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Introducción: a pesar de los avances en tratamiento antirretroviral, existe la posibilidad de que personas que viven con el virus de la inmunodeficiencia humana (VIH) experimenten falla terapéutica vinculada a múltiples factores que impactan en la respuesta al fármaco. Objetivos: evaluar la utilidad de aplicar un modelo farmacocinético en pacientes con diagnóstico de VIH en tratamiento con dolutegravir para el análisis de las concentraciones plasmáticas experimentales. Adicionalmente, se pretende identificar potenciales interacciones farmacológicas, evaluar adherencia y fallo terapéutico. Material y método: se realizó un estudio piloto transversal y observacional en pacientes VIH tratados con dolutegravir que incluyó la dosificación de la concentración plasmática, evaluación de adherencia mediante el cuestionario simplificado de adherencia a la medicación (SMAQ) y retiro de medicación. Se utilizó un modelo poblacional referenciado en la bibliografía para la predicción de concentraciones de dolutegravir en cada paciente y se compararon con las concentraciones experimentales. Resultados: fueron incluidos en el estudio 21 pacientes. Al cotejar las concentraciones plasmáticas experimentales con la simulación farmacocinética se encontraron diferencias para 12 pacientes, las cuales se explican por posibles interacciones farmacológicas, mala adherencia u otros factores que afectan la farmacocinética. Se detectó 38% de no adherencia de acuerdo con SMAQ y 23% de acuerdo con el retiro de medicación. Conclusiones: se expone el rol potencial de los modelos farmacocinéticos para la interpretación de concentraciones plasmáticas y se genera la necesidad de avanzar en este tipo de estudios para el establecimiento de rango terapéutico y aplicabilidad clínica.
Introduction: Despite advances in antiretroviral treatment, there is a possibility that people living with HIV may experience treatment failure linked to multiple factors that impact drug response. Objective: To evaluate the usefulness of applying a pharmacokinetic model in patients diagnosed with HIV undergoing treatment with dolutegravir for the analysis of experimental plasma concentrations. Additionally, the aim is to identify potential drug interactions, assess adherence, and therapeutic failure. Method: A cross-sectional, observational pilot study was conducted in HIV patients treated with dolutegravir, which included plasma concentration dosing, assessment of adherence using the Simplified Medication Adherence Questionnaire (SMAQ), and medication withdrawal. A population-based model referenced in the literature was used to predict dolutegravir concentrations in each patient and these were compared with experimental concentrations. Results: Twenty-one patients were included in the study. When comparing experimental plasma concentrations with pharmacokinetic simulation, differences were found for 12 patients, which can be explained by possible drug interactions, poor adherence, or other factors affecting pharmacokinetics. Non-adherence was detected in 38% according to the SMAQ and 23% according to medication withdrawal. Conclusions: The potential role of pharmacokinetic models in the interpretation of plasma concentrations is highlighted, emphasizing the need to advance in this type of studies to establish therapeutic ranges and clinical applicability.
Introdução: Apesar dos avanços no tratamento antirretroviral, existe a possibilidade de que pessoas que vivem com HIV experimentem falha terapêutica ligada a múltiplos fatores que impactam na resposta ao medicamento. Objetivos: Avaliar a utilidade da aplicação de um modelo farmacocinético em pacientes com diagnóstico de HIV em tratamento com dolutegravir para análise de concentrações plasmáticas experimentais. Além disso, pretende-se identificar potenciais interações medicamentosas, avaliar a adesão e a falha terapêutica. Método: Um estudo piloto observacional transversal foi conduzido em pacientes HIV tratados com dolutegravir que incluiu dosagem de concentração plasmática, avaliação de adesão usando o questionário simplificado de adesão à medicação (SMAQ) e retirada da medicação. Um modelo populacional referenciado na literatura foi utilizado para prever as concentrações de dolutegravir em cada paciente e compará-las com as concentrações experimentais. Resultados: 21 pacientes foram incluídos no estudo. Ao comparar as concentrações plasmáticas experimentais com a simulação farmacocinética, foram encontradas diferenças em 12 pacientes, que são explicadas por possíveis interações medicamentosas, má adesão ou outros fatores que afetam a farmacocinética. Foram detectadas 38% de não adesão segundo o SMAQ e 23% segundo retirada da medicação. Conclusões: Fica exposto o papel potencial dos modelos farmacocinéticos para a interpretação das concentrações plasmáticas e gera-se a necessidade de avançar neste tipo de estudos para estabelecer a faixa terapêutica e a aplicabilidade clínica.
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Abstract A novel, simple and sensitive high-performance liquid chromatography with fluorescence detection method was developed and validated for the characterization of the preclinical pharmacokinetics of melatonin under pregnant conditions. Plasma samples (25 µL) were treated with 30 µL of ethanol absolute (containing the internal standard, IS). After a centrifugation process, aliquots of supernant (5 µL) were injected into the chromatographic system. Compounds were eluted on a Xbridge C18 (150 mm x 4.6 mm i.d., 5 µm particle size) maintained at 30°C. The mobile phase consisted in a mixture of aqueous solution of 0.4% phosphoric acid and acetonitrile (70:30 v/v). The wavelengths were set at 305 nm (excitation) and 408 nm (emission) and the total analysis time was 8 min/sample. All validation tests were obtained with accuracy and precision, according to FDA guidelines, over the concentration range of 0.005-20 µg/mL. Pharmacokinetic study showed that melatonin systemic exposure increased from day 14, with a significant difference at 19 days of gestation compared to the control group. Our findings suggest a decreased metabolism of melatonin as result of temporary physiological changes that occur throughout pregnancy. However, other maternal physiological changes cannot be ruled out.
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ObjectiveTo study the plasma pharmacokinetics and tissue distribution of five representative components in Wujiwan， and to illustrate the difference of metabolism and tissue distribution before and after compatibility. MethodHealthy male SD rats were divided into four groups， including Wujiwan group（A group， 62.96 g·L-1）， Coptidis Rhizoma group（B group， 38.4 g·L-1）， processed Euodiae Fructus group（C group， 5.88 g·L-1） and fried Paeoniae Radix Alba group（D group， 18.68 g·L-1）， with 65 rats in each group， and were administered the drugs according to the clinical dose of decoction pieces converted into the dose of the extracts. Then plasma， liver， small intestine and brain were taken at pharmacokinetic set time in each group after administration. Ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry was developed for the quantitative analysis of five representative components［berberine（Ber）， palmatine（Pal）， evodiamine（Evo）， rutecarpine（Rut） and paeoniflorin（Pae）］ in Wujiwan， their concentrations in plasma， liver， small intestine and brain were detected at different time， plasma samples were processed by protein precipitation， and tissue samples were pretreated by protein precipitation plus liquid-liquid extraction. Non-atrioventricular model was used to calculate the pharmacokinetic parameters of each component， and the parameters of each group were compared. ResultPharmacokinetic results of A group showed that area under the curve（AUC0-t） of the five representative components were ranked as follows：Ber and Pal were small intestine>liver>blood， Evo and Rut were liver>small intestine>plasma， Pae was small intestine>plasma， which was not detected in the liver， no other components were detected in brain except for Ber. In comparison with plasma and other tissues， peak concentration（Cmax） of Ber， Pal， Evo， and Rut were the highest and time to peak（tmax） were the lowest in the liver of A group. In plasma， the AUC0-t and Cmax of Evo and Rut were increased in A group compared with C group， tmax of Pea was elevated and its Cmax was decreased in A group compared with D group. In the liver， compared with B-D groups， Cmax values of 5 representative components except Pae were elevated， AUC0-t of Pae was decreased and AUC0-t of Evo and Rut were increased in the A group. In the small intestine， half-life（t1/2） of each representative components in A group was elevated and tmax was decreased， and Cmax of each representative ingredient except Pal was decreased， AUC0-t values of Ber and Pal were increased， whereas the AUC0-t values of Evo and Rut were decreased. ConclusionThe small intestine， as the effector organ， is the most distributed， followed by the liver. The pharmacokinetic parameters of the representative components in Wujiwan are changed before and after compatibility， which is more favorable to the exertion of its pharmacodynamic effects.
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ObjectiveTo clarify the scientific validity of in vivo pharmacokinetic determination of the whole drug composition in Shenbai nanosuspension in rats， and to provide methodological guidance and theoretical basis for the in vivo study of multi-component complex system of traditional Chinese medicine（TCM） preparations. MethodThe concentration of the overall components， mainly total saponins and total polysaccharides in Shenbai decoction and Shenbai nanosuspension， was determined in rat plasma at different times by area under the absorbance-wavelength curve method（AUAWC）， and the concentration of individual ginsenoside Rg1 was determined by high performance liquid chromatography（HPLC）， and the methodology was verified. The pharmacokinetic parameters of the whole component were compared with those of ginsenoside Rg1 to evaluate the in vivo operational characteristics of the two preparations. ResultThe methodological investigations of AUAWC and HPLC were in accordance with the requirements. AUAWC analysis showed that the overall components in both the decoction group and the nanosuspension group showed a one-compartment model， with half-life（t1/2） of 2.43 h and 2.04 h， respectively. The relative bioavailability of Shenbai nanosuspension was 138.99%. HPLC assay showed that ginsenoside Rg1 in the decoction group and the nanosuspension group showed a two-compartment model， with distribution half-life（t1/2α） of 0.13 h and 2.55 h， and elimination half-life（t1/2β） were 14.28 h and 3.85 h， respectively. The relative bioavailability of Shenbai nanosuspension was 127.49%. Compared with Shenbai decoction， the time to peak（tmax）， peak concentration（Cmax） and area under the drug-time curve（AUC） of the overall components and ginsenoside Rg1 in Shenbai nanosuspension were increased. ConclusionThe established AUAWC can be used for the pharmacokinetic study of the overall components of TCM preparations， which is complementary to the results of individual components measured by HPLC， and can provide useful reference for the in vivo study of new dosage forms of TCM.
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Paridis Rhizoma possesses the functions of clearing heat and detoxifying， alleviating swelling and relieving pain， cooling the liver and calming the convulsion. Saponins are the main active components of Paridis Rhizoma. Studies have shown that total saponins in Paridis Rhizoma have obvious inhibitory effect on solid tumors such as breast cancer， lung cancer， gastric cancer， and liver cancer and non-solid tumors such as leukemia. The saponins may exert the anti-tumor effects by inhibiting the proliferation， migration， and invasion of tumor cells， regulating cell cycle， inducing apoptotic and non-apoptotic death pathways， and regulating metabolism and tumor microenvironment. Furthermore， total saponins in Paridis Rhizoma showed anti-inflammatory， antioxidant， antimicrobial， hemostatic， and uterus-contracting activities. At the same time， they may induce apoptosis of normal cells， inflammation and oxidative stress， and metabolic disorders. In recent years， the reports of liver injury， reproductive injury， gastrointestinal injury， hemolysis， and other adverse reactions caused by total saponins in Paridis Rhizoma have been increasing. Pharmacokinetic studies have shown that there are significant differences in the metabolism of total saponins in Paridis Rhizoma administrated in different ways. Injection has a fast clearance rate， while oral administration may have hepatoenteric circulation. Meanwhile， due to the low solubility and activation of P-glycoprotein （P-gp） molecular pump， the prototype absorption， intestinal permeability， and recovery rate of total saponins in Paridis Rhizoma are poor， which affects the bioavailability. The bioavailability can be improved to some extent by preparing new dosage forms or new drug delivery systems with advanced technology. This paper reviews the pharmacological effect， pharmacokinetics， and adverse reactions of Rhizoma Paridis total saponins by searching the China National Knowledge Infrastructure （CNKI）， VIP， and Web of Science with ''Rhizoma Paridis total saponins'' as the keywords， hoping to provide references for the research， development， and clinical application of such components.
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The relationship between cardiac output and anesthetic drugs is important to anesthesiologists, since cardiac output determines the speed with which a drug infused into the bloodstream reaches its target and the intensity of the drug's effect. But rather than focus on how anesthetic drugs affect cardiac output, this narrative review focuses on how changes in cardiac output affect the pharmacokinetics and pharmacodynamics of general anesthetics during the three phases of anesthesia. At induction, an increase in cardiac output shortens both the onset time of propofol for hypnosis and the neuromuscular blocking effect of rapid-acting neuromuscular blockers, favoring the conditions for rapid sequence intubation. During maintenance, changes in cardiac output are followed by opposite changes in the drug plasma concentration of anesthetic drugs. Thus, an increase in cardiac output followed by a decrease in the plasma concentration of the anesthetic could expose the patient to a real risk of intraoperative awakening, which can be avoided by increasing the dose of hypnotic drugs. At emergence, an increase in cardiac output secondary to an increase in pC02 allows for a more rapid recovery from anesthesia. The pC02 can be increased by adding CO2 to the respiratory circuit, lowering the ventilatory rate, or placing the patient on partial rebreathing. Finally, the reversal action of sugammadex for rocuronium-induced neuromuscular block can be shortened by increasing the cardiac output.
La relación entre el gasto cardíaco y los fármacos anestésicos es importante para los anestesiólogos puesto que el gasto cardíaco determina la velocidad con la cual un medicamento que se infunde al torrente sanguíneo llega a su diana y la intensidad del efecto del agente. Pero en lugar de concentrarnos en cómo los fármacos anestésicos afectan el gasto cardíaco, esta revisión narrativa se enfoca en cómo los cambios en el gasto cardíaco afectan la farmacocinética y la farmacodinámica de los agentes anestésicos generales durante las tres fases de la anestesia. En el momento de la inducción, un incremento en el gasto cardíaco acorta tanto el tiempo de inicio del efecto del propofol para la hipnosis como el efecto del bloqueo neuromuscular causado por los bloqueadores neuromusculares de acción rápida, favoreciendo las condiciones para la intubación de secuencia rápida. Durante la fase de mantenimiento, los cambios en el gasto cardíaco vienen seguidos de cambios opuestos en la concentración plasmática del medicamento de los agentes anestésicos. Por lo tanto, un aumento del gasto cardíaco, seguido de una reducción en la concentración plasmática del anestésico, podría exponer al paciente a un riesgo real de despertar intraoperatorio, lo cual puede evitarse aumentando la dosis de los fármacos hipnóticos. En la educción, un aumento en el gasto cardíaco secundario al incremento en el pCO2 permite una recuperación más rápida de la anestesia. El pCO2 puede aumentar agregando CO2 al circuito de la respiración, reduciendo la tasa ventilatoria, o colocando al paciente en re-inhalación parcial. Finalmente, la acción de reversión de sugammadex en caso de bloqueo neuromuscular inducido por rocuronio, puede acortarse aumentando el gasto cardíaco.
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Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (Cmax) of RMP was significantly higher (RMP: 8.5 ?g/ml vs. 5.5 ?g/ml; P=0.003) and Cmax of INH was significantly lower (INH: 4.8 ?g/ml vs. 10.9 ?g/ml; P<0.001) in case of daily dosing compared to thrice-weekly ATT. Cmax of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP Cmax (8.0 ?g/ml) during thrice-weekly compared to daily ATT (78% vs. 36%; P=0.004). Multiple linear regression analysis showed that Cmax of RMP was significantly influenced by the dosing rhythm, pulmonary TB and Cmax of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.
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Introduction: Montelukast, a selective and active leukotriene receptor antagonist, is one of the most common agents in asthma treatment for both adults and children. Objective: To assess whether the pharmacokinetic profiles of two formulations of montelukast were similar after a single 5 mg dose (chewable tablets), administered orally under fasting conditions, sampling blood before and 36 hours after administration. Methods: This was a randomized, 2-sequence, 2-period, crossover study of 2 chewable tablet formulations of the drug: Singulair®, provided by Merck Sharp and Dohme Farmacêutica Ltda. (reference), and generic montelukast, manufactured by Eurofarma Laboratórios S.A. (test). Plasma samples obtained from 35 participants were analyzed for montelukast through high-performance liquid chromatography coupled to tandem mass spectrometry, with montelukast-d6 as the internal standard. Peak montelukast concentrations were 299.313 (SD, 11.039) ng/mL for the reference formulation and 279.803 (SD, 10.085) ng/mL for test formulation. Results: Statistical analysis showed no significant differences between AUC0-36h, AUC0-inf, or Cmax between formulations, with the following test/reference ratios: 102.458 for AUC0-36h, 102.522 for AUC0-inf, and 93.490 for Cmax. No serious adverse events were reported during the trial. Our results demonstrated the bioequivalence of Singulair® and Eurofarma's generic montelukast. Conclusions: Our results revealed that the new generic tablets are clinically safe and can be used interchangeably with the brand name product. Eurofarma's montelukast offers a safe, effective, and cheaper treatment option for people with asthma or allergic rhinitis.
Introdução: O montelucaste, um antagonista seletivo e ativo dos receptores de leucotrienos, é um dos agentes mais comumente usados na prática clínica no tratamento da asma, tanto em adultos quanto em crianças. Objetivo: Avaliar se os perfis farmacocinéticos de duas formulações de montelucaste eram semelhantes após uma dose única de comprimidos mastigáveis de 5 mg, administrados por via oral em jejum, coletando amostras de sangue desde antes da administração até 36 horas depois disso. Métodos: Estudo comparativo randomizado, 2 sequências e 2 períodos, cruzado, de dois medicamentos em comprimidos mastigáveis: Singulair®, fornecido pela Merck Sharp e Dohme Farmacêutica Ltda. (referência) e Montelucaste 5 mg, fabricado pela Eurofarma Laboratórios S.A. (teste). Amostras de plasma obtidas de 35 indivíduos elegíveis foram analisadas para montelucaste por cromatografia líquida de alta eficiência acoplada a espectrometria de massa em tandem, tendo Montelucaste-d6 como padrão interno. As concentrações máximas de montelucaste foram 299,313±11,039 ng/mL para referência e 279,803±10,085 ng/mL para formulação de teste. Resultados: A análise estatística não mostrou diferenças significativas para AUC0-36h, AUC0-inf e nem para Cmax entre as formulações, apresentando as razões Teste/Referência: 102,458 para AUC0-36h, 102,522 para AUC0-inf e 93,490 para Cmax. Nenhum evento adverso grave foi relatado durante o estudo. De acordo com a regulamentação brasileira, o atual estudo farmacocinético demonstrou bioequivalência entre os agentes individuais e forneceu evidências de bioequivalência entre Singulair® e Montelukast fabricado pela Eurofarma. Resultado: Os resultados mostraram que os novos comprimidos genéricos são clinicamente seguros e podem ser trocados pela marca original. O montelucaste da Eurofarma oferece uma opção de tratamento mais barata, segura e eficaz para indivíduos com asma ou rinite alérgica.
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Humans , Adolescent , Adult , Middle AgedABSTRACT
Clinical pharmacy is a health discipline in which pharmacists provide patient care that optimizes rational medication use and promotes health, wellness and disease prevention. The beginnings of clinical pharmacy in Chile were inspired by the origin in the School of Pharmacy of the University of California, San Francisco (UCSF), in the mid-1960s. However, the historical development in our country, both in teaching and in the professional field, was accompanied by difficulties and success, which became a long and winding road. This article shares the events that gave rise to its beginnings in Chile, first through teaching, then in pharmacovigilance and clinical pharmacokinetics, to later describe its professional expansion and recognition as a specialty of pharmacy. This article briefly recounts the history of the Chilean clinical pharmacy to this day. Some names of people or institutions were not mentioned. Therefore the authors apologize in advance to pharmacists and organizations whose contribution cannot be recognized in this way. However, we know that this specialty has not been forged only by the names that appear, but by all those who love and respect the work of the clinical pharmacy.
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Humans , History, 20th Century , History, 21st Century , Pharmacy , Pharmacy Service, Hospital/history , Pharmacists , ChileABSTRACT
Atherosclerotic cardiovascular disease(ASCVD)frequently results in sudden death and poses a serious threat to public health worldwide.The drugs approved for the prevention and treatment of ASCVD are usually used in combination but are inefficient owing to their side effects and single therapeutic targets.Therefore,the use of natural products in developing drugs for the prevention and treatment of ASCVD has received great scholarly attention.Andrographolide(AG)is a diterpenoid lactone compound extracted from Andrographis paniculata.In addition to its use in conditions such as sore throat,AG can be used to prevent and treat ASCVD.It is different from drugs that are commonly used in the prevention and treatment of ASCVD and can not only treat obesity,diabetes,hyperlipidaemia and ASCVD but also inhibit the pathological process of atherosclerosis(AS)including lipid accumulation,inflammation,oxidative stress and cellular abnormalities by regulating various targets and pathways.However,the pharmaco-logical mechanisms of AG underlying the prevention and treatment of ASCVD have not been corrobo-rated,which may hinder its clinical development and application.Therefore,this review summarizes the physiological and pathological mechanisms underlying the development of ASCVD and the in vivo and in vitro pharmacological effects of AG on the relative risk factors of AS and ASCVD.The findings support the use of the old pharmacological compound('old bottle')as a novel drug('novel wine')for the pre-vention and treatment of ASCVD.Additionally,this review summarizes studies on the availability as well as pharmaceutical and pharmacokinetic properties of AG,aiming to provide more information regarding the clinical application and further research and development of AG.
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On December 22,2021,the United States Food and Drug Administration approved the first main protease inhibitor,i.e.,oral antiviral nirmatrelvir(PF-07321332)/ritonavir(Paxlovid),for the treatment of early severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Nirmatrelvir inhibits SARS-CoV-2 infection,but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression.The chiral structure of nirmatrelvir plays a key role in its antiviral activity.Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites.Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir.However,Paxlovid has many contraindications.Some patients treated with Paxlovid experience a second round of coronavirus disease 2019(COVID-19)symptoms soon after re-covery.Interestingly,the antiviral activity of nirmatrelvir metabolites,such as compounds 12-18,is similar to or higher than that of nirmatrelvir.Herein,we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.
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OBJECTIVE To establish a physiologically-based pharmacokinetic （PBPK） model of amikacin in elderly patients with renal insufficiency. METHODS PK-SIM® software was adopted for model building， optimization and simulation. The physical and chemical properties and pharmacokinetic parameters related to amikacin were collected by literature review. The PBPK model on adults was established and extrapolated to the elderly population based on the built-in human model. Data from clinical PK studies were used to optimize and validate the model. The goodness of fit， relative residual， and mean folding error （MFE） were used to evaluate the performance of forecasting. The final model was employed to simulate the exposure of amikacin in the elderly population with renal insufficiency， and the efficacy and safety of commonly used clinical dosing regimens were evaluated， and the recommended regimens were proposed. RESULTS The established PBPK model of amikacin had good prediction performance in both adult and elderly populations， with the absolute mean of relative residual value of 25%； the MFE of peak concentration （cmax） and area under the plasma concentration curve （AUC0－∞） in all simulation occasions ranged ＞0.5-＜2. The simulation results showed that， compared with healthy adults， no significant clinical difference in cmax was observed in the elderly with renal insufficiency at the same dosing regimen， but the trough concentration increased significantly due to accumulation. Prolonging the administration interval of amikacin rather than reducing the dosage was more helpful to ensure the efficacy and to reduce the occurrence of nephrotoxicity. CONCLUSIONS The PBPK model for amikacin is successfully established in the elderly patient with renal insufficiency， and shows good predictive performance.
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OBJECTIVE To investigate the effects of Yiru tiaojing granules on the pharmacokinetics of olanzapine in rats. METHODS SD rats were randomly divided into 4 groups according to single-dose administration and multiple-dose administration， with 6 rats in each group. Groups A and B were given olanzapine （5 mg/kg） or olanzapine （5 mg/kg）+Yiru tiaojing granules （0.972 g/kg） in a single gavage， and groups C and D were administered with the same method once a day for 14 d. Blood was collected from the orbital venous plexus before administration and 5， 15， 30 min and 1， 2， 3， 6， 8， 12， 24 h after the last administration， respectively. The blood concentration was determined by LC-MS， and the pharmacokinetic parameters were calculated by using DAS 2.0 software. RESULTS Compared with group A， group B showed a significant decrease in AUC0－24 h， AUC0－∞ and cmax （P＜0.05）， and a significant prolongation of MRT0－24 h， MRT0－∞ and CLz/F （P＜0.05）； there was no statistically significant difference in the pharmacokinetic parameters between group C and group D （P＞0.05）. CONCLUSIONS A single administration of Yiru tiaojing granules can inhibit the absorption of olanzapine in rats， and long-term administration of Yiru tiaojing granules does not have a significant effect on the pharmacokinetic process of olanzapine.
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OBJECTIVE To study the pharmacokinetics of small molecule inhibitor SYHA1809 in Beagle dogs. METHODS LC-MS/MS method was adopted. Beagle dogs were randomly divided into single intravenous administration group （3.75 mg/kg）， single low-dose intragastric administration group （3.75 mg/kg）， single medium-dose intragastric administration group （7.5 mg/kg）， single high-dose intragastric administration group （15 mg/kg） and multiple intragastric administration group （7.5 mg/kg， once a day， for 7 consecutive days）， with 6 dogs in each group， half male and half female. The plasma samples of Beagle dogs were collected in each group according to the set time point， and underwent LC-MS/MS quantitative analysis after preprocessing. The pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.0 software using obtained data. RESULTS After intravenous injection， CL of SYHA1809 in Beagle dogs was （2.70±0.48） mL/（min·kg）， steady-state distribution volume was 0.757 L/kg， and t1/2 was （3.35±1.36） h； after single intragastric administration of low-dose， medium-dose and high-dose of SYHA1809， average tmax was （0.53±0.02） h， and the blood drug concentration increased with the increase of dose； after single intragastric administration of 3.75 mg/kg SYHA1809， the absolute bioavailability was 83.5%； within the dose range of 3.75-15 mg/kg， the increase in cmax and AUC of SYHA1809 was positively correlated with the dose； after intragastric administration of 7.5 mg/kg SYHA1809 for 7 consecutive days， the pharmacokinetic parameters of SYHA1809 were comparable to those of a single intragastric administration of the same dose， with no statistically significant difference （P＞0.05）. CONCLUSIONS SYHA1809 is absorbed rapidly in Beagle dogs， shows the dose-dependent blood concentration， high bioavailability， no obvious accumulation after multiple intragastric administration， and good pharmacokinetic behavior.
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OBJECTIVE@#To prepare vitamin E polyethylene glycol 1000 succinate (TPGS)-modified insulin-loaded liposomes (T-LPs/INS) and evaluate its safety, corneal permeability, ocular surface retention and pharmacokinetics in rabbit eyes.@*METHODS@#The safety of the preparation was investigated in human corneal endothelial cells (HCECs) using CCK8 assay and live/dead cell staining. In the ocular surface retention study, 6 rabbits were randomized into 2 equal groups for application of fluorescein sodium dilution or T-LPs/INS labeled with fluorescein in both eyes, which were photographed under cobalt blue light at different time points. In the cornea penetration test, another 6 rabbits divided into 2 groups for application of Nile red diluent or T-LPs/INS labeled with Nile red in both eyes, after which the corneas were harvested for microscopic observation. In the pharmacokinetic study, 2 groups of rabbits (n=24) were treated with eye drops of T-LPs/INS or insulin, and the aqueous humor and cornea were collected at different time points for measurement of insulin concentrations using enzyme linked immunosorbent assay. DAS2 software was used to analyze the pharmacokinetic parameters.@*RESULTS@#The prepared T-LPs/INS showed good safety in cultured HCECs. Corneal permeability assay and fluorescence tracer ocular surface retention assay demonstrated a significantly higher corneal permeability of T-LPs/INS with a prolonged drug residence in the cornea. In the pharmacokinetic study, insulin concentrations in the cornea at 6, 15, 45, 60, and 120 min (P < 0.01) and in the aqueous humor at 15, 45, 60, and 120 min after dosing were significantly higher in T-LPs/INS group. The changes in insulin concentrations in the cornea and aqueous humor were consistent with a two-compartment model in T-LPs/INS group and with the one-compartment model in the insulin group.@*CONCLUSION@#The prepared T-LPs/INS shows an improved corneal permeability, ocular surface retention capacity and eye tissue concentration of insulin in rabbits.
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Humans , Animals , Rabbits , Insulin , Liposomes , Endothelial Cells , Lipopolysaccharides , Vitamin E , Cornea , FluoresceinABSTRACT
Objective To study the eye irritation and the pharmacokinetics of tacrolimus-loaded cationic nanoemulsion-based in-situ gel in rabbits. Methods The eye irritation of tacrolimus-loaded cationic nanoemulsion-based in-situ gel in rabbits was observed by histological cross-sections of external ocular tissues stained with HE. The aqueous humor of rabbit eyes was extracted by corneal puncture and analyzed by HPLC-MS for pharmacokinetic study. Results Tacrolimus-loaded cationic nanoemulsion-based in-situ gel had no significant irritation on rabbit eyes. The pharmacokinetic parameter showed that the AUC of tacrolimus-loaded cationic nanoemulsion-based in-situ gel was (128.34±13.09) ng·h/ml, which was 1.13 times of tacrolimus-loaded cationic nanoemulsion (113.61±12.36) ng·h/ml and 1.88 times of Talymus® (68.25±10.82) ng·h /ml. Conclusion Tacrolimus-loaded cationic nanoemulsion-based in-situ gel had the advantages of low irritation, long retention time and high bioavailability in rabbit eyes. It has a good potential for clinical application.
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Objective To study the pharmacokinetics of HMS-01 in mice and provide support for subsequent studies. Methods Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to establish a sensitive and specific method for the determination of the concentration of HMS-01 in plasma and other biological samples. The pharmacokinetics of HMS-01 in C57BL/6J mice were studied by the established method. To obtain the basic pharmacokinetic parameters, three doses of HMS-01 were given orally and one dose of HMS-01 was given intravenously. Results The pharmacokinetic results of mice showed that the intestinal absorption of HMS-01 was fast, the oral bioavailability of HMS-01 in mice was moderate (50% to 70%). The exposure levels (AUC and cmax) of HMS-01 in mice increased with the increase of dosage, while the AUC was linearly correlated with the increase of dosage. After intravenous administration of HMS-01, the half-life period in mice was about 1 h which was not long. The plasma clearance rate (CLtotal.p) was 2.8 L/h·kg, which was similar to the hepatic blood flow of mice. The apparent volume of distribution (VSS) was 5 L/kg, which was much larger than the total mouse fluid. There were significant differences in AUC and F (P<0.05), but no significant differences in parameters such as cmax,AUC0−∞,t1/2,CLtot,p,MRT,Vss in male and female mice which were given 30 and 60mg/kg HWS-01 orally. Conclusion The pharmacokinetic process of HMS-01 in mice showed gender differences, and the area under the curve of blood concentration time and bioavailability of female mice were higher than that of male mice. As oral bioavailability was reasonable, further in vivo studies on HMS-01 in mice with heart failure by oral administration could be considered to provide evidence.
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OBJECTIVE To investigate the effects of omeprazole on pharmacokinetic parameters of imatinib in rats. METHODS According to body weight， the rats were divided into imatinib+low-dose， medium-dose， and high-dose omeprazole groups， imatinib group， with 6 rats in each group. They were given omeprazole suspension at the doses of 1.8， 3.6 and 7.2 g/kg， or 0.5% sodium carboxymethyl cellulose solution intragastrically respectively； one hour later， imatinib suspension was administered by oral gavage at a the dose of 10 mg/kg. Blood sample （100 μL） was taken from the orbit before and 0.5， 1， 2， 2.5， 3， 4， 5， 6， 8， 12， 24 and 36 hours after intragastric administration of imatinib. Using imatinib-d3 as internal standard， the plasma concentrations of imatinib and its metabolite N-desmethyl imatinib in rat were determined by high performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were calculated by DAS 2.0 software and compared. RESULTS Compared with imatinib group， AUC0－∞ and AUMC0－∞ of imatinib in rat plasma of imatinib+medium-dose omeprazole group， cmax， t1/2， AUC0－∞ and AUMC0－∞ of imatinib in rat plasma of imatinib+high-dose omeprazole group were all increased or prolonged significantly （P＜0.05）. Compared with imatinib group， AUC0－∞ and AUMC0－∞ of N-desmethyl imatinib in rat plasma of imatinib+medium-dose omeprazole group， and cmax and AUC0→∞ of N-desmethyl imatinib in rat plasma of imatinib+high-dose omeprazole group were decreased significantly （P＜0.05）. CONCLUSIONS Omeprazole may increase the plasma concentration of imatinib in rats and reduce the plasma concentration of N-desmethyl imatinib in rats， which may be associated with inhibiting the metabolism of imatinib.
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@#To evaluate bioequivalence and safety of two kinds of metformin hydrochloride sustained-release tablets (test preparation vs reference preparation) under the condition of fed and single administration.A single center, randomized, open, single-dose, two-period, two-sequence, and double-crossover design was used.32 healthy subjects took 0.5 g of test preparation or reference preparation under fed and single-dose administration.4 mL of venous blood was collected from before administration (0 h) to 1, 3, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 15, 24, 36 and 48 h after administration.The concentration of metformin in plasma samples was detected, and then the pharmacokinetic parameters were calculated by WinNonlin 7.0 software.When the 90% confidence intervals of cmax, AUC0-t and AUC0-∞ geometric mean ratio of test preparation and reference preparation were within 80.00%-125.00% equivalent intervals respectively, the bioequivalence of the two preparations was proved.One subject fell off due to adverse events.The main pharmacokinetic parameters of test preparation and reference preparation as follows: cmax were (0.68 ± 0.14) and (0.65 ± 0.11) mg/L, AUC0-t were (7.33 ± 1.65) and (7.00 ± 1.89) h·mg/L, AUC0-∞ were (7.39 ± 1.67) and (7.06 ± 1.91) h·mg/L, respectively.The 90% confidence intervals of the geometric mean ratio of the two main pharmacokinetic parameters were 101.45%-109.14%, 100.08%-112.32% and 100.24%-112.28%, respectively, which fell within the bioequivalence interval of 80.00%-125.00%.There were no serious adverse events and unexpected adverse events during the trial.The results show that test preparation and reference preparation are bioequivalent under fed and single-dose administration, safe and well tolerated in healthy subjects.
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As a rare Chinese medicinal material， Paridis Rhizoma is mainly distributed in Yunnan， Guangxi， and Guizhou in southwestern China， with the effect of clearing heat and detoxifying， alleviating edema and relieving pain， cooling liver and tranquilizing mind. It is particularly effective for injuries from falls， fractures， contusions and strains， snake bites， cold wind-induced convulsion， and other diseases， which has been used for more than 2 000 years. According to modern research， polyphyllin Ⅱ， one of the main active components of Paridis Rhizoma， belongs to diosgenin in structure. It has the anti-tumor， anti-inflammatory， antiviral， antibacterial， immune-regulating， antioxidant， and multidrug resistance-reversing activities， showing good application prospect. Especially， the anti-tumor effect of polyphyllin Ⅱ has attracted wide attention， and the mechanism is inhibiting proliferation， migration， and invasion of tumor cells， inducing cell cycle arrest， apoptosis， and autophagy， suppressing angiogenesis， and modulating tumor microenvironment. However， the pharmacokinetic results show that polyphyllin Ⅱ has low bioavailability in vivo due to the low solubility， poor absorption， unsatisfactory distribution， and slow metabolism， which limit the clinical application. In recent years， there has been an explosion of research on the adverse reactions of polyphyllin Ⅱ， such as the strong hemolytic activity and obvious cytotoxicity to liver， kidney， myocardium and cardiovascular cells. Thus， papers were retrieved from "CNKI"， "VIP"， "Wanfang Data"， "PubMed"， "Web of Science"， and "Elsevier SD" with "Paris saponin Ⅱ"， "Polyphyllin Ⅱ" as the main keywords， and the pharmacological activities and mechanisms， pharmacokinetics， and adverse reactions were summarized. The findings are expected to serve as a reference for the in-depth research， development， and utilization of polyphyllin Ⅱ.