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BACKGROUND: The objective of this study was to investigate the serum concentrations of olanzapine in relation to age, sex, and other factors in Chinese patients aged between 10 and 90 years. METHODS: Data for 884 olanzapine patients, deposited between 2016 and 2017, were retrieved from the therapeutic drug monitoring database of the Affiliated Brain Hospital of Guangzhou Medical University. The effects of covariates on serum olanzapine concentration, dose-normalized concentration (C/D ratio), and normalized concentration (C/D/weight) were investigated. RESULTS: Generally, male patients had lower olanzapine concentration, C/D ratio, and C/D/weight than female patients (P < 0.001). Smoking and drinking reduced olanzapine concentration, C/D ratio, and C/D/weight (P < 0.001). Coadministration with valproate decreased olanzapine concentration, C/D ratio, and C/D/weight by about 16%, 30%, and 40%, respectively (P < 0.001). Patients younger than 60 years had higher olanzapine concentrations (P < 0.05) but lower C/D ratios and C/D/weight (P < 0.001) than patients older than 60 years. Age was correlated with olanzapine concentration (r = -0.082, P < 0.05), C/D ratio (r = 0.196, P < 0.001), and C/D/weight (r = 0.169, P < 0.001). Sample timing after dose and diagnostic factors also contributed to the olanzapine concentrations. Multiple linear regression analysis revealed significant influences of dosage, age, sex, valproate comedication, smoking, postdose interval, and schizophrenia (vs bipolar affective disorders) on serum olanzapine concentrations. CONCLUSIONS: The metabolism of olanzapine may be altered by several factors. Patients characterized with a combination of factors may benefit from therapeutic drug monitoring for the adjustment of olanzapine dose to minimize adverse reactions.
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Antipsicóticos/sangue , Olanzapina/sangue , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Povo Asiático , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina/uso terapêutico , Estudos Retrospectivos , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Fatores Sexuais , Fumar/sangue , Ácido Valproico/sangue , Ácido Valproico/uso terapêutico , Adulto JovemRESUMO
PURPOSE: This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). METHODS: A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. RESULTS: We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. CONCLUSION: Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.
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Succinato de Desvenlafaxina/farmacocinética , Ácido Valproico/farmacologia , Cloridrato de Venlafaxina/farmacocinética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Clozapina/farmacologia , Succinato de Desvenlafaxina/sangue , Interações Medicamentosas , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimedicação , Estudos Retrospectivos , Fatores Sexuais , Cloridrato de Venlafaxina/sangue , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to investigate the potential effects of a meal and grapefruit juice on the pharmacokinetics of blonanserin and its metabolite N-desethyl blonanserin in healthy Chinese volunteers. METHODS: This was a single-centre, open-label, fixed-sequence study, where 12 healthy Chinese volunteers received a single dose of 8 mg blonanserin after an overnight fast in period 1 (reference), a high-fat meal during period 2 and with co-administration of 250 mL of grapefruit juice in period 3. The washout period was 7 days. Series of plasma samples were collected after each dose to determine concentrations of blonanserin and its metabolite N-desethyl blonanserin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated by non-compartmental analysis and compared between periods by standard average bioequivalence ANOVA. Adverse events were monitored throughout the study. RESULTS: All subjects completed the study. High-fat meals significantly increased blonanserin exposure (AUCt) 2.58-fold (90% CI 2.21, 3.02), relative to the reference period. Co-administration of blonanserin with grapefruit juice remarkably prolonged elimination half-life of blonanserin (from 9.7 to 21.4 h) and significantly increased exposures to blonanserin and N-desethyl blonanserin by 5.82-fold (90% CI 4.57, 7.42) and 1.81-fold (90% CI 1.65, 1.98), respectively. CONCLUSIONS: These results suggested that blonanserin was largely metabolised in the intestinal tract before becoming systemically available, and both food and grapefruit juice enhanced exposure to blonanserin and N-desethyl blonanserin. Grapefruit juice increased bioavailability and may have reduced systemic clearance of blonanserin. Further intestinal CYP3A4 and hepatic CYP3A4 might be postulated to explain the delayed elimination of blonanserin. Dose adjustment of blonanserin is needed on the basis of co-intake of known strong CYP3A4 inhibitor. Patients taking high-dose blonanserin also need to be cautious about the ingestion of grapefruit juice.
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Citrus paradisi , Interações Alimento-Droga , Sucos de Frutas e Vegetais , Piperazinas/sangue , Piperidinas/sangue , Adulto , Área Sob a Curva , Disponibilidade Biológica , Citocromo P-450 CYP3A/metabolismo , Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Intestinos/enzimologia , Masculino , Piperazinas/administração & dosagem , Piperidinas/administração & dosagem , Adulto JovemRESUMO
Background: In recent years, there has been a significant worldwide increase in the use of generic drugs. China has committed to a consistency evaluation of generic drugs, with the aim to improve the rate of substitution. However, there is little research on physicians' perceptions of generic drugs in China. Objective: The study aimed to explore the perceptions of physicians in China toward generic drugs. Methods: Perceptions of Chinese physicians towards generic drugs were evaluated by a cross-sectional study from June to July 2020. The online survey tool Sojump was adopted to distribute the questionnaires using convenience sampling. A total of 598 questionnaires were analyzed. Results: Perceptions of Chinese physicians towards generic drugs are generally positive. However, not all physicians appear to have sufficient knowledge about generic drugs and some of them expressed negative perceptions of generic drugs, such as perceiving generic drugs as less effective and more likely to cause side effects compared to brand-name drugs. There were significant differences in physicians' opinions about generic drugs according to age group, years in practice, educational background, clinical specialty and residential area. Conclusion: It is imperative to provide physicians with more extensive education about the consistency evaluation of generic drugs to meet the policy goal of reducing overall national medical healthcare costs.
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A high-performance liquid chromatographic method coupled with triple quadrupole mass spectrometry (LC-MS/MS) for the analysis of blonanserin and its active metabolite, N-desethyl blonanserin, in rat plasma has been developed and validated. The biological samples were treated by simple direct protein precipitation before separation on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 3.5 µm) with a column temperature of 35°C at a flow rate of 0.5 mL/min. The mobile phase A is a mixture of methanol and water (75 : 25, v/v, 5 mM ammonium formate), and the mobile phase B is acetonitrile containing 0.1% formic acid. The ratio of mobile phase A to mobile phase B is 15 : 85. Electrospray ionization (ESI) multiple reaction monitoring modes are used for detection, which are m/z 368.10 ⶠ296.90 (blonanserin), m/z 340.15 ⶠ297.05(N-desethyl blonanserin), and m/z 348.15ⶠ302.05 (N-desethyl blonanserin-d8). The linear response range was 0.1-100.0 ng/mL for blonanserin and N-desethyl blonanserin. The lower limit of quantification (LLOQ), calibration curves, carryover, and matrix effects were sufficiently accurate and precise according to the National Medical Products Administration (NMPA) guidelines for bioanalytical method validation. This analytical method was successfully applied in a blonanserin-poloxamer thermosensitive gel pharmacokinetic study in rats.
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To prepare rivastigmine liposome, rivastigmine was loaded into liposome via ammonium sulfate gradient method. Its pharmacokinetic profile in rats was evaluated after intranasal administration. The size, zeta potential, entrapped efficiency and release of rivastigmine from the liposome in vitro were determined. Plasma concentration of rivastigmine was determined by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS) using antipyrine as internal standard. The pharmacokinetic parameters were calculated by DAS 2.0. The entrapped efficiency of rivastigmine liposome was (33.41 +/- 6.58) %, with the mean diameter of 154-236 nm and zeta potential of (-10.47 +/- 2.41) mV. The release behavior of rivastigmine was fitting the first order equation in vitro. The pharmacokinetic studies indicated that the C(max), T(max) and AUC(0-infinity), of rivastigmine liposome were (1.50 +/- 0.15) mg x L(-1), 15 min and (89.06 +/- 8.30) mg x L(-') x min, respectively. Rivastimine liposome was absorbed rapidly, and could reach a certain concentration in rat plasma after intranasal delivery.
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Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacocinética , Fenilcarbamatos/administração & dosagem , Fenilcarbamatos/farmacocinética , Administração Intranasal , Animais , Área Sob a Curva , Cromatografia Líquida , Portadores de Fármacos , Composição de Medicamentos , Lipossomos , Masculino , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/química , Tamanho da Partícula , Fenilcarbamatos/sangue , Fenilcarbamatos/química , Ratos , Ratos Sprague-Dawley , Rivastigmina , Espectrometria de Massas em TandemRESUMO
Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13-65 years of age.
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Adjunctive therapy with olanzapine and fluoxetine has been shown to be beneficial in treatment-resistant depression and the depressive phase of bipolar disorder. Consensus guidelines issued by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie strongly recommend that patients taking olanzapine undergo therapeutic drug monitoring (TDM), and suggest that TDM is useful for patients taking fluoxetine. The aim of the current study was to develop and validate a sensitive, practical, and robust liquid chromatography-tandem mass spectrometry method (LC-MS/MS) for simultaneous determination of olanzapine, fluoxetine, and norfluoxetine in human plasma for routine TDM. Simple liquid-liquid extraction using ethyl acetate was used to extract olanzapine, fluoxetine, and norfluoxetine from 200⯵L of pre-basified human plasma. Analytes were separated on an Agilent Eclipse Plus C18 column (4.6â¯×â¯100â¯mm, 5⯵m) eluted with a mobile phase consisting of methanol:20â¯mM ammonium formate buffer (82.5:17.5, v/v), and then quantified using an electrospray ionization source operated in positive ion multiple reaction monitoring mode. The linear range for the analytes was 0.2-25â¯ng/mL, covering the vast majority of levels encountered in real-life samples. A weighting factor of 1/x2 best fit the calibration curves. The mean internal standard-normalized matrix effects for all analytes were 99.5%-110%. The extraction recoveries were 75%-85% for olanzapine and olanzapined3, and 58%-69% for fluoxetine, norfluoxetine, and their deuterated internal standards. Accuracy and precision values also met the acceptance criteria. The stability assessments showed that QC samples containing the three analytes were stable for at least 1â¯d at room temperature, 21â¯d at -70⯰C, and through three freeze-thaw cycles. Post-preparation storage for 2â¯d in the autosampler did not cause obvious degradation of the investigated compounds. This validated high performance LC-MS/MS method was successfully applied to a pharmacokinetic study in healthy male volunteers.
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Benzodiazepinas/sangue , Cromatografia Líquida/métodos , Fluoxetina/análogos & derivados , Fluoxetina/sangue , Espectrometria de Massas/métodos , Monitoramento de Medicamentos , Humanos , Modelos Lineares , Masculino , Olanzapina , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Quantification of polar compounds such as chloroquine by revered-phase LC is a challenge because of poor retention and silanol interactions with stationary phase. Strong ion-pairing reagents added to mobile phases to improve reversed-phase retention and improve peak shape can be harmful for MS. RESULTS: This new approach provides a rapid and sensitive method for the detection of chloroquine using hydrophilic interaction LC coupled to MS/MS (HILIC-MS/MS). Ammonium formate and formic acid were added to mobile phase to attain good peak shapes and the salified chloroquine as well retained in an HILIC column. Linearity, intra- and inter-day precision, accuracy, recovery, matrix effect and stability were evaluated during the validation process. CONCLUSION: The validated method has been successfully used in a PK study in miniature pigs, and paves way for future development.
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Antimaláricos/sangue , Cloroquina/sangue , Porco Miniatura/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Cromatografia Líquida/métodos , Limite de Detecção , SuínosRESUMO
BACKGROUND AND OBJECTIVES: Peramivir, an antiviral agent for intravenous administration, is used to treat progressive influenza in patients with serious complications. The present study was designed to determine the pharmacokinetics of single and multiple intravenous infusions of peramivir in healthy Chinese subjects. METHODS: Single (150, 300 and 600 mg) and multiple (600 mg) doses of peramivir were intravenously administered to 12 healthy Chinese subjects. There was a 7-day washout period between dosing periods. Blood samples were collected in heparinized tubes at various times. Plasma peramivir and urine peramivir concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry method. RESULTS: Following single doses of peramivir (150, 300 and 600 mg), the maximum concentration (C max) values were 12,416 ± 3078, 23,147 ± 3668 and 44,113 ± 3787 µg/L, respectively, and the area under the plasma concentration-time curve (AUC) from 0 h to infinity post-dose (AUC∞) values were 24.68 ± 6.48, 47.33 ± 9.22 and 92.43 ± 12.72 mg·h/L, respectively. C max, AUC from 0 to 36 h (AUC0-36) and AUC∞ of peramivir increased proportionally with the dose, and no trend towards accumulation after multiple doses was observed. About 65 % of the peramivir was excreted unchanged in the urine within the first 24 h. CONCLUSIONS: Peramivir pharmacokinetics were dose proportional with increasing doses, with no accumulation after multiple dosing. Peramivir was generally well tolerated, and no serious adverse events occurred.
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Antivirais/farmacocinética , Ciclopentanos/farmacocinética , Guanidinas/farmacocinética , Ácidos Carbocíclicos , Adolescente , Adulto , Antivirais/administração & dosagem , Antivirais/urina , Área Sob a Curva , Povo Asiático , Biotransformação , Cromatografia Líquida de Alta Pressão , Ciclopentanos/administração & dosagem , Ciclopentanos/urina , Feminino , Guanidinas/administração & dosagem , Guanidinas/urina , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Espectrometria de Massas em Tandem , Adulto JovemRESUMO
AIM: Peramivir is a newly approved selective neuraminidase inhibitor designed to inhibit influenza virus infection. METHODOLOGY/RESULTS: We report a robust and sensitive method utilizing simple precipitation extraction with LC-MS/MS for the high-throughput quantification. Addition of 0.06 M of ammonium formate and 0.1% formic acid in mobile phase could help reduce the matrix effect. This method uses 100 µl of plasma and covers a linear concentration range from 5 to 10,000 ng/ml. Other validation parameters are also evaluated and meet regulatory expectations by US FDA guidelines. CONCLUSION: The developed HPLC-MS/MS method has been successfully applied to support a clinical pharmacokinetic study. The strategy presented here can be applied elsewhere and may be useful for other amphiphilic drugs.
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Métodos Analíticos de Preparação de Amostras/economia , Precipitação Química , Ciclopentanos/análise , Ciclopentanos/isolamento & purificação , Guanidinas/análise , Guanidinas/isolamento & purificação , Espectrometria de Massas em Tandem , Ácidos Carbocíclicos , Adulto , Cromatografia Líquida , Ciclopentanos/sangue , Ciclopentanos/farmacocinética , Guanidinas/sangue , Guanidinas/farmacocinética , Humanos , Masculino , Fatores de TempoRESUMO
We developed and validated a high performance liquid chromatographic method coupled with triple quadrupole mass spectrometry for analysis of nizatidine in human plasma and urine. The biological samples were precipitated with methanol before separation on an Agilent Eclipse Plus C18 column (100mm×46mm, 5µm) with a mixture of methanol and water (95:5, plus 5mM ammonium formate) as the mobile phase at 0.5mL/min. Detection was performed using multiple reaction monitoring modes via electrospray ionization (ESI) at m/z 332.1â155.1 (for nizatidine) and m/z 335.1â155.1 (for [(2)H3]-nizatidine, the internal standard). The linear response range was 5-2000ng/mL and 0.5-80µg/mL for human plasma and urine, with the lower limits of quantification of 5ng/mL and 0.5µg/mL, respectively. The method was validated according to the biological method validation guidelines of the Food and Drug Administration and proved acceptable. This newly developed analytical method was successfully applied in a pharmacokinetic study following single oral administration of a 150mg nizatidine capsule in to 16 healthy Chinese subjects. Maximum and endpoint concentrations in plasma and urine were quantifiable, suggesting our method is appropriate for routine pharmacokinetic analysis.
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Cromatografia Líquida de Alta Pressão/métodos , Antagonistas dos Receptores H2 da Histamina/sangue , Antagonistas dos Receptores H2 da Histamina/urina , Nizatidina/sangue , Nizatidina/urina , Espectrometria de Massas em Tandem/métodos , Adulto , Feminino , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Humanos , Masculino , Nizatidina/farmacocinética , Sensibilidade e Especificidade , Adulto JovemRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Shunaoxin pills, a traditional Chinese medicine (TCM) product, have been used to treat cerebrovascular diseases in China since 2005. The main active components of Shunaoxin pills are ferulic acid and ligustilide from Chuanxiong (Ligusticum chuanxiong Hort, Umbelliferae) and Danggui (Angelica sinensis radix, Umbelliferae). As Shunaoxin shows excellent activity in the central nervous system (CNS), the extent to which the major constituents of Shunaoxin reach the CNS should be investigated. Moreover, the in vivo-in vitro correlations (IVIVC) of the formulation should be studied to elucidate the mechanisms of action of TCM in the CNS. However, these data have not previously been available. Thus we intended to investigate what the extent when these constituents of Shunaoxin pills reach the CNS, and evaluate the IVIVC of release and pharmacokinetics. MATERIALS AND METHODS: In this study, we evaluated the release of ferulic acid and ligustilide from Shunaoxin pills, and their transport across an in vitro model of the BBB. We also evaluated their pharmacokinetics and brain distribution in vivo. High-performance liquid chromatography (HPLC) was used to quantify both compounds simultaneously. Based on the release in vitro and absorption of ferulic acid and ligustilide in vivo, IVIVC permitted prediction of the pharmacokinetics of these compounds. RESULTS: The release of ferulic acid and ligustilide reached a platform phase within 1h. Ferulic acid and ligustilide rapidly crossed the BBB in different patterns; the transport ratio increased over time. After intragastric (i.g.) administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed into brain, which may result in a rapid onset of action. CONCLUSIONS: Ferulic acid and ligustilide were transported across a model BBB. After i.g. administration of Shunaoxin pills, ferulic acid and ligustilide were rapidly absorbed and distributed in brain; this may lead to rapid pharmacological onset. The IVIVC can be used to predict in vivo pharmacokinetics from in vitro experimental results. These results provide support for the clinical use of Shunaoxin pills.
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Encéfalo/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , 4-Butirolactona/análogos & derivados , 4-Butirolactona/análise , 4-Butirolactona/metabolismo , 4-Butirolactona/farmacologia , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ácidos Cumáricos/análise , Ácidos Cumáricos/metabolismo , Ácidos Cumáricos/farmacologia , Cães , Medicamentos de Ervas Chinesas/química , Masculino , Ratos , Ratos Sprague-Dawley , ComprimidosRESUMO
Combinations of drugs promoting anti-angiogenesis and apoptosis effects are meaningful for cancer therapy. In the present study, dual peptides-modified liposomes were designed by attaching two receptor-specific peptides, specifically low-density lipoprotein receptor-related protein receptor (Angiopep-2) and neuropilin-1 receptor (tLyP-1) for brain tumor targeting and tumor penetration. Vascular endothelial growth factor (VEGF) siRNA and chemotherapeutic docetaxel (DTX) were chosen as the two payloads because VEGF is closely associated with angiogenesis, and DTX can kill tumor cells efficiently. Binding to glioma cells, co-delivery of siRNA and DTX in human glioblastoma cells (U87 MG) and murine brain microvascular endothelial cells (BMVEC), VEGF gene silencing, antiproliferation and anti-tumor effects of the dual peptides-modified liposomes were evaluated in vitro and in vivo. The dual peptides-modified liposomes persisted the binding ability to glioma cells, enhanced the internalization via specific receptor mediated endocytosis and tissue penetration, thus the dual peptides-modified liposomes loading VEGF siRNA and DTX possessed stimulative gene silencing and antiproliferation activity compared with non-modified and single peptide-modified liposomes. The co-delivery research revealed different intracellular behavior of hydrophilic large molecular and lipophilic small molecule, the former involves endocytosis and subsequent escape of endosome/lysosomes, while the latter experiences passive diffusion of lipophilic small drugs after its release. Furthermore, the dual peptides-modified liposomes showed superiority in anti-tumor efficacy, combination of anti-angiogenesis by VEGF siRNA and apoptosis effects by DTX, after both intratumor and system application against mice with U87 MG tumors, and the treatment did not activate system-associated toxicity or the innate immune response. Combination with the dual peptides-guided tumor homing and penetration, the dual peptides-modified liposomes provide a strategy for effective targeting delivery of siRNA and DTX into the glioma cell and inhibition of tumor growth in a synergistic manner.
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Glioma/tratamento farmacológico , Lipossomos/química , Peptídeos/química , RNA Interferente Pequeno/administração & dosagem , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Animais , Linhagem Celular Tumoral , Docetaxel , Humanos , Masculino , Camundongos , Camundongos NusRESUMO
A simple and rapid analytical method for the simultaneous determination of pirfenidone and its metabolite, 5-carboxy-pirfenidone, in human plasma using liquid chromatography-tandem mass spectrometry has been developed and validated. Aliquots of plasma (0.1 mL) containing pirfenidone and 5-carboxy-pirfenidone, as well as deuterium-labeled internal standards (ISs), were deproteinized using acetonitrile. An Agilent Zorbax Plus C18 column was used for the chromatography, with isocratic elution. The mobile phase was a mixture of acetonitrile and aqueous ammonium formate solution (5 mM) containing 0.1% formic acid (60 : 40, v/v). Using multiple reaction monitoring in positive ionization mode, transitions m/z 186.1 â 65.1, m/z 216.0 â 77.0, m/z 191.1 â 65.1 and m/z 221.0 â 81.0 were chosen to quantify pirfenidone, 5-carboxy-pirfenidone and the two ISs, respectively. The time of analysis was <3 min. The calibration curve was linear over the concentration ranges 0.005-25 µg/mL for pirfenidone, and 0.005-15 µg/mL for 5-carboxy-pirfenidone. The lower limit of quantification for both analytes was 0.005 µg/mL. The intra- and interday precision and relative errors in quality control samples were between -11.7 and 1.3% for pirfenidone and between -5.6 and 2.5% for 5-carboxy-pirfenidone, with mean recoveries ≥90%. The method that has been developed is easy to carry out, sensitive and rapid, and has been successfully used to investigate the pharmacokinetics of pirfenidone in healthy human volunteers.
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Cromatografia Líquida/métodos , Piridonas/sangue , Espectrometria de Massas em Tandem/métodos , Calibragem , Voluntários Saudáveis , Humanos , Limite de Detecção , Piridonas/farmacocinética , Controle de Qualidade , Reprodutibilidade dos TestesRESUMO
The rapid, sensitive, and selective liquid chromatography-electrospray ionization-tandem mass spectrometry method (LC-ESI-MS/MS) for the simultaneous estimation and pharmacokinetic investigation of glimepiride and pioglitazone in human plasma has been developed and fully validated. Glimepiride and pioglitazone, compounds which exert synergistic effects on blood glucose control, were investigated in human plasma using deuterium-labeled analogs as internal standards (IS). Liquid-liquid extraction was carried out on 0.2 mL of human plasma using ethyl acetate, and chromatographic separation was performed on an Agilent Eclipse plus C18 column (4.6 mm × 100 mm, 3.5 µm) using a mobile phase consisting of methanol-water-formic acid (95:5:0.1, v/v/v, plus 5mM ammonium acetate) at a flow rate of 0.8 mL/min. To quantify glimepiride, pioglitazone and their IS, multiple reaction monitoring (MRM) transitions of m/z 491.2â352.2, m/z 496.2â357.2, m/z 357.2â134.2 and m/z 361.2â138.2 were performed in positive mode. The total run time was 3.0 min and the elution time was about 2.4 min. The method exhibited good separation of analytes, without interference from endogenous substances. The linear calibration curves were 0.2-250 ng/mL for glimepiride and 0.2-1,250 ng/mL for pioglitazone; the lower limit of quantification (LLOQ) was 0.2 ng/mL for both analytes. Intra- and inter-day reproducibility was less than 10% for glimepiride and less than 5% for pioglitazone, with relative errors ranging from -8.00% to 2.80% at the three concentrations of analytes used for quality control (QC). The matrix effect was negligible and recoveries were similar for each analyte and its IS. Glimepiride and pioglitazone were found to be stable under the assay conditions and the method was successfully applied to the evaluation of pharmacokinetic studies of glimepiride and pioglitazone, following oral doses of 2mg glimepiride tablets and 15 mg pioglitazone tablets to 16 healthy volunteers.
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Cromatografia Líquida de Alta Pressão/métodos , Compostos de Sulfonilureia/sangue , Espectrometria de Massas em Tandem/métodos , Tiazolidinedionas/sangue , Adulto , Humanos , Modelos Lineares , Masculino , Pioglitazona , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinética , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética , Adulto JovemRESUMO
Alzheimer's disease (AD) is a common progressive neurodegenerative disorder associated with cholinergic neurons degeneration. The blood-brain barrier (BBB) not only provides protection for the brain but also hinders the treatment and diagnosis of this neurological disease, because the drugs must cross BBB to reach the lesions. The present work was aimed at formulating rivastigmine liposomes (Lp) and cell-penetrating peptide (CPP) modified liposomes (CPP-Lp) to improve rivastigmine distribution in brain and proceed to enhance pharmacodynamics by intranasal (IN) administration and minimize side effects. The results revealed that Lp especially the CPP-Lp can enhance the permeability across the BBB by murine brain microvascular endothelial cells model in vitro. IN administration of rivastigmine solution and rivastigmine liposomes demonstrated the capacity to improve rivastigmine distribution and adequate retention in CNS regions especially in hippocampus and cortex, which were the regions most affected by AD, than that of IV administration. Importantly, the lagging but intense inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities were relative to the extended release, absorption and retention. In addition, there was very mild nasal toxicity of liposomal formulations. The data suggest that rivastigmine liposomes especially CPP-Lp improve the brain delivery and enhance pharmacodynamics which respect to BBB penetration and nasal olfactory pathway into brain after IN administration, and simultaneously decrease the hepatic first pass metabolism and gastrointestinal adverse effects.
Assuntos
Encéfalo/metabolismo , Peptídeos Penetradores de Células/farmacocinética , Inibidores da Colinesterase/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Fenilcarbamatos/farmacocinética , Acetilcolinesterase/metabolismo , Administração Intranasal , Animais , Anuros , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Linhagem Celular , Peptídeos Penetradores de Células/administração & dosagem , Peptídeos Penetradores de Células/química , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/química , Cílios/efeitos dos fármacos , Cílios/fisiologia , Lipossomos , Masculino , Camundongos , Mucosa Nasal/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Fenilcarbamatos/administração & dosagem , Fenilcarbamatos/química , Ratos , Ratos Sprague-Dawley , Rivastigmina , Distribuição TecidualRESUMO
The aim of the study was mainly to investigate the relationship between concentration of rivastigmine and its inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) following intranasal (IN) and intravenous (IV) administration in rats, and to provide a novel nasal delivery route for the brain disease therapy. Rivastigmine was administered to male rats at 2 mg/kg by IN and IV route. Drug concentration, AChE and BuChE activity were measured in the plasma, central nervous system (CNS) regions i.e. olfactory region, hippocampus, cerebrum and cerebellum, and peripheral tissues. It was determined that rivastigmine was characterized by extremely rapid and complete absorption into the systemic circulation followed by a rapid decline in the plasma concentrations, and can also quickly distribute into CNS and peripheral tissues by the two routes. IN administration showed higher concentration in CNS regions and longer action on inhibiting the activity of AChE and BuChE than IV administration. More significant decrease of the two enzymes was observed in CNS regions than in peripheral tissues for both administrations. A close relationship was found between the concentration of rivastigmine and enzyme inhibition in plasma and CNS tissues in rats. Based on these findings, it was concluded that rivastigmine could cause relatively strong inhibition of AChE and BuChE in plasma and brain tissues, especially in hippocampus, cortex and cerebrum. The pharmacodynamics was closely related to its concentration in vivo. The intranasal route can be strategy for delivering the drug into brain.