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1.
Clin Pharmacol Ther ; 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38923506

RESUMEN

This research study investigates the intricate relationship among COVID-19, maternal and infant health, and breastfeeding practices, with a specific focus on assessing the transfer of nirmatrelvir and ritonavir into human milk. Our aim is to provide critical insights to those managing COVID-19 treatment in lactating individuals. The InfantRisk Center Human Milk Biorepository contained human milk and corresponding health information for eight mother-infant dyads exposed to standard doses of maternal nirmatrelvir with ritonavir (300 mg nirmatrelvir and 100 mg ritonavir taken orally twice daily for 5 days). The primary outcomes measured were drug levels in milk using liquid chromatography-mass spectrometry and reporting the tolerance of the breastfed infant. Nirmatrelvir with ritonavir was measurable in all participants at a mean concentration of 33.48 ng/mL (ritonavir) and 729 ng/mL (nirmatrelvir). The estimated infant dose via milk was 0.0024 mg/kg/12 h (ritonavir) and 0.054 mg/kg/12 h (nirmatrelvir). The estimated relative infant dose was 0.19% (ritonavir) and 1.43% (nirmatrelvir) well under the standard 10% safety threshold. Among the eight infants exposed in this study, there were no reported adverse events. Nirmatrelvir with ritonavir is the recommended treatment for ambulatory COVID-19 patients with mild-to-moderate COVID-19 infection at high risk for progression to severe disease. Although its use is recommended in lactating women, there are no previous studies on the transfer of nirmatrelvir into human milk. The study findings endorse the current approach of nirmatrelvir/ritonavir use in lactating women and encourage healthcare providers to consider prescribing this treatment irrespective of lactation status when indicated.

2.
J Pharmacol Exp Ther ; 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38777603

RESUMEN

Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant pre-clinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant pre-clinical doses to study pharmacodynamics (PD) in stroke and related neurodegenerative diseases. An LC-MS/MS method to measure metformin levels in plasma, brain, and cerebrospinal fluid (CSF) was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous (IV) bolus administration of metformin to C57BL6 mice covered low to high dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain pharmacokinetic parameters, such as unidirectional blood-to-brain constant (Kin) and unbound brain-to-plasma ratio (Kp, uu, brain). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A Kin value of 1.87 {plus minus} 0.27 µl/g/min was obtained. As the dose increased, Kp, uu, brain showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the CSF at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on pharmacokinetic parameters for pre-clinical pharmacological studies. We anticipate further investigations focusing on pharmacokinetics and pharmacodynamics (PKPD) in disease conditions, such as stroke. Significance Statement The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant pre-clinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in pre-clinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease (s).

3.
ACS Pharmacol Transl Sci ; 7(3): 654-666, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38481688

RESUMEN

Opioids represent the most extensive category of abused substances in the United States, and the number of fatalities caused by these drugs exceeds those associated with all other drug overdoses combined. The administration of naltrexone, a potent pan-opioid receptor antagonist, to an individual dependent on opioids can trigger opioid withdrawal and induce severe side effects. There is a pressing demand for opioid antagonists free of opioid withdrawal effects. In our laboratory, we have identified a compound with affinity to mu, delta, and kappa opioid receptors in the range of 150-250 nM. This blood-brain barrier (BBB)-permeant compound was metabolically stable in vitro and in vivo. Our in vivo work demonstrated that 1-10 mg/kg intraperitoneal administration of our compound produces moderate efficacy in antagonizing morphine-induced antiallodynia effects in the chemotherapy-induced peripheral neuropathy (CIPN) model. The treatment was well-tolerated and did not cause behavioral changes. We have observed a fast elimination rate of this metabolically stable molecule. Furthermore, no organ toxicity was observed during the chronic administration of the compound over a 14-day period. Overall, we report a novel functional opioid antagonist holds promise for developing an opioid withdrawal therapeutic.

4.
Pharmaceutics ; 16(1)2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38276505

RESUMEN

We have recently shown that the volatile anesthetics isoflurane and sevoflurane acutely enhance the brain uptake of the hydrophilic markers sucrose and mannitol about two-fold from an awake condition, while the combined injection of the anesthetic agents ketamine and xylazine has no effect. The present study investigated two small-molecule hydrophilic drugs with potential neurotoxicity, the antibiotic agents ceftazidime and gentamicin. Transport studies using an in vitro blood-brain barrier (BBB) model, a monolayer of induced pluripotent stem cell-derived human brain microvascular endothelial cells seeded on Transwells, and LC-MS/MS analysis demonstrated the low permeability of both drugs in the range of sucrose, with permeability coefficients of 6.62 × 10-7 ± 2.34 × 10-7 cm/s for ceftazidime and 7.38 × 10-7 ± 2.29 × 10-7 cm/s for gentamicin. In vivo brain uptake studies of ceftazidime or gentamicin after IV doses of 25 mg/kg were performed in groups of 5-6 mice anesthetized at typical doses for surgical procedures with either isoflurane (1.5-2% v/v) or ketamine/xylazine (100:10 mg/kg I.P.). The brain uptake clearance, Kin, for ceftazidime increased from 0.033 ± 0.003 µL min-1 g-1 in the ketamine/xylazine group to 0.057 ± 0.006 µL min-1 g-1 in the isoflurane group (p = 0.0001), and from 0.052 ± 0.016 µL min-1 g-1 to 0.101 ± 0.034 µL min-1 g-1 (p = 0.0005) for gentamicin. We did not test the dose dependency of the uptake, because neither ceftazidime nor gentamicin are known substrates of any active uptake or efflux transporters at the BBB. In conclusion, the present study extends our previous findings with permeability markers and suggests that inhalational anesthetic isoflurane increases the BBB permeability of hydrophilic small-molecule endobiotics or xenobiotics when compared to the injection of ketamine/xylazine. This may be of clinical relevance in the case of potential neurotoxic substances.

5.
Int J Pharm ; 652: 123849, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38266938

RESUMEN

This feasibility study evaluates a cleaning process designed to avoid the use of detergents and reduce operator exposure to the active pharmaceutical ingredient (API). The continuous manufacturing equipment was cleaned using excipients to displace ibuprofen residues from the system. The cleaning process was performed using 3.0 kg of Prosolv® and 3.0 kg of Tablettose® 70. The impact of different volumetric feed rates of the cleaning excipient was assessed. The displacement of API and blend residues was evaluated with in-line near infrared (NIR) spectroscopy. Principal component analysis (PCA) was performed to evaluate the cleaning progress as the Prosolv® flowed through the feeder, mixer and stream sampler. In-place Raman spectra were acquired from the material sticking to detect the ibuprofen residues. The study showed that Prosolv® and Tablettose® can remove ibuprofen residues effectively from the hopper, feeder screw, mixer paddles, shaft and stream sampler. The Process Analytical Technology (PAT) system can be utilized to detect API displacement during the cleaning process. However, dismantling and manual cleaning was required to remove material sticking at the surfaces adjacent to the rotating feeder screws and mixer paddles.


Asunto(s)
Química Farmacéutica , Tecnología Farmacéutica , Tecnología Farmacéutica/métodos , Química Farmacéutica/métodos , Excipientes/química , Ibuprofeno/química , Polvos/química , Comprimidos , Composición de Medicamentos/métodos
6.
Pharm Res ; 40(11): 2747-2758, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37833570

RESUMEN

PURPOSE: There is growing interest in seeking pharmacological activation of neurolysin (Nln) for stroke treatment. Discovery of central nervous system drugs remains challenging due to the protection of the blood-brain barrier (BBB). The previously reported peptidomimetic Nln activators display unsatisfactory BBB penetration. Herein, we investigate the next generation of non-peptidomimetic Nln activators with high BBB permeability. METHODS: A BBB-mimicking model was used to evaluate their in vitro BBB permeability. Protein binding, metabolic stability, and efflux assays were performed to determine their unbound fraction, half-lives in plasma and brains, and dependence of BBB transporter P-glycoprotein (P-gp). The in vivo pharmacokinetic profiles were elucidated in healthy and stroke mice. RESULTS: Compounds KS52 and KS73 out of this generation exhibit improved peptidase activity and BBB permeability compared to the endogenous activator and previous peptidomimetic activators. They show reasonable plasma and brain protein binding, improved metabolic stability, and independence of P-gp-mediated efflux. In healthy animals, they rapidly distribute into brains and reach peak levels of 18.69% and 12.10% injected dose (ID)/ml at 10 min. After 4 h, their total brain concentrations remain 7.78 and 12.34 times higher than their A50(minimal concentration required for enhancing 50% peptidase activity). Moreover, the ipsilateral hemispheres of stroke animals show comparable uptake to the corresponding contralateral hemispheres and healthy brains. CONCLUSIONS: This study provides essential details about the pharmacokinetic properties of a new generation of potent non-peptidomimetic Nln activators with high BBB permeability and warrants the future development of these agents as potential neuroprotective pharmaceutics for stroke treatment.


Asunto(s)
Peptidomiméticos , Accidente Cerebrovascular , Ratones , Animales , Barrera Hematoencefálica/metabolismo , Peptidomiméticos/metabolismo , Metaloendopeptidasas/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Permeabilidad
7.
Microvasc Res ; 150: 104585, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37437687

RESUMEN

Glucose constitutes the main source of energy for the central nervous system (CNS), its entry occurring at the blood-brain barrier (BBB) via the presence of glucose transporter 1 (GLUT1). However, under food intake restrictions, the CNS can utilize ketone bodies (KB) as an alternative source of energy. Notably, the relationship between the BBB and KBs and its effect on their glucose metabolism remains poorly understood. In this study, we investigated the effect of glucose deprivation on the brain endothelium in vitro, and supplementation with KBs using induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cell-like cells (iBMECs). Glucose-free environment significantly decreased cell metabolic activity and negatively impacted the barrier function. In addition, glucose deprivation did not increase GLUT1 expression but also resulted in a decrease in glucose uptake and glycolysis. Supplementation of glucose-deprived iBMECs monolayers with KB showed no improvement and even worsened upon treatment with acetoacetate. However, under a hypoglycemic condition in the presence of KBs, we noted a slight improvement of the barrier function, with no changes in glucose uptake. Notably, hypoglycemia and/or KB pre-treatment elicited a saturable beta-hydroxybutyrate diffusion across iBMECs monolayers, such diffusion occurred partially via an MCT1-dependent mechanism. Taken together, our study highlights the importance of glucose metabolism and the reliance of the brain endothelium on glucose and glycolysis for its function, such dependence is unlikely to be covered by KBs supplementation. In addition, KB diffusion at the BBB appeared induced by KB pre-treatment and appears to involve an MCT1-dependent mechanism.


Asunto(s)
Células Madre Pluripotentes Inducidas , Cuerpos Cetónicos , Ácido 3-Hidroxibutírico/farmacología , Ácido 3-Hidroxibutírico/metabolismo , Cuerpos Cetónicos/metabolismo , Cuerpos Cetónicos/farmacología , Células Endoteliales/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Encéfalo/metabolismo , Barrera Hematoencefálica/metabolismo , Glucosa/metabolismo , Endotelio/metabolismo , Suplementos Dietéticos
8.
Pharmaceutics ; 15(5)2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37242599

RESUMEN

Our lab previously established that metformin, a first-line type two diabetes treatment, activates the Nrf2 pathway and improves post-stroke recovery. Metformin's brain permeability value and potential interaction with blood-brain barrier (BBB) uptake and efflux transporters are currently unknown. Metformin has been shown to be a substrate of organic cationic transporters (Octs) in the liver and kidneys. Brain endothelial cells at the BBB have been shown to express Octs; thus, we hypothesize that metformin uses Octs for its transport across the BBB. We used a co-culture model of brain endothelial cells and primary astrocytes as an in vitro BBB model to conduct permeability studies during normoxia and hypoxia using oxygen-glucose deprivation (OGD) conditions. Metformin was quantified using a highly sensitive LC-MS/MS method. We further checked Octs protein expression using Western blot analysis. Lastly, we completed a plasma glycoprotein (P-GP) efflux assay. Our results showed that metformin is a highly permeable molecule, uses Oct1 for its transport, and does not interact with P-GP. During OGD, we found alterations in Oct1 expression and increased permeability for metformin. Additionally, we showed that selective transport is a key determinant of metformin's permeability during OGD, thus, providing a novel target for improving ischemic drug delivery.

9.
Eur J Med Chem ; 254: 115309, 2023 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-37054561

RESUMEN

Using the structure of gliotoxin as a starting point, we have prepared two different chemotypes with selective affinity to the kappa opioid receptor (KOR). Using medicinal chemistry approaches and structure-activity relationship (SAR) studies, structural features required for the observed affinity were identified, and advanced molecules with favorable Multiparameter Optimization (MPO) and Ligand Lipophilicity (LLE) profiles were prepared. Using the Thermal Place Preference Test (TPPT), we have shown that compound2 blocks the antinociceptive effect of U50488, a known KOR agonist. Multiple reports suggest that modulation of KOR signaling is a promising therapeutic strategy in treating neuropathic pain (NP). As a proof-of-concept study, we tested compound 2 in a rat model of NP and recorded its ability to modulate sensory and emotional pain-related behaviors. Observed in vitro and in vivo results suggest that these ligands can be used to develop compounds with potential application as pain therapeutics.


Asunto(s)
Neuralgia , Receptores Opioides , Animales , Ratas , Analgésicos Opioides/química , Dicetopiperazinas , Ligandos , Receptores Opioides kappa , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/química
10.
Biomed Chromatogr ; 37(8): e5637, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37002730

RESUMEN

The Northern Bobwhite (Colinus virginianus) is an economically important game bird within the Rolling Plains Ecoregion. Within this region, bobwhite is experiencing extreme cyclic population fluctuations which are resulting in a net decline in total population. It is suspected that within this region two helminth parasites, an eyeworm (Oxyspirura petrowi) and a cecal worm (Aulonocephalus pennula), are contributing to this phenomenon. However, this has been difficult to study as the primary mode of investigation would be the deployment of anthelmintic treatment. Unfortunately, no registered treatments for wild bobwhite currently exist. Thus, utilizing an anthelmintictreatment for wild bobwhite would require registration of that treatment with the U.S. Food and Drug Administration (FDA). As bobwhite are game birds that are hunted, they are considered food-producing animals to the FDA, and as such require the assessment for the withdrawal of the drug residues to be assessed for human food safety. In this study, we optimized and validated a bioanalytical method for the quantification of fenbendazole sulfone in bobwhite following the U.S. FDA Center for Veterinary Medicine Guidance for Industry #208 [VICH GL 49 (R)] for assessment of fenbendazole sulfone drug residue in Northern bobwhite liver. The official method for quantifying fenbendazole sulfone in domestic chicken (Gallus gallus) was adapted for use in bobwhite. The validated method quantitation range is 2.5-30 ng/mL for fenbendazole with an average recovery of 89.9% in bobwhite liver.


Asunto(s)
Enfermedades de las Aves , Colinus , Residuos de Medicamentos , Thelazioidea , Animales , Humanos , Colinus/parasitología , Fenbendazol , Cromatografía Liquida , Enfermedades de las Aves/epidemiología , Enfermedades de las Aves/parasitología , Espectrometría de Masas en Tándem , Pollos , Hígado , Sulfonas
11.
J Pharmacol Exp Ther ; 385(1): 35-49, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36746610

RESUMEN

Existing vascular endothelial growth factor-oriented antiangiogenic approaches are known for their high potency. However, significant side effects associated with their use drive the need for novel antiangiogenic strategies. The small GTPase RhoA is an established regulator of actin cytoskeletal dynamics. Previous studies have highlighted the impact of endothelial RhoA pathway on angiogenesis. Rho-associate kinase (ROCK), a direct RhoA effector, is potently inhibited by Fasudil, a clinically relevant ROCK inhibitor. Here, we aimed to target the RhoA signaling in endothelial cells by generating Fasudil-encapsulated CD31-targeting liposomes as a potential antiangiogenic therapy. The liposomes presented desirable characteristics, preferential binding to CD31-expressing HEK293T cells and to endothelial cells, inhibited stress fiber formation and cytoskeletal-related morphometric parameters, and inhibited in vitro angiogenic functions. Overall, this work shows that the nanodelivery-mediated endothelial targeting of RhoA signaling can offer a promising strategy for angiogenesis inhibition in vascular-related diseases. SIGNIFICANCE STATEMENT: Systemic administration of antiangiogenic therapeutics induces side effects to non-targeted tissues. This study, among others, has shown the impact of the RhoA signaling in the endothelial cells and their angiogenic functions. Here, to minimize potential toxicity, this study generated CD31-targeting liposomes with encapsulated Fasudil, a clinically relevant Rho kinase inhibitor, and successfully targeted endothelial cells. In this proof-of-principle study, the efficient Fasudil delivery, its impact on the endothelial signaling, morphometric alterations, and angiogenic functions verify the benefits of site-targeted antiangiogenic therapy.


Asunto(s)
Células Endoteliales , Factor A de Crecimiento Endotelial Vascular , Humanos , Células Endoteliales/metabolismo , Células HEK293 , Liposomas , Quinasas Asociadas a rho/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
12.
J Pharmacol Exp Ther ; 385(2): 135-145, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36828631

RESUMEN

The purpose of this study was to investigate the effects of the volatile anesthetic agents isoflurane and sevoflurane, at clinically relevant concentrations, on the fluidity of lipid membranes and permeability of the blood-brain barrier (BBB). We analyzed the in vitro effects of isoflurane or ketamine using erythrocyte ghosts (sodium fluorescein permeability), monolayers of brain microvascular endothelial cells ([13C]sucrose and fluorescein permeability), or liposomes (fluorescence anisotropy). Additionally, we determined the effects of 30-minute exposure of mice to isoflurane on the brain tight junction proteins. Finally, we investigated in vivo brain uptake of [13C]mannitol and [13C]sucrose after intravenous administration in mice under anesthesia with isoflurane, sevoflurane, or ketamine/xylazine in addition to the awake condition. Isoflurane at 1-mM and 5-mM concentrations increased fluorescein efflux from the erythrocyte ghosts in a concentration-dependent manner. Similarly, in endothelial cell monolayers exposed to 3% (v/v) isoflurane, permeability coefficients rose by about 25% for fluorescein and 40% for [13C]sucrose, whereas transendothelial resistance and cell viability remained unaffected. Although isoflurane caused a significant decrease in liposomes anisotropy values, ketamine/xylazine did not show any effects. Brain uptake clearance (apparent Kin) of the passive permeability markers in vivo in mice approximately doubled under isoflurane or sevoflurane anesthesia compared with either ketamine/xylazine anesthesia or the awake condition. In vivo exposure of mice to isoflurane did not change any of the brain tight junction proteins. Our data support membrane permeabilization rather than loosening of intercellular tight junctions as an underlying mechanism for increased permeability of the endothelial cell monolayers and the BBB in vivo. SIGNIFICANCE STATEMENT: The blood-brain barrier controls the entry of endogenous substances and xenobiotics from the circulation into the central nervous system. Volatile anesthetic agents like isoflurane alter the lipid structure of cell membranes, transiently facilitating the brain uptake of otherwise poorly permeable, hydrophilic small molecules. Clinical implications may arise when potentially neurotoxic drugs gain enhanced access to the central nervous system under inhalational anesthetics.


Asunto(s)
Anestésicos por Inhalación , Anestésicos , Isoflurano , Ketamina , Ratones , Animales , Isoflurano/farmacología , Barrera Hematoencefálica/metabolismo , Sevoflurano/metabolismo , Sevoflurano/farmacología , Células Endoteliales/metabolismo , Xilazina/metabolismo , Xilazina/farmacología , Liposomas , Anestésicos/farmacología , Anestésicos por Inhalación/farmacología , Anestésicos por Inhalación/metabolismo , Uniones Estrechas/metabolismo , Permeabilidad , Proteínas de Uniones Estrechas/metabolismo , Fluoresceínas , Lípidos
13.
Pharmaceutics ; 16(1)2023 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-38258064

RESUMEN

Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor, clinically used for the treatment of major depression or fibromyalgia. Currently, there are no studies reporting the pharmacokinetics (PK) of milnacipran after intraperitoneal (IP) injection, despite this being the primary administration route in numerous experimental studies using the drug. Therefore, the present study was designed to investigate the PK profile of IP-administered milnacipran in mice and compare it to the intravenous (IV) route. First a liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated to accurately quantify milnacipran in biological samples. The method was used to quantify milnacipran in blood and brain samples collected at various time-points post-administration. Non-compartmental and PK analyses were employed to determine key PK parameters. The maximum concentration (Cmax) of the drug in plasma was at 5 min after IP administration, whereas in the brain, it was at 60 min for both routes of administration. Curiously, the majority of PK parameters were similar irrespective of the administration route, and the bioavailability was 92.5% after the IP injection. These findings provide insight into milnacipran's absorption, distribution, and elimination characteristics in mice after IP administration for the first time and should be valuable for future pharmacological studies.

14.
J Clin Med ; 11(23)2022 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-36498463

RESUMEN

BACKGROUND AND AIM: We analyzed an inclusive gradient boosting model to predict hospital admission from the emergency department (ED) at different time points. We compared its results to multiple models built exclusively at each time point. METHODS: This retrospective multisite study utilized ED data from the Mount Sinai Health System, NY, during 2015-2019. Data included tabular clinical features and free-text triage notes represented using bag-of-words. A full gradient boosting model, trained on data available at different time points (30, 60, 90, 120, and 150 min), was compared to single models trained exclusively at data available at each time point. This was conducted by concatenating the rows of data available at each time point to one data matrix for the full model, where each row is considered a separate case. RESULTS: The cohort included 1,043,345 ED visits. The full model showed comparable results to the single models at all time points (AUCs 0.84-0.88 for different time points for both the full and single models). CONCLUSION: A full model trained on data concatenated from different time points showed similar results to single models trained at each time point. An ML-based prediction model can use used for identifying hospital admission.

15.
Anal Bioanal Chem ; 414(19): 5943-5966, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35754089

RESUMEN

Epidemiological studies often call for analytical methods that use a small biospecimen volume to quantify trace level exposures to environmental chemical mixtures. Currently, as many as 150 polar metabolites of environmental chemicals have been found in urine. Therefore, we developed a multi-class method for quantitation of biomarkers in urine. A single sample preparation followed by three LC injections was optimized in a proof-of-approach for a multi-class method. The assay was validated to quantify 50 biomarkers of exposure in urine, belonging to 7 chemical classes and 16 sub-classes. The classes represent metabolites of 12 personal care and consumer product chemicals (PCPs), 5 polycyclic aromatic hydrocarbons (PAHs), 5 organophosphate flame retardants (OPFRs), 18 pesticides, 5 volatile organic compounds (VOCs), 4 tobacco alkaloids, and 1 drug of abuse. Human urine (0.2 mL) was spiked with isotope-labeled internal standards, enzymatically deconjugated, extracted by solid-phase extraction, and analyzed using high-performance liquid chromatography-tandem mass spectrometry. The methanol eluate from the cleanup was split in half and the first half analyzed for PCPs, PAH, and OPFR on a Betasil C18 column; and pesticides and VOC on a Hypersil Gold AQ column. The second half was analyzed for tobacco smoke metabolites and a drug of abuse on a Synergi Polar RP column. Limits of detection ranged from 0.01 to 1.0 ng/mL of urine, with the majority ≤0.5 ng/mL (42/50). Analytical precision, estimated as relative standard deviation of intra- and inter-batch uncertainty, variabilities, was <20%. Extraction recoveries ranged from 83 to 109%. Results from the optimized multi-class method were qualified in formal international proficiency testing programs. Further method customization options were explored and method expansion was demonstrated by inclusion of up to 101 analytes of endo- and exogenous chemicals. This exposome-scale assay is being used for population studies with savings of assay costs and biospecimens, providing both quantitative results and the discovery of unexpected exposures.


Asunto(s)
Retardadores de Llama , Plaguicidas , Biomarcadores/orina , Exposición a Riesgos Ambientales/análisis , Retardadores de Llama/análisis , Humanos , Plaguicidas/análisis , Espectrometría de Masas en Tándem/métodos
16.
Pharm Res ; 39(2): 251-261, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35146590

RESUMEN

PURPOSE: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake. METHODS: Stable isotope-labeled [13C]sucrose and [13C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (Kin) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance. RESULTS: The three-compartment model was able to describe the experimental data well, yielding estimates for Kin of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 µl.min-1.g-1, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) µl.min-1.g-1, which were not statistically different. Kin values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points. CONCLUSIONS: Using the three-compartment model allows determination of Kin for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.


Asunto(s)
Encéfalo/metabolismo , Manitol/farmacocinética , Modelos Biológicos , Sacarosa/farmacocinética , Animales , Cromatografía Liquida , Vías de Eliminación de Fármacos , Inyecciones Intravenosas , Masculino , Manitol/administración & dosificación , Manitol/sangre , Ratones Endogámicos C57BL , Permeabilidad , Sacarosa/administración & dosificación , Sacarosa/sangre , Espectrometría de Masas en Tándem , Distribución Tisular , Vigilia
17.
Curr Cancer Drug Targets ; 22(4): 312-327, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34951367

RESUMEN

BACKGROUND: Aberrant expression of the MET receptor tyrosine kinase is an oncogenic determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting MET are under clinical trials. OBJECTIVE: Here, we report the preclinical and therapeutic evaluation of a novel anti-MET antibody- drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy. METHODS: The monoclonal antibody PCMC1D3 (IgG1a/κ), generated by a hybridoma technique and specific to one of the MET extracellular domains, was selected based on its high specificity to human MET with a binding affinity of 1.60 nM. PCMC1D3 was conjugated to DCM via a cleavable valine-citrulline dipeptide linker to form an antibody-drug conjugate with a drug-to-antibody ratio of 3.6:1. PCMC1D3-DCM in vitro rapidly induced MET internalization with an internalization efficacy ranging from 6.5 to 17.2h dependent on individual cell lines. RESULTS: Studies using different types of cancer cell lines showed that PCMC1D3-DCM disrupted the cell cycle, reduced cell viability, and caused massive cell death within 96h after treatment initiation. The calculated IC50 values for cell viability reduction were 1.5 to 15.3 nM. Results from mouse xenograft tumor models demonstrated that PCMC1D3-DCM in a single dose injection at 10 mg/kg body weight effectively delayed xenograft tumor growth up to two weeks without signs of tumor regrowth. The calculated tumoristatic concentration, a minimal dose required to balance tumor growth and inhibition, was around 2 mg/kg body weight. Taken together, PCMC1D3-DCM was effective in targeting the inhibition of tumor growth in xenograft models. CONCLUSION: This work provides the basis for the development of humanized PCMC1D3-DCM for MET-targeted cancer therapy in the future.


Asunto(s)
Inmunoconjugados , Neoplasias , Animales , Peso Corporal , Línea Celular Tumoral , Duocarmicinas , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Cardiovasc Revasc Med ; 40: 163-171, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34952824

RESUMEN

The transradial approach for cardiac catheterization, coronary angiography, and percutaneous intervention is associated with a lower risk of access site-related complications compared to the transfemoral approach. However, with increasing utilization of transradial access for not only coronary procedures but also peripheral vascular procedures, healthcare personnel are more likely to encounter radial access site complications, which can be associated with morbidity and mortality. There is significant heterogeneity in the reporting of incidence, manifestations, and management of radial access site complications, at least partly due to vague presentation and under-diagnosis. Therefore, physicians performing procedures via transradial access should be aware of possible complications and remain vigilant to prevent their occurrence. Intraprocedural complications of transradial access procedures, which include spasm, catheter kinking, and arterial dissection or perforation, may lead to patient discomfort, increased procedure time, and a higher rate of access site cross over. Post-procedural complications such as radial artery occlusion, hematoma, pseudoaneurysm, arteriovenous fistula, or nerve injury could lead to patient discomfort and limb dysfunction. When radial access site complications occur, comprehensive evaluation and prompt treatment is necessary to reduce long-term consequences. In this report, we review the incidence, clinical factors, and management strategies for radial access site complications associated with cardiac catheterization.


Asunto(s)
Aneurisma Falso , Arteriopatías Oclusivas , Intervención Coronaria Percutánea , Aneurisma Falso/etiología , Arteriopatías Oclusivas/complicaciones , Cateterismo Cardíaco/efectos adversos , Cateterismo Cardíaco/métodos , Angiografía Coronaria/efectos adversos , Angiografía Coronaria/métodos , Humanos , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Arteria Radial/diagnóstico por imagen , Arteria Radial/lesiones
19.
Cureus ; 13(11): e19643, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34956765

RESUMEN

BACKGROUND: Orthopedic surgery is considered among the highly competitive medical specialties to get in as a career in the United States. San Francisco Match (SF Match) is the matching service for orthopedic subspecialty fellowship programs, and the internet is the main source for applicants to obtain program information in the modern era. We aimed to determine and compare the accessibility, content, and accreditation details of the various orthopedic fellowship programs available at the Match website and alternative online resources. METHODS: We studied eight subspecialties (Adult Reconstruction, Musculoskeletal Oncology, Foot and Ankle, Pediatric Orthopedics, Shoulder and Elbow, Orthopedic Spine Surgery, Sports Medicine, and Trauma) in a cross-sectional design during August/September 2019 for programs starting in July/August 2021. We registered the available baseline information at the SF Match site under various categories. We tried to reach the program-specific webpage through SF Match hyperlink and categorized our results into successful (direct and indirect) links and unsuccessful links with subcategorization. We also analyzed the information available at sponsoring society, FREIDA (Fellowship and Residency Electronic Interactive Database), and ACGME (Accreditation Council for Graduate Medical Education) websites. RESULT: We analyzed 465 programs (874 positions) available through the SF Match website. A standardized program description was available for >80% of the programs in each subspecialty. The availability of a successful link for the program-specific webpage ranges from 35% (Pediatric Orthopedics) to 77% (Sports Medicine). Indirect links were almost twice as common as direct links. The success rates through the sponsoring society webpages vary from 3% (Shoulder and Elbow) to 53% (Pediatric Orthopedics). Failure rates after trying both (the Match and Society links) range from 10% (Musculoskeletal Oncology) to 34% (Shoulder and Elbow). FREIDA provides comprehensive information but is limited to accredited programs. ACGME accreditation rate varied from 14.6% (Foot and Ankle) to 98.9% (Sports Medicine). CONCLUSION: The selection of a subspecialty fellowship program is crucial for most applicants. There are plenty of resources for the orthopedic fellowship programs' online presence after two decades since the first orthopedic fellowship match inception. Match website is the primary resource for the applicants. All parties could be benefited if both the programs and the sponsoring societies offer adequate online information to the Match, leading to ideal fellow-program matches and improved educational experiences. Our study may stand as a reference for future comparison possibly due to post-COVID evolution in the Match process. We recommend that consistent availability of direct functional program website links, point-based program description, and filter/comparison options may further improve online accessibility and quality of the content of the Match website.

20.
Nutrients ; 13(7)2021 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-34371807

RESUMEN

The endocannabinoid system is involved in the regulation of a variety of physiological and cognitive processes. While the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (N-arachidonoylethanolamine, AEA) have been found in breast milk, their role(s) have yet to be determined. This study determined the normal concentration ranges of endocannabinoids (2-AG and AEA) in breast milk and the influences, if any, of obesity and diurnal rhythms on their levels. Milk samples were collected from 36 breastfeeding mothers at 4-8 weeks postpartum at each feed over a 24-h period, and further stratified into three groups based on body mass index (BMI). The samples were analyzed using liquid chromatography mass spectrometry. AEA was below the limit of detection and 2-AG levels averaged 59.3 ± 18.3 ng/mL (± SD) in women with normal BMI. Wide-ranging 2-AG concentrations in the overweight (65.5 ± 41.9 ng/mL) /obese (66.1 ± 40.6 ng/mL) groups suggest BMI may be a contributing factor influencing its levels. Following a diurnal pattern, there was a significantly higher 2-AG concentration observed during the day, as compared to night time samples. In conclusion, our study clearly suggests that appropriate milk collection and storage conditions are critical. Further, body weight and diurnal rhythm appear to influence levels of 2-AG. Based on these results, future studies are underway to determine what specific roles endocannabinoids may play in human milk and how elevated levels of 2-AG may modulate infant appetite and health.


Asunto(s)
Ácidos Araquidónicos/análisis , Ritmo Circadiano/fisiología , Endocannabinoides/análisis , Glicéridos/análisis , Leche Humana/química , Obesidad/metabolismo , Alcamidas Poliinsaturadas/análisis , Adulto , Índice de Masa Corporal , Cromatografía Liquida , Femenino , Humanos , Estudios Longitudinales , Espectrometría de Masas , Fenómenos Fisiologicos Nutricionales Maternos , Sobrepeso/fisiopatología
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