RESUMEN
BACKGROUND: Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating Helicobacter pylori. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects. METHODS: An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14-20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21-27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period. RESULTS: The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve over the dosing interval (AUCτ) at steady state were 195.93% (175.52-218.71%) and 287.54% (263.28-314.04%) for tegoprazan and 423.23% (382.57-468.22%) and 385.61% (354.62-419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of Cmax,ss and AUCτ were 83.69% (77.44-90.45%) and 110.30% (102.74-118.41%) for clarithromycin, 126.25% (114.73-138.93%) and 146.94% (135.33-159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73-82.60%) and 94.34% (87.94-101.20%) for amoxicillin, and 158.43% (125.43-200.11%) and 183.63% (156.42-215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages. CONCLUSION: The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability. CLINICAL TRIALS REGISTRATION: CTR20230643.
Asunto(s)
Amoxicilina , Derivados del Benceno , Bismuto , Claritromicina , Interacciones Farmacológicas , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Amoxicilina/efectos adversos , Amoxicilina/farmacocinética , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Área Bajo la Curva , Bismuto/efectos adversos , Bismuto/farmacocinética , China , Claritromicina/efectos adversos , Claritromicina/farmacocinética , Pueblos del Este de Asia , Voluntarios Sanos , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacocinética , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Derivados del Benceno/efectos adversos , Derivados del Benceno/farmacocinéticaRESUMEN
PURPOSE: Tegoprazan is a potassium-competitive acid blocker used for gastric acid suppression, which may be used with Helicobacter pylori eradication therapies. The goal of this study was to evaluate the pharmacokinetic interaction between tegoprazan and triple-antibiotic therapy containing metronidazole, tetracycline, and bismuth. METHODS: An open-label, 2-cohort, randomized, multiple-dose, crossover study was conducted in healthy subjects. In cohort 1, tegoprazan (100 mg/d) was administered orally with or without triple-antibiotic therapy (1500 mg/d metronidazole, 2000 mg/d tetracycline, and 1200 mg/d bismuth) for 7 days in each period. In cohort 2, triple-antibiotic therapy was administered orally with or without tegoprazan for 7 days in each period. Pharmacokinetic blood samples were collected within 24 h after the last dose. Safety assessments were performed. FINDINGS: Eleven cohort 1 subjects and ten cohort 2 subjects were included in the pharmacokinetic analysis. The AUCτ and Cmax at steady state geometric mean ratios (90% CIs) were 0.78 (0.73-0.83) and 0.75 (0.68-0.82) for tegoprazan; 0.77 (0.68-0.88) and 0.84 (0.72-0.98) for tegoprazan metabolite M1; 1.03 (0.98-1.08) and 1.08 (0.99-1.18) for metronidazole; 0.63 (0.56-0.70) and 0.64 (0.56-0.74) for tetracycline; and 1.55 (0.99-2.44) and 1.38 (0.72-2.66) for bismuth, respectively. All reported adverse events were mild. IMPLICATIONS: Changes in the tegoprazan, tetracycline, and bismuth pharmacokinetic parameters were detected after concurrent administration. These changes were considered mainly due to the pharmacodynamic effect of tegoprazan. The adverse events were predictable and reported as frequent adverse events during triple-antibiotic therapy. There were no significant differences in safety or tolerability between quadruple therapy, including tegoprazan and triple-antibiotic therapy. ClinicalTrials.gov identifier: NCT04066257.
Asunto(s)
Antibacterianos , Derivados del Benceno , Infecciones por Helicobacter , Helicobacter pylori , Imidazoles , Metronidazol , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Derivados del Benceno/farmacocinética , Bismuto/farmacocinética , Bismuto/uso terapéutico , Estudios Cruzados , Quimioterapia Combinada , Voluntarios Sanos , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Imidazoles/farmacocinética , Masculino , Metronidazol/efectos adversos , Metronidazol/farmacocinética , República de Corea , Tetraciclina/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVES: Tegoprazan is one of the potassium-competitive acid blockers (P-CABs). It exhibits its anti-secretory effects by competitively and reversibly blocking the availability of K+ of the H+, K+-ATPase. This study was designed to investigate the safety and pharmacokinetics of tegoprazan in healthy Chinese subjects. METHODS: Thirty-eight healthy Chinese subjects were recruited in this randomized, single-center, double-blind, placebo-controlled study, with a single ascending dose of 50, 100, 200 mg and a multiple dose of 100 mg for 10 days. The plasma concentration of tegoprazan was determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetics were evaluated via non-compartmental and compartmental model analysis. Safety was assessed by physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. RESULTS: No serious adverse event was observed in this study. After single-dose administration (50, 100 and 200 mg), tegoprazan was rapidly absorbed with a median maximum measure plasma concentration (Tmax) at 0.5 h and declined with a terminal (elimination) half-life (t1/2) of 3.87-4.57 h. The maximum measured plasma concentration (Cmax) for tegoprazan was 813.80, 1494.60 and 2829.00 ng/mL. Meanwhile, the corresponding area under the concentration-time curve (AUC) from time zero to infinity (AUC0-inf) was 2761.00, 5980.05 and 11,044.72 ngâh/mL in 50, 100, 200 mg group, respectively. Dose-dependent increase was observed in the value of Cmax and AUC after administration of tegoprazan 50 to 200 mg. The two-compartment model well described the pharmacokinetic profile of tegoprazan. In the steady state, no accumulation was found after repeated administration at the 100-mg dose level. No experimental differences were found based on gender. CONCLUSIONS: Tegoprazan was well tolerated in the dose range of 50-200 mg in single- and 100 mg in multiple-dose studies. Tegoprazan shows dose linearity with oral administration after a single dose of 50 to 200 mg and less drug accumulation after 10 days of continuous administration in 100 mg.
Asunto(s)
Derivados del Benceno/administración & dosificación , Cromatografía Liquida , Imidazoles/administración & dosificación , Espectrometría de Masas en Tándem , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico , Derivados del Benceno/efectos adversos , Derivados del Benceno/farmacocinética , Método Doble Ciego , Femenino , Humanos , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Masculino , Adulto JovenRESUMEN
This clinical trial was conducted to evaluate the pharmacokinetics and pharmacodynamics of tegoprazan when coadministered with amoxicillin/clarithromycin in healthy subjects. Cohort 1 was an open-label, randomized multiple-dose study to evaluate the mutual interaction of tegoprazan and amoxicillin/clarithromycin on the disposition of 3 tested drugs including tegoprazan M1 metabolite and 14-hydroxyclarithromycin (14-OH-clarithromycin). Cohort 2 was an open-label, randomized, active-controlled, parallel multiple-dose study to compare the intragastric pH profile after multiple oral doses of 50 or 100 mg tegoprazan coadministered with amoxicillin/clarithromycin 1000/500 mg for 7 days and pantoprazole-based triple therapy as the comparator arm. The coadministration of tegoprazan with amoxicillin/clarithromycin increased Css,max (2.2-fold) and AUCτ (2.7-fold) of tegoprazan and M1 (2.1- and 2.2-fold for Css,max and AUCτ , respectively) compared with administration of tegoprazan alone. The Css,max and AUCτ of 14-OH-clarithromycin increased by 1.7- and 1.8-fold, respectively; the disposition of amoxicillin and clarithromycin were not significantly changed. On days 1 and 7 of treatment, tegoprazan-based therapies (both 50- and 100-mg therapies) maintained pH above 6 for more than 88% of the 24-hour period, which was significantly longer compared with pantoprazole-based therapy. Tegoprazan either alone or in combination with amoxicillin/clarithromycin was well tolerated in healthy subjects. In conclusion, the exposure of tegoprazan was increased after coadministration of amoxicillin/clarithromycin, which led to increase pharmacodynamic response measured by intragastric pH compared with tegoprazan alone. Therefore, tegoprazan-based triple therapy would be effective therapeutic regimen to manage intragastric pH in terms of gastric or duodenal ulcers healing, treatment of gastroesophageal reflux disease, and Helicobacter pylori eradication.
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Amoxicilina/farmacocinética , Derivados del Benceno/farmacocinética , Claritromicina/farmacocinética , Fármacos Gastrointestinales/farmacocinética , Imidazoles/farmacocinética , Adulto , Amoxicilina/administración & dosificación , Amoxicilina/farmacología , Área Bajo la Curva , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacología , Claritromicina/administración & dosificación , Claritromicina/análogos & derivados , Claritromicina/metabolismo , Claritromicina/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/farmacología , Voluntarios Sanos , Humanos , Concentración de Iones de Hidrógeno , Imidazoles/administración & dosificación , Imidazoles/farmacología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
Tegoprazan, a novel potassium-competitive acid blocker, is used to treat acid-related diseases. However, there is no information on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of the marketed dosage of tegoprazan under various meal timings in a fed and fasted state. The study aimed to assess the effect of meal timing on PKs and PDs of tegoprazan 50 mg after a single administration in healthy male subjects. An open-label, single-dose, three-treatment, three-period crossover study was conducted. A total of 12 subjects were orally administered a single dose of tegoprazan 50 mg among various conditions: in a fasted state, at 30 min before or 30 min after a high-fat meal. PK parameters were estimated by the noncompartmental method. Continuous 24-h intragastric pH monitoring was done for PD analysis. The PKs and PDs of tegoprazan were compared among the various meal timings. Compared with the fasting condition, the PK profile of tegoprazan was similar when administered 30 min before a high-fat meal; however, delayed absorption with similar systemic exposure was observed when administered 30 min after a high-fat meal. The magnitude of acid suppression evaluated through the PD parameters increased when administered 30 min after a high-fat meal compared with fasting the condition and when administered 30 min before a high-fat meal. However, the increased difference in acid suppression was not clinically significant. Meal timing had no clinically significant effect on the PKs and PDs of tegoprazan 50 mg. Therefore, the marketed dosage of tegoprazan could be administered regardless of the meal timing. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tegoprazan, a novel potassium-competitive acid blocker, is used to treat acid-related diseases. WHAT QUESTION DID THIS STUDY ADDRESS? This study evaluated the effect of food on pharmacokinetics (PKs) and pharmacodynamics (PDs) of tegoprazan under various mealtime conditions. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? This study showed that delayed absorption of tegoprazan was observed at "after meal condition," however, the amount of systemic exposure of "after meal condition" was similar to "fasting condition" and "before meal condition." In addition, gastric acid suppression of tegoprazan was similar between fasting condition and before meal condition, whereas increased gastric acid suppression was observed at after meal condition. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? In the actual clinical environment, patients take medicine under various fed conditions. This study evaluated the effect of food on PKs and PDs of tegoprazan in various clinical conditions, and provided the important information about meal timing when administering tegoprazan.
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Derivados del Benceno/farmacocinética , Interacciones Alimento-Droga/fisiología , Imidazoles/farmacocinética , Comidas/fisiología , Administración Oral , Adulto , Antiácidos/administración & dosificación , Área Bajo la Curva , Derivados del Benceno/administración & dosificación , Disponibilidad Biológica , Estudios Cruzados , Ayuno , Ácido Gástrico/metabolismo , Reflujo Gastroesofágico/tratamiento farmacológico , Voluntarios Sanos , Humanos , Imidazoles/administración & dosificación , Masculino , Úlcera Péptica/tratamiento farmacológico , Factores de TiempoRESUMEN
Combined environmental exposures to the volatile organic compounds (VOCs) Benzene, Toluene, Ethylbenzene, and Xylene (BTEX) pose clear risks to public health. Research into these risks is under-studied even as BTEX levels in the atmosphere are predicted to rise. This review focuses on the available literature using single- and combined-BTEX component inhaled solvent exposures in animal models, necessarily also drawing on findings from models of inhalant abuse and occupational exposures. Health effects of these exposures are discussed for multiple organ systems, but with particular attention on neurobehavioral outcomes such as locomotor activity, impulsivity, learning, and psychopharmacological responses. It is clear that animal models have significant differences in the concentrations, durations and patterns of exposure. Experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX were found, but these effects were typically assessed using concentrations and exposure patterns not characteristic of environmental exposure. Future studies with animal models designed appropriately to explore combined BTEX will be necessary and advantageous to discovering health outcomes and more subtle neurobehavioral impacts of long-term environmental exposures.
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Derivados del Benceno , Benceno , Exposición a Riesgos Ambientales , Contaminantes Ambientales , Modelos Teóricos , Tolueno , Xilenos , Animales , Conducta/efectos de los fármacos , Benceno/análisis , Benceno/química , Benceno/farmacocinética , Benceno/toxicidad , Derivados del Benceno/análisis , Derivados del Benceno/química , Derivados del Benceno/farmacocinética , Derivados del Benceno/toxicidad , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisis , Contaminantes Ambientales/análisis , Contaminantes Ambientales/química , Contaminantes Ambientales/farmacocinética , Contaminantes Ambientales/toxicidad , Humanos , Solventes/análisis , Solventes/química , Solventes/farmacocinética , Solventes/toxicidad , Tolueno/análisis , Tolueno/química , Tolueno/farmacocinética , Tolueno/toxicidad , Xilenos/análisis , Xilenos/química , Xilenos/farmacocinética , Xilenos/toxicidadRESUMEN
A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4'-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (Ki = 0.11-1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [18F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [18F]7a exhibited the highest uptake in the midbrain, whereas [18F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [18F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [18F]7a is a promising lead for the further development of novel [18F]-labeled PET imaging agents for SERT binding sites in the brain.
Asunto(s)
Derivados del Benceno/química , Radioisótopos de Flúor/química , Tomografía de Emisión de Positrones/métodos , Proteínas de Transporte de Serotonina en la Membrana Plasmática/análisis , Sulfuros/química , Animales , Derivados del Benceno/síntesis química , Derivados del Benceno/metabolismo , Derivados del Benceno/farmacocinética , Encéfalo/metabolismo , Química Encefálica , Técnicas de Química Sintética , Radioisótopos de Flúor/metabolismo , Radioisótopos de Flúor/farmacocinética , Masculino , Unión Proteica , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Sulfuros/síntesis química , Sulfuros/metabolismo , Sulfuros/farmacocinéticaRESUMEN
Tumor targeting using agents with slow pharmacokinetics represents a major challenge in nuclear imaging and targeted radionuclide therapy as they most often result in low imaging contrast and high radiation dose to healthy tissue. To address this challenge, we developed a polymer-based targeting agent that can be used for pretargeted imaging and thus separates tumor accumulation from the imaging step in time. The developed targeting agent is based on polypeptide-graft-polypeptoid polymers (PeptoBrushes) functionalized with trans-cyclooctene (TCO). The complementary 111In-labeled imaging agent is a 1,2,4,5-tetrazine derivative, which can react with aforementioned TCO-modified PeptoBrushes in a rapid bioorthogonal ligation. A high degree of TCO loading (up to 30%) was achieved, without altering the physicochemical properties of the polymeric nanoparticle. The highest degree of TCO loading resulted in significantly increased reaction rates (77-fold enhancement) compared to those with small molecule TCO moieties when using lipophilic tetrazines. Based on computer simulations, we hypothesize that this increase is a result of hydrophobic effects and significant rearrangements within the polymer framework, in which hydrophobic patches of TCO moieties are formed. These patches attract lipophilic tetrazines, leading to increased reaction rates in the bioorthogonal ligation. The most reactive system was evaluated as a targeting agent for pretargeted imaging in tumor-bearing mice. After the setup was optimized, sufficient tumor-to-background ratios were achieved as early as 2 h after administration of the tetrazine imaging agent, which further improved at 22 h, enabling clear visualization of CT-26 tumors. These findings show the potential of PeptoBrushes to be used as a pretargeting agent when an optimized dose of polymer is used.
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Compuestos Aza/química , Derivados del Benceno/química , Neoplasias del Colon/diagnóstico por imagen , Ciclooctanos/química , Imagen Óptica , Péptidos/química , Peptoides/química , Animales , Compuestos Aza/farmacocinética , Derivados del Benceno/farmacocinética , Línea Celular Tumoral , Ciclooctanos/farmacocinética , Radioisótopos de Indio/química , Cinética , Ratones , Estructura Molecular , Tamaño de la Partícula , Péptidos/farmacocinética , Peptoides/farmacocinética , Espectroscopía de Protones por Resonancia Magnética , Propiedades de Superficie , Distribución TisularRESUMEN
The development of fluorogens with deep-red emission is one of the hottest topics of investigation in the field of bio/chemosensors and bioimaging. Herein, the tunable fluorescence of perylene diimide (PDI) derivatives was achieved by the incorporation of varied isolation groups linked on the PDI core. With the enlarged sizes of isolation groups, the conversion from aggregation caused quenching to aggregation-induced emission was obtained in their fluorescence variations from solutions to nanoparticles, as the result of the efficient inhibition of π-π stacking by the larger isolation groups. Accordingly, DCzPDI bearing 1,3-di(9H-carbazol-9-yl)benzene as the biggest isolation group exhibited the bright deep-red emission in the aggregated state with a quantum yield of 12.3%. Combined with the three-photon excited fluorescence microscopy (3PFM) technology, through-skull 3PFM imaging of mouse cerebral vasculature can be realized by DCzPDI nanoparticles with good biocompatibility, and the penetration depth can be as deep as 450 µm.
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Derivados del Benceno/química , Carbazoles/química , Colorantes Fluorescentes/química , Imidas/química , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Nanopartículas/química , Imagen Óptica/métodos , Perileno/análogos & derivados , Animales , Derivados del Benceno/farmacocinética , Derivados del Benceno/toxicidad , Vasos Sanguíneos/diagnóstico por imagen , Vasos Sanguíneos/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/diagnóstico por imagen , Carbazoles/farmacocinética , Carbazoles/toxicidad , Supervivencia Celular/efectos de los fármacos , Colorantes Fluorescentes/farmacocinética , Colorantes Fluorescentes/toxicidad , Células HeLa , Humanos , Imidas/farmacocinética , Imidas/toxicidad , Ratones , Perileno/química , Perileno/farmacocinética , Perileno/toxicidad , Distribución TisularRESUMEN
BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Teorema de Bayes , Derivados del Benceno/administración & dosificación , Derivados del Benceno/efectos adversos , Derivados del Benceno/farmacocinética , Carcinoma Ductal Pancreático/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/metabolismo , Propionatos/administración & dosificación , Propionatos/efectos adversos , Propionatos/farmacocinética , Receptores Notch/antagonistas & inhibidores , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfonas/administración & dosificación , Sulfonas/efectos adversos , Sulfonas/farmacocinética , GemcitabinaRESUMEN
Photoswitch compounds such as DENAQ confer light-sensitivity on endogenous neuronal ion channels, enabling photocontrol of neuronal activity without genetic manipulation. DENAQ treatment restores both retinal light responses and visual behaviors in rodent models of Retinitis pigmentosa. However, retinal photosensitization requires a high dose of DENAQ and disappears within several days after treatment. Here we report that BENAQ, an improved photoswitch, is 20-fold more potent than DENAQ and persists in restoring visual responses to the retina for almost 1 month after a single intraocular injection. Studies on mice and rabbits show that BENAQ is non-toxic at concentrations 10-fold higher than required to impart light-sensitivity. These favorable properties make BENAQ a potential drug candidate for vision restoration in patients with degenerative blinding diseases.
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Compuestos Azo/farmacología , Derivados del Benceno/farmacología , Fármacos Fotosensibilizantes/farmacología , Retina/fisiología , Visión Ocular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Compuestos Azo/química , Compuestos Azo/farmacocinética , Derivados del Benceno/química , Derivados del Benceno/farmacocinética , Modelos Animales de Enfermedad , Semivida , Luz , Ratones , Ratones Endogámicos C57BL , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacocinética , Compuestos de Amonio Cuaternario/farmacología , Conejos , Retina/efectos de los fármacos , Retina/efectos de la radiación , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/fisiología , Células Ganglionares de la Retina/efectos de la radiación , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patologíaRESUMEN
A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor.
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Antineoplásicos/química , Antineoplásicos/farmacología , Derivados del Benceno/química , Derivados del Benceno/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Derivados del Benceno/farmacocinética , Derivados del Benceno/uso terapéutico , Línea Celular Tumoral , Descubrimiento de Drogas , Humanos , Ratones , Células 3T3 NIH , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/metabolismo , Oxidación-Reducción , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismo , Regulador Transcripcional ERG/metabolismoRESUMEN
The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.
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Compuestos de Anilina/toxicidad , Derivados del Benceno/toxicidad , Cloroformo/toxicidad , Dimetilformamida/toxicidad , Glicoles de Etileno/toxicidad , Furanos/toxicidad , Metaboloma , Metabolómica , Pruebas de Toxicidad , Administración por Inhalación , Administración Oral , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/farmacocinética , Animales , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacocinética , Cloroformo/administración & dosificación , Cloroformo/farmacocinética , Bases de Datos Factuales , Dimetilformamida/administración & dosificación , Dimetilformamida/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Glicoles de Etileno/administración & dosificación , Glicoles de Etileno/farmacocinética , Femenino , Furanos/administración & dosificación , Furanos/farmacocinética , Exposición por Inhalación , Masculino , Análisis de Componente Principal , Ratas Wistar , Medición de RiesgoRESUMEN
CONTEXT: Urinary biomarkers are widely used among biomonitoring studies because of their ease of collection and nonintrusiveness. Chloroform and TEX (i.e., toluene, ethylbenzene, and m-xylene) are chemicals that are often found together because of common use. Although interactions occurring among TEX are well-known, no information exists on possible kinetic interactions between these chemicals and chloroform at the level of parent compound or urinary biomarkers. OBJECTIVE: The objective of this study was therefore to study the possible interactions between these compounds in human volunteers with special emphasis on the potential impact on urinary biomarkers. MATERIALS AND METHODS: Five male volunteers were exposed by inhalation for 6 h to single, binary, and quaternary mixtures that included chloroform. Exhaled air and blood samples were collected and analyzed for parent compound concentrations. Urinary biomarkers (o-cresol, mandelic, and m-methylhippuric acids) were quantified in urine samples. Published PBPK model for chloroform was used, and a Vmax of 3.4 mg/h/kg was optimized to provide a better fit with blood data. Adapted PBPK models from our previous study were used for parent compounds and urinary biomarkers for TEX. RESULTS: Binary exposures with chloroform resulted in no significant interactions. Experimental data for quaternary mixture exposures were well predicted by PBPK models using published description of competitive inhibition among TEX components. However, no significant interactions were observed at levels used in this study. CONCLUSION: PBPK models for urinary biomarkers proved to be a good tool in quantifying exposure to VOC.
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Cloroformo/farmacocinética , Cloroformo/orina , Monitoreo del Ambiente/métodos , Modelos Biológicos , Compuestos Orgánicos Volátiles/farmacocinética , Compuestos Orgánicos Volátiles/orina , Adolescente , Adulto , Derivados del Benceno/farmacocinética , Derivados del Benceno/orina , Biomarcadores/sangre , Biomarcadores/orina , Cloroformo/administración & dosificación , Simulación por Computador , Cresoles/orina , Hipuratos/orina , Humanos , Exposición por Inhalación , Masculino , Ácidos Mandélicos/orina , Valor Predictivo de las Pruebas , Tolueno/farmacocinética , Tolueno/orina , Urinálisis , Compuestos Orgánicos Volátiles/administración & dosificación , Compuestos Orgánicos Volátiles/sangre , Xilenos/farmacocinética , Xilenos/orina , Adulto JovenRESUMEN
γ-Secretase mediates amyloid production in Alzheimer's disease (AD) and oncogenic activity of Notch. γ-Secretase inhibitors (GSIs) are thus of interest for AD and oncology. A peripheral biomarker of Notch activity would aid determination of the therapeutic window and dosing regimen for GSIs, given toxicities associated with chronic Notch inhibition. This study examined the effects of GSI MK-0752 on blood and hair follicle transcriptomes in healthy volunteers. The effects of a structurally diverse GSI on rhesus blood and hair follicles were also compared. Significant dose-related effects of MK-0752 on transcription were observed in hair follicles, but not blood. The GSI biomarker identified in follicles exhibited 100% accuracy in a clinical test cohort, and was regulated in rhesus by a structurally diverse GSI. This study identified a translatable, accessible pharmacodynamic biomarker of GSI target engagement and provides proof of concept of hair follicle RNA as a translatable biomarker source.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Derivados del Benceno/farmacología , Monitoreo de Drogas , Folículo Piloso/efectos de los fármacos , Propionatos/farmacología , Inhibidores de Proteasas/farmacología , Receptores Notch/antagonistas & inhibidores , Sulfonas/farmacología , Transcripción Genética/efectos de los fármacos , Adolescente , Adulto , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Baltimore , Derivados del Benceno/administración & dosificación , Derivados del Benceno/sangre , Derivados del Benceno/farmacocinética , Biomarcadores Farmacológicos/sangre , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Monitoreo de Drogas/métodos , Perfilación de la Expresión Génica/métodos , Folículo Piloso/metabolismo , Voluntarios Sanos , Humanos , Macaca mulatta , Masculino , Modelos Animales , Terapia Molecular Dirigida , Análisis de Secuencia por Matrices de Oligonucleótidos , Propionatos/administración & dosificación , Propionatos/sangre , Propionatos/farmacocinética , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/sangre , Inhibidores de Proteasas/farmacocinética , ARN Mensajero/biosíntesis , ARN Mensajero/sangre , Receptores Notch/metabolismo , Sulfonas/administración & dosificación , Sulfonas/sangre , Sulfonas/farmacocinética , Adulto JovenRESUMEN
The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P2.
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Derivados del Benceno/química , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Administración Oral , Animales , Derivados del Benceno/síntesis química , Derivados del Benceno/farmacocinética , Disponibilidad Biológica , Perros , Evaluación Preclínica de Medicamentos , Semivida , Haplorrinos , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratas , Receptores de Lisoesfingolípidos/metabolismo , Receptores de Esfingosina-1-Fosfato , Relación Estructura-ActividadRESUMEN
Two benzazaborinine analogues of propranolol were synthesized and extensively profiled in vitro and in vivo. These analogues showed potency and physicochemical and in vitro ADME-tox profiles comparable to propranolol. In addition, both benzazaborinine analogues showed excellent bioavailability and brain penetration following subcutaneous administration in a pharmacokinetic study in rats. These studies unveil the potential of aromatic azaborinines as bioisosteric replacements of naphthalene in drug discovery programs.
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Antagonistas Adrenérgicos beta/química , Compuestos Aza/química , Derivados del Benceno/química , Ácidos Borínicos/química , Propranolol/análogos & derivados , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/farmacología , Animales , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Disponibilidad Biológica , Ácidos Borínicos/farmacocinética , Ácidos Borínicos/farmacología , Encéfalo/metabolismo , Células CHO , Línea Celular , Cricetulus , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Ratones , Modelos Moleculares , RatasRESUMEN
S1P5 is one of 5 receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood-brain barrier, where it maintains barrier integrity in in vitro models (J. Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P5 modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris, 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam , , AAIC 2014). Herein we describe the development of a series of selective S1P5 agonists that led to the identification of compound 29, which is highly selective for S1P5 and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P5 biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P1 and S1P3 function in rats. In addition, we found that 29 improves blood-brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P5 agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood-brain barrier such as Alzheimer's disease or multiple sclerosis.
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Ácido Azetidinocarboxílico/análogos & derivados , Derivados del Benceno/química , Derivados del Benceno/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Ácido Azetidinocarboxílico/administración & dosificación , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacocinética , Ácido Azetidinocarboxílico/farmacología , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacocinética , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Línea Celular , Envejecimiento Cognitivo , Perros , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Ratas , Ratas Sprague-Dawley , Receptores de Lisoesfingolípidos/metabolismoRESUMEN
A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively.
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Aminoquinolinas/química , Aminoquinolinas/uso terapéutico , Antimaláricos/química , Antimaláricos/uso terapéutico , Malaria/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Derivados del Benceno/química , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Derivados del Benceno/uso terapéutico , Humanos , Malaria Falciparum/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Relación Estructura-ActividadRESUMEN
A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 µg/L for blood samples, dynamic range 3.6-200 µg/L, intra-day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti-cancer drug BP-С1, a complex of cis-configured platinum and benzene-poly-carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half-life times for α- and ß-phase) were estimated for two dosage forms of BP-C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP-C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days' break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. 'Slow' phase of platinum excretion kinetics may be related to the muscles at the injection site.