Integrated Exposure-Response of Dupilumab in Children, Adolescents, and Adults With Atopic Dermatitis Using Categorical and Continuous Efficacy Assessments: A Population Analysis.

BACKGROUND: While the majority of patients with atopic dermatitis (AD) achieve disease control with dupilumab treatment, there is variability in which patients achieve clear disease. The predictors of these responses are currently unclear. Integrated models were developed to evaluate the exposure-response (E-R) relationship of dupilumab in children, adolescents, and adults with AD. METHODS: Data from six Phase II and III clinical studies were pooled (2,366 adults [> 18 years], 243 adolescents [≥ 12 to < 18 years] and 359 children [≥ 6 to < 12 years]) for model development. Efficacy was assessed using the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA). Indirect response models were applied to link measures of efficacy and functional serum dupilumab concentrations. The covariates on individual placebo-corrected response were assessed. Clinical trial scenarios were simulated to compare E-R relationships across age groups. Safety was not explored. RESULTS: After correcting for differences in placebo response and dupilumab exposure: 1) older age, higher body weight, lower baseline thymus and activation-regulated chemokine, and Asian race were associated with slightly lower EASI response, and no clear covariates were identified on IGA response; 2) clinical trial simulations generally showed slightly higher response at a given dupilumab concentration in children compared to adults and adolescents with severe and moderate AD. CONCLUSIONS: The collectively tested covariates explain some of the variability in dupilumab response in patients with AD. Patients in all age groups showed adequate response to dupilumab; however, children showed slightly higher drug effects compared to adults and adolescents at equivalent concentrations.

Physiological Dynamics in the Upper Gastrointestinal Tract and the Development of Gastrointestinal Absorption Models for the Immediate-Release Oral Dosage Forms in Healthy Adult Human.

This review is a revisit of various oral drug absorption models developed in the past decades, focusing on how to incorporate the physiological dynamics in the upper gastrointestinal (GI) tract. For immediate-release oral drugs, GI absorption is a critical input of drug exposure and subsequent human body response, yet difficult to model largely due to the complex GI environment. One of the biggest hurdles lies at capturing the high within-subject variability (WSV) of bioavailability measures, which can be mechanistically explained by the GI physiological dynamics. A thorough summary of how GI dynamics is handled in the absorption models would promote the development of mechanism-based oral drug absorption models, aid in the design of clinical studies regarding dosing regimens and bioequivalence studies based on WSV, and advance the decision-making on formulation selection.

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.

Physiologically-Based Pharmacokinetic Modeling to Predict Methylphenidate Exposure Affected by Interplay Among Carboxylesterase 1 Pharmacogenetics, Drug-Drug Interactions, and Sex.

BACKGROUND AND OBJECTIVE: The pharmacokinetics (PK) of methylphenidate (MPH) differ significantly among individuals. Carboxylesterase 1 (CES1) is the primary enzyme metabolizing MPH, and its function is affected by genetic variants, drug-drug interaction (DDI), and sex. The object of this study is to evaluate CES1 pharmacogenetics as related to MPH metabolism using human liver samples and develop a physiologically-based pharmacokinetic (PBPK) modeling approach to investigate the influence of CES1 genotypes and other factors on MPH PK. METHODS: The effect of the CES1 variant G143E (rs71647871) on MPH metabolism was studied utilizing 102 individual human liver S9 (HLS9) fraction samples. PBPK models were developed using the population-based PBPK software PK-Sim® by incorporating the HLS9 incubation data. The established models were applied to simulate MPH PK profiles under various clinical scenarios, including different genotypes, drug-alcohol interactions, and the difference between males and females. RESULTS: The HLS9 incubation study showed that subjects heterozygous for the CES1 variant G143E metabolized MPH at a rate of approximately 50% of that in non-carriers. The developed PBPK models successfully predicted the exposure alteration of MPH from the G143E genetic variant, ethanol-MPH DDI, and sex. Importantly, the study suggests that male G143E carriers who are alcohol consumers are at a higher risk of MPH overexposure. CONCLUSION: PBPK modeling provides a means for better understanding the mechanisms underlying interindividual variability in MPH PK and PD and could be utilized to develop a safer and more effective MPH pharmacotherapy regimen.

Proposing a "Brain Health Checkup (BHC)" as a Global Potential "Standard of Care" to Overcome Reward Dysregulation in Primary Care Medicine: Coupling Genetic Risk Testing and Induction of "Dopamine Homeostasis".

In 2021, over 100,000 people died prematurely from opioid overdoses. Neuropsychiatric and cognitive impairments are underreported comorbidities of reward dysregulation due to genetic antecedents and epigenetic insults. Recent genome-wide association studies involving millions of subjects revealed frequent comorbidity with substance use disorder (SUD) in a sizeable meta-analysis of depression. It found significant associations with the expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. However, despite the rise in SUD and neuropsychiatric illness, there are currently no standard objective brain assessments being performed on a routine basis. The rationale for encouraging a standard objective Brain Health Check (BHC) is to have extensive data available to treat clinical syndromes in psychiatric patients. The BHC would consist of a group of reliable, accurate, cost-effective, objective assessments involving the following domains: Memory, Attention, Neuropsychiatry, and Neurological Imaging. Utilizing primarily PUBMED, over 36 years of virtually all the computerized and written-based assessments of Memory, Attention, Psychiatric, and Neurological imaging were reviewed, and the following assessments are recommended for use in the BHC: Central Nervous System Vital Signs (Memory), Test of Variables of Attention (Attention), Millon Clinical Multiaxial Inventory III (Neuropsychiatric), and Quantitative Electroencephalogram/P300/Evoked Potential (Neurological Imaging). Finally, we suggest continuing research into incorporating a new standard BHC coupled with qEEG/P300/Evoked Potentials and genetically guided precision induction of "dopamine homeostasis" to diagnose and treat reward dysregulation to prevent the consequences of dopamine dysregulation from being epigenetically passed on to generations of our children.

In Vitro Predictive Dissolution Test Should Be Developed and Recommended as a Bioequivalence Standard for the Immediate-Release Solid Oral Dosage Forms of the Highly Variable Mycophenolate Mofetil.

The prodrug mycophenolate mofetil (MMF), which is presystemically hydrolyzed into the pharmacologically active compound mycophenolic acid (MPA), has been widely used for the prophylaxis of acute allograft rejection in solid organ transplantation. However, the huge variability in the plasma concentration level makes the development of MMF drug products difficult due to the great challenge of meeting the traditional bioequivalence (BE) limits. Numerous models have been developed in the past decade to explain the variability, with the emphasis on characterizing the enterohepatic circulation. While the variability arising from systemic appearance can also contribute to the remarkable MPA variability to a great extent, it has been ignored for long for this Biopharmaceutics Classification System class 2 drug. To improve the design of the BE study for this highly variable (HV) drug, the variability of MMF pharmacokinetic (PK) profiles focusing on the absorption process was explored in a population approach. A total of 81 Chinese adult liver transplant recipients were enrolled and had their plasma concentrations of MPA and its metabolites measured by HPLC during one visit or multiple visits in a long-term MMF regimen. The population models were developed using NONMEM, and the data and the results of the model were analyzed by R. Two population PK models of MMF focusing on the absorption process were developed based on the plasma concentrations of MPA and its major metabolite 7-O-MPA-ß-glucuronide (MPAG). The MPA PK profiles were best characterized by a two-compartment disposition model with zero inter-individual variability (IIV) of elimination coefficient (K20), lag time, but considerable intra-individual variability (IAV) in the form of inter-occasion variability regarding systemic appearance coefficient, K20, and central volume of distribution, when just using MPA plasma concentrations as observations. The second model took into consideration the EHC by including MPAG profiles as well. The results from both models showcased that the IAV played a far more significant role than the IIV in accounting for the variability of the MMF systemic appearance. This is in line with what was found in the BE study: the within-subject variability (WSV) of BE measures largely exceeded the corresponding between-subject variability. The great WSV of MMF can be mechanistically explained by the interplay of dissolution and solubility with the gastrointestinal (GI) physiological dynamics, especially the gastric emptying (GE) in the fasting state regulated by migrating motor complex, and GE and pH variations in the fed state by the caloric content with irregular patterns of GI motility and secretion. The results implied that for the immediate-release solid oral dosage forms of MMF, running a regular in vitro dissolution test for the fasting state and developing a predictive in vitro dissolution test with sufficient simulation of the GE dynamics and proximal small intestinal pH fluctuations for the fed state would be excellent surrogates for the in vivo BE test. Furthermore, a physiologically based predictive in vitro dissolution test under both fasting and fed conditions would be a new trend for the BE studies of all other HV drug products.

The potential of psychedelic medicine - A personal account.

In 1965, I was training in clinical toxicology in the pharmacology department of the University of California San Francisco (UCSF) and living in the Haight Ashbury. I studied various psychedelics, including LSD, mescaline, and ibogaine, in human and animal models. The psychedelics were then being used as a therapeutic drug in clinical settings and researched as a potential antipersonnel agent by the U.S. government. Then, using psychedelics became a rite of passage for the emerging countercultural movement. After adverse reactions and negative publicity, states began to criminalize these drugs, beginning in 1966. The federal government eventually moved these drugs to Schedule 1 classification, shutting down research almost entirely.

Efficacy of an eConsult service to cure hepatitis C in primary care.

In 2016, an eConsult service was developed within a safety net health system to expand access to hepatitis C (HCV) treatment in the primary care setting. The eConsult system provides individualized treatment recommendations from specially trained primary care pharmacists and primary care physicians to primary care providers with less experience in the rapidly changing treatment of HCV. Since its launch, this service has had a large impact in expanding care to a largely homeless and low-income urban population within our health system. We now aim to evaluate its efficacy in curing HCV. In this retrospective cohort study, we describe rates of sustained virologic response 12 weeks after treatment completion (SVR12) for those who received primary care-based HCV treatment through the eConsult system with those who were treated in primary care independent of an eConsult from 2017 to 2019. We found there was no significant difference in the proportion of patients who achieved SVR12 between the two groups. Overall, >90% of patients who received treatment achieved SVR12. Approximately 40% of patients treated for HCV received an eConsult, suggesting utility of the eConsult in expanding access and coordinating treatment for patients within our network.

Small All-Range Lidar for Asteroid and Comet Core Missions.

We report the development of a new type of space lidar specifically designed for missions to small planetary bodies for both topographic mapping and support of sample collection or landing. The instrument is designed to have a wide dynamic range with several operation modes for different mission phases. The laser transmitter consists of a fiber laser that is intensity modulated with a return-to-zero pseudo-noise (RZPN) code. The receiver detects the coded pulse-train by correlating the detected signal with the RZPN kernel. Unlike regular pseudo noise (PN) lidars, the RZPN kernel is set to zero outside laser firing windows, which removes most of the background noise over the receiver integration time. This technique enables the use of low peak-power but high pulse-rate lasers, such as fiber lasers, for long-distance ranging without aliasing. The laser power and the internal gain of the detector can both be adjusted to give a wide measurement dynamic range. The laser modulation code pattern can also be reconfigured in orbit to optimize measurements to different measurement environments. The receiver uses a multi-pixel linear mode photon-counting HgCdTe avalanche photodiode (APD) array with near quantum limited sensitivity at near to mid infrared wavelengths where many fiber lasers and diode lasers operate. The instrument is modular and versatile and can be built mostly with components developed by the optical communication industry.

High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial.

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30-600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.

Neurobiology and Spirituality in Addiction Recovery.

This commentary explores the neurobiology of spirituality and asks whether it is possible or desirable to apply genetic engineering to increase human spiritual and religious experience - (gene-spirituality) to deal better with the ever-increasing catastrophes that face humanity? Neurological connections between spirituality and reward genes, reward deficiencies (RDS) (hypodopaminergia), the mirror neuron system, and the default mode network are examined. Some interventions from addiction medicine that may be useful to enhance the neuro-spirituality connectome identified as a cornerstone of the Purpose and Meaning of Life as Reward (PMLR) are identified as reasonable targets for interventions to treat RDS and balance DMN activity.

Improving naltrexone compliance and outcomes with putative pro- dopamine regulator KB220, compared to treatment as usual.

A recent analysis from Stanford University suggested that without any changes in currently available treatment, prevention, and public health approaches, we should expect to have 510,000 deaths from prescription opioids and street heroin from 2016 to 2025 in the US. In a recent review, Mayo Clinic Proceedings (October 2019), Gold and colleagues at Mayo Clinic reviewed the available medications used in opioid use disorders and concluded that in private and community practice adherence is more important as a limiting factor to retention, relapse, and repeat overdose. It is agreed that the primary utilization of known opioid agonists like methadone, buprenorphine and naloxone combinations, while useful as a way of reducing societal harm, is limited by 50% of more discontinuing treatment within 6 months, their diversion, and addiction liability. Opioid agonists may have other unintended consequences, like continuing the down regulation of dopamine systems. While naltrexone would be expected to have opposite effects, adherence is also low even after detoxification and long acting naltrexone injections. Recent studies have shown Naltrexone is beneficial by attenuation of craving via "psychological extinction" and reducing relapse. Buprenorphine is the MAT of choice currently but injectable Naltrexone plus an agent to improve dopaminergic function and tone may renew interest amongst addiction physicians and patients. Understanding this dilemma there is increasing movement to opt for the non-addicting narcotic antagonist Naltrexone. Even with extended injectable option there is still poor compliance. As such, we describe an open label investigation in humans showing improvement of naltrexone compliance and outcomes with dopamine augmentation with the pro- dopamine regulator KB220 (262 days) compared to naltrexone alone (37days). This well studied complex consists of amino-acid neurotransmitter precursors and enkephalinase inhibitor therapy compared to treatment as usual. Consideration of this novel paradigm shift may assist in not only addressing the current opioid epidemic but the broader question of reward deficiency in general.

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.

Optical characterization of laser retroreflector arrays for lunar landers.

The Laser Retroreflector Array for Lunar Landers (LRALL) is a small optical instrument designed to provide a target for precision laser ranging from a spacecraft in lunar orbit, enabling geolocation of the lander and its instrument suite and establishing a fiducial maker on the lunar surface. Here we describe the optical performance of LRALL at visible and near-infrared wavelengths. Individual corner cube reflectors (CCRs) within LRALL were tested for surface flatness and dihedral angle values. We also imaged the far-field diffraction patterns of individual CCRs as well as the entire retroreflector array over the range of possible incident angles to extract the optical cross section as a function of viewing angle. We also measured the optical properties of one of the CCRs over the lunar temperature range (100-380 K) and found no significant temperature-dependent variance. The test results show LRALL meets the design criteria and can be ranged to elevation angles above 30° with respect to the instrument base from an orbital laser altimeter such as the Lunar Orbiter Laser Altimeter on the Lunar Reconnaissance Orbiter. This work summarizes the test data and serves as a guide for future laser ranging to these retroreflector arrays.

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.