RESUMEN
SCOPE: The present study assesses the absorption, pharmacokinetics, and urinary excretion of coffee pyridines and their metabolites after daily regular exposure to specific dosages of coffee or cocoa-based products containing coffee (CBPCC), considering different patterns of consumption. METHODS AND RESULTS: In a three-arm, crossover, randomized trial, 21 volunteers are requested to randomly consume for 1 month: one cup of espresso coffee per day, three cups of espresso coffee per day, or one cup of espresso coffee plus two CBPCC twice per day. The last day of the one-month treatment, blood and urine samples are collected for 24 h. Trigonelline, N-methylpyridinium, N-methylnicotinamide, and N-methyl-4-pyridone-5-carboxamide are quantified. Trigonelline and N-methylpyridinium absorption curves and 24-h urinary excretion reflect the daily consumption of different servings of coffee or CBPCC, showing also significant differences in main pharmacokinetic parameters. Moreover, inter-subject variability due to sex and smoking is assessed, showing sex-related differences in the metabolism of trigonelline and smoking-related ones for N-methylpyridinium. CONCLUSION: The daily exposure to coffee pyridines after consumption of different coffee dosages in a real-life setting is established. This data will be useful for future studies aiming at evaluating the bioactivity of coffee-derived circulating metabolites in cell experiments, mimicking more realistic experimental conditions.
Asunto(s)
Cacao , Café , Piridinas/farmacocinética , Piridinas/orina , Adulto , Alcaloides/sangre , Alcaloides/orina , Estudios Cruzados , Femenino , Humanos , Masculino , Niacinamida/análogos & derivados , Niacinamida/sangre , Niacinamida/orina , Piridinas/sangre , Compuestos de Piridinio/sangre , Compuestos de Piridinio/orina , Factores Sexuales , FumarRESUMEN
Oximes such as pralidoxime (2-PAM), obidoxime (Obi), and HI-6 are the only currently available therapeutic agents to reactivate inhibited acetylcholinesterase (AChE) in case of intoxications with organophosphorus (OP) compounds. However, each oxime has characteristic agent-dependent reactivating efficacy, and therefore the combined administration of complementary oximes might be a promising approach to improve therapy. Accordingly, a new high-performance liquid chromatography method with diode-array detection (HPLC-DAD) was developed and validated allowing for simultaneous or single quantification of 2-PAM, Obi, and HI-6 in human plasma. Plasma was precipitated using 5% w/v aqueous zinc sulfate solution and subsequently acetonitrile yielding high recoveries of 94.2%-101.0%. An Atlantis T3 column (150 × 2.1mm I.D., 3 µm) was used for chromatographic separation with a total run time of 15 min. Quantification was possible without interferences within a linear range from 0.12 to 120 µg/mL for all oximes. Excellent intra-day (accuracy 91.7%-98.6%, precision 0.5%-4.4%) and inter-day characteristics (accuracy 89.4%-97.4%, precision 0.4%-2.2%) as well as good ruggedness were found. Oximes in processed samples were stable for at least 12 h in the autosampler at 15°C as well as in human plasma for at least four freeze-thaw cycles. Finally, the method was applied to plasma samples of a clinical case of pesticide poisoning.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Cloruro de Obidoxima/análisis , Oximas/análisis , Compuestos de Pralidoxima/análisis , Compuestos de Piridinio/análisis , Reactivadores de la Colinesterasa/análisis , Reactivadores de la Colinesterasa/sangre , Humanos , Masculino , Cloruro de Obidoxima/sangre , Oximas/sangre , Compuestos de Pralidoxima/sangre , Compuestos de Piridinio/sangre , Reproducibilidad de los ResultadosRESUMEN
Distigmine is a cholinesterase (ChE) inhibitor used for the treatment of detrusor underactivity in Japan. Distigmine's pharmacological effects are known to be long-lasting, but the duration of its effect on urinary bladder contractile function has not been fully elucidated. The present study aimed to determine these effects in relation to the plasma concentrations of distigmine and its inhibition of ChE activities in blood, plasma, and bladder tissue. Intravesical pressures were recorded in anesthetized guinea-pigs for 12 h after the intravenous administration of saline or distigmine (0.01-0.1 mg/kg). Plasma distigmine concentrations were measured by liquid chromatograph-tandem mass spectrometry (LC-MS/MS), while ChE activities were assayed using 5,5'-dithiobis(2-nitrobenzoic acid). Distigmine (0.1 mg/kg) significantly increased the maximum intravesical pressure at micturition reflex for 12 h post-administration. In contrast, plasma distigmine was only detectable for 6 h post-administration in these animals and a one-compartment model calculated an elimination half-life of 0.7 h. However, bladder and blood acetylcholinesterase activities were significantly inhibited for 12 h after distigmine administration, although plasma ChE activities were not affected. The pharmacodynamic effects of distigmine thus persisted after its elimination from the circulation, indicating that it may bind to bladder acetylcholinesterase, producing sustained enzyme inhibition and enhancement of bladder contractility.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Compuestos de Piridinio/farmacología , Vejiga Urinaria/efectos de los fármacos , Animales , Inhibidores de la Colinesterasa/sangre , Inhibidores de la Colinesterasa/farmacocinética , Femenino , Cobayas , Compuestos de Piridinio/sangre , Compuestos de Piridinio/farmacocinética , Vejiga Urinaria/metabolismo , Vejiga Urinaria/fisiologíaRESUMEN
Standard treatment of organophosphorus compounds (OPs) poisoning includes administration of an anti-muscarinic (atropine), anticonvulsive (diazepam) and acetylcholinesterase reactivator (oxime). From a wide group of newly synthesized oximes, oxime K027 and oxime K203 seem to be perspective compounds in some specific OPs intoxication. The available in vitro and in vivo preclinical data indicate that both oximes may be considered for potential human use. The main aim of this study was to establish plasmatic concentration curves of both oximes after intramuscular (i.m.) and intragastric (i.g.) application with subsequent pharmacokinetic analysis and study distribution after (i.m.) application on a non-rodent animal model (experimental pigs; 1500mg/animal). According to the results, both oximes had similar Cmax (K027: 106±19µg/mL and K203: 111±8µg/mL) in Tmax 19±5min, respectively, in 22±3min. Bioavailability of oxime K027 calculated as AUCtotal (8389±1024minµg/mL) was halved compared to oxime K203 (16938±795minµg/mL). The highest concentration from peripheral tissues was found in the kidney and lung, but the brain concentrations stay very low, the plasma/brain ratio being approximately 1%. The applied doses were derived from the recommendation where it is possible to use three autoinjectors to save human life. The results provide us with knowledge about the pharmacokinetics and distribution of these new oximes and may help us to better estimate the human pharmacokinetic profile.
Asunto(s)
Acetilcolinesterasa/metabolismo , Reactivadores de la Colinesterasa/farmacocinética , Oximas/farmacocinética , Compuestos de Piridinio/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Reactivadores de la Colinesterasa/administración & dosificación , Reactivadores de la Colinesterasa/sangre , Cromatografía Líquida de Alta Presión , Femenino , Inyecciones Intramusculares , Especificidad de Órganos , Oximas/administración & dosificación , Oximas/sangre , Compuestos de Piridinio/administración & dosificación , Compuestos de Piridinio/sangre , Sus scrofa , Distribución TisularRESUMEN
Hierarchical assemblies of biomolecular subunits can carry out versatile tasks at the cellular level with remarkable spatial and temporal precision. As an example, the collective motion and mutual cooperation between complex protein machines mediate essential functions for life, such as replication, synthesis, degradation, repair and transport. Nucleic acid molecules are far less dynamic than proteins and need to bind to specific proteins to form hierarchical structures. The simplest example of these nucleic acid-based structures is provided by a rod-shaped tobacco mosaic virus, which consists of genetic material surrounded by coat proteins. Inspired by the complexity and hierarchical assembly of viruses, a great deal of effort has been devoted to design similarly constructed artificial viruses. However, such a wrapping approach makes nucleic acid dynamics insensitive to environmental changes. This limitation generally restricts, for example, the amplification of the conformational dynamics between the right-handed B form to the left-handed Z form of double-stranded deoxyribonucleic acid (DNA). Here we report a virus-like hierarchical assembly in which the native DNA and a synthetic coat undergo repeated collective helicity switching triggered by pH change under physiological conditions. We also show that this collective helicity inversion occurs during translocation of the DNA-coat assembly into intracellular compartments. Translating DNA conformational dynamics into a higher level of hierarchical dynamics may provide an approach to create DNA-based nanomachines.
Asunto(s)
Materiales Biocompatibles Revestidos/química , Conformación de Ácido Nucleico , Compuestos de Piridinio/sangre , Animales , Dicroismo Circular , ADN , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Microscopía Electrónica de Transmisión , SalmónRESUMEN
In the case of poisoning by organophosphorus nerve agents or pesticides, there is still a lack of pharmacological treatment of the cholinergic crisis selectively targeting the nicotinic acetylcholine receptor. Recently, the compound MB327 was identified as a potential novel lead structure to close this gap, thus demanding a quantitative assay for initial pharmacokinetic (PK) studies. MB327 is a salt consisting of the dicationic bispyridinium compound (BPC) 1,1´-(propane-1,3-diyl)bis(4-tert-butylpyridinium) and two iodide counter ions. Due to the permanent positive charge of the BPC, an isocratic reversed-phase ion-pair chromatographic separation (RPIPC) was developed using heptanesulfonic acid as ion-pairing reagent and 45% v/v methanol as organic modifier (1 mL/min). Selective UV-detection (230 nm) was done by a diode array detector (DAD) for reliable, rugged, precise (RSD < 7%) and accurate (96-104%) quantitative analysis of 50 µL swine plasma (linear range 1-1000 µg BPC/mL plasma, lower limit of quantification 2 µg/mL). During method validation, diverse parameters essential for the chromatographic process were investigated to generate van´t Hoff, van Deemter and width plots allowing calculation of thermodynamic data like the distribution constant K (5.7 ± 0.3), change in enthalpy, ΔH(0) : -23.66 kJ/mol, and entropy, ΔS(0) : -65 J/(mol*K). In addition, RPIPC-DAD analysis enabled calculation of molar absorptivities of the BPC, ε230 : 17 400 ± 1100 L/(mol*cm), and iodide, ε230 : 9900 ± 400 L/(mol*cm), which determination was hampered by interference with each other in conventional cuvette UV-spectrophotometric measurements. Finally, the RPIPC-DAD procedure was applied to samples from an in vivo study of swine.
Asunto(s)
Antídotos/análisis , Intoxicación por Organofosfatos/tratamiento farmacológico , Compuestos de Piridinio/sangre , Animales , Antídotos/uso terapéutico , Enfermedades del Sistema Nervioso Autónomo/inducido químicamente , Enfermedades del Sistema Nervioso Autónomo/tratamiento farmacológico , Sustancias para la Guerra Química/envenenamiento , Cromatografía Líquida de Alta Presión , Cromatografía por Intercambio Iónico , Cromatografía de Fase Inversa , Masculino , Compuestos Organotiofosforados/envenenamiento , Compuestos de Piridinio/uso terapéutico , Receptores Nicotínicos/efectos de los fármacos , Reproducibilidad de los Resultados , Espectrofotometría Ultravioleta , PorcinosRESUMEN
Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22µM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision.
Asunto(s)
Antídotos/farmacocinética , Agentes Nerviosos , Antagonistas Nicotínicos/farmacocinética , Intoxicación/tratamiento farmacológico , Compuestos de Piridinio/farmacocinética , Soman , Animales , Anticonvulsivantes/administración & dosificación , Antídotos/administración & dosificación , Antídotos/toxicidad , Atropina/administración & dosificación , Dipéptidos/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Cobayas , Dosificación Letal Mediana , Masculino , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Nicotínicos/administración & dosificación , Antagonistas Nicotínicos/sangre , Antagonistas Nicotínicos/toxicidad , Intoxicación/sangre , Intoxicación/diagnóstico , Intoxicación/fisiopatología , Compuestos de Piridinio/administración & dosificación , Compuestos de Piridinio/sangre , Compuestos de Piridinio/toxicidadRESUMEN
PURPOSE: The hypothesis was tested that coffee types differing in content of major constituents also differ with regard to cardiometabolic effects. METHODS: Overweight persons (n = 118) were randomized to consume a dark roast [rich in N-methylpyridinium (NMP)] or medium roast (rich in caffeoylquinic acids, trigonelline) coffee blend for 3 months, after a washout period of 4 weeks. Before and after the intervention period, body weight and 15 further general and biochemical parameters were determined. RESULTS: Participants consumed an average of 4-5 cups per day. Mean body weight, body mass index and waist circumference did not change during the coffee consumption phase in either of the study groups. Systolic blood pressure decreased in the dark roast coffee group only (p < 0.05). High-density lipoprotein cholesterol levels increased in the medium roast coffee group only, and triglyceride levels increased in the dark roast coffee group only. Glucoregulation and insulin levels were not affected, although there was a small increase of hemoglobin A1c values in both groups. An increase of adiponectin levels occurred in the medium roast coffee group only and was negatively associated with NMP concentrations. Differences did not remain statistically significant after correction for multiple testing. CONCLUSIONS: Medium and dark roast coffee blends exert small but possibly relevant different cardiometabolic effects. Further studies of health outcomes in relation to coffee constituents seem warranted.
Asunto(s)
Sistema Cardiovascular/efectos de los fármacos , Café/química , Sobrepeso/metabolismo , Adiponectina/sangre , Adolescente , Adulto , Anciano , Alcaloides/administración & dosificación , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Índice de Masa Corporal , Peso Corporal , Proteína C-Reactiva , Sistema Cardiovascular/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Ayuno , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Insulina/sangre , Modelos Lineales , Masculino , Persona de Mediana Edad , Osteopontina/sangre , Estudios Prospectivos , Compuestos de Piridinio/administración & dosificación , Compuestos de Piridinio/sangre , Ácido Quínico/administración & dosificación , Ácido Quínico/análogos & derivados , Circunferencia de la Cintura , Pérdida de Peso/efectos de los fármacos , Adulto JovenRESUMEN
BACKGROUND: Extreme efforts are made for the structural diversification of oximes used as AChE reactivators. Co-administration of different oximes should also be considered as a solution in therapy. Consequently, development of selective assays of oximes in biological matrices is of major importance. RESULTS: Three chromatographic separation mechanisms were evaluated: hydrophilic-interaction LC; mixed reversed-phase/cation exchange (DUET); and reversed-phase ion pairing based on per-fluorinated agents. MS was used to identify and quantify oximes. Alternative preparation of whole blood and plasma samples were used based on protein precipitation through addition of acetonitrile or ionic liquids. Quality characteristics of the proposed analytical approaches are discussed. CONCLUSION: The reversed-phase ion pairing based on per-fluorinated agents chromatographic separation mechanism and positive ESI-MS/MS detection produced the best results for the assay of bis-quaternary pyridinium oximes. LLOQ in the tenths of nanogram per milliliter range are achievable.
Asunto(s)
Reactivadores de la Colinesterasa/química , Cromatografía Liquida/métodos , Oximas/sangre , Oximas/química , Compuestos de Piridinio/sangre , Compuestos de Piridinio/química , Espectrometría de Masas en Tándem/métodos , Acetilcolinesterasa/química , HumanosRESUMEN
K203 is an experimental bis-pyridinium mono-aldoxime type cholinesterase reactivator of potential use in organophosphate/ organophosphonate poisoning. Pharmacokinetics of K203 were examined in Wistar rats and beagle dogs using ion-pair HPLC. Serum and cerebrospinal fluid concentrations of K203 were determined using ion-pair reversedphase chromatography on octadecyl silica column. HPLC with ultraviolet detection was used for determination of serum concentration of K203 higher than 0.1 µg/mL while its low concentrations in cerebrospinal fluid required electrochemical detection (0.015 through 4 µg/mL range). In rats the serum levels of K203 followed zero order pharmacokinetics from 15 to 120 minutes post administration. Zero order pharmacokinetics was also observed in beagle dogs after low dose (15 µmol/kg) of K203 administration. High dose administration (250 µmol/kg) led to subsequent hindered elimination from both cerebrospinal fluid and serum.
Asunto(s)
Oximas/sangre , Oximas/líquido cefalorraquídeo , Compuestos de Piridinio/sangre , Compuestos de Piridinio/líquido cefalorraquídeo , Animales , Calibración , Cromatografía Líquida de Alta Presión/métodos , Perros , Monitoreo de Drogas/métodos , Femenino , Masculino , Oximas/administración & dosificación , Compuestos de Piridinio/administración & dosificación , Ratas , Ratas WistarRESUMEN
Small-molecule inhibitors are promising antitumor drugs. We have designed and synthesized a novel multi-targeted inhibitor, 2-methylcarbamoyl-4-{4-[3-(trifluoro-methyl)benzamido]phenoxy}pyridinium (SKLB610), that potently inhibits human tumor growth. In the study, the pharmacokinetic profile of SKLB610 was investigated. A simple, rapid and sensitive high-performance liquid chromatography-ultraviolet detection method was developed for the determination of SKLB610 in rat plasma. Samples were extracted with methanol and SKLB610 was separated on a C18 column using a mobile phase system consisting of 55% acetonitrile and 45% water, with ultraviolet detection at 270 nm. Sorafenib was used as the internal standard. The retention times of SKLB610 and the internal standard were 5.6 and 8.1 min, respectively. The quantification limit was 67 ng/mL. The calibration curves were linear over a concentration range of 0.1-50 µg/mL. The inter-day and intra-day accuracy and precision were within ± 10%. The recovery and stability of the assay were evaluated from spiked rat plasma. The method was successfully applied to a pharmacokinetic study of SKLB610 in rats. The pharmacokinetic profile of SKLB610 indicated that the oral formulations should be further optimized to improve bioavailability and intravenous formulation of SKLB610 should be developed.
Asunto(s)
Antineoplásicos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Compuestos de Piridinio/farmacocinética , Animales , Antineoplásicos/sangre , Antineoplásicos/química , Estabilidad de Medicamentos , Análisis de los Mínimos Cuadrados , Masculino , Compuestos de Piridinio/sangre , Compuestos de Piridinio/química , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
A sensitive and specific liquid chromatography electrospray ionization-mass spectrometry method for determination of 1,4-dimethylpyridinium (1,4-DMP) in rat plasma has been developed and validated. Chromatography was performed on an Aquasil C(18) analytical column (4.6 × 150 mm, 5 µm, Thermo Scientific, Rockford, IL, USA) with isocratic elution using a mobile phase containing acetonitrile and water with an addition of 0.1% of formic acid. Detection was achieved by an Applied Biosystems MDS Sciex (Concord, Ontario, Canada) API 2000 triple quadrupole mass spectrometer. Electrospray ionization was used for ion production. The limit of detection in the single ion monitoring mode was found to be 10 ng/mL. The limit of quantification was 50 ng/mL. The precision and accuracy for both within-day and between-day determination of 1,4-dimethylpyridinium was 2.4-7.56 and 90.93-111.48%. The results of this analytical method validation allow pharmacokinetic studies to be carried out in rats. The method was used for the pilot study of the pharmacokinetic behavior of 1,4-DMP in rats after intravenous administration.
Asunto(s)
Cromatografía Liquida/métodos , Compuestos de Piridinio/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Límite de Detección , Modelos Lineales , Masculino , Compuestos de Piridinio/química , Compuestos de Piridinio/farmacocinética , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-propane dibromide] is a promising new reactivator of organophosphate- or organophosphonate-inhibited acetylcholinesterase (AChE) with low acute toxicity and broad spectrum efficacy. The aim of the present study was to compare the pharmacokinetics of both compounds. Male Wistar rats (body weight = 320 ± 10 g) were administered a single intramuscular dose of K027 (22.07 mg kg(-1)) and an equimolar dose of trimedoxime. Blood was collected at various time intervals until 180 min. Plasma samples were analyzed by reversed-phase HPLC with ultraviolet (UV) detection. The recovery of both oximes from the plasma was approximately 90% and a linear relationship (R(2) > 0.998) was observed between the peak areas and concentrations of calibrated standards in the range 1-100 µg ml(-1). Near-identical plasma profiles were obtained for both compounds. No differences were found in the mean ± SD values of C(max) (18.6 ± 2.5 vs 20.0 ± 6.3 µg ml(-1), P = 0.72) and AUC(0-180min) (2290 ± 304 vs 2269 ± 197 min µg ml(-1), P = 0.84). However, the percentage coefficient of variation of the first-order rate constant of absorption (k(a)) was 3-fold higher (P < 0.01) providing evidence for more erratic absorption of intramuscular trimedoxime as compared with K027. In conclusion, oxime K027 might have superior pK properties that may be translated in its faster absorption and subsequent tissue distribution.
Asunto(s)
Reactivadores de la Colinesterasa/farmacocinética , Oximas/farmacocinética , Compuestos de Piridinio/farmacocinética , Trimedoxima/farmacocinética , Animales , Reactivadores de la Colinesterasa/sangre , Cromatografía Líquida de Alta Presión , Inyecciones Intramusculares , Masculino , Oximas/sangre , Compuestos de Piridinio/sangre , Ratas , Ratas Wistar , Espectrofotometría Ultravioleta/métodos , Distribución Tisular , Trimedoxima/sangreRESUMEN
PURPOSE: Dinaciclib, a selective inhibitor of cyclin-dependent kinase (CDK) 1, CDK2, CDK5, and CDK9, is metabolized via CYP3A4. Aprepitant, a neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting, is an inhibitor and inducer of CYP3A4. We conducted a randomized, crossover study to investigate the effects of single oral doses of aprepitant when coadministered with dinaciclib. METHODS: As part of a phase 1 dose-escalation trial, subjects with advanced malignancies were randomized into a 2-period, multi-cycle, crossover study to investigate the effect of single doses of oral aprepitant on the pharmacokinetics of 29.6 mg/m(2) dinaciclib administered by 2-h intravenous infusion. During cycle 1 and cycle 2, subjects received dinaciclib with aprepitant in one cycle and dinaciclib without aprepitant in the other cycle; aprepitant was administered at a dose of 125 mg orally on day 1 and 80 mg orally on days 2 and 3, along with standard dosing regimens of ondansetron and dexamethasone. RESULTS: Twelve patients completed the study; T (max) occurred approximately 2 h after the initiation of the infusion. The percent geometric mean ratio (dinaciclib + aprepitant vs. dinaciclib alone) was 106 % (90 % confidence interval [CI] 89-126 %) and 111 % (90 % CI 93-132 %) for dinaciclib C(max) and AUC([I]), respectively. The half-life and clearance of dinaciclib were similar, with or without aprepitant. CONCLUSIONS: Coadministration of dinaciclib with aprepitant resulted in no clinically significant effect on the pharmacokinetics and did not alter the safety profile of dinaciclib in patients with advanced malignancies.
Asunto(s)
Antieméticos/farmacología , Antineoplásicos/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Morfolinas/farmacología , Náusea/prevención & control , Neoplasias/tratamiento farmacológico , Compuestos de Piridinio/farmacocinética , Vómitos/prevención & control , Administración Oral , Adulto , Anciano , Análisis de Varianza , Antieméticos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Aprepitant , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/sangre , Estudios Cruzados , Óxidos N-Cíclicos , Dexametasona/administración & dosificación , Esquema de Medicación , Femenino , Semivida , Humanos , Indolizinas , Infusiones Intravenosas , Modelos Lineales , Masculino , Persona de Mediana Edad , Morfolinas/administración & dosificación , Náusea/inducido químicamente , Ondansetrón/administración & dosificación , Compuestos de Piridinio/administración & dosificación , Compuestos de Piridinio/efectos adversos , Compuestos de Piridinio/sangre , Insuficiencia del Tratamiento , Vómitos/inducido químicamenteRESUMEN
Asoxime (HI-6) is a well known oxime reactivator used for counteracting intoxication by nerve agents. It is able to reactivate acetylcholinesterase (AChE) inhibited even by sarin or soman. The present experiment was aimed to determine markers of oxidative stress represented by thiobarbituric acid reactive substances and antioxidants represented by ferric reducing antioxidant power, reduced and oxidized glutathione in a Beagle dog model. Two groups of dogs were intramuscularly exposed to single (11.4 mg/kg.b.wt.) or tenfold (114 mg/kg.b.wt.) human therapeutically doses of HI-6. HI-6 affinity for AChE in vitro was evaluated in a separate experiment. Complete serum biochemistry and pharmacokinetics were also performed with significant alteration in blood urea nitrogen, creatine phosphokinase, glucose and triglycerides. Blood samples were collected before HI-6 application and after 30, 60, and 120 min. The overall HI-6 impact on organism is discussed.
Asunto(s)
Reactivadores de la Colinesterasa/administración & dosificación , Estrés Oxidativo , Oximas/administración & dosificación , Compuestos de Piridinio/administración & dosificación , Acetilcolinesterasa/metabolismo , Animales , Glucemia/análisis , Nitrógeno de la Urea Sanguínea , Reactivadores de la Colinesterasa/sangre , Reactivadores de la Colinesterasa/farmacocinética , Creatina Quinasa/sangre , Perros , Glutatión/sangre , Disulfuro de Glutatión/sangre , Hiperglucemia/sangre , Hiperglucemia/inducido químicamente , Oximas/sangre , Oximas/farmacocinética , Compuestos de Piridinio/sangre , Compuestos de Piridinio/farmacocinética , Compuestos de Sulfhidrilo/sangre , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Triglicéridos/sangreRESUMEN
One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures. An explanation for limited penetration might be that oximes are substrates for the active P-glycoprotein (Pgp) efflux transporter located in the BBB. Using quantitative brain microdialysis in rats, the effect of i.v. injected tariquidar, a non-competitive, specific Pgp-inhibitor, on HI-6 levels in blood and brain was investigated. It appeared that tariquidar enhanced HI-6 levels in the brain approximately 2-fold during the first hour after HI-6 administration, whereas plasma levels did not differ between the treatment groups. A subsequent proof-of-concept study in rats showed that soman-induced seizures and convulsions were prevented almost completely when they were, in addition to HI-6 and atropine, pretreated with tariquidar. Moreover, twice as much AChE activity was present in their brains as compared to control rats. These results in rats indicate that modulation of the BBB by a drug like tariquidar, which is non-toxic by itself, is of great value in enhancing the efficacy of oximes.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antídotos/farmacocinética , Barrera Hematoencefálica/efectos de los fármacos , Oximas/farmacocinética , Compuestos de Piridinio/farmacocinética , Quinolinas/farmacología , Animales , Antídotos/uso terapéutico , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Colinesterasas/metabolismo , Electroforesis Capilar , Masculino , Microdiálisis , Oximas/sangre , Oximas/uso terapéutico , Compuestos de Piridinio/sangre , Compuestos de Piridinio/uso terapéutico , Ratas , Ratas Wistar , Convulsiones/inducido químicamente , Soman/toxicidadRESUMEN
The penetration of acetylcholinesterase reactivators (oximes) into the central nervous system is typically restricted by the blood-brain barrier. Although oximes are highly hydrophilic compounds, some contradictory results confirming permeation into the brain exist. The aim of this study is to verify the penetration of oximes through the blood-brain barrier and to detect their levels achieved in different brain regions 60 min after the administration. It was confirmed that oximes are able to penetrate into the brain after injection of therapeutic doses corresponding with 5% of LD(50). The level in whole brain was 0.58% for trimedoxime and 0.85% for the experimental drug oxime K074 as the percentage of their plasma concentration. The highest concentration was found in frontal cortex (trimedoxime 2.27%; oxime K074 0.95%) and lowest in basal ganglia (trimedoxime 0.86%; oxime K074 0.42%). Entry of oximes into the brain is minimal, but some low reactivation effect should be expected. The reactivation potency of oximes might be higher or lower, depending on the real oxime concentration in a given area.
Asunto(s)
Encéfalo/metabolismo , Butanos/aislamiento & purificación , Reactivadores de la Colinesterasa/aislamiento & purificación , Oximas/aislamiento & purificación , Compuestos de Piridinio/aislamiento & purificación , Trimedoxima/aislamiento & purificación , Animales , Butanos/administración & dosificación , Butanos/sangre , Butanos/farmacocinética , Butanos/farmacología , Calibración , Reactivadores de la Colinesterasa/administración & dosificación , Reactivadores de la Colinesterasa/sangre , Reactivadores de la Colinesterasa/farmacocinética , Reactivadores de la Colinesterasa/farmacología , Cromatografía Líquida de Alta Presión/instrumentación , Inyecciones Intramusculares , Límite de Detección , Masculino , Estructura Molecular , Oximas/administración & dosificación , Oximas/sangre , Oximas/farmacocinética , Oximas/farmacología , Compuestos de Piridinio/administración & dosificación , Compuestos de Piridinio/sangre , Compuestos de Piridinio/farmacocinética , Compuestos de Piridinio/farmacología , Ratas , Ratas Wistar , Estándares de Referencia , Análisis de Regresión , Reproducibilidad de los Resultados , Distribución Tisular , Trimedoxima/administración & dosificación , Trimedoxima/sangre , Trimedoxima/farmacocinética , Trimedoxima/farmacologíaRESUMEN
Cholinergic crisis is an adverse effect of an anticholinesterase agent, which is one of the cholinergic agents. Cholinergic crisis may induce serious conditions such as breathing difficulties. Cholinergic crisis is often diagnosed by an abnormally low level of serum cholinesterase (ChE). However, ChE value is not an appropriate indicator of cholinergic crisis since it has a high inter-individual variation, even though its intra-individual variation is low. Therefore, an indicator with less inter-individual variation capable of preventing the risk of cholinergic crisis was investigated. The results of correlation test between ChE and serum albumin (Alb) showed a strong positive correlation; r = 0.778 in BCG method(Bromo cresol green method) and r = 0.766 in the BCP-improved method for Alb. In addition, the variations of Alb values are much lower than the drastic depression of ChE values in cholinergic crisis. Thus, it is considered that the ratio of ChE and Alb (ChE/Alb) can be a useful indicator of cholinergic crisis. As a result of ROC (Receiver operating characteristic) analysis, the ratios of ChE and Alb values using the BCG method (ChE/Alb (BCG)) were 20.7, 87.0, 156.8 for the Cutoff value, Likelihood ratio and Odds ratio respectively. When using the BCP-improved method for Alb, the ratios of ChE and Alb (ChE/Alb(BCP improved)) were 25.0, 93.7, 180.1 for the Cutoff value, Likelihood ratio and Odds ratio respectively. The ChE/Alb ratio appears to be an excellent indicator of cholinergic crisis diagnosis since it shows a high likelihood ratio as well as a high odds ratio.
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Inhibidores de la Colinesterasa/envenenamiento , Colinesterasas/sangre , Albúmina Sérica/análisis , Inhibidores de la Colinesterasa/sangre , Humanos , Compuestos de Piridinio/sangreRESUMEN
The study of human metabolism of endo-8[bis(2-chlorophenyl)methyl]-3-(2-pyrimidinyl)-8-azabicyclo[3.2.1]octan-3-ol (SCH 486757) after a 200-mg oral dose of the drug to healthy volunteers in the first-in-human study is presented. The structural elucidation of two unique metabolites, which were detected in the process of metabolite characterization in human plasma and urine by liquid chromatography-mass spectrometry (LC-MS), is described. These metabolites (M27 and M34) were initially detected in human plasma at high levels (>35% of the LC-MS response of the parent drug). Additional LC-MS experiments (hydrogen/deuterium exchange and accurate mass measurement) were used to determine structures of metabolites. It was found that both metabolites were formed through a loss of the C-C bridge from the tropane moiety with the conversion into a substituted pyridinium compound. This metabolic process has not been reported previously. Because of the apparent high abundance of metabolites based on the LC-MS response, actual circulating amounts of these metabolites relative to the parent drug were determined semiquantitatively to evaluate their coverage in preclinical species. With the use of reference standards, it was shown that the LC-MS response of M27 and M34 in human plasma was much higher than that of the parent compound. Actual amounts of M27 and M34 metabolites were less than 5% of the level of the parent drug; therefore, additional assessment was not required.
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Antitusígenos/metabolismo , Compuestos de Azabiciclo/metabolismo , Compuestos de Piridinio/metabolismo , Pirimidinas/metabolismo , Receptores Opioides/agonistas , Animales , Antitusígenos/sangre , Antitusígenos/farmacocinética , Antitusígenos/farmacología , Antitusígenos/orina , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/orina , Biotransformación , Cromatografía Líquida de Alta Presión , Humanos , Masculino , Conformación Molecular , Compuestos de Piridinio/sangre , Compuestos de Piridinio/química , Compuestos de Piridinio/orina , Pirimidinas/sangre , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/orina , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Receptor de NociceptinaRESUMEN
Distigmine bromide (distigmine) is associated with a serious adverse reaction, cholinergic crisis, due to a marked decrease in serum acetylcholinesterase (AChE) levels. Clarifying the relationship between the plasma concentration and the inhibitory effect on AChE of distigmine is thus important for the proper use of the drug. The plasma drug concentration and AChE activity in whole blood from rats were measured simultaneously 3 min to 12 h after the oral administration of distigmine at different doses, and the data were subjected to a pharmacokinetic/pharmacodynamic (PK/PD) analysis. Clockwise hysteresis was observed between the plasma concentration of distigmine and the time course of AChE inhibition. Distigmine also displayed a delayed and sustained inhibition of blood AChE activity. We then assumed an effect compartment for the relationship between the plasma concentration of distigmine and AChE inhibition and analyzed the time course of AChE activity using a sigmoid maximum inhibitory effect model as the pharmacodynamic model. In conclusion, there is a time lag between the plasma concentration and inhibitory effect of distigmine in rats, and such a relationship could be resolved with an effect compartment model. Thus, the inhibitory effect of distigmine on AChE could be predicted by the PK/PD analysis.