively, significantly higher than those in the matching maternal decidua samples (5.96, 10.8, 1.44, and 0.26 ng/g of dw, respectively). The ratios of concentrations in chorionic villi (containing embryos) to those in maternal deciduae (CMRs) were 4.17, 3.82, 2.81, and 2.00 for EHDPP, TPHP, TBP, and TCEP, respectively, which correlated with their log K ow values (p = 0.003). The results of transthyretin (TTR) binding assays indicated that the stronger the binding ability to TTR, the higher the CMRs. The median concentrations of the metabolites diphenyl phosphate (DPHP), dibutyl phosphate (DBP), and bis(2-chloroethyl) phosphate (BCEP) were 4.11, 429, and 157 ng/g of dw in chorionic villi, higher than those in deciduae (1.64, 181, and 25.4 ng/g of dw, respectively). The ratios of DPHP/TPHP and DPHP/EHDPP were 0.20 and 0.43 in chorionic villi and 1.24 and 2.03 in deciduae, respectively, much lower than those of DBP/TBP and BCEP/TCEP (20.9 and 165.6 in chorionic villi and 13.1 and 35.3 in deciduae, respectively), suggesting that the difference in metabolism between the deciduae and chorionic villi would affect their maternal transfer.