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1.
J Agric Food Chem ; 72(12): 6613-6624, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38501445

RESUMEN

Propaquizafop is a highly efficient aryloxy phenoxy propionate chiral herbicide. However, the use of propaquizafop, including its safe use methods, residue patterns, dietary risk assessment, and maximum residue limits, for ginseng, a traditional Chinese medicinal plant, has not been studied. An analytical method was established for the simultaneous determination of propaquizafop and its four metabolites in ginseng soil, fresh ginseng, ginseng plant, and dried ginseng using HPLC-MS/MS. This approach showed good linearity (R2 ranging from 0.9827 to 0.9999) and limit of quantification ranging from 0.01 to 0.05 mg/kg. The intra- and interday recovery rates of this method ranged from 71.6 to 107.1% with relative standard deviation ranging from 1.3 to 23.2%. The method was applied to detect residual samples in the field, and it was found that the degradation of propaquizafop in ginseng plants and soil followed a first-order kinetic equation. R2 was between 0.8913 and 0.9666, and the half-life (t1/2) ranged from 5.04 to 8.05 days, indicating that it was an easily degradable pesticide (T1/2 < 30 days). The final propaquizafop residues in ginseng soil, plants, fresh ginseng, and dried ginseng ranged from 0.017 to 0.691 mg/kg. A dietary risk assessment was conducted on the final propaquizafop residue in fresh and dried ginseng. The results showed that the chronic exposure risk quotient values were less than 100% for fresh and dried ginseng (1.15% for fresh ginseng and 1.13% for dried ginseng). This illustrates that the dietary risk associated with the use of 10% propaquizafop emulsifiable concentrate in ginseng is very low. Thus, applying 750 mL/ha of propaquizafop on ginseng could not pose an unacceptable risk to public health. The results of the present study support the registration of propaquizafop in ginseng.


Asunto(s)
Panax , Residuos de Plaguicidas , Contaminantes del Suelo , Espectrometría de Masas en Tándem/métodos , Panax/química , Residuos de Plaguicidas/análisis , Contaminantes del Suelo/química , Medición de Riesgo , Semivida , Suelo/química , China
2.
J Agric Food Chem ; 71(44): 16669-16680, 2023 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-37812684

RESUMEN

ß-Glycosidase from Sulfolobus solfataricus (SS-BGL) is a highly effective biocatalyst for the synthesis of compound K (CK) from glycosylated protopanaxadiol ginsenosides. In order to improve the thermal stability of SS-BGL, molecular dynamics simulations were used to determine the residue-level binding energetics of ginsenoside Rd in the SS-BGL-Rd docked complex and to identify the top ten critical contributors. Target sites for mutations were determined using dynamic cross-correlation mapping of residues via the Ohm server to identify networks of distal residues that interact with the key binding residues. Target mutations were determined rationally based on site characteristics. Single mutants and then recombination of top hits led to the two most promising variants SS-BGL-Q96E/N97D/N302D and SS-BGL-Q96E/N97D/N128D/N302D with 2.5-fold and 3.3-fold increased half-lives at 95 °C, respectively. The enzyme activities relative to those of wild-type for ginsenoside conversion were 161 and 116%, respectively..


Asunto(s)
Ginsenósidos , Ginsenósidos/química , Glicósido Hidrolasas/genética , Glicósido Hidrolasas/metabolismo , Extractos Vegetales/química , Semivida
3.
Chemosphere ; 337: 139264, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37348617

RESUMEN

Pollution from the oil industries and refineries has worsened various environmental compartments. In this study, indigenous oil degrading bacteria were isolated from crude oil obtained from an Oil and Natural Gas Corporation (ONGC) asset in Ankleshwar, Gujarat, India. Based on 16S rRNA phylogeny, they were identified as Pseudomonas boreopolis IITR108, Microbacterium schleiferi IITR109, Pseudomonas aeruginosa IITR110, and Bacillus velezensis IITR111. The strain IITR108, IITR109, IITR110, and IITR111 showed 80-89% and 71-78% degradation of aliphatic (C8-C40) and aromatic (4-5 ring) hydrocarbons respectively in 45 d when supplemented with 3% (v/v) waste crude oil. When compared to individual bacteria, the consortium degrades 93.2% of aliphatic hydrocarbons and 85.5% of polyaromatic hydrocarbons. It was observed that the total aliphatic and aromatic content of crude oil 394,470 µg/mL and 47,050 µg/mL was reduced up to 9617.75 µg/mL and 4586 µg/mL respectively in 45 d when consortium was employed. The rate kinetics analysis revealed that the biodegradation isotherm followed first order kinetics, with a linear correlation between concentration (hydrocarbons) and time intervals. The half-life of aliphatic (C8-C40) and aromatic hydrocarbons ranged from 200 to 453 h and 459-714 h respectively. All the bacteria efficiently produced catabolic enzymes such as alkane monooxygenase, alcohol dehydrogenase, and lipase during the degradation of crude oil. These findings indicated that the bacterial consortium can be a better candidate for bioremediation and reclamation of aliphatic and aromatics hydrocarbon contaminated sites.


Asunto(s)
Hidrocarburos Aromáticos , Petróleo , Contaminantes del Suelo , Petróleo/análisis , Cinética , Semivida , Suelo , ARN Ribosómico 16S/genética , ARN Ribosómico 16S/metabolismo , Hidrocarburos Aromáticos/análisis , Hidrocarburos/metabolismo , Bacterias/metabolismo , Biodegradación Ambiental , Contaminantes del Suelo/análisis
4.
Environ Sci Pollut Res Int ; 30(17): 50225-50233, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36790701

RESUMEN

Supervised field trail on dissipation of co-formulation with herbicides clodinafop-propargyl and oxyfluorfen in spring onion showed similar pattern of dissipation during two different seasons. Residues of clodinafop-propargyl reached ≤ limit of quantitation (LOQ, 0.05 mg kg-1) on 3rd day after application at both standard and double dose during both the seasons. Oxyfluorfen residues followed first-order kinetics in both the doses during first season with half-life of 0.81 to 3.14 days. The residues of clodinafop-propargyl were detected in soil at both the doses during first season. However, residues were ≤ LOQ (0.05 mg kg-1) during second season. The residues of oxyfluorfen were detected only in double dose during first season in soil. In all other cases and in onion bulb, residues were ≤ LOQ (0.05 mg kg-1) at the time of harvest. As the residues were either ≤ LOQ (0.05 mg kg-1) on 3rd day or have a half-life of 3.14 days, the co-formulation can be used safely, provided a pre harvest interval (PHI) of 3 days is followed. On the basis of maximum residue limits (MRLs) in other commodities and from the data of present study, a default MRL of 0.05 mg kg-1 is proposed for both the pesticides.


Asunto(s)
Herbicidas , Residuos de Plaguicidas , Contaminantes del Suelo , Cebollas/química , Cinética , Herbicidas/análisis , Contaminantes del Suelo/análisis , Semivida , Suelo/química , Residuos de Plaguicidas/análisis
5.
J Nanobiotechnology ; 20(1): 509, 2022 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-36463199

RESUMEN

Norcantharidin (NCTD) is a demethylated derivative of cantharidin (CTD), the main anticancer active ingredient isolated from traditional Chinese medicine Mylabris. NCTD has been approved by the State Food and Drug Administration for the treatment of various solid tumors, especially liver cancer. Although NCTD greatly reduces the toxicity of CTD, there is still a certain degree of urinary toxicity and organ toxicity, and the poor solubility, short half-life, fast metabolism, as well as high venous irritation and weak tumor targeting ability limit its widespread application in the clinic. To reduce its toxicity and improve its efficacy, design of targeted drug delivery systems based on biomaterials and nanomaterials is one of the most feasible strategies. Therefore, this review focused on the studies of targeted drug delivery systems combined with NCTD in recent years, including passive and active targeted drug delivery systems, and physicochemical targeted drug delivery systems for improving drug bioavailability and enhancing its efficacy, as well as increasing drug targeting ability and reducing its adverse effects.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Neoplasias , Estados Unidos , Sistemas de Liberación de Medicamentos , Semivida , Disponibilidad Biológica , Neoplasias/tratamiento farmacológico
6.
Environ Sci Pollut Res Int ; 29(53): 80612-80623, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35723826

RESUMEN

The dissipation and risk assessment studies on fluopyram, trifloxystrobin and their metabolites were carried out on onion under field conditions after two treatments of fluopyram 250 g/L + trifloxystrobin 250 g/L SC @ 150 and 300 g a.i. ha-1. The onion bulb samples were collected at 0, 3, 7, 14, and 21 days after second spray to study the pattern of dissipation using QuEChERS methodology for processing and analysis on GC-MS/MS. The total initial residues of fluopyram (fluopyram + fluopyram benzamide) in immature onion bulb were 2.14 and 4.93 mg kg-1, at single and double dose, respectively. The residues of 0.02 and 0.06 mg kg-1 persisted in the mature onion bulb collected at the harvest (30 days after treatment). The total initial residues of trifloxystrobin (trifloxystrobin + CGA 321113) in immature onion bulb were 0.65 and 1.97 mg kg-1, at single and double dose, respectively, which reached < LOQ and 0.06 mg kg-1 at the respective doses at the harvest time. Dissipation of fluopyram followed second-order kinetics with DT50 values of 1.83 and 1.74 days, whereas trifloxystrobin followed first-order kinetics with DT50 values of 4.73 and 4.78 days, at single and double dose respectively. Risk assessment in terms of hazard quotient was done to estimate the risk that can occur due to application of this combination pesticide. It was observed that even the spray at the double recommended dose could not have dietary risks on the consumers.


Asunto(s)
Fungicidas Industriales , Residuos de Plaguicidas , Contaminantes del Suelo , Cebollas/química , Fungicidas Industriales/análisis , Residuos de Plaguicidas/análisis , Cromatografía de Gases y Espectrometría de Masas , Espectrometría de Masas en Tándem , Contaminantes del Suelo/análisis , Triazoles/análisis , Benzamidas/análisis , Medición de Riesgo , Semivida
7.
J Biomed Nanotechnol ; 18(3): 922-927, 2022 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-35715901

RESUMEN

Vitamin C is an important antioxidant in the human body that plays a role in many body functions. Liposomal encapsulation is a technology commonly used in food processing and medicine. This study determines whether Double Nutri (liposomal encapsulation) increases the absorption rate for vitamin C supplementation. Subjects enrolled in this study took vitamin C without liposome; then, 14 d washout was given with liposomal process A vitamin C. After 14 d washout, the subjects took liposomal process B vitamin C (Double Nutri) was given. After taking the test sample, the vitamin C concentration in venous blood was measured from the baseline (0 h), 0.5, 1, 2, 3, 4, and 8 h. Eleven healthy subjects were recruited for three tests. The vitamin C concentration for liposomal process B vitamin C (Double Nutri) group is higher (7.26±3.52, p<0.01) than that for the liposomal process A vitamin C group (6.41±3.80, p<0.05) and for vitamin C without liposome (2.21±4.07). This shows that Double Nutri has better bioavailability and can last up in the body to 8 hours. In addition, this study shows that Double Nutri increases the half-life of vitamin C in plasma and has higher bioavailability.


Asunto(s)
Ácido Ascórbico , Complejo Vitamínico B , Disponibilidad Biológica , Semivida , Humanos , Liposomas
8.
J Ethnopharmacol ; 290: 115123, 2022 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-35183691

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb. (PM) is a common traditional Chinese medicine with diverse biological activities of resolving toxins, nourishing livers and promoting hairs. Nevertheless, in recent years hepatotoxic adverse reactions caused by the administration of PM have raised worldwide concerns. In our previous study, we found that emodin dianthrones showed hepatotoxicity and may be potential toxicity markers. However, the metabolic transformation and pharmacokinetic behavior of emodin dianthrones in vivo have still not been elucidated. AIM OF THE STUDY: Taking trans-emodin dianthrones (TED) as an example, the present study was conducted to investigate the pharmacokinetics and bioavailability of TED in rats and characterized its metabolic transformation in the plasma, urine and feces of rats. MATERIALS AND METHODS: A rapid and sensitive UPLC-qqq-MS/MS method was developed for accurate quantification of TED in plasma and successfully applied to the pharmacokinetic evaluation of TED in rats after intravenous and oral administration. A reliable UFLC-Q-TOF-MS high resolution mass spectrometry combined with a scientific metabolite identification strategy was used to comprehensively characterize the metabolic transformation of TED in plasma, urine and feces in rats. RESULTS: The established UPLC-qqq-MS/MS method had a linear range of 1-500 ng/mL, and the method was accurate and reliable to meet the quantitative requirements. When 20 mg/kg TED was given by gavage rats, it was rapidly absorbed into the circulatory system and had a long half-life time of 6.44 h and wide tissue distribution in vivo. While intravenous injection of 0.4 mg/kg TED in rats, it was rapidly metabolized and eliminated with a half-life time of 1.82 h. The oral absorption bioavailability of TED was only 2.83%. Furthermore with a sensitive UFLC-Q-TOF-MS technique and metabolite identification strategy, 21 metabolites were successfully identified, including 11 in plasma, 12 in urine and 18 in feces. The main Ⅰ and Ⅱ phase metabolic processes involved glucuronidation, oxidation, carbonylation, (de)methylation, sulfation and hydrogenation. CONCLUSION: TED could be rapidly absorbed into the blood circulation and widely distributed and slowly metabolized in the body and underwent extensive cleavage and metabolic transformation in vivo. The study provided a basis for in-depth elucidation of the toxicology and mechanism research of TED, but also laid the foundation for further research on the material basis of hepatotoxicity of PM.


Asunto(s)
Emodina/química , Emodina/farmacocinética , Administración Oral , Animales , Antracenos/química , Antracenos/farmacocinética , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos , Emodina/sangre , Emodina/orina , Fallopia multiflora , Heces/química , Semivida , Masculino , Medicina Tradicional China , Tasa de Depuración Metabólica , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem
9.
J Ethnopharmacol ; 282: 114650, 2022 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-34536515

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese Medicine, Rehmannia glutinosa (Gaertn.) DC., as the principle herb of ShengDiHuang Decotion (SDHD), has the effect of cooling blood and hemostasis, and tonifying the yin and kidney. Rheum L., as adjuvant herbs, assist Rehmannia glutinosa (Gaertn.) DC. to promote blood circulation to remove blood stasis. AIM OF STUDY: To study the mechanism of Rhein (RH) involved in the promotion of Rehmannioside D (RD) absorption by pharmacokinetic studies, single-pass intestinal perfusion, Caco-2 cell models, molecular docking technique and western blotting. MATERIALS AND METHODS: Initially, the intestinal absorption of RD in the presence or absence of RH was conducted through pharmacokinetic studies. Thereafter, the intestinal absorption of RD and RH was studied using the single-pass intestinal perfusion and Caco-2 cell models. Finally, using molecular docking technique and western blotting. RESULTS: We found that the promotion of RD absorption by RH was mediated by breast cancer resistance and multidrug resistance-associated protein 2, thereby affecting the permeability of the intestinal epithelium. Additionally, RH and RD can competitively bind to breast cancer resistance and multidrug resistance-associated protein 2, and that RH inhibits the expression of breast cancer resistance and multidrug resistance-associated protein 2 in the ileum to promote the intestinal absorption of RD. CONCLUSION: This study reveals the mechanisms associated with the RH-mediated promotion of RD absorption and provides a basis for further exploring the synergistic effect of Rehmannia glutinosa (Gaertn.) DC and rhubarb.


Asunto(s)
Antraquinonas , Animales , Humanos , Masculino , Ratas , Antraquinonas/química , Antraquinonas/farmacocinética , Área Bajo la Curva , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/química , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transporte Biológico , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Simulación por Computador , Interacciones Farmacológicas , Regulación de la Expresión Génica/efectos de los fármacos , Semivida , Modelos Moleculares , Estructura Molecular , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Conformación Proteica , Distribución Aleatoria , Ratas Sprague-Dawley
10.
J Ethnopharmacol ; 285: 114872, 2022 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-34838618

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal formulas have unique efficacy and are of great significance to the theory and practice of Chinese medicine and are therefore gaining increasing attention in research. Painong powder (PNS), composed of Aurantii fructus immaturus (Zhishi in Chinese, ZS), Paeoniae Radix Alba (Baishao in Chinese, BS), and Platycodonis Radix (Jiegeng in Chinese, JG), has remarkable effects on the detoxification and discharge of pus. JG is traditionally used to treat pulmonary carbuncles and is considered a 'medicinal guide'. According to the composition theory of prescriptions, JG is an 'assistant and guide' medicine. The role of JG as an adjuvant has gained increasing attention. AIM OF THE STUDY: The study was designed to prove the efficacy of PNS in ulcerative colitis (UC) and to study the role of JG in PNS via pharmacodynamic, pharmacokinetic, and tissue distribution analyses. MATERIALS AND METHODS: For the pharmacodynamic study, the UC rat model was induced using 5% trinitrobenzene sulfonic acid (TNBS). The results of the macroscopic characterization, histological analysis, and cytokine levels, including those of tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-κB), were integrated to evaluate the treatment of UC with PNS. In addition, an LC-MS/MS method was established and validated to analyze the blood pharmacokinetic parameters and tissue distribution of naringin and paeoniflorin. RESULTS: After the administration of high-dose PNS, the UC rats showed amelioration of macroscopic damage at the lesion site. The cytokine levels in the plasma, colon, and lung tissues were also decreased. The pharmacokinetic parameters showed that compared with UC rats administered with PNS-JG, those administered with PNS showed an increase in the AUC, MRT, and Tmax of naringin and paeoniflorin, and a decrease in their clearance rate. Furthermore, naringin and paeoniflorin had higher concentrations in the colon and lung tissues in the normal and model groups administered with PNS than in those administered with PNS-JG. CONCLUSIONS: PNS was shown to have marked therapeutic efficacy against TNBS-induced UC in rats. The effect of JG in PNS was reflected by the differences in the pharmacokinetic parameters and tissue distribution of the active components, providing valuable information for the clinical application of PNS in the treatment of UC. However, knowledge about how JG works as an adjuvant medicine in PNS is still lacking.


Asunto(s)
Campanulaceae , Colitis Ulcerosa , Medicamentos Herbarios Chinos , Fitoterapia , Animales , Ratas , Área Bajo la Curva , Campanulaceae/química , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Citocinas/genética , Citocinas/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Semivida , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Polvos , Ratas Sprague-Dawley , Distribución Tisular , Ácido Trinitrobencenosulfónico/toxicidad
11.
Molecules ; 26(23)2021 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-34885653

RESUMEN

In this research, the effects of drying method, storage temperature, and color protector glucose on anthocyanin preservation in the Lycium ruthenicum Murr. fruit were studied. Compared with hot-air drying, vacuum freeze-drying preserved about 5.8-fold more anthocyanins. The half-life of anthocyanins in the freeze-dried fruit samples with glucose was 3.6 days, 1.8 days, and 1.7 days at 4 °C, 20 °C, and 37 °C, respectively. On the other hand, the half-life values without glucose addition were 2.2 days, 2.3 days, and 2.1 days at each temperature, respectively, indicating that glucose protected anthocyanins at low temperature. The composition and contents of anthocyanins and anthocyanidins in the freeze-dried Lycium ruthenicum Murr., stored for 20 days, were investigated with a HPLC-MS/MS setup. It was found that most anthocyanidins in Lycium ruthenicum Murr. are linked with coumaroyl glucose to form anthocyanins, while glycosylated and acetyl-glycosylated anthocyanins were also detected. Five anthocyanidins were detected: delphinidin, cyanidin, petunidin, malvidin, and peonidin, and delphinidin accounts for about half of the total amount of anthocyanidins. It is much more economic to conserve anthocyanins in situ with freeze-drying methods and to store the fruits at low temperatures with glucose.


Asunto(s)
Antocianinas/análisis , Frutas/química , Lycium/química , Pigmentos Biológicos/análisis , Extractos Vegetales/análisis , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Liofilización/métodos , Glucosa/química , Semivida , Espectrometría de Masas en Tándem/métodos , Temperatura
12.
J Med Chem ; 64(23): 17239-17258, 2021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34797051

RESUMEN

Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and ß-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.


Asunto(s)
Agonistas de Dopamina/química , Agonistas de Dopamina/farmacología , Diseño de Fármacos , Receptores de Dopamina D2/agonistas , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Agonistas de Dopamina/síntesis química , Agonistas de Dopamina/farmacocinética , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Ratones , Ratones Endogámicos ICR , Estereoisomerismo , Relación Estructura-Actividad
13.
J Environ Sci Health B ; 56(12): 1042-1050, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34846269

RESUMEN

In the present study, an analytical method that combined a modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) method and high-performance liquid chromatography coupled with tandem mass spectrometry was developed to determine trifluorocide in fresh and dried ginseng roots, plants (stems and leaves), and soil. At three spiked levels (0.01, 0.1, and 1.0 mg kg-1), the mean recoveries (n = 15) of trifluorocide from fresh and dried ginseng roots, plants, and soil were in the range of 95.6 - 109.7%, with relative standard deviations less than 10.0%. The limits of quantitation of different matrices were determined to be 0.01 mg kg-1. Dissipation and residue study of trifluorocide was conducted in ginseng cultivation ecosystems in Northeast China. The t1/2 (half-life) of trifluorocide in ginseng fresh roots, plants, and soil were 8.3-13.1 days, 7.4-10.9 days, and 8.8-10.6 days, respectively. The terminal residues of trifluorocide in ginseng fresh roots were less than 0.01 mg kg-1 after 35 days of trifluorocide application. This study could be beneficial in residue analysis and assist in the scientific application of trifluorocide during ginseng cultivation.


Asunto(s)
Panax , Residuos de Plaguicidas , Contaminantes del Suelo , Cromatografía Líquida de Alta Presión , Ecosistema , Monitoreo del Ambiente/métodos , Semivida , Panax/química , Residuos de Plaguicidas/análisis , Suelo/química , Contaminantes del Suelo/análisis , Espectrometría de Masas en Tándem/métodos
14.
Pharm Biol ; 59(1): 1528-1532, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34726569

RESUMEN

CONTEXT: The interaction between nobiletin and anemarsaponin BII could affect the pharmacological activity of these two drugs during their combination. OBJECTIVE: The co-administration of nobiletin and anemarsaponin BII was investigated to explore the interaction and the potential mechanism. MATERIALS AND METHODS: Male Sprague-Dawley rats were only orally administrated with 50 mg/kg nobiletin as the control and another six rats were pre-treated with 100 mg/kg anemarsaponin BII for 7 d followed by the administration of nobiletin. The transport and metabolic stability of nobiletin were evaluated in vitro, and the effect of anemarsaponin BII on the activity of CYP3A4 was also assessed to explore the potential mechanism underlying the interaction. RESULTS: The increasing Cmax (2309.67 ± 68.06 µg/L vs. 1767.67 ± 68.86 µg/L), AUC (28.84 ± 1.34 mg/L × h vs. 19.57 ± 2.76 mg/L × h), prolonged t1/2 (9.80 ± 2.33 h vs. 6.24 ± 1.53 h), and decreased clearance rate (1.46 ± 0.26 vs. 2.42 ± 0.40) of nobilein was observed in rats. Anemarsaponin BII significantly enhanced the metabolic stability of nobiletin in rat liver microsomes (half-life increased from 31.56 min to 39.44 min) and suppressed the transport of nobiletin in Caco-2 cells (efflux rate decreased from 1.57 ± 0.04 to 1.30 ± 0.03). The inhibitory effect of anemarsaponin BII on CYP3A4 was also found with an IC50 value of 10.23 µM. DISCUSSION AND CONCLUSIONS: The interaction between anemarsaponin BII and nobiletin was induced by the inhibition of CYP3A4, which should draw special attention in their clinical co-administration.


Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacología , Citocromo P-450 CYP3A/efectos de los fármacos , Flavonas/farmacocinética , Saponinas/farmacología , Triterpenos/farmacología , Animales , Área Bajo la Curva , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Interacciones Farmacológicas , Flavonas/administración & dosificación , Semivida , Humanos , Concentración 50 Inhibidora , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Saponinas/administración & dosificación , Triterpenos/administración & dosificación
15.
Drug Deliv ; 28(1): 2205-2217, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34662257

RESUMEN

Therapeutic efficacies of orally administrated hydrophobic chemodrugs are decreased by poor water solubilities and reduced oral bioavailabilities by P-glycoprotein (P-gp) and CYP450. In this study, CPT11 alone or combined with dual-function inhibitors (baicalein (BA) silymarin (SM), glycyrrhizic acid (GA), and glycyrrhetinic acid (GLA)) of P-gp and CYP450 loaded in a lecithin-based self-nanoemulsifying nanoemulsion preconcentrate (LBSNENP) to improve the solubility and inhibit the elimination by P-gp and CYP450. Results revealed that the LBSNENP composed of Capryol 90, lecithin/Tween 80/Cremophor EL, and propylene glycol at a weight ratio of 18:58:24 (designated PC90C10P0) was optimally selected. Encapsulating CPT11 with PEO-7000K in PC90C10P10/30 further enhanced the resultant hydrogel to be gastro-retainable and to release CPT11 in a sustained manner. Pharmacokinetic study of CPT11-loaded PC90C10P0 administered orally revealed an absolute bioavailability (FAB, vs. intravenous CPT11) of 7.8 ± 1.01% and a relative bioavailability (FRB1, vs. oral solution of CPT11) of 70.7 ± 8.6% with a longer half-life (T1/2) and mean residence time (MRT). Among the dual-function inhibitors, SM was shown to be the most influential in increasing the oral bioavailability of CPT11. SM also increased the plasma concentration of the SN-38 active metabolite, which formed from the enhanced plasma concentration of CPT11. It is concluded that treatment with CPT11 loaded in PC90C10P0 with or without solubilization with SM could expose tumors to higher plasma concentrations of both CPT11 and SN-38 leading to enhancement of tumor growth inhibition with no signs of adverse effects.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/farmacología , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Irinotecán/farmacología , Nanopartículas/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Supervivencia Celular/efectos de los fármacos , Química Farmacéutica , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Emulsiones/química , Flavanonas/farmacología , Ácido Glicirretínico/farmacología , Ácido Glicirrínico/farmacología , Semivida , Irinotecán/administración & dosificación , Irinotecán/farmacocinética , Ratones , Neoplasias Pancreáticas , Conejos , Distribución Aleatoria , Silimarina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Mol Pharm ; 18(9): 3260-3271, 2021 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-34482698

RESUMEN

Hypoparathyroidism (HP) is a rare disease with clinical manifestations of hypocalcemia and hyperphosphatemia, resulting from deficient or absent parathyroid hormone (PTH) secretion. Conventional treatment for patients with HP involves extensive calcium and vitamin D supplementation. In 2015, PTH1-84 was approved by the United States Food and Drug Administration as an adjunct for HP patients who cannot be well-controlled on conventional treatment. However, PTH1-84 therapy requires a daily injection, leading to poor patient compliance. The purpose of this study was to develop a long-acting PTH1-34 analogue by increasing its affinity to albumin. Three PTH1-34 variants were generated by substituting two of the three lysine (Lys) residues with arginine, reserving a single Lys as the modification site in each sequence. A series of side chains, containing fatty acid, deoxycholic acid, or biotin groups, were synthesized to modify these PTH1-34 variants by using a solid-liquid phase synthesis approach. In vitro bioactivity and albumin affinity tests were used to screen these new PTH1-34 analogues. Finally, Lys27-AAPC was selected from 69 synthesized analogues as a candidate therapeutic compound because it retained potency and exhibited a high albumin-binding capacity. In pharmacodynamic experiments, Lys27-AAPC demonstrated enhanced and prolonged efficacy in serum calcium elevating relative to PTH1-84. Moreover, a lyophilized powder for injection containing Lys27-AAPC was developed for further testing and represented a potential long-acting HP treatment.


Asunto(s)
Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Péptidos/administración & dosificación , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Calcio/sangre , Esquema de Medicación , Semivida , Humanos , Hipoparatiroidismo/sangre , Inyecciones Subcutáneas , Masculino , Cumplimiento de la Medicación , Ratones , Modelos Animales , Hormona Paratiroidea/genética , Hormona Paratiroidea/farmacocinética , Péptidos/genética , Péptidos/farmacocinética , Ratas , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacocinética , Relación Estructura-Actividad
17.
BMJ Open ; 11(9): e044997, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34475142

RESUMEN

INTRODUCTION: Haemophilia A is a rare bleeding disorder caused by defects in coagulation factor VIII (FVIII). Damoctocog alfa pegol (BAY 94-9027, Jivi, Bayer, Germany) is a site-specifically PEGylated, extended-half-life, recombinant FVIII, approved for use in previously treated patients (PTPs) aged ≥12 years with haemophilia A. However, a real-world evidence regarding routine clinical use of damoctocog alfa pegol is limited. METHODS AND ANALYSIS: HEM-POWR is a multinational, multicentre, non-interventional, prospective, postmarketing cohort study evaluating the effectiveness and safety of real-world treatment with damoctocog alfa pegol. Estimated enrolment is ≥200 PTPs with haemophilia A, receiving damoctocog alfa pegol (on-demand, prophylaxis or intermittent prophylaxis (as per local label)), observed for 36 months. Primary outcomes are total bleeding events and annualised bleeding rate; secondary outcomes include long-term safety, joint health, pharmacokinetics, patient-reported outcomes (PROs) from validated questionnaires and perioperative haemostasis. Where applicable, reasons for switching to damoctocog alfa pegol, choice of treatment regimen and dose will also be captured. Exploratory and descriptive statistical analyses will be performed, and will be stratified by parameters including, but not limited to, prophylaxis regimen and haemophilia severity. Patients can record bleeds and consumption in electronic (e) Diaries, ePROs, and can access non-promotional study information (videos explaining study procedures) via an online patient portal. Optionally, patients can enrol in the LIFE-ACTIVE substudy designed to investigate the relationship between activity (measured by the ActiGraph CP Insight watch) and effectiveness parameters collected from HEM-POWR. ETHICS AND DISSEMINATION: Study approval was obtained by local independent ethics committees and authorities in participating study centres across Europe, the Americas and Asia. Informed consent from patients or their legal representative is a requirement for participation. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences. TRIAL REGISTRATION NUMBERS: NCT03932201, EUPAS26416. PROTOCOL VERSION AND DATE: V.1.2, 27 September 2019.


Asunto(s)
Hemofilia A , Estudios de Cohortes , Semivida , Hemofilia A/tratamiento farmacológico , Humanos , Estudios Prospectivos , Resultado del Tratamiento
18.
J Ethnopharmacol ; 281: 114544, 2021 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-34419608

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima (Roxb.) Wight et Arn is a medicinal plant mainly distributed in southwest China. It is used in folk medicine for the treatment of tumors and is synergistic with chemotherapies. In our previous study, 11α-O-2-methybutyryl-12ß-O-tigloyl-tenacigenin B (MT2), a main steroid aglycone isolated from the total aglycones of M. tenacissima, significantly enhanced the in vivo antitumor effect of paclitaxel in mice bearing human tumor xenografts, showing its potential as a chemosensitizer. However, the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 remain unclear. AIM OF THE STUDY: To elucidate the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 in rats. MATERIALS AND METHODS: MT2 in rat plasma and phosphate-buffered saline was quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method, while the MT2 metabolites in rat liver microsomes were analyzed using UPLC-triple time-of-flight MS/MS. RESULTS: For intravenously administered MT2, the maximum plasma concentration and the area under the plasma concentration-time curve indicated dose dependency, while the elimination half-life time, the mean residence time, apparent volume of distribution and total apparent clearance values remained relatively unchanged in both the 5 mg/kg and 10 mg/kg groups. For orally administered MT2, the bioavailability was 1.08-1.11%. In rat plasma, MT2 exhibited a protein binding rate of 93.84-94.96%. In rat liver microsomes, MT2 was metabolized by oxidation alone or in combination with demethylation, and five MT2 metabolites were identified. CONCLUSION: MT2 has low oral bioavailability and a high plasma protein binding rate in rats. After administration, MT2 is transformed into oxidative metabolites in the liver. To achieve a high blood concentration of MT2, it should be administered intravenously. These findings would serve as a reference for further MT2-based pharmacological study and drug development.


Asunto(s)
Productos Biológicos/farmacocinética , Proteínas Sanguíneas/metabolismo , Marsdenia/química , Extractos Vegetales/farmacocinética , Administración Oral , Adsorción , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Productos Biológicos/metabolismo , Proteínas Sanguíneas/química , Cromatografía Liquida , Medicamentos Herbarios Chinos , Semivida , Inyecciones Intravenosas , Masculino , Microsomas Hepáticos/metabolismo , Estructura Molecular , Paclitaxel/análogos & derivados , Paclitaxel/química , Fitoterapia , Extractos Vegetales/química , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem
19.
Artículo en Inglés | MEDLINE | ID: mdl-34266375

RESUMEN

Honey is a traditional food additive that can be used to preserve food, increase the flavour of food, and enhance the effect of some functional foods. Mulberry leaf is a popular tea, and it is also an anti-diabetic medicinal material. In the traditional processing of mulberry leaf tea, honey is a commonly used additive. This study used ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to measure the changes in the contents of 11 components of mulberry leaves before and after processing using honey as an additive. We analysed the absorption and elimination characteristics of mulberry leaves before and after processing in diabetes in vivo models, and then compared the effect of mulberry leaves before and after processing in resisting hyperglycaemia and hyperlipidaemia damage in in vitro models. The results showed that honey, as an additive, not only improves the dissolution of mulberry leaves, but in diabetes models also increases the utilisation of some components. In an in vitro model, honey mulberry leaves could significantly reduce the apoptosis of vascular endothelial cells. This demonstrated that the traditional processing method using honey as an additive could promote the anti-diabetic effect of mulberry tea. So far, this is the first research report on the quality and role of honey as an additive in mulberry leaf processing.Abbreviations: ML: mulberry leaves; HML: honey mulberry leaves; QC: quality control; HQC: high quality control sample; LLOQ: lower limit of quantification; LQC: low-quality control sample; MQC: medium-quality control sample; MRM: multiple reaction monitoring; STZ: streptozotocin.


Asunto(s)
Bebidas/análisis , Diabetes Mellitus/inducido químicamente , Miel/análisis , Morus/química , Hojas de la Planta/química , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Área Bajo la Curva , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cromatografía Liquida , Dieta Alta en Grasa , Azúcares de la Dieta/administración & dosificación , Azúcares de la Dieta/efectos adversos , Células Endoteliales/efectos de los fármacos , Manipulación de Alimentos , Semivida , Masculino , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem
20.
Eur J Drug Metab Pharmacokinet ; 46(4): 547-554, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34231117

RESUMEN

BACKGROUND AND OBJECTIVE: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (Ctrough; Cmax) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose. METHODS: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal ß-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) and Cmax/MIC. RESULTS: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin Cmax and Ctrough were 54.1 µg/mL (CV: 0.32) and 8.7 µg/mL (CV: 0.59), respectively; the mean calculated AUC0-24 was 742.7 µg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (Vd,ss) and the half-life (t1/2) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CLwp) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average Cmax and AUC0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers. CONCLUSIONS: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested.


Asunto(s)
Antibacterianos/administración & dosificación , Daptomicina/administración & dosificación , Endocarditis Bacteriana/tratamiento farmacológico , Metadona/administración & dosificación , Adulto , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Área Bajo la Curva , Daptomicina/farmacocinética , Daptomicina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Endocarditis Bacteriana/microbiología , Femenino , Semivida , Humanos , Masculino , Metadona/farmacología , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/aislamiento & purificación , Distribución Tisular
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