RESUMO
A simple HPLC-MS/MS method has been developed for the determination of peramivir in rat plasma in the present study. The analytes were separated on a C18 column (50 × 2.1 mm, 1.7 µm) and a triple-quadrupole mass spectrometer equipped with an electrospray ionization source was applied for the detection. A phospholipid-free cartridge solid-phase extraction was used to pretreat the plasma and eliminate the endogenous phospholipid. The in-source collision-induced dissociation approach showed that this pretreatment could result in negligible ion suppression from the extracted sample and could produce cleaner samples when compared with the protein precipitation. The method was linear over the concentration range of 0.12-1200.0 ng/mL for peramivir. The method was validated and successfully applied to a pharmacokinetic study after peramivir was orally and intravenously administered to Sprague-Dawley rats.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciclopentanos/sangue , Ciclopentanos/isolamento & purificação , Guanidinas/sangue , Guanidinas/isolamento & purificação , Fosfolipídeos/química , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodos , Ácidos Carbocíclicos , Animais , Ciclopentanos/química , Guanidinas/química , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIMS: Increasing evidence indicates that the ATP-generating enzyme creatine kinase (CK) is involved in hypertension. CK rapidly regenerates ATP from creatine phosphate and ADP. Recently, it has been shown that beta-guanidinopropionic acid (GPA), a kidney-synthesized creatine analogue and competitive CK inhibitor, reduced blood pressure in spontaneously hypertensive rats. To further develop the substance as a potential blood pressure-lowering agent, we assessed the tolerability of a sub-therapeutic GPA dose in healthy men. METHODS: In this active and placebo-controlled, triple-blind, single-centre trial, we recruited 24 healthy men (18-50 years old, BMI 18.5-29.9 kg m-2 ) in the Netherlands. Participants were randomized (1:1:1) to one week daily oral administration of GPA 100 mg, creatine 5 g, or matching placebo. The primary outcome was the tolerability of GPA, in an intent-to-treat analysis. RESULTS: Twenty-four randomized participants received the allocated intervention and 23 completed the study. One participant in the placebo arm dropped out for personal reasons. GPA was well tolerated, without serious or severe adverse events. No abnormalities were reported with GPA use in clinical safety parameters, including physical examination, laboratory studies, or 12-Lead ECG. At day 8, mean plasma GPA was 213.88 (SE 0.07) in the GPA arm vs. 32.75 (0.00) nmol l-1 in the placebo arm, a mean difference of 181.13 (95% CI 26.53-335.72). CONCLUSION: In this first-in-human trial, low-dose GPA was safe and well-tolerated when used during 1 week in healthy men. Subsequent studies should focus on human pharmacokinetic and pharmacodynamic assessments with different doses.
Assuntos
Anti-Hipertensivos/administração & dosagem , Creatina/administração & dosagem , Guanidinas/administração & dosagem , Propionatos/administração & dosagem , Administração Oral , Adolescente , Adulto , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Creatina/efeitos adversos , Esquema de Medicação , Guanidinas/efeitos adversos , Guanidinas/sangue , Voluntários Saudáveis , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Países Baixos , Propionatos/efeitos adversos , Propionatos/sangue , Resultado do Tratamento , Adulto JovemRESUMO
A simple, sensitive and specific UHPLC-MS/MS method for quantification of plantagoguanidinic acid (PGA) in rat plasma was applied to investigate the pharmacokinetic behavior in vivo, using protopine as internal standard. The chromatography was separated on a Phenomenex® Luna-C18 column (2.1 × 150 mm, 3.0 µm) within 7.0 min using a mobile phase consisting of acetonitrile-0.1% formic acid solution under gradient elution at a flow rate of 0.4 mL/min. Prepared samples were monitored by multiple reaction monitoring mode, with the target fragmentions m/z 226.2 â 84.2 for PGA and m/z 354.2 â 188.9 for IS in positive electrospray ionization. The calibration curve of PGA was linear throughout the range 1-1000 ng/mL (r = 0.9962). The lower limit of quantitation in plasma for PGA was 0.1 ng/mL, and the recovery was >88.6%. Intra- and interday accuracy ranged from -8.6 to 4.9%. Furthermore, this validated method was successfully used for a pre-clinical pharmacokinetic study of PGA at a single dose of 20 and 5 mg/kg in rats via oral and intravenous administration. The study showed that PGA was absorpted rapidly and eliminated gradually with a greater absolute oral bioavailability of 70.1% in rats.
Assuntos
Alcaloides/sangue , Anti-Inflamatórios/sangue , Cromatografia Líquida de Alta Pressão/métodos , Guanidinas/sangue , Hipoglicemiantes/sangue , Plantago/química , Espectrometria de Massas em Tandem/métodos , Administração Intravenosa , Administração Oral , Animais , Disponibilidade Biológica , Medicamentos de Ervas Chinesas/farmacocinética , Limite de Detecção , Masculino , Psyllium/química , Ratos Sprague-DawleyRESUMO
UNLABELLED: Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. SUBJECTS: Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.
Assuntos
Ciclopentanos/sangue , Ciclopentanos/farmacocinética , Guanidinas/sangue , Guanidinas/farmacocinética , Influenza Humana/sangue , Ácidos Carbocíclicos , Voluntários Saudáveis , Humanos , Japão , Modelos Teóricos , Método de Monte Carlo , Estados UnidosRESUMO
1.The aim of the study was to evaluate the pharmacokinetics of peramivir after single intravenous (i.v.) doses in healthy Chinese subjects. 2.In a cross-over study, 12 subjects were given 300 and 600 mg peramivir by i.v. infusion. Blood and urine samples were collected at 17 designated time points and 7 designated intervals up to 36 h post-dose. Plasma and urine concentrations of peramivir were quantified by LC-MS/MS. 3.After single i.v. doses of 300 and 600 mg peramivir, Cmax and AUC0-t of peramivir were 21.4 ± 3.7, 41.1 ± 5.3 mgcL(-1) and 55.90 ± 10.62, 112.1 ± 13.2 mgch L(-1), respectively. Cmax and AUC increased in proportion to the dose. Within 12 h, accumulative urinary recoveries of peramivir after single i.v. doses of 300 and 600 mg peramivir were 84.31 ± 11.75% and 88.10 ± 7.39%, respectively. 4.In healthy Chinese subjects, peramivir displayed linear pharmacokinetics in the range of 300-600 mg, and was primarily excreted via urine as unchanged drug.
Assuntos
Povo Asiático , Ciclopentanos/administração & dosagem , Ciclopentanos/farmacocinética , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Voluntários Saudáveis , Ácidos Carbocíclicos , Administração Intravenosa , Adulto , China , Ciclopentanos/sangue , Ciclopentanos/química , Demografia , Relação Dose-Resposta a Droga , Feminino , Guanidinas/sangue , Guanidinas/química , Humanos , Masculino , Adulto JovemRESUMO
A liquid chromatography-electrospray-mass spectrometry method (LC/MS) has been developed and validated for determination of praziquantel (PZQ), pyrantel (PYR), febantel (FBT), and the active metabolites fenbendazole (FEN) and oxfendazole (OXF), in dog plasma, using mebendazole as internal standard (IS). The method consists of solid-phase extractions on Strata-X polymeric cartridges. Chromatographic separation was carried out on a Phenomenex Gemini C6 -Phenyl column using binary gradient elution containing methanol and 50 mm ammonium-formate (pH 3). The method was linear (r(2) ≥ 0.990) over concentration ranges of 3-250 ng/mL for PYR andFEB, 5-250 ng/mL for OXF and FEN, and 24-1000 ng/mL for PZQ. The mean precisions were 1.3-10.6% (within-run) and 2.5-9.1% (between-run), and mean accuracies were 90.7-109.4% (within-run) and 91.6-108.2% (between-run). The relative standard deviations (RSD) were <9.1%. The mean recoveries of five targeted compounds from dog plasma ranged from 77 to 94%.The new LC/MS method described herein was fully validated and successfully applied to the bioequivalence studies of different anthelmintic formulations such as tablets containing PZQ, PYR embonate and FBT in dogs after oral administration.
Assuntos
Benzimidazóis/sangue , Cromatografia Líquida/métodos , Fenbendazol/sangue , Guanidinas/sangue , Espectrometria de Massas/métodos , Praziquantel/sangue , Pamoato de Pirantel/sangue , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Cães , Feminino , Fenbendazol/química , Fenbendazol/farmacocinética , Guanidinas/química , Guanidinas/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Praziquantel/química , Praziquantel/farmacocinética , Pamoato de Pirantel/química , Pamoato de Pirantel/farmacocinética , Reprodutibilidade dos Testes , Extração em Fase Sólida , Equivalência TerapêuticaRESUMO
In previous nephrotoxicity metabonomic studies, several potential biomarkers were found and evaluated. To investigate the relationship between the nephrotoxicity biomarkers and the therapeutic role of Radix Glycyrrhizae extract on Semen Strychni-induced renal failure, 12 typical biomarkers are selected and a simple LC-MS method has been developed and validated. Citric acid, guanidinosuccinic acid, taurine, guanidinoacetic acid, uric acid, creatinine, hippuric acid, xanthurenic acid, kynurenic acid, 3-indoxyl sulfate, indole-3-acetic acid, and phenaceturic acid were separated by a Phenomenex Luna C18 column and a methanol/water (5 mM ammonium acetate) gradient program with a runtime of 20 min. The prepared calibration curves showed good linearity with regression coefficients all above 0.9913. The absolute recoveries of analytes from serum and urine were all more than 70.4%. With the developed method, analytes were successfully determined in serum and urine samples within 52 days. Results showed that guanidinosuccinic acid, guanidinoacetic acid, 3-indoxyl sulfate, and indole-3-acetic acid (only in urine) were more sensitive than the conventional renal function markers in evaluating the therapeutic role of Radix Glycyrrhizae extract on Semen Strychni-induced renal failure. The method could be further used in predicting and monitoring renal failure cause by other reasons in the following researches.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Insuficiência Renal/tratamento farmacológico , Animais , Biomarcadores/sangue , Biomarcadores/urina , Cromatografia Líquida , Ácido Cítrico/sangue , Ácido Cítrico/urina , Creatinina/sangue , Creatinina/urina , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/toxicidade , Glicina/análogos & derivados , Glicina/sangue , Glicina/urina , Guanidinas/sangue , Guanidinas/urina , Hipuratos/sangue , Hipuratos/urina , Indicã/sangue , Indicã/urina , Ácidos Indolacéticos/sangue , Ácidos Indolacéticos/urina , Ácido Cinurênico/sangue , Ácido Cinurênico/urina , Masculino , Espectrometria de Massas , Medicina Tradicional Chinesa , Estrutura Molecular , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Insuficiência Renal/induzido quimicamente , Succinatos/sangue , Succinatos/urina , Taurina/sangue , Taurina/urina , Ácido Úrico/sangue , Ácido Úrico/urina , Xanturenatos/sangue , Xanturenatos/urinaRESUMO
The monitoring and precise determination of pesticides and pharmaceutical drugs and their residues have become increasingly important in the field of food safety and water contamination issues. Herein, a fluorescent aluminium MOF-based sensor (1) was developed for the selective recognition of neonicotinoid insecticide dinotefuran and anti-Parkinson's drug entacapone. Guest-free MOF 1' exhibited ultra-fast response (<5â s) and ultra-low detection limits of 2.3 and 7.6â nM for dinotefuran and entacapone, which are lower than the previously reported MOF-based sensors. In the presence of other competitive analytes, great selectivity was achieved towards both analytes. The probe was recyclable up to five cycles. The sensing ability was explored towards entacapone in human serum, urine and dinotefuran in real soil, rice, honey samples, different fruits, vegetables, real water specimens and a wide range of pH media. A low-cost, handy MOF-based polymer thin-film composite (1'@PVDF-PVP) was developed for the on-site detection of dinotefuran and entacapone. Mechanistic studies involving analytical techniques and theoretical calculations suggested that FRET and PET are the probable reasons for entacapone sensing whereas IFE is responsible for dinotefuran detection. The entire work presents a low cost, multi-use photoluminescent sensor of entacapone and dinotefuran to address the environmental pollution.
Assuntos
Guanidinas , Inseticidas , Estruturas Metalorgânicas , Neonicotinoides , Nitrilas , Neonicotinoides/análise , Neonicotinoides/urina , Estruturas Metalorgânicas/química , Humanos , Inseticidas/análise , Inseticidas/sangue , Nitrilas/química , Guanidinas/análise , Guanidinas/química , Guanidinas/sangue , Nitrofuranos/análise , Antiparkinsonianos/análise , Antiparkinsonianos/sangue , Corantes Fluorescentes/química , Estrutura Molecular , Limite de Detecção , NitrocompostosRESUMO
Elevated plasma concentrations of the asymmetric (ADMA) and symmetric (SDMA) dimethylarginine have repeatedly been linked to adverse cardiovascular clinical outcomes. Both dimethylarginines can be degraded by alanine-glyoxylate aminotransferase 2 (Agxt2), which is also the key enzyme responsible for the degradation of endogenously formed ß-aminoisobutyrate (BAIB). In the present study we wanted to investigate the effect of BAIB on Agxt2 expression and Agxt2-mediated metabolism of dimethylarginines. We infused BAIB or saline intraperitoneally for 7days in C57/BL6 mice via minipumps. Expression of Agxt2 was determined in liver and kidney. The concentrations of BAIB, dimethylarginines and the Agxt2-specific ADMA metabolite α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid (DMGV) was determined by LC-MS/MS in plasma and urine. As compared to controls systemic administration of BAIB increased plasma and urine BAIB levels by a factor of 26.5 (p<0.001) and 25.8 (p<0.01), respectively. BAIB infusion resulted in an increase of the plasma ADMA and SDMA concentrations of 27% and 31%, respectively, (both p<0.05) and a 24% decrease of plasma DMGV levels (p<0.05), while expression of Agxt2 was not different. Our data demonstrate that BAIB can inhibit Agxt2-mediated metabolism of dimethylarginines and show for the first time that endogenous Agxt2 is involved in the regulation of systemic ADMA, SDMA and DMGV levels. The effect of BAIB excess on endogenous dimethylarginine levels may have direct clinical implications for humans with the relatively common genetic trait of hyper-ß-aminoisobutyric aciduria.
Assuntos
Ácidos Aminoisobutíricos/administração & dosagem , Arginina/análogos & derivados , Transaminases/antagonistas & inibidores , Animais , Arginina/sangue , Arginina/metabolismo , Guanidinas/sangue , Células HEK293 , Humanos , Cetoácidos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transaminases/metabolismoRESUMO
BACKGROUND: Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the κ opioid receptor. METHODS: To evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS). RESULTS: In each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of κ antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism. CONCLUSIONS: The negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.
Assuntos
Guanidinas/farmacocinética , Morfinanos/farmacocinética , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/farmacocinética , Piperidinas/farmacocinética , Receptores Opioides kappa/metabolismo , Tetra-Hidroisoquinolinas/farmacocinética , Animais , Transporte Biológico , Encéfalo/metabolismo , Guanidinas/sangue , Interações Hidrofóbicas e Hidrofílicas , Injeções Intraperitoneais , Células LLC-PK1 , Masculino , Camundongos , Morfinanos/sangue , Naltrexona/sangue , Naltrexona/farmacocinética , Antagonistas de Entorpecentes/sangue , Permeabilidade , Piperidinas/sangue , Suínos , Tetra-Hidroisoquinolinas/sangueRESUMO
Nitric oxide is an ubiquitary cell signaling substance. Its enzymatic production rate by nitric oxide synthase is regulated by the concentrations of the substrate L-arginine and the competitive inhibitor asymmetric dimethylarginine (ADMA). A newly recognized elimination pathway for ADMA is the transamination to α-keto-δ-(N(G),N(G)-dimethylguanidino)valeric acid (DMGV) by the enzyme alanine-glyoxylate aminotransferase 2 (AGXT2). This pathway has been proven to be relevant for nitric oxide regulation, but up to now no method exists for the determination of DMGV in biological fluids. We have developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of DMGV. D(6)-DMGV was used as internal standard. Samples were purified online by column switching, and separation was achieved on a porous graphitic carbon column. The calibration was linear over ranges of 10 to 200 nmol/L for plasma and 0.1 to 20 µmol/L for urine. The intra- and interday accuracies and precisions in plasma and urine were better than 10%. In plasma samples, DMGV was present in concentrations between 19.1 and 77.5 nmol/L. In urine samples, concentrations between 0.0114 and 1.03 µmol/mmol creatinine were found. This method can be used as a tool for the scientific investigation of the ADMA conversion to DMGV via the enzyme AGXT2.
Assuntos
Arginina/análogos & derivados , Bioquímica/métodos , Guanidinas/análise , Cetoácidos/análise , Adulto , Arginina/sangue , Arginina/química , Arginina/metabolismo , Arginina/urina , Calibragem , Cromatografia Líquida de Alta Pressão , Feminino , Guanidinas/sangue , Guanidinas/química , Guanidinas/urina , Humanos , Cetoácidos/sangue , Cetoácidos/química , Cetoácidos/urina , Limite de Detecção , Masculino , Espectrometria de Massas , Pessoa de Meia-IdadeRESUMO
AIMS: To examine the metabolic adaptation to an 80-day exercise intervention in healthy young male adults where lifestyle factors such as diet, sleep, and physical activities are controlled. METHODS AND RESULTS: This study involved cross-sectional analysis before and after an 80-day aerobic and strength exercise intervention in 52 young, adult, male, newly enlisted soldiers in 2015. Plasma metabolomic analyses were performed using liquid chromatography, tandem mass spectrometry. Data analyses were performed between March and August 2019. We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation. For statistical analyses, a paired t-test was used and Bonferroni-adjusted P-value of <0.0004 was considered to be statistically significant. The metabolite dimethylguanidino valeric acid (DMGV) (recently shown to predict lack of metabolic response to exercise) tracked maladaptive metabolic changes to exercise; those with increases in DMGV levels had increases in several cardiovascular risk factors; changes in DMGV levels were significantly positively correlated with increases in body fat (P = 0.049), total and LDL cholesterol (P = 0.003 and P = 0.007), and systolic blood pressure (P = 0.006). This study was approved by the Departments of Defence and Veterans' Affairs Human Research Ethics Committee and written informed consent was obtained from each subject. CONCLUSION: For the first time, the true magnitude and extent of metabolic adaptation to chronic exercise training are revealed in this carefully designed study, which can be leveraged for novel therapeutic strategies in cardiometabolic disease. Extending the recent report of DMGV's predictive utility in sedentary, overweight individuals, we found that it is also a useful marker of poor metabolic response to exercise in young, healthy, fit males.
Assuntos
Metabolismo Energético , Exercício Físico , Guanidinas/sangue , Metaboloma , Metabolômica , Valeratos/sangue , Adaptação Fisiológica , Adolescente , Adulto , Fatores Etários , Biomarcadores/sangue , Estudos Transversais , Humanos , Masculino , Militares , Fatores Sexuais , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVES: Camostat mesilate is a drug that is being repurposed for new applications such as that against COVID-19 and prostate cancer. This induces a need for the development of an analytical method for the quantification of camostat and its metabolites in plasma samples. Camostat is, however, very unstable in whole blood and plasma due to its two ester bonds. The molecule is readily hydrolysed by esterases to 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) and further to 4-guanidinobenzoic acid (GBA). For reliable quantification of camostat, a technique is required that can instantly inhibit esterases when blood samples are collected. DESIGN AND METHODS: An ultra-high-performance liquid chromatography-tandem mass spectrometry method (UHPLC-ESI-MS/MS) using stable isotopically labelled analogues as internal standards was developed and validated. Different esterase inhibitors were tested for their ability to stop the hydrolysis of camostat ester bonds. RESULTS: Both diisopropylfluorophosphate (DFP) and paraoxon were discovered as efficient inhibitors of camostat metabolism at 10 mM concentrations. No significant changes in camostat and GBPA concentrations were observed in fluoride-citrate-DFP/paraoxon-preserved plasma after 24 h of storage at room temperature or 4 months of storage at -20 °C and -80 °C. The lower limits of quantification were 0.1 ng/mL for camostat and GBPA and 0.2 ng/mL for GBA. The mean true extraction recoveries were greater than 90%. The relative intra-laboratory reproducibility standard deviations were at a maximum of 8% at concentrations of 1-800 ng/mL. The trueness expressed as the relative bias of the test results was within ±3% at concentrations of 1-800 ng/mL. CONCLUSIONS: A methodology was developed that preserves camostat and GBPA in plasma samples and provides accurate and sensitive quantification of camostat, GBPA and GBA by UHPLC-MS/MS.
Assuntos
Coleta de Amostras Sanguíneas/métodos , Cromatografia Líquida de Alta Pressão/métodos , Ésteres/sangue , Guanidinas/sangue , Espectrometria de Massas em Tandem/métodos , COVID-19/sangue , Inibidores Enzimáticos/farmacologia , Esterases/antagonistas & inibidores , Esterases/metabolismo , Ésteres/metabolismo , Ésteres/farmacologia , Guanidinas/farmacologia , Humanos , Hidrólise/efeitos dos fármacos , Isoflurofato/química , Isoflurofato/farmacologia , Paraoxon/sangue , Paraoxon/química , Paraoxon/farmacologia , Reprodutibilidade dos Testes , SARS-CoV-2/isolamento & purificação , Tratamento Farmacológico da COVID-19RESUMO
The paucity of hyperammonemic crises together with spasticity, only seen in human arginase I deficient patients and not in patients with other urea cycle disorders, forces a search for candidates other than ammonia to associate with the pathophysiology and symptomatology. Therefore, we determined arginine together with some catabolites of arginine in blood and cerebrospinal fluid of these patients as well as in extremely rare post-mortem brain material of two patients with argininemia. The levels of alpha-keto-delta-guanidinovaleric acid, argininic acid and alpha-N-acetylarginine correlate with the arginine levels in blood and cerebrospinal fluid of patients with imposed or spontaneous protein restriction. The levels in blood are higher than the upper limit of normal in all studied patients. In addition to the highly increased levels of these same compounds in blood of a child with argininemia, the increase of guanidinoacetic acid, 24h before death, is remarkable. However, the manifest increases of these studied catabolites of arginine are not seen in post-mortem brain material of the same pediatric patient. Otherwise a clear increase of guanidinoacetic acid in post-mortem brain material of an adult patient was shown. A similar, comparable increase of homoarginine in both studied post-mortem brain materials is observed. Therefore the study of the pathobiochemistry of arginine in argininemia must be completed in the future by the determination of the end catabolites of the nitric oxide and agmatine biosynthesis pathways in the knockouts as well as in the patients to evaluate their role, together with the here studied catabolites, as candidates for association with pathophysiology and symptomatology.
Assuntos
Encéfalo/patologia , Guanidinas/sangue , Guanidinas/líquido cefalorraquidiano , Hiperargininemia/sangue , Hiperargininemia/líquido cefalorraquidiano , Adolescente , Adulto , Autopsia , Criança , Pré-Escolar , Seguimentos , Humanos , Hiperargininemia/patologia , Masculino , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/líquido cefalorraquidiano , Insuficiência de Múltiplos Órgãos/complicações , Fatores de Tempo , Ureia/sangue , Adulto JovemRESUMO
Peramivir, a neuraminidase inhibitor, was approved globally and is indicated for the treatment of uncomplicated influenza in adults and children. However, the only approved intravenous formulation of peramivir limits its clinical application due to the need for the specialized dosing techniques and increases the risk of contracting influenza virus infection among healthcare professionals when dosing within a short distance to the patient. The purpose of this study was to investigate the pharmacokinetic profile of peramivir in plasma and the lung of rats and to compare the profiles following administration through trans-nasal aerosol inhalation (0.0888, 0.1776, and 0.3552 mg/kg) and intravenous injection (30 mg/kg). The plasma concentration reached the Cmax within 1.0 h (upon inhalation) and decreased at a t1/2 of 6.71 and 10.9 h after inhalation and injection, respectively. The absolute bioavailability of peramivir after inhalation was 78.2 %. Overall, the pharmacokinetic exposure of peramivir in the lungs was higher than that in the plasma after aerosol inhalation. After inhalation, the Cmax of peramivir in the lung was achieved within 1.0 h, and the elimination of the drug was slower than in the case of intravenous injection with t1/2 values 1.81 h for injection and 5.72, 53.5, and 32.1 h for low, middle, and high doses administered through inhalation. The Cmax and AUC0-t values for peramivir in the lungs increased linearly with the increased inhalation dose. The results elucidate the pharmacokinetic process of peramivir after trans-nasal aerosol inhalation to rats and provide useful information for further rational application of this drug formulation.
Assuntos
Ácidos Carbocíclicos/administração & dosagem , Ácidos Carbocíclicos/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Pulmão/metabolismo , Ácidos Carbocíclicos/sangue , Administração por Inalação , Aerossóis , Animais , Disponibilidade Biológica , Inibidores Enzimáticos/sangue , Guanidinas/sangue , Meia-Vida , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Neuraminidase/antagonistas & inibidores , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Neonicotinoids (NNs), a widely used class of systemic pesticides, are regarded as exhibiting selective toxicity in insects. However, NNs are suspected of exerting adverse effects on mammals as well, including humans. To date, only adult male animal models have been subjected to general toxicity studies of NNs; fetuses have yet to be considered in this context. Here, we focused on the NN clothianidin (CLO) for the first quantitative LC-MS/MS analysis of maternal-to-fetal transfer and residual property of once-daily (single or multiple days), orally administered CLO and its metabolites in mice. The results revealed the presence of CLO and its five metabolites at approximately the same respective blood levels in both dams and fetuses. In the dams, CLO showed a peak value 1 h after administration, after which levels rapidly decreased at 3 and 6 h. In the fetuses of each group, levels of CLO were almost the same as those observed in the corresponding dams. The present results clearly demonstrated rapid passage of CLO through the placental barrier. However, metabolite-dependent differences observed in blood pharmacokinetics and residual levels. This is the first quantitative demonstration of the presence of CLO and its metabolites in fetal mouse blood.
Assuntos
Sangue Fetal/metabolismo , Guanidinas/sangue , Inseticidas/sangue , Troca Materno-Fetal , Neonicotinoides/sangue , Tiazóis/sangue , Animais , Biotransformação , Feminino , Guanidinas/administração & dosagem , Guanidinas/farmacocinética , Guanidinas/toxicidade , Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Inseticidas/toxicidade , Exposição Materna , Camundongos Endogâmicos ICR , Neonicotinoides/administração & dosagem , Neonicotinoides/farmacocinética , Neonicotinoides/toxicidade , Gravidez , Medição de Risco , Tiazóis/administração & dosagem , Tiazóis/farmacocinética , Tiazóis/toxicidade , ToxicocinéticaRESUMO
Dinotefuran (DIN) belongs to the neonicotinoids (NNs), a class of globally applied pesticides originally developed to exhibit selective toxicity in insects. However, several reports have suggested that NNs also exert neurotoxic effects in mammals. We previously demonstrated neurobehavioral effects of DIN on mice under non-stressful conditions. For further toxicity assessments in the present study, we investigated the effects of DIN on mice exposed to stressful conditions. After subacutely administering a no-observed-effect-level (NOEL) dose of DIN and/or chronic unpredictable mild stress (CUMS) to mice, we conducted three behavioral tests (i.e., open field test [OFT], tail suspension test [TST] and forced swimming test [FST]). In addition, serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) of the dorsal raphe nuclei (DRN) and median raphe nuclei (MRN) and tyrosine hydroxylase (TH) of the ventral tegmental area and substantia nigra (SN) were evaluated immunohistochemically. A NOEL dose of DIN or CUMS alone increased of the total distance in OFT, decreased or increased the immobility time in TST or FST, respectively, and increased the positive intensity of 5-HT and TPH2 in the DRN/MRN, and TH in the SN. These changes were suppressed under the conditions of combined exposure to DIN and CUMS, though the blood corticosterone level was increased depending on the blood DIN values and the presence of CUMS. The present study suggests the multifaceted toxicity of the neurotoxin DIN.
Assuntos
Encéfalo/metabolismo , Guanidinas/toxicidade , Neonicotinoides/toxicidade , Nitrocompostos/toxicidade , Estresse Psicológico , Animais , Comportamento Animal/efeitos dos fármacos , Corticosterona/sangue , Emoções/fisiologia , Comportamento Exploratório/efeitos dos fármacos , Guanidinas/sangue , Elevação dos Membros Posteriores , Inseticidas/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Neonicotinoides/sangue , Nitrocompostos/sangue , Serotonina/metabolismo , Natação , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
This study aimed to determine the plasma disposition and faecal excretion of netobimin (NTB) and its respective metabolites as well as the efficacy against strongyles in horses following oral administration. Netobimin (10mg/kg) was administered orally to 8 horses. Blood and faecal samples were collected from 1 to 120h post-treatment and analysed by high performance liquid chromatography (HPLC). Using a chiral phase-based HPLC, plasma disposition of ABZSO enantiomers produced was also determined. Faecal strongyle egg counts (EPG) were performed by a modified McMaster's technique before and after the treatment. Neither NTB nor ABZ were present and only albendazole sulphoxide (ABZSO) and sulphone metabolites (ABZSO(2)) were detected in the plasma samples. Maximum plasma concentration of ABZSO (0.53+/-0.14microg/ml) and ABZSO(2) (0.36+/-0.09microg/ml) were observed at (t(max)) 10.50 and 19.50h, respectively following administration of NTB. The area under the curve (AUC) of the two metabolites was similar to each other. Netobimin was not detected, and ABZ was predominant in faecal samples. The maximum plasma concentration (C(max)) of (-)ABZSO was significantly higher than (+)ABZSO, but the area under the curves (AUCs) of the enantiomer were not significantly different each other in plasma samples. The enantiomers of ABZSO were close to racemate in the faecal samples analyzed. Netobimin reduced the EPG by 100%, 100%, 77%, 80% and 75% 2, 4, 6, 8 and 10 weeks post-treatment, respectively. The specific behaviour of the two enantiomers probably reflects different enantioselectivity of the enzymatic systems of the liver which are responsible for sulphoxidation and sulphonation of ABZ. Considering the pharmacokinetic and efficacy parameters NTB could be used as an anthelmintic in horses.
Assuntos
Anti-Helmínticos/farmacocinética , Guanidinas/farmacocinética , Helmintíase/tratamento farmacológico , Doenças dos Cavalos/parasitologia , Albendazol/análogos & derivados , Albendazol/farmacocinética , Animais , Anti-Helmínticos/sangue , Anti-Helmínticos/uso terapêutico , Calibragem , Fezes/química , Guanidinas/sangue , Guanidinas/uso terapêutico , Helmintíase/sangue , Doenças dos Cavalos/sangue , Doenças dos Cavalos/tratamento farmacológico , Cavalos , Absorção Intestinal , Sulfonas/farmacocinética , Distribuição TecidualRESUMO
The nonpeptide small molecule, MES207, exhibits 17-fold preferential binding to the neuropeptide FF receptor 1 (NPFFR1) over NPFFR2 and shows antagonist functionality at NPFF receptors. In order to further the development of MES207 as a NPFFR1 probe, an UPLC-MS/MS bioanalytical method was developed and validated to quantify MES207 in rat plasma for a linearity range of 3-200â¯ng/mL. The method was applied in the analysis of the plasma, brain, and urine samples collected during pharmacokinetic studies in healthy male and female Sprague Dawley rats. The animals were dosed through oral gavage (50â¯mg/kg) and intravenously (2.5â¯mg/kg). Test samples were analyzed using the validated bioanalytical method to generate plasma concentration-time profiles. The results were further subjected to non-compartmental analysis using Phoenix 6.4®. MES207 exhibits a large volume of distribution (1.2⯱â¯0.6â¯L), high clearance (0.8⯱â¯0.1â¯L/h), and a poor oral bioavailability (1.7⯱â¯0.4%). The compound also showed a multiple peak phenomenon with a very short absorption phase. It appears that gender does not significantly influence the differences in pharmacokinetic parameters of this NPFF probe.
Assuntos
Guanidinas/sangue , Guanidinas/farmacocinética , Piperidinas/sangue , Piperidinas/farmacocinética , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Feminino , Guanidinas/química , Limite de Detecção , Modelos Lineares , Masculino , Piperidinas/química , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodosRESUMO
Background Identification of lifestyle modifiable metabolic pathways related to cardiometabolic disease risk is essential for improvement of primary prevention in susceptible individuals. It was recently shown that plasma dimethylguanidino valerate (DMGV) levels are associated with incident type 2 diabetes mellitus. Our aims were to investigate whether plasma DMGV is related to risk of future coronary artery disease and with cardiovascular mortality and to replicate the association with type 2 diabetes mellitus and pinpoint candidate lifestyle interventions susceptible to modulate DMGV levels. Methods and Results Plasma DMGV levels were measured using liquid chromatography-mass spectrometry in a total of 5768 participants from the MDC (Malmö Diet and Cancer Study-Cardiovascular Cohort), MPP (Malmö Preventive Project), and MOS (Malmö Offspring Study). Dietary intake assessment was performed in the MOS. Baseline levels of DMGV associated with incident coronary artery disease in both the MDC (hazard ratio=1.29; CI=1.16-1.43; P<0.001) and MPP (odds ratio=1.25; CI=1.08-1.44; P=2.4e-3). In the MDC, DMGV was associated with cardiovascular mortality and incident coronary artery disease, independently of traditional risk factors. Furthermore, the association between DMGV and incident type 2 diabetes mellitus was replicated in both the MDC (hazard ratio=1.83; CI=1.63-2.05; P<0.001) and MPP (odds ratio=1.65; CI=1.38-1.98; P<0.001). Intake of sugar-sweetened beverages was associated with increased levels of DMGV, whereas intake of vegetables and level of physical activity was associated with lower DMGV. Conclusions We discovered novel independent associations between plasma DMGV and incident coronary artery disease and cardiovascular mortality, while replicating the previously reported association with incident type 2 diabetes mellitus. Additionally, strong associations with sugar-sweetened beverages, vegetable intake, and physical activity suggest the potential to modify DMGV levels using lifestyle interventions.