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Here we present the discovery and development of a highly selective aromatic C-H amination reaction. This electrochemical strategy involves a cathodic reduction process that generates highly electrophilic dicationic N-centered radicals that can efficiently engage in aromatic C-H functionalization and channel the regioselectivity of the aromatic substitution. The nitrogen-radical cation-pi interaction with arenes used throughout nature leads to a charge transfer mechanism, with subsequent aromatic C-N bond formation. This electrochemical process generates aryl DABCOnium salts in excellent yields and regioselectivities (single regioisomer in most cases). The scope of the reaction on arene is broad where various functionalities such as aryl halides (bromides, chlorides, fluorides), carbonyls (ketones, esters, imides), sulfonamides, and heteroarenes (pyridines, bipyridines, and terpyridines) are well tolerated. Moreover, we disclose the synthetic utility of the aryl DABCOnium salt adducts leading to the direct access of diverse aryl piperazines and the chemoselective cleavage of the exocyclic aryl C(sp2)-N bond over electrophilic C(sp3)-N+ bonds via photoredox catalysis to afford synthetically useful aryl radicals that can engage in aryl C-C and C-P bond formation.
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BACKGROUND/AIMS: The pediatric Difficult Airway Consultation Service (pDACS) was created in 2017 to identify patients with potentially difficult airways and create airway management plans prior to airway management. METHODS: Consults were either nurse-initiated, physician-initiated, or both nurse-and-physician-initiated and were examined for demographic and clinical factors. If a child had difficult airway risk factors, a consult note with airway management recommendations was completed. RESULTS: We included 419 consults from the 4-year study period for analysis. Sixty-one patients had chronic tracheostomies in place and thus, were analyzed separately. Of the remaining 358 consults, 50% (n = 179) were nurse-initiated, 30.2% (n = 108) physician-initiated, and 19.8% (n = 71) nurse-and-physician-initiated consults. Differences in observed frequency of airway edema (difference, 6.3%; 95%CI 0.1%-12.5%; p = .04), cleft lip/palate (difference, 8.1%; 95%CI 0.07%-16.3%, p = .04), craniofacial abnormalities (difference, 12.3%; 95%CI 1.9%-22.7%, p = .02), and trauma/burn (difference, 6.5%; 95%CI 0.09%-12.8%, p = .04) were calculated. Observed frequencies were higher in physician-initiated compared to nurse-initiated consults. Airway edema was also more prevalent in dual nurse-and-physician-initiated consults (difference, 8.7%; 95%CI 1.6%-15.8%; p = .01). Physician-initiated consults were associated with a greater proportion of high-risk difficult airways than nurse-initiated consults (difference, 26.7%; 95%CI 14.0%-39.4%, p < .001). Approximately 41.9% of patients at high-risk for having a difficult airway were identified by nurse-screening only. Using bag-valve-mask was often the primary ventilation recommendation (89.3%, n = 108) and supraglottic airway placement was the most common tertiary plan (74.2%, n = 83). Direct laryngoscopy (47.1%, n = 65) and videolaryngoscopy (40.6%, n = 56) were the most recommended modes of intubation. Three patients with airway emergencies had previously documented airway management plans and were successfully intubated without complications following the primary intubation technique recommended in their consult note. CONCLUSIONS: In our study, nurse-screening identified patients at high-risk for a difficult airway that would likely not have been identified prior to initiation of a screening protocol. Furthermore, airway management plans outlined prior to an emergent difficult airway event may increase first-attempt success at securing the difficult airway, reducing morbidity and mortality.
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Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. However, there is a lack of comprehensive data from low- and middle-income countries (LMICs) regarding factors influencing COPD outcomes, particularly in regions where biomass exposure is prevalent. Objective: The Factors Affecting Survival in Severe and Very Severe COPD Patients Admitted to Tertiary Centers of India (FAST) study aims to address this gap by evaluating factors impacting survival and exacerbation rates among COPD patients in LMICs like India, with a specific focus on biomass exposure, clinical phenotypes, and nutritional status in patients admitted to the Intensive Care Unit (ICU). Methods: The FAST study is an observational cohort study conducted in university teaching hospitals across India. The study aims to enroll 1000 COPD patients admitted to the ICU meeting specific inclusion criteria, with follow-up assessments conducted every 6 months over a 2-year period. Data collection includes demographic information, clinical manifestations, laboratory investigations, pulmonary function tests, medications, nutritional status, mental health, and health-related quality of life. Adjudication of exacerbations and mortality will also be undertaken. The FAST study seeks to provide crucial insights into COPD outcomes in LMICs, informing more precise management strategies and mitigating the burden of COPD in these settings. By evaluating factors such as biomass exposure, clinical phenotypes, and nutritional status, the study aims to address key knowledge gaps in COPD research. How to cite this article: Arunachala S, Devapal S, Swamy DSN, Greeshma MV, Ul Hussain I, Siddaiah JB, et al. Factors Affecting Survival in Severe and Very Severe COPD after Admission in ICUs of Tertiary Care Centers of India (FAST COPD): Study Protocol for a Multicentric Cohort Study. Indian J Crit Care Med 2024;28(6):552-560.
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Food allergy is an important cause of morbidity, significantly affecting the quality of life of the sufferer. Most food allergy research has been undertaken in high-income countries. Here, we summarize literature regarding food allergy in India and other low-middle-income countries (LMIC). We provide summaries of self-reported adverse food reactions and food sensitization in these regions by reviewing published community-based studies of prevalence, burden, and risk factors. We identified 2 community-based studies of food allergy prevalence in Karnataka, India, which estimate that food allergy affects just 0.14% of children and 1.2% of adults. The overall prevalence of allergic sensitization to 'any' food was 26.5% in adults and 19.1% in children by serum-specific IgE; but only 4.48% in children by skin prick test. We identified a further 28 studies in other LMICs, mainly from China but also Turkey, South Africa, Ghana, Mexico, Brazil, Thailand, Philippines, and Korea. The overall prevalence of allergic sensitization to 'any' food ranged from 0.11% to 16.8% in children using serum-specific IgE and 0.14% to 9.6% in children by skin prick test. The questionnaires and skin prick testing materials used and number of allergens tested varied significantly between studies. Other than Karnataka, there is no information on prevalence of food sensitization and probable food allergy in the community in India. Similar lack of information is noted among the majority of the 136 LMICs. Where community-based studies have been undertaken, there is wide variation in the prevalence and patterns of food sensitization across different LMICs, at least partly due to variations in study methodology. International collaboration is required in order to formally assess food allergy prevalence and burden across representative samples from multiple LMICs.
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Países en Desarrollo , Hipersensibilidad a los Alimentos , Niño , Adulto , Humanos , Calidad de Vida , India/epidemiología , Inmunoglobulina E , Hipersensibilidad a los Alimentos/epidemiología , Alérgenos , Prevalencia , Pruebas CutáneasRESUMEN
Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to describe the in vivo situation, which can affect downstream development decisions. Implementing in vitro-in vivo-in silico strategies throughout the drug development process is effective in identifying and mitigating risks while speeding up their development. Risdiplam (Evrysdi)-an orally bioavailable, small molecule approved by the US Food and Drug Administration and more recently by the European Medicines Agency for the treatment of patients ≥2 months of age with spinal muscular atrophy-is presented here as a case study. Risdiplam is a low-turnover compound whose metabolism is mediated through a non-cytochrome P450 enzymatic pathway. Four main challenges of risdiplam are discussed: predicting in vivo hepatic clearance, determining in vitro metabolites with regard to metabolites in safety testing guidelines, elucidating enzymes responsible for clearance, and estimating potential drug-drug interactions. A combination of in vitro and in vivo results was successfully extrapolated and used to develop a robust physiologically based pharmacokinetic model of risdiplam. These results were verified through early clinical studies, further strengthening the understanding of the ADME properties of risdiplam in humans. These approaches can be applied to other compounds with similar ADME profiles, which may be difficult to investigate using standard methods. SIGNIFICANCE STATEMENT: Risdiplam is the first approved, small-molecule, survival of motor neuron 2 mRNA splicing modifier for the treatment of spinal muscular atrophy. The approach taken to characterize the absorption, distribution, metabolism, and excretion (ADME) properties of risdiplam during clinical development incorporated in vitro-in vivo-in silico techniques, which may be applicable to other small molecules with challenging ADME. These strategies may be useful in improving the speed at which future drug molecules can be developed.
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Compuestos Azo/metabolismo , Compuestos Azo/farmacocinética , Preparaciones Farmacéuticas/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Empalme del ARN/efectos de los fármacos , ARN Mensajero/metabolismo , Distribución Tisular , Animales , Humanos , Técnicas In Vitro , Proteína 2 para la Supervivencia de la Neurona Motora/metabolismoRESUMEN
Background Entrectinib is a CNS-active, potent inhibitor of tyrosine receptor kinases A/B/C, ROS1 and anaplastic lymphoma kinase approved for use in patients with solid tumors. We describe the in vitro and clinical studies investigating potential entrectinib drug-drug interactions. Methods In vitro studies with human biomaterials assessed the enzymes involved in entrectinib metabolism, and whether entrectinib modulates the activity of the major cytochrome P450 (CYP) enzymes or drug transporter P-glycoprotein. Clinical studies investigated the effect of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on single-dose entrectinib pharmacokinetics. The effect of entrectinib on sensitive probe substrates for CYP3A4 (midazolam) and P-glycoprotein (digoxin) were also investigated. Results Entrectinib is primarily metabolized by CYP3A4. In vitro, entrectinib is a CYP3A4/5 inhibitor (IC50 2 µM) and a weak CYP3A4 inducer. Entrectinib inhibited P-glycoprotein (IC50 1.33 µM) but is a poor substrate. In healthy subjects, itraconazole increased entrectinib Cmax and AUC by 73% and 504%, respectively, and rifampin decreased entrectinib Cmax and AUC by 56% and 77%, respectively. Single dose entrectinib did not affect midazolam AUC, although Cmax decreased by 34%. Multiple dose entrectinib increased midazolam AUC by 50% and decreased Cmax by 21%. Single dose entrectinib increased digoxin AUC and Cmax by 18% and 28%, respectively, but did not affect digoxin renal clearance. Conclusions Entrectinib is a CYP3A4 substrate and is sensitive to the effects of coadministered moderate/strong CYP3A4 inhibitors and strong inducers, and requires dose adjustment. Entrectinib is a weak inhibitor of CYP3A4 and P-glycoprotein and no dose adjustments are required with CYP3A4/P- glycoprotein substrates.Registration Number (Study 2) NCT03330990 (first posted online November 6, 2017) As studies 1 and 3 are phase 1 trials in healthy subjects, they are not required to be registered.
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Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Indazoles/farmacocinética , Proteínas Tirosina Quinasas Receptoras/farmacocinética , Adulto , Antineoplásicos/farmacología , Área Bajo la Curva , Benzamidas/farmacología , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Femenino , Semivida , Voluntarios Sanos , Hepatocitos/efectos de los fármacos , Humanos , Indazoles/farmacología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Proteínas Tirosina Quinasas Receptoras/farmacologíaRESUMEN
Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). Loss of PGRN leads to lysosome dysfunction during aging. TMEM106B, a gene encoding a lysosomal membrane protein, is the main risk factor for FTLD with PGRN haploinsufficiency. But how TMEM106B affects FTLD disease progression remains to be determined. Here, we report that TMEM106B deficiency in mice leads to accumulation of lysosome vacuoles at the distal end of the axon initial segment in motor neurons and the development of FTLD-related pathology during aging. Ablation of both PGRN and TMEM106B in mice results in severe neuronal loss and glial activation in the spinal cord, retina, and brain. Enlarged lysosomes are frequently found in both microglia and astrocytes. Loss of both PGRN and TMEM106B results in an increased accumulation of lysosomal vacuoles in the axon initial segment of motor neurons and enhances the manifestation of FTLD phenotypes with a much earlier onset. These results provide novel insights into the role of TMEM106B in the lysosome, in brain aging, and in FTLD pathogenesis.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Animales , Péptidos y Proteínas de Señalización Intercelular/genética , Lisosomas , Proteínas de la Membrana , Ratones , Proteínas del Tejido Nervioso , ProgranulinasRESUMEN
P-glycoprotein (P-gp) is a major blood-brain barrier (BBB) efflux transporter. In vitro approaches, including bidirectional efflux ratio (ER), are used to measure P-gp-mediated transport, but findings can be inconsistent across models. We propose a novel, more physiologically relevant, in vitro model: unidirectional apical efflux ratio (AP-ER)-a ratio of permeability rates at the apical side of the BBB with and without P-gp inhibitor. To test our approach, ER and AP-ER were calculated for 3227 structurally diverse compounds in porcine kidney epithelial cells (LLC-PK1) overexpressing human or mouse P-gp and classified based on their passive transcellular P-gp permeability or charged properties. In vivo rat infusion studies were performed for selected compounds with high ER but low AP-ER. One-third of the 3227 compounds had bidirectional ER that was much higher than AP-ER; very few had AP-ER higher than ER. Compounds with a large difference between AP-ER and ER were typically basic compounds with low-to-medium passive permeability and high lipophilicity and/or amphiphilicity, leading to strong membrane binding. Outcomes in the human model were similar to those in mice, suggesting AP-ER/ER ratios may be conserved for at least two species. AP-ER predicted measured cerebrospinal fluid (CSF) concentration better than ER for the five compounds tested in our in vivo rat infusion studies. We report superior estimations of the CSF concentrations of the compounds when based on less resource-intensive AP-ER versus classic ER. Better understanding of the properties leading to high P-gp-mediated efflux in vivo could support more efficient brain-penetrant compound screening and optimization. SIGNIFICANCE STATEMENT: To address inconsistencies associated with the historical, bidirectional efflux ratio (ER) calculation of P-glycoprotein-mediated transport, we propose to use the novel, more physiologically relevant, unidirectional apical efflux ratio (AP-ER) model. In vitro experiments suggested that compounds with strong membrane binding showed the largest difference between AP-ER and ER, and in vivo infusion studies showed that AP-ER predicted cerebrospinal fluid concentrations of compounds better than ER; outcomes in the human model were similar to those in mice.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/líquido cefalorraquídeo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Descubrimiento de Drogas , Animales , Pruebas de Química Clínica , Evaluación Preclínica de Medicamentos , Transporte de Proteínas , RatasRESUMEN
TMEM106B encodes a lysosomal membrane protein and was initially identified as a risk factor for frontotemporal lobar degeneration. Recently, a dominant D252N mutation in TMEM106B was shown to cause hypomyelinating leukodystrophy. However, how TMEM106B regulates myelination is still unclear. Here we show that TMEM106B is expressed and localized to the lysosome compartment in oligodendrocytes. TMEM106B deficiency in mice results in myelination defects with a significant reduction of protein levels of proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), the membrane proteins found in the myelin sheath. The levels of many lysosome proteins are significantly decreased in the TMEM106B-deficient Oli-neu oligodendroglial precursor cell line. TMEM106B physically interacts with the lysosomal protease cathepsin D and is required to maintain proper cathepsin D levels in oligodendrocytes. Furthermore, we found that TMEM106B deficiency results in lysosome clustering in the perinuclear region and a decrease in lysosome exocytosis and cell surface PLP levels. Moreover, we found that the D252N mutation abolished lysosome enlargement and lysosome acidification induced by wild-type TMEM106B overexpression. Instead, it stimulates lysosome clustering near the nucleus as seen in TMEM106B-deficient cells. Our results support that TMEM106B regulates myelination through modulation of lysosome function in oligodendrocytes.
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Encéfalo/metabolismo , Lisosomas/metabolismo , Proteínas de la Membrana/metabolismo , Vaina de Mielina/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Oligodendroglía/metabolismo , Animales , Femenino , Degeneración Lobar Frontotemporal/genética , Humanos , Masculino , Proteínas de la Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/deficienciaRESUMEN
In vitro to in vivo extrapolation (IVIVE) to predict human hepatic clearance, including metabolism and transport, requires extensive experimental resources. In addition, there may be technical challenges to measure low clearance values. Therefore, prospective identification of rate-determining step(s) in hepatic clearance through application of the Extended Clearance Classification System (ECCS) could be beneficial for optimal compound characterization. IVIVE for hepatic intrinsic clearance (CLint,h) prediction is conducted for a set of 36 marketed drugs with low-to-high in vivo clearance, which are substrates of metabolic enzymes and active uptake transporters in the liver. The compounds were assigned to the ECCS classes, and CLint,h, estimated with HepatoPac (a micropatterned hepatocyte coculture system), was compared with values calculated based on suspended hepatocyte incubates. An apparent permeability threshold (apical to basal) of 50 nm/s in LLC-PK1 cells proved optimal for ECCS classification. A reasonable performance of the IVIVE for compounds across multiple classes using HepatoPac was achieved (with 2-3-fold error), except for substrates of uptake transporters (class 3b), for which scaling of uptake clearance using plated hepatocytes is more appropriate. Irrespective of the ECCS assignment, metabolic clearance can be estimated well using HepatoPac. The validation and approach elaborated in the present study can result in proposed decision trees for the selection of the optimal in vitro assays guided by ECCS class assignment, to support compound optimization and candidate selection. SIGNIFICANCE STATEMENT: Characterization of the rate-determining step(s) in hepatic elimination could be on the critical path of compound optimization during drug discovery. This study demonstrated that HepatoPac and plated hepatocytes are suitable tools for the estimation of metabolic and active uptake clearance, respectively, for a larger set of marketed drugs, supporting a comprehensive strategy to select optimal in vitro tools and to achieve Extended Clearance Classification System-dependent in vitro to in vivo extrapolation for human clearance prediction.
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Desarrollo de Medicamentos/métodos , Descubrimiento de Drogas/métodos , Modelos Biológicos , Células Cultivadas , Técnicas de Cocultivo , Femenino , Hepatocitos , Humanos , Masculino , Tasa de Depuración Metabólica , Cultivo Primario de CélulasRESUMEN
Long-term in vitro liver models are now widely explored for human hepatic metabolic clearance prediction, enzyme phenotyping, cross-species metabolism, comparison of low clearance drugs, and induction studies. Here, we present studies using a long-term liver model, which show how metabolism and active transport, drug-drug interactions, and enzyme induction in healthy and diseased states, such as hepatitis B virus (HBV) infection, may be assessed in a single test system to enable effective data integration for physiologically based pharmacokinetic (PBPK) modeling. The approach is exemplified in the case of (3S)-4-[[(4R)-4-(2-Chloro-4-fluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid RO6889678, a novel inhibitor of HBV with a complex absorption, distribution, metabolism, and excretion (ADME) profile. RO6889678 showed an intracellular enrichment of 78-fold in hepatocytes, with an apparent intrinsic clearance of 5.2 µl/min per mg protein and uptake and biliary clearances of 2.6 and 1.6 µl/min per mg protein, respectively. When apparent intrinsic clearance was incorporated into a PBPK model, the simulated oral human profiles were in good agreement with observed data at low doses but were underestimated at high doses due to unexpected overproportional increases in exposure with dose. In addition, the induction potential of RO6889678 on cytochrome P450 (P450) enzymes and transporters at steady state was assessed and cotreatment with ritonavir revealed a complex drug-drug interaction with concurrent P450 inhibition and moderate UDP-glucuronosyltransferase induction. Furthermore, we report on the first evaluation of in vitro pharmacokinetics studies using HBV-infected HepatoPac cocultures. Thus, long-term liver models have great potential as translational research tools exploring pharmacokinetics of novel drugs in vitro in health and disease.
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Antivirales/metabolismo , Antivirales/farmacología , Virus de la Hepatitis B/efectos de los fármacos , Hígado/metabolismo , Antivirales/farmacocinética , Transporte Biológico , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Hepatocitos/metabolismo , Humanos , Cinética , Hígado/efectos de los fármacos , Factores de Tiempo , Distribución TisularRESUMEN
We determined whether in vivo transporter-mediated hepatobiliary clearance (CL) and hepatic concentrations of rosuvastatin (RSV) in the rat could be predicted by transport activity in sandwich-cultured rat hepatocytes (SCRHs) and/or transporter-expressing cell lines scaled by differences in transporter protein expression between SCRHs, cell lines, and rat liver. The predicted hepatobiliary CLs and hepatic concentrations of RSV were compared with our previously published positron emission tomography imaging data. Sinusoidal uptake CL ([Formula: see text]) and efflux (canalicular and sinusoidal) CLs of [3H]-RSV in SCRHs were evaluated in the presence and absence of Ca2+ and in the absence and presence of 1 mM unlabeled RSV (to estimate passive diffusion CL). [Formula: see text] of RSV into cells expressing organic anion transporting polypeptide (Oatp) 1a1, 1a4, and 1b2 was also determined. Protein expression of Oatps in SCRHs and Oatp-expressing cells was quantified by liquid chromatography tandem mass spectrometry. SCRHs well predicted the in vivo RSV sinusoidal and canalicular efflux CLs but significantly underestimated in vivo [Formula: see text]. Oatp expression in SCRHs was significantly lower than that in the rat liver. [Formula: see text], based on RSV [Formula: see text] into Oatp-expressing cells (active transport) plus passive diffusion CL in SCRHs, scaled by the difference in protein expression in Oatp cells versus SCRH versus rat liver, was within 2-fold of that observed in SCRHs or in vivo. In vivo hepatic RSV concentrations were well predicted by Oatp-expressing cells after correcting [Formula: see text] for Oatp protein expression. This is the first demonstration of the successful prediction of in vivo hepatobiliary CLs and hepatic concentrations of RSV using transporter-expressing cells and SCRHs.
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Eliminación Hepatobiliar , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Modelos Biológicos , Transportadores de Anión Orgánico/metabolismo , Rosuvastatina Cálcica/farmacocinética , Animales , Técnicas de Cultivo de Célula/métodos , Línea Celular , Cromatografía Líquida de Alta Presión/métodos , Hepatocitos/metabolismo , Hígado/citología , Hígado/metabolismo , Masculino , Proteínas de Transporte de Membrana , Modelos Animales , Proteómica/métodos , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodosRESUMEN
For successful in vitro-to-in vivo extrapolation of hepatic drug uptake and drug-drug interactions (DDI), it is important to characterize the kinetic properties of the individual transporters involved, their fraction (ft) contribution to hepatic uptake, and their selective inhibitors. Here, we characterized the in vitro transport kinetics of two model drugs, rosuvastatin (RSV) and olmesartan acid (OLM), by rat hepatic organic anion transporting polypeptides (Oatp1a1, 1a4, and 1b2) and identified selective inhibitors of these transporters. [3H]-RSV was transported by Oatp1a1, 1a4, and 1b2, and their Michaelis-Menten constant (Km) values were estimated to be 9.61, 67.2, and 28.1 µM, respectively. In contrast, [3H]-OLM was transported by only Oatp1b2 (Km: 72.8 µM). Digoxin (IC50: 0.107 µM) and rifamycin SV (IC50: 0.140 and 0.088 µM for RSV and OLM, respectively) were potent and selective inhibitors of Oatp1a4 and 1b2, respectively, and glyburide (100 µM) completely inhibited all three rat hepatic Oatps. These inhibitors can therefore be used alone and in combination to determine the contribution of each Oatp to hepatic influx. In addition, the magnitude of in vivo inhibition of sinusoidal uptake clearance of RSV by rifampin was well predicted using rifampin IC50 profiles for each Oatps and RSV ft by each Oatp. This is the first report to 1) detail the transport kinetics of RSV and OLM by rat hepatic Oatps, 2) identify selective inhibitor concentrations of rat Oatps, and 3) demonstrate successful prediction of the magnitude of transporter-mediated in vivo DDI from IC50 profiles of an inhibitor and ft of a drug by each transporter.
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Hepatocitos/metabolismo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Transportadores de Anión Orgánico/metabolismo , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Predicción , Células HEK293 , Hepatocitos/efectos de los fármacos , Humanos , Imidazoles/farmacología , Cinética , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratas , Rosuvastatina Cálcica/farmacología , Tetrazoles/farmacologíaRESUMEN
OBJECTIVES: There has been increasing medical literature showing worse outcomes in patients admitted for medical and surgical conditions on the weekend. This has been termed the weekend effect. Little is known whether this weekend effect occurs for patients with cholangitis who require endoscopic retrograde cholangiopancreatography (ERCP), a procedure that requires many resources from the nursing staff, anesthesia, and the endoscopist. METHODS: Retrospective analysis from the National Inpatient Sample (NIS) database from 2009 through 2012. Patient data were abstracted from the database for patients admitted on the weekend and weekday with cholangitis who underwent ERCP. Time to ERCP, length of stay, total cost, and mortality were compared in patients admitted with cholangitis on the weekend vs. weekday who required ERCP. ERCP adverse events were recorded from the weekend vs. weekday as well. RESULTS: Twenty-three thousand six-hundred sixty-one patients were identified in the NIS database who were admitted for cholangitis who required ERCP in the study period, of which 18,106 (76.5%) patients were admitted on the weekday, whereas 5,555 (23.5%) were admitted on the weekend. By 24 h, the weekday group had undergone ERCP more frequently than the weekend group (54.6 vs. 43%; P<0.001). By 48 h, the weekday group had undergone ERCP more frequently than the weekend group (70 vs. 65.4%; P<0.001). By 72 h, both groups had undergone a similar rate of ERCP (79.7 vs. 78.9%; P=0.17). There was no statistical difference between the groups for in-hospital all-cause mortality (2.86 vs. 2.56%; P=0.24), length of stay (6.97 days vs. 6.88 days; P=0.28), or total cost of hospitalization ($71,552 vs $71,469; P=0.94). CONCLUSIONS: Despite a delay in regard to time to ERCP for weekend admissions, there was no weekend effect observed in regard to length of stay, mortality, or total cost of hospitalization. Although biliary drainage with ERCP is important, these results suggest that other factors in the management of cholangitis (e.g., antibiotics and intravenous fluids) contribute to outcomes.
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Colangiopancreatografia Retrógrada Endoscópica , Colangitis/diagnóstico , Hospitalización , Complicaciones Posoperatorias , Anciano , Colangiopancreatografia Retrógrada Endoscópica/efectos adversos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangiopancreatografia Retrógrada Endoscópica/mortalidad , Costos y Análisis de Costo , Femenino , Mortalidad Hospitalaria , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Grupo de Atención al Paciente/organización & administración , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Factores de Tiempo , Tiempo de Tratamiento/estadística & datos numéricos , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
Although the multiplicity in transport proteins assessed during drug development is continuously increasing, the clinical relevance of the breast cancer resistance protein (BCRP) is still under debate. Here, our aim is to rationalize the need to consider BCRP substrate and inhibitor interactions and to define optimum selection and acceptance criteria between cell-based and vesicle-based assays in vitro. Information on the preclinical and clinical pharmacokinetics (PK), drug-drug interactions, and pharmacogenomics data was collated for 13 marketed drugs whose PK is reportedly associated with BCRP interaction. Clinical examples where BCRP impacts drug PK and efficacy appear to be rare and confounded by interactions with other transporters. Thirty-seven compounds were selected to be tested as BCRP substrates in a cell-based assay using MDCKII cells (Madin-Darby canine kidney cells) and 18 in membrane vesicles. Depending on the physicochemical compound properties, we observed both in vitro systems to give false-negative readouts. In addition, the inhibition potential of 19 compounds against BCRP was assessed in vesicles and in MDCKII cells, where we observed significant system and substrate-dependent IC50 values. Therefore, neither of the two test systems is superior to the other. Instead, one system may offer advantages under certain situations (e.g., low permeability) and thus should be selected based on the physicochemical compound properties. Finally, given the clinical relevance of BCRP, we propose that its evaluation should remain issue-driven: for low permeable, low bioavailable drugs, in particular when other more common processes do not allow a mechanistic understanding of any unexpected absorption or brain disposition, and for drugs with a low therapeutic window.
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Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Preparaciones Farmacéuticas/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Animales , Disponibilidad Biológica , Línea Celular , Perros , Descubrimiento de Drogas/métodos , Interacciones Farmacológicas/fisiología , Humanos , Células LLC-PK1 , Células de Riñón Canino Madin Darby , Proteínas de Transporte de Membrana/metabolismo , PorcinosRESUMEN
The multidrug resistance protein 1 (MDR1) is known to limit brain penetration of drugs and play a key role in drug-drug interactions (DDIs). Theoretical cut-offs from regulatory guidelines are used to extrapolate MDR1 interactions from in vitro to in vivo. However, these cut-offs do not account for interlaboratory variability. Our aim was to calibrate our experimental system to allow better in vivo predictions. We selected 166 central nervous system (CNS) and non-CNS drugs to calibrate the MDR1 transport screening assay using Lewis lung cancer porcine kidney 1 epithelial cells overexpressing MDR1 (L-MDR1). A threshold efflux ratio (ER) of 2 was established as one parameter to assess brain penetration in lead optimization. The inhibitory potential of 57 molecules was evaluated using IC50 values based on the digoxin ER-IC50(ER)-or apparent permeability-IC50(Papp)-in L-MDR1 cells. Published clinical data for 68 DDIs involving digoxin as the victim drug were collected. DDI risk assessments were based on intestinal concentrations ([I2]) as well as unbound [I1u] and total plasma [I1T] concentrations. A receiver operating characteristic analysis identified an [I2]/IC50(ER) of 6.5 as the best predictor of a potential interaction with digoxin in patients. The model was further evaluated with a test set of 11 digoxin DDIs and 16 nondigoxin DDIs, resulting in only one false negative for each test set, no false positives among the digoxin DDIs, and two among the nondigoxin DDIs. Future refinements might include using cerebrospinal fluid to unbound plasma concentration ratios rather than therapeutic class, better estimation of [I2], and dynamic modeling of MDR1-mediated DDIs.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Interacciones Farmacológicas/fisiología , Preparaciones Farmacéuticas/metabolismo , Animales , Bioensayo/métodos , Transporte Biológico/fisiología , Calibración , Línea Celular Tumoral , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Digoxina/metabolismo , Humanos , Técnicas In Vitro/métodos , Permeabilidad , PorcinosRESUMEN
Background: Pulmonary tuberculosis (TB) remains a major public health issue in India, with high incidence and mortality. The current literature on post-TB sequelae functional defects focuses heavily on spirometry, with conflicting obstruction vs. restriction data, lacks advanced statistical analysis, and has insufficient data on diffusion limitation and functional impairment. Objective: This study aimed to thoroughly evaluate post-tubercular sequelae after treatment, assessing chest radiology, spirometry, diffusing capacity, and exercise capacity. Methods: A total of 85 patients were studied at a university teaching hospital in Mysuru. The data collected included characteristics, comorbidities, smoking history, and respiratory symptoms. The investigations included spirometry, DLCO, chest X-rays with scoring, and 6MWT. Results: Of the patients, 70% had abnormal X-rays post-treatment, correlating with reduced lung function. Additionally, 70% had impaired spirometry with obstructive/restrictive patterns, and 62.2% had reduced DLCO, with females at higher risk. Smoking increased the risk of sequelae. Conclusions: Most patients had residual radiological/lung function abnormalities post-treatment. Advanced analyses provide insights into obstructive vs. restrictive defects. Ongoing research should explore pathogenetic mechanisms and therapeutic modalities to minimize long-term post-TB disability.
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Telemedicine is a promising solution to the challenges of delivering equitable and quality primary healthcare, especially in LMICs. This review evaluated peer-reviewed literature on telehealth interventions in Indian primary care published from Jan 1, 2011 to Dec 31, 2021, from PubMed, Scopus, TRIP, Google Scholar, Indian Kanoon, and Cochrane database The majority of Indian studies focus on key health issues like maternal and child health, mental health, diabetes, infectious diseases, and hypertension, mainly through patient education, monitoring, and diagnostics. Yet, there's a lack of research on telemedicine's cost-effectiveness, communication among providers, and the role of leadership in its quality and accessibility. The current research has gaps, including small sample sizes and inconsistent methodologies, which hamper the evaluation of telemedicine's effectiveness. India's varied healthcare landscape, technological limitations, and social factors further challenge telemedicine's adoption. Despite regulatory efforts, issues like the digital divide and data privacy persist. Addressing these challenges with a context-aware, technologically driven approach is crucial for enhancing healthcare through telemedicine in India.
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Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 × 10(-6) cm/s). Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not BCRP. Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC50 values of 3 µM and 4.4 µM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified because an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlus simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 transfected human embryonic kidney 293 (HEK293) cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [(14)C]axitinib-equivalents showed rapid absorption and distribution to all tissues except the brain. This suggests that efflux transport of axitinib may occur at the mouse blood-brain barrier.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/fisiología , Transportadoras de Casetes de Unión a ATP/fisiología , Imidazoles/metabolismo , Indazoles/metabolismo , Hígado/metabolismo , Proteínas de Neoplasias/fisiología , Inhibidores de Proteínas Quinasas/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Autorradiografía , Axitinib , Células CACO-2 , Interacciones Farmacológicas , Hepatocitos/metabolismo , Humanos , Imidazoles/química , Indazoles/química , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Permeabilidad , Medición de Riesgo , SolubilidadRESUMEN
High-flow nasal cannula (HFNC) and ventilator-delivered non-invasive mechanical ventilation (NIV) were used to treat acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia, especially in low- and middle-income countries (LMICs), due to lack of ventilators and manpower resources despite the paucity of data regarding their efficacy. This prospective study aimed to analyse the efficacy of HFNC versus NIV in the management of COVID-19 ARDS. A total of 88 RT-PCR-confirmed COVID-19 patients with moderate ARDS were recruited. Linear regression and generalized estimating equations (GEEs) were used for trends in vital parameters over time. A total of 37 patients were on HFNC, and 51 were on NIV. Patients in the HFNC group stayed slightly but not significantly longer in the ICU as compared to their NIV counterparts (HFNC vs. NIV: 8.00 (4.0-12.0) days vs. 7.00 (2.0-12.0) days; p = 0.055). Intubation rates, complications, and mortality were similar in both groups. The switch to HFNC from NIV was 5.8%, while 37.8% required a switch to NIV from HFNC. The resolution of respiratory alkalosis was better with NIV. We conclude that in patients with COVID-19 pneumonia with moderate ARDS, the duration of treatment in the ICU, intubation rate, and mortality did not differ significantly with the use of HFNC or NIV for respiratory support.