Papel de la persona navegadora del paciente en el cáncer de pulmón / The Role of the Navigator Person for a Patient with Lung Cancer

Introducción: la medicina basada en el valor ha logrado mejorar la calidad de atención del paciente y/o la satisfacción de las personas, reduciendo costos y obteniendo mejores resultados. Se apoya sobre tres pilares básicos: la medicina basada en la evidencia, la atención centralizada en el paciente, y la sustentabilidad. Sin embargo, existen pocas publicaciones sobre la estrategia de personas navegadoras para pacientes con cáncer de pulmón, que podrían ser una herramienta clave para brindar apoyo, asegurando que tengan acceso al conocimiento y los recursos necesarios a fin de completar la vía de atención clínica recomendada. Estado del arte: se trata de una intervención en salud cuyo objetivo principal es lograr vencer las barreras relacionadas con la atención (p. ej., logísticas, burocrático-administrativas, de comunicación y financieras) para poder mejorar la calidad y el acceso a la salud en el marco de la atención del cáncer. Estas personas cumplen un papel de guía para pacientes durante el proceso de diagnóstico y tratamiento activo. Su labor consiste en vincular al paciente con los proveedores clínicos, brindar un sistema de apoyo, asegurar un acompañamiento individualizado, garantizar que tengan acceso al conocimiento y a los recursos necesarios para completar el seguimiento y/o tratamiento adecuado. Discusión/Conclusión: indudablemente, es un elemento cada vez más reconocido en los programas de cáncer, centrado en el paciente y de alta calidad. Su implementación será de especial interés en la Unidad de Práctica Integrada para personas con cáncer de pulmón. (AU)

Introduction: Value-based medicine has succeeded in improving the quality of patient care and or patient satisfaction, reducing costs, and obtaining better outcomes. It rests on three fundamental pillars: evidence-based medicine, patient-centered care, and sustainability. However, there are few publications on the people navigator strategy for lung cancer patients, which could be a crucial tool for providing support, ensuring that they have access to the knowledge and resources needed to complete the recommended clinical care pathway. State of the art: It is a health intervention whose main objective is to overcome care-related barriers (e.g., logistical, bureaucratic-administrative, communication, and financial) to improve quality and access to health in the context of cancer care. These individuals play a guiding role for patients during the diagnostic and active treatment process. Their job is to link the patient with clinical providers, provide a support system, ensure individualized accompaniment, and guarantee that they get access to the knowledge and resources necessary to complete the appropriate follow-up and, or treatment. Discussion/Conclusion: Undoubtedly, patient navigators represent an increasingly recognized element of high-quality, patient-centered cancer programs. Its implementation will be of specific interest in the Integrated Practice Unit for people with lung cancer. (AU)

Stochastic Differential Equation-based Mixed Effects Model of the Fluid Volume in the Fasted Stomach in Healthy Adult Human.

The rate and extent of drug dissolution and absorption from a solid oral dosage form depend largely on the fluid volume along the gastrointestinal tract. Hence, a model built upon the gastric fluid volume profiles can help to predict drug dissolution and subsequent absorption. To capture the great inter- and intra-individual variability (IAV) of the gastric fluid volume in fasted human, a stochastic differential equation (SDE)-based mixed effects model was developed and compared with the ordinary differential equation (ODE)-based model. Twelve fasted healthy adult subjects were enrolled and had their gastric fluid volume measured before and after consumption of 240 mL of water at pre-determined intervals for up to 2 hours post ingestion. The SDE- and ODE-based mixed effects models were implemented and compared using extended Kalman filter algorithm via NONMEM. The SDE approach greatly improved the goodness of fit compared with the ODE counterpart. The proportional and additive measurement error of the final SDE model decreased from 14.4 to 4.10% and from 17.6 to 4.74 mL, respectively. The SDE-based mixed effects model successfully characterized the gastric volume profiles in the fasted healthy subjects, and provided a robust approximation of the physiological parameters in the very dynamic system. The remarkable IAV could be further separated into system dynamics terms and measurement error terms in the SDE model instead of only empirically attributing IAV to measurement errors in the traditional ODE method. The system dynamics were best captured by the random fluctuations of gastric emptying coefficient Kge.

Characterization of the cellular transport mechanisms for the anti-cachexia candidate compound TCMCB07.

BACKGROUND: Cachexia is a debilitating, life-threatening condition whose pathology includes reduced food intake accompanied by hypermetabolism, leading to a catabolic state. The hypothalamic melanocortin system is a critical regulator of metabolic rate with effects being mediated through the melanocortin-4 receptor (MC4R). MC4R activation is also critical to the initiation and maintenance of cachexia. A major problem in the design of anti-cachexia drugs has been the need to cross the blood-brain barrier to access the metabolic rate-controlling centres in the hypothalamus. The overwhelming majority of anti-cachexia drugs are only effective when administered intracerebroventricularly. TCMCB07 is a cyclic nonapeptide peptide MC4R antagonist with parenteral anti-cachexia activity in both small and large animal models. This suggests it can cross the blood-brain barrier. The aim of this study was to examine potential transport mechanisms of TCMCB07 furthering its preclinical development for subsequent studies in humans. METHODS: In vitro studies were performed in transporter-transfected cells to study whether or not TCMCB07 was an inhibitor as well as substrate for OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT2, OAT1, OAT3, MATE1, MATE2-K, P-gp (MDR1), and BCRP. In vivo mass balance studies were also performed in mice to evaluate the absorption and disposition of TCMCB07 after oral and intravenous bolus administrations. RESULTS: TCMCB07 inhibited the uptake of prototypical substrates in cells transfected with OATP1A2 (IC50 24.0 µM), OATP1B1 (IC50 6.8 µM), OATP1B3 (IC50 307 µM), OATP2B1 (IC50 524 µM), OCT2 (IC50 1,169 µM), MATE1 (IC50 8.7 µM), and MATE2-K (IC50 20.7 µM) but not in cells transfected with OAT1 and OAT3. TCMCB07 did not affect the P-gp (MDR1)-mediated and BCRP-mediated permeability of prototypical substrates in transfected cells. Importantly, direct evidence was shown for the uptake of TCMCB07 in OATP1A2-transfected cells (i.e. Vmax 236 pmol/mg, Km 58.4 µM, and Kd 0.39 µL/mg), demonstrating that the nonapeptide was a substrate for this transporter. Mass balance studies demonstrated that 24.2% of TCMCB07 was absorbed orally in vivo (P = 0.0033) and excreted primarily in the bile after both oral and intravenous administrations. CONCLUSIONS: OATP1A2 is the transporter responsible for the oral absorption of TCMCB07 in the intestine and for its pharmacologic response in the brain.

Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice.

Gemcitabine is an intravenously administered anti-cancer nucleoside analogue. Systemic exposure following oral administration of gemcitabine is limited by extensive first-pass metabolism via cytidine deaminase (CDA) and potentially by saturation of nucleoside transporter-mediated intestinal uptake. An amino acid ester prodrug of gemcitabine, 5'-l-valyl-gemcitabine (V-Gem), was previously shown to be a substrate of the intestinally expressed peptide transporter 1 (PEPT1) and stable against CDA-mediated metabolism. However, preliminary studies did not evaluate the in vivo oral performance of V-Gem as compared to parent drug. In the present study, we evaluated the pharmacokinetics and in vivo oral absorption of gemcitabine and V-Gem following intravenous and oral administrations in mice. These studies revealed that V-Gem undergoes rapid systemic elimination (half-life < 1 min) and has a low oral bioavailability (<1%). Most importantly, the systemic exposure of gemcitabine was not different following oral administration of equimolar doses of gemcitabine (gemcitabine bioavailability of 18.3%) and V-Gem (gemcitabine bioavailability of 16.7%). Single-pass intestinal perfusions with portal blood sampling in mice revealed that V-Gem undergoes extensive activation in intestinal epithelial cells and that gemcitabine undergoes first-pass metabolism in intestinal epithelial cells. Thus, formulation of gemcitabine as the prodrug V-Gem does not increase systemic gemcitabine exposure following oral dosing, due, in part, to the instability of V-Gem in intestinal epithelial cells.

Chemoproteomic Identification of Serine Hydrolase RBBP9 as a Valacyclovir-Activating Enzyme.

Prodrug discovery and development in the pharmaceutical industry have been hampered by a lack of knowledge of prodrug activation pathways. Such knowledge would minimize the risks of prodrug failure by enabling proper selection of preclinical animal models, prediction of pharmacogenomic variability, and identification of drug-drug interactions. Technologies for annotation of activating enzymes have not kept pace with the growing need. Activity-based protein profiling (ABPP) has matured considerably in recent decades, leading to widespread use in the pharmaceutical industry. Here, we report the extension of competitive ABPP (cABPP) to prodrug-activating enzyme identification in stable isotope-labeled cell lysates using a modified fluorophosphonate probe. Focusing on the antiviral ester prodrug valacyclovir (VACV), we identified serine hydrolase RBBP9 as an activating enzyme in Caco-2 cells via shotgun proteomics, validating the activity via the selective inhibitor emetine (EME). Kinetic characterization of RBBP9 revealed a catalytic efficiency (kcat·KM-1 = 104 mM-1·s-1) comparable to that of BPHL, the only known VACV-activating enzyme prior to this work. EME incubation in wild-type and Bphl-knockout jejunum and liver lysates demonstrated the near-exclusivity of VACV activation by RBBP9 in the intestine. Additionally, these studies showed that RBBP9 and BPHL are the two major and coequal VACV-activating enzymes in the liver. Single-pass intestinal perfusions of VACV ± EME in mice showed EME coperfusion significantly inhibited the intestinal activation of VACV, implying the in vivo relevance of RBBP9-mediated VACV activation. We envision that others might use the cABPP approach in the future for global, rapid, and efficient discovery of prodrug-activating enzymes.

[Ectopic hyperparathyroidism. Detection of mediastinal localization]. / Hiperparatiroidismo ectópico. Detección de la localización mediastinal.

The ectopic parathyroid tissue is a frequent cause of recurrent hyperparathyroidism (HPT), accounting 16% in primary HPT and 14% in secondary cases. Although intrathoracic ectopic glands represent 25-35% of all ectopic cases, only 2% requires thoracic surgery. The aim of this study is to report a case series of patients with ectopic mediastinal HPT treated by thoracic approach in a private institution in Argentina. This is a retrospective analysis from January 2006 to June 2019. All patients diagnosed with ectopic hyperparathyroidism who required a thoracic surgical approach were included. During this period, 728 patients with primary HPT and secondary HPT were treated. Six with primary HPT and 3 with secondary HPT required a thoracic approach. Six video-assisted thoracoscopy surgeries (VATS) and 3 sternotomies were performed. None of them presented serious posoperative complications. Frozen section biopsy was used in all cases. iPTH was measured in 8 cases, with a mean drop of 65% after 15 minutes. Final pathology reports confirmed 5 adenomas and 4 hyperplasias. Our case series reported an incidence of 1.65% (12/728) mediastinal parathyroids, while 1.24% (9/728) received surgical treatment at our institution. Intraoperative frozen section and PTHi are useful to confirm the diagnosis and to avoid recurrences. Although VATS is a safe and efficient treatment option, it depends on surgical training and availability. In terms of diagnostic imaging resources, sestamibi remains the current gold standard. However, 18F-choline PET/CT may arise as a new diagnostic tool. The possibility of obtaining evidence-based conclusions requires studies with higher number of patients.

El tejido paratiroideo ectópico es una causa frecuente de recurrencia del hiperparatiroidismo (HPT) siendo de 16% en primarios y 14% en secundarios. La localización intratorácica representa el 20-35%, pero solo un 2% requiere una cirugía torácica. El objetivo fue analizar una cohorte de pacientes con diagnóstico de HPT mediastinal operados en un hospital de alta complejidad de Argentina. Se realizó un estudio retrospectivo de todos los operados por HPT entre enero de 2006 y julio 2019 en ese hospital. Se incluyeron aquellos que requirieron acceso torácico por HPT ectópico. En este período se trataron 728 pacientes con HPT primario y secundario. Seis con primario y 3 con secundario requirieron cirugía torácica. Se realizaron 6 videotoracoscopias (VATS) y 3 esternotomías, sin complicaciones graves. Se utilizó biopsia por congelación en todos y dosaje de paratohormona intraoperatoria (PTHi) en 8 casos, que descendió en promedio 65% respecto al valor basal. Se confirmaron 5 adenomas y 4 hiperplasias. La enfermedad paratiroi dea mediastinal representó el 1.65% (12/728), mientras que recibieron tratamiento quirúrgico en nuestra institución 1.24% (9/728). La biopsia por congelación y el descenso de PTHi resultan útiles para confirmar el foco y eventualmente disminuir el riesgo de recurrencia. La VATS es segura pero depende del entrenamiento y de la disponibilidad en el medio asistencial. Si bien el sestamibi es el método con mayor sensibilidad, se propone el uso de 18F-colina PET/TC ante la sospecha de HPT ectópico. La posibilidad de obtener conclusiones basadas en la evidencia requiere de estudios con mayor número de pacientes.

Accuracy of positron emission tomography and computed tomography (PET/CT) in detecting nodal metastasis according to histology of non-small cell lung cancer.

Positron emission tomography and computed tomography (PET-CT) is the non-invasive gold standard method for determining the oncological stage of patient with diagnosis of lung cancer. A correct preoperative staging is significant because only patients who do not have a history of regional or distant disease are those who will benefit from a surgical treatment. However, due to the different values of the PET-CT in terms of sensitivity and specificity to evaluate the mediastinal lymph node involvement, it is often necessary to perform a surgical mediastinal sampling through a cervical video mediastinoscopy (VM). Patient's risk factors which could modify the results of the PET scan, performing differences between non-invasive staging and the lymph node sampling due to VM are not yet clearly established in the literature. This knowledge will allow to identify in whom a surgical staging by sampling the mediastinal lymph nodes is needed. We included 234 patients with diagnosis of lung cancer who underwent a mediastinal lymph node staging by PET-CT images and histopathological results of mediastinal sampling by VM, analyzing the sensitivity and specificity of this non-invasive imaging study. We also analyzed variables that could modify the results of PET-CT, such as tumor type, location of the tumor and patient's history. We showed that those PET-CT presented an overall sensitivity and specificity of 93.8 and 62.7%, respectively, with negative and positive predictive values of 95.05 and 57.1%, respectively. The false-positive rate was 25% (57 of 234 patients). Analyzing risk factors involved in this false-positive rate (n = 57), we found that the only statistically significant factor that could explain these results was the histology of squamous carcinoma (p < 0.03). In this group of patients, it is essential to perform a mediastinal lymph node biopsy to know the real state of lymph node involvement.

Effect of biphenyl hydrolase-like (BPHL) gene disruption on the intestinal stability, permeability and absorption of valacyclovir in wildtype and Bphl knockout mice.

Biphenyl hydrolase-like protein (BPHL) is a novel human serine hydrolase that was originally cloned from a breast carcinoma cDNA library and shown to convert valacyclovir to acyclovir and valganciclovir to ganciclovir. However, the exclusivity of this process has not been determined and, indeed, it is possible that a number of esterases/proteases may mediate the hydrolysis of valacyclovir and similar prodrugs. The objectives of the present study were to evaluate the in situ intestinal permeability and stability of valacyclovir in wildtype (WT) and Bphl knockout (KO) mice, as well as the in vivo oral absorption and intravenous disposition of valacyclovir and acyclovir in the two mouse genotypes. We found that Bphl knockout mice had no obvious phenotype and that Bphl ablation did not alter the jejunal permeability of valacyclovir during in situ perfusions (i.e., 0.54 × 10-4 in WT vs. 0.53 × 10-4 cm/s in KO). Whereas no meaningful changes occurred between genotypes in the gene expression of proton-coupled oligopeptide transporters (i.e., PepT1, PepT2, PhT1, PhT2), enzymatic upregulation of Cyp3a11, Cyp3a16, Abhd14a and Abhd14b was observed in some tissues of Bphl knockout mice. Most importantly, we found that valacyclovir was rapidly and efficiently hydrolyzed to acyclovir in the absence of BPHL, and that hydrolysis was more extensive after the oral vs. intravenous route of administration (for both genotypes). Taken as a whole, BPHL is not obligatory for the conversion of valacyclovir to acyclovir either presystemically or systemically.

Regulation and biological role of the peptide/histidine transporter SLC15A3 in Toll-like receptor-mediated inflammatory responses in macrophage.

The peptide/histidine transporter SLC15A3 is responsible for transporting histidine, certain dipeptide and peptidomimetics from inside the lysosome to cytosol. Previous studies have indicated that SLC15A3 transcripts are mainly expressed in the lymphatic system, however, its regulation and biological role in innate immune responses and inflammatory diseases are as yet unknown. In this study, mouse peritoneal macrophages (PMs), mouse bone marrow-derived macrophages (BMDMs), the human acute monocytic leukemia cell line THP-1 and the human lung epithelial carcinoma cell line A549 were used to investigate the regulation and biological role of SLC15A3 in TLR-mediated inflammatory responses. Our results showed that SLC15A3 was upregulated by TLR2, TLR4, TLR7 and TLR9 ligands in macrophages at both the mRNA and protein levels via activation of NF-κB (nuclear factor-kappa-B), MAPK (mitogen-activated protein kinase) and IRF3 (interferon regulatory factor 3). Furthermore, knockdown or overexpression of SLC15A3 influenced the TLR4-triggered expression of proinflammatory cytokines. A reporter gene assay showed that the SLC15A3 promotor contained potential NF-κB binding sites, which were reasonable for regulating SLC15A3 by TLR-activation through NF-κB signaling. Additionally, SLC15A3 expression was increased and positively related to inflammation in mice with bacterial peritonitis. The collective findings suggest that SLC15A3 is regulated by various TLRs, and that it plays an important role in regulating TLR4-mediated inflammatory responses.

SLC15A2 and SLC15A4 Mediate the Transport of Bacterially Derived Di/Tripeptides To Enhance the Nucleotide-Binding Oligomerization Domain-Dependent Immune Response in Mouse Bone Marrow-Derived Macrophages.

There is increasing evidence that proton-coupled oligopeptide transporters (POTs) can transport bacterially derived chemotactic peptides and therefore reside at the critical interface of innate immune responses and regulation. However, there is substantial contention regarding how these bacterial peptides access the cytosol to exert their effects and which POTs are involved in facilitating this process. Thus, the current study proposed to determine the (sub)cellular expression and functional activity of POTs in macrophages derived from mouse bone marrow and to evaluate the effect of specific POT deletion on the production of inflammatory cytokines in wild-type, Pept2 knockout and Pht1 knockout mice. We found that PEPT2 and PHT1 were highly expressed and functionally active in mouse macrophages, but PEPT1 was absent. The fluorescent imaging of muramyl dipeptide-rhodamine clearly demonstrated that PEPT2 was expressed on the plasma membrane of macrophages, whereas PHT1 was expressed on endosomal membranes. Moreover, both transporters could significantly influence the effect of bacterially derived peptide ligands on cytokine stimulation, as shown by the reduced responses in Pept2 knockout and Pht1 knockout mice as compared with wild-type animals. Taken as a whole, our results point to PEPT2 (at plasma membranes) and PHT1 (at endosomal membranes) working in concert to optimize the uptake of bacterial ligands into the cytosol of macrophages, thereby enhancing the production of proinflammatory cytokines. This new paradigm offers significant insight into potential drug development strategies along with transporter-targeted therapies for endocrine, inflammatory, and autoimmune diseases.

Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening.

Molecular imaging is advantageous for screening diseases such as breast cancer by providing precise spatial information on disease-associated biomarkers, something neither blood tests nor anatomical imaging can achieve. However, the high cost and risks of ionizing radiation for several molecular imaging modalities have prevented a feasible and scalable approach for screening. Clinical studies have demonstrated the ability to detect breast tumors using nonspecific probes such as indocyanine green, but the lack of molecular information and required intravenous contrast agent does not provide a significant benefit over current noninvasive imaging techniques. Here we demonstrate that negatively charged sulfate groups, commonly used to improve solubility of near-infrared fluorophores, enable sufficient oral absorption and targeting of fluorescent molecular imaging agents for completely noninvasive detection of diseased tissue such as breast cancer. These functional groups improve the pharmacokinetic properties of affinity ligands to achieve targeting efficiencies compatible with clinical imaging devices using safe, nonionizing radiation (near-infrared light). Together, this enables development of a "disease screening pill" capable of oral absorption and systemic availability, target binding, background clearance, and imaging at clinically relevant depths for breast cancer screening. This approach should be adaptable to other molecular targets and diseases for use as a new class of screening agents.

Revisiting atenolol as a low passive permeability marker.

BACKGROUND: Atenolol, a hydrophilic beta blocker, has been used as a model drug for studying passive permeability of biological membranes such as the blood-brain barrier (BBB) and the intestinal epithelium. However, the extent of S-atenolol (the active enantiomer) distribution in brain has never been evaluated, at equilibrium, to confirm that no transporters are involved in its transport at the BBB. METHODS: To assess whether S-atenolol, in fact, depicts the characteristics of a low passive permeable drug at the BBB, a microdialysis study was performed in rats to monitor the unbound concentrations of S-atenolol in brain extracellular fluid (ECF) and plasma during and after intravenous infusion. A pharmacokinetic model was developed, based on the microdialysis data, to estimate the permeability clearance of S-atenolol into and out of brain. In addition, the nonspecific binding of S-atenolol in brain homogenate was evaluated using equilibrium dialysis. RESULTS: The steady-state ratio of unbound S-atenolol concentrations in brain ECF to that in plasma (i.e., Kp,uu,brain) was 3.5% ± 0.4%, a value much less than unity. The unbound volume of distribution in brain (Vu, brain) of S-atenolol was also calculated as 0.69 ± 0.10 mL/g brain, indicating that S-atenolol is evenly distributed within brain parenchyma. Lastly, equilibrium dialysis showed limited nonspecific binding of S-atenolol in brain homogenate with an unbound fraction (fu,brain) of 0.88 ± 0.07. CONCLUSIONS: It is concluded, based on Kp,uu,brain being much smaller than unity, that S-atenolol is actively effluxed at the BBB, indicating the need to re-consider S-atenolol as a model drug for passive permeability studies of BBB transport or intestinal absorption.

Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine.

One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.

Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, Senicapoc, in non-alcoholic liver disease.

AIM: To evaluate a calcium activated potassium channel (KCa3.1) inhibitor attenuates liver disease in models of non-alcoholic fatty liver disease (NAFLD). METHODS: We have performed a series of in vitro and in vivo studies using the KCa3.1 channel inhibitor, Senicapoc. Efficacy studies of Senicapoc were conducted in toxin-, thioacetamide (TAA) and high fat diet (HFD)-induced models of liver fibrosis in rats. Efficacy and pharmacodynamic effects of Senicapoc was determined through biomarkers of apoptosis, inflammation, steatosis and fibrosis. RESULTS: Upregulation of KCa3.1 expression was recorded in TAA-induced and high fat diet-induced liver disease. Treatment with Senicapoc decreased palmitic acid-driven HepG2 cell death. (P < 0.05 vs control) supporting the finding that Senicapoc reduces lipid-driven apoptosis in HepG2 cell cultures. In animals fed a HFD for 6 wk, co-treatment with Senicapoc, (1) reduced non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8 scale), (2) decreased steatosis and (3) decreased hepatic lipid content (Oil Red O, P < 0.05 vs vehicle). Randomization of TAA animals and HFD fed animals to Senicapoc was associated with a decrease in liver fibrosis as evidenced by hydroxyproline and Masson's trichrome staining (P < 0.05 vs vehicle). These results demonstrated that Senicapoc mitigates both steatosis and fibrosis in liver fibrosis models. CONCLUSION: These data suggest that Senicapoc interrupts more than one node in progressive fatty liver disease by its anti-steatotic and anti-fibrotic activities, serving as a double-edged therapeutic sword.

Influence of route of administration and lipidation of apolipoprotein A-I peptide on pharmacokinetics and cholesterol mobilization.

apoA-I, apoA-I mimetic peptides, and their lipid complexes or reconstituted high-density lipoprotein (HDL) have been studied as treatments for various pathologies. However, consensus is lacking about the best method for administration, by intravenous (IV) or intraperitoneal (IP) routes, and formulation, as an HDL particle or in a lipid-free form. The objective of this study was to systematically examine peptide plasma levels, cholesterol mobilization, and lipoprotein remodeling in vivo following administration of lipid-free apoA-I peptide (22A) or phospholipid reconstituted 22A-sHDL by IV and IP routes. The mean circulation half-life was longer for 22A-sHDL (T1/2 = 6.27 h) than for free 22A (T1/2 = 3.81 h). The percentage of 22A absorbed by the vascular compartment after the IP dosing was ∼50% for both 22A and 22A-sHDL. The strongest pharmacologic response came from IV injection of 22A-sHDL, specifically a 5.3-fold transient increase in plasma-free cholesterol (FC) level compared with 1.3- and 1.8-fold FC increases for 22A-IV and 22A-sHDL-IP groups. Addition of either 22A or 22A-sHDL to rat plasma caused lipoprotein remodeling and appearance of a lipid-poor apoA-I. Hence, both the route of administration and the formulation of apoA-I peptide significantly affect its pharmacokinetics and pharmacodynamics.

Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis.

1. Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF). 2. A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95 L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12 L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition. 3. The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.

Computing Substrate Selectivity in a Peptide Transporter.

The human proton-coupled peptide transporter 1 (PepT1) is responsible for the absorption of di- and tri-peptides from the diet and peptide-like drugs. In this issue of Cell Chemical Biology, Samsudin et al. (2016) use an integrated computational and experimental approach to provide new insights into understanding substrate selectivity of PepTSt, a prokaryotic homolog of the human PepT1.