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1.
Pest Manag Sci ; 79(10): 3593-3601, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37183359

RESUMO

BACKGROUND: Feeding is the basis of animal survival and reproduction. In insects, the neuropeptide F (NPF), a homologous polypeptide of NPY in vertebrates, plays an important role in regulation of feeding behavior. However, relatively little has been known about the molecular mechanism of feeding. RESULTS: In this study, we show that the cholinergic pathway is very important in signaling transmission of NPF feeding regulation in Ostrinia furnacalis larvae, in which the choline acetyltransferase (ChAT), the vesicular acetylcholine transporter (vAChT) in presynaptic membrane and the nicotinic acetylcholine receptor (nAChR) in postsynaptic membrane are positively regulated by NPF, while the ace1 and ace2 encoding the acetylcholinesterase (AChE) are negatively regulated by NPF, leading to a balance of acetylcholine (ACh)-the excitatory transmitter. More, the cholinergic pathway further transmits signaling to the downstream pathways of the phosphoInositide-3 kinase (PI3K) and the cAMP responsive element binding protein (CREB), respectively. CONCLUSION: The cholinergic transmission, positively regulated by NPF, is involved in feeding of O. furnacalis larvae via downstream PI3K and the CREB pathways, respectively. The deexcitation of cell cholinergic pathway or inhibition of PI3K and CREB lead to decreases of larval feeding amount. © 2023 Society of Chemical Industry.

2.
Cells ; 12(1)2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36611986

RESUMO

Feeding is crucial for the growth and survival of animals, including humans, but relatively little is known about how it is regulated. Here, we show that larval feeding in Ostrinia furnacalis is regulated by neuropeptide F (NPF, the homologous peptide of mammalian NPY) via the insulin signalling pathway in the midgut. Furthermore, the genes pi3k and mtor in the insulin pathway positively regulate α-amylase and lipase of the midgut by recruiting the transcription factors c-Myc and PPARγ for binding to the promotors of these two enzymes. Importantly, we find that the feeding behaviour and the digestive system of midgut in O. furnacalis larvae are closely related and interactive in that knocking down α-amylase or lipase induces a reduction in larval feeding, while food-deprived larvae lead to fewer expressions of α-amylase and lipase. Importantly, it is the gut NPF that regulates the α-amylase and lipase, while variations of α-amylase and lipase may feed back to the brain NPF. This current study reveals a molecular feedback mechanism between feeding behaviour and the digestive system that is regulated by the conserved NPF via insulin signalling systems in the midgut of O. furnacalis larvae.


Assuntos
Insulinas , Mariposas , Animais , Humanos , Larva/genética , Lipase , Digestão , alfa-Amilases/genética , Mamíferos
3.
Pest Manag Sci ; 79(3): 1193-1203, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36396604

RESUMO

BACKGROUND: Feeding by pests is one of the most important reasons for reductions in agricultural crop yield. This study aimed to reveal how juvenile hormone (JH) participates in larval feeding regulation of the Asian corn borer Ostrinia furnacalis. RESULTS: Larvae of O. furnacalis exhibit a daily circadian feeding rhythm, with a peak at ZT18 and a trough at ZT6 under both photoperiod (LD) and constant dark (DD) conditions, which may be eliminated by application of fenoxycarb, a JH active analogue. JH negatively regulates larval feeding as a downstream factor of neuropeptide F (NPF), in which knocking down JH increases larval feeding amount along with body weight and length. The production of JH in the brain-corpora cardiaca-corpora allata (brain-CC-CA) is regulated by brain NPF rather than gut NPF, which was demonstrated in Drosophila larvae through GAL4/UAS genetic analysis. In addition, feeding regulation of JH is closely related to energy homeostasis in the fat body by inhibiting energy storage and promoting degradation. The JH analogue fenoxycarb is an effective pesticide against O. furnacalis, controlling feeding and metabolism. CONCLUSION: The brain NPF system regulates JH, with functions in food consumption, feeding rhythms, energy homeostasis and body size. This study provides an important basis for understanding the feeding mechanism and potential pest control of O. furnacalis. © 2022 Society of Chemical Industry.


Assuntos
Hormônios Juvenis , Mariposas , Animais , Larva , Hormônios Juvenis/farmacologia , Hormônios Juvenis/metabolismo , Drosophila
4.
Plants (Basel) ; 12(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36616307

RESUMO

Emerging evidence indicates that long non-coding RNAs (lncRNAs) play important roles in diverse biological processes. However, the biological functions of most plant lncRNAs are still unknown. We previously discovered a soybean abiotic-stress-related lncRNA, lncRNA77580, and cloned the entire full-length sequence. Here, in order to fully identify the function of lncRNA77580 in soybean stress response, we created transgenic soybean lines overexpressing lncRNA77580. Compared with the wild type, overexpression of lncRNA77580 enhances the drought tolerance of soybean. However, the transgenic plants exhibit increased sensitivity to high salinity at the seedling stage. We found that lncRNA77580 modulates the transcription of different gene sets during salt and drought stress response. Under water deficit at the reproductive stage, lncRNA77580 overexpression increases the seed yield by increasing the seed number per plant. These results provide insight into the role of lncRNA77580 in soybean stress response.

5.
Clin Transl Sci ; 14(3): 942-953, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33493392

RESUMO

Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure-response (efficacy [n = 201] and safety [n = 253]), and concentration-corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300-1200 mg q.d.). Ivosidenib disposition was well-described by a two-compartment PK model with first-order absorption and elimination. Between-subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration-time curve at steady state (AUCss ) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss , there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration-QT analysis showed a mean change in QTc using Fridericia's method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model-based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure-response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.


Assuntos
Antineoplásicos/farmacocinética , Glicina/análogos & derivados , Isocitrato Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Síndrome do QT Longo/diagnóstico , Piridinas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Área Sob a Curva , Variação Biológica da População , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Eletrocardiografia , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/farmacocinética , Humanos , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Síndrome do QT Longo/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Distribuição Tecidual , Resultado do Tratamento , Adulto Jovem
6.
Clin Pharmacokinet ; 60(3): 365-378, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33047216

RESUMO

BACKGROUND: Cemdisiran, an N-acetylgalactosamine (GalNAc) conjugated RNA interference (RNAi) therapeutic, is currently under development for the treatment of complement-mediated diseases by suppressing liver production of complement 5 (C5) protein. This study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cemdisiran in healthy subjects and in patients with paroxysmal nocturnal hemoglobinuria (PNH) in order to support dose selection for late-stage clinical trials. METHODS: Healthy volunteers (HVs; n = 32, including 12 Japanese subjects) were randomized (3:1) to receive single doses of subcutaneous cemdisiran (50-900 mg) or placebo, or repeat doses of subcutaneous cemdisiran (100-600 mg) or placebo weekly, biweekly, weekly/biweekly, or weekly/monthly for 5, 8, or 13 weeks (n = 24). Cemdisiran 200 or 400 mg was administered weekly in an open-label manner, for varying durations, as monotherapy in three eculizumab-naïve PNH patients or in combination with eculizumab in three PNH patients who were receiving stable label doses of eculizumab (900 or 1200 mg biweekly) before the start of the study. After the last dose of cemdisiran, patients were followed for safety and ongoing pharmacologic effects with the eculizumab regimen (600 or 900 mg every month). RESULTS: In HVs, cemdisiran was rapidly converted to a major active metabolite, AS(N-2)3'-cemdisiran, both declining below the lower limit of quantification (LLOQ) in plasma within 48 h, and showing minimal renal excretion. AS(N-2)3'-cemdisiran exhibited more than dose-proportional PK. The C5 protein reductions were dose-dependent, with > 90% reduction of C5 protein beginning on days 21-28 and maintained for 10-13 months following single and biweekly doses of 600 mg. The dose-response relationship, described by an inhibitory sigmoid maximum effect (Emax) model, estimated half-maximal effective dose (ED50) of 14.0 mg and maximum C5 reduction of 99% at 600 mg. The PK and PD were similar between Japanese and non-Japanese subjects, and PNH patients and HVs. One of 48 subjects tested transiently positive for antidrug antibody with low titer, with no impact on PK or PD. In PNH patients, C5 suppression by cemdisiran enabled effective inhibition of residual C5 levels with lower dose and/or dosing frequency of eculizumab, which was maintained for 6-10 months after the last dose of cemdisiran. CONCLUSIONS: Consistent with the PK/PD properties of liver targeting GalNac conjugates, cemdisiran and AS(N-2)3'-cemdisiran plasma concentrations declined rapidly while showing rapid and robust C5 suppression maintained up to 13 months following single and multiple doses, which indicates long residence times of cemdisiran within hepatocytes. The long PD duration of action in liver, low immunogenicity and acceptable safety profiles enables low, infrequent SC dosing and support further evaluation of cemdisiran in complement-mediated diseases as monotherapy or in combination with a C5 inhibitor antibody. CLINICAL TRIAL REGISTRATION NO: NCT02352493.


Assuntos
Complemento C5 , Hemoglobinúria Paroxística , Complemento C5/farmacocinética , Voluntários Saudáveis , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Interferência de RNA , Terapêutica com RNAi
7.
Br J Clin Pharmacol ; 69(5): 508-15, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20573086

RESUMO

AIMS: This study investigated the pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. METHODS: This was an open-label, randomized, three-treatment, cross-over, clinical trial in healthy male subjects (n= 12) of known CYP2C9 and VKORC1 genotype who received a single oral dose of warfarin alone or after 2 weeks of pre-treatment with each herbal medicine at recommended doses. Pharmacodynamic (INR, platelet activity) and pharmacokinetic (warfarin enantiomer concentrations) end points were evaluated. RESULTS: The apparent clearance of (S)-warfarin (90% CI of ratio; 1.01, 1.18) was significantly higher during concomitant treatment with echinacea but this did not lead to a clinically significant change in INR (90% CI of AUC of INR; 0.91, 1.31). Policosanol did not significantly affect warfarin enantiomer pharmacokinetics or warfarin response. Neither echinacea nor policosanol had a significant effect on platelet aggregation after 2 weeks of pre-treatment with the respective herbal medicines. CONCLUSION: Echinacea significantly reduced plasma concentrations of S-warfarin. However, neither echinacea nor policosanol significantly affected warfarin pharmacodynamics, platelet aggregation or baseline clotting status in healthy subjects.


Assuntos
Anticoagulantes/farmacocinética , Echinacea , Álcoois Graxos/farmacocinética , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacocinética , Varfarina/farmacocinética , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Estudos Cross-Over , Citocromo P-450 CYP2C9 , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Oxigenases de Função Mista/genética , Vitamina K Epóxido Redutases , Adulto Jovem
8.
Br J Clin Pharmacol ; 65(3): 326-33, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17961191

RESUMO

UNLABELLED: What is already known about this subject. Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin. the impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood. what this study adds. this study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions. gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration. the clinical implications of this observation remain to be established. AIMS: To characterize the population pharmacokinetics of gemcitabine and its metabolite (dfdu) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design. METHODS: Gemcitabine and dfdu plasma concentration-time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates. RESULTS: Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (V(C)) for gemcitabine were 2.7 l min(-1) (31%) and 15 l (39%), respectively, and 0.04 l min(-1) (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU V(C) by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone. CONCLUSIONS: Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.


Assuntos
Desoxicitidina/análogos & derivados , Modelos Biológicos , Neoplasias/metabolismo , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto/métodos , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/metabolismo , Interações Medicamentosas/fisiologia , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Oxaliplatina , Gencitabina
9.
Arch Dis Child Fetal Neonatal Ed ; 92(3): F204-9, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-16690639

RESUMO

AIMS: To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. METHODS: A prospective open-labelled, dose-escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 microg/kg/min (n = 8) and 0.5 microg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4-5 blood samples for concentration-time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180-300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). RESULTS: Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one-compartment model with first-order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half-life of 10 h. The 0.25 and 0.5 microg/kg/min dosage regimens did not achieve optimal milrinone concentration-time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 microg/kg/min for 3 h) followed by maintenance infusion (0.2 microg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. CONCLUSION: Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças do Prematuro/tratamento farmacológico , Milrinona/farmacocinética , Vasodilatadores/farmacocinética , Doenças Cardiovasculares/fisiopatologia , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/fisiopatologia , Milrinona/administração & dosagem , Estudos Prospectivos , Vasodilatadores/administração & dosagem
10.
Clin Pharmacol Drug Dev ; 6(1): 19-26, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27138546

RESUMO

The objectives of this analysis were to establish the exposure-response relationship between plasma rifampicin and 4ß-hydroxycholesterol (4ßHC) concentration and to estimate the effect of weak, moderate, and potent CYP3A induction. Plasma rifampicin and 4ßHC concentration-time data from a drug-drug interaction study with rifampicin 600 mg were used for model development. An indirect response model with an effect compartment described the relationship between rifampicin and 4ßHC concentrations. The model predicted that the equilibration t1/2 and 4ßHC t1/2 were 72.8 and 142 hours, respectively. EM50 and Emax of rifampicin induction were 32.6 µg and 8.39-fold, respectively. The population PK-PD model was then used to simulate the effects of rifampicin 10, 20, and 100 mg on plasma 4ßHC for up to 21 days, in which rifampicin 10, 20, and 100 mg were used to represent weak, moderate, and strong inducers, respectively. The model-predicted median (5th, 95th percentiles) 1.13 (1.04, 1.44)-, 1.28 (1.10, 1.71)-, and 2.10 (1.45, 3.49)-fold increases in plasma 4ßHC after 14-day treatment with rifampicin 10, 20, and 100 mg, respectively. A new drug candidate can likely be classified as a weak, moderate, or strong inducer if baseline-normalized plasma 4ßHC increases by <1.13-, 1.13- to 2.10-, or >2.10-fold, respectively, after 14 days of dosing.


Assuntos
Indutores do Citocromo P-450 CYP3A/administração & dosagem , Hidroxicolesteróis/sangue , Rifampina/administração & dosagem , Adulto , Indutores do Citocromo P-450 CYP3A/sangue , Indutores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Hidroxicolesteróis/administração & dosagem , Hidroxicolesteróis/farmacologia , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Rifampina/sangue , Rifampina/farmacocinética , Adulto Jovem
12.
J Clin Pharmacol ; 46(11): 1370-8, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17050802

RESUMO

Systematic evidence regarding herb-drug interactions is lacking. This study investigated herb-drug interactions with warfarin. S-warfarin concentration and response (prothrombin complex activity) data from healthy subjects (n = 24) who received a single warfarin dose (25 mg) and either St John's wort, Asian ginseng, Ginkgo biloba, or ginger were analyzed using a population pharmacokinetic-pharmacodynamic modeling approach. The ratio of S-warfarin apparent clearance (CL/F) compared to control was 1.39 +/- 0.06 and 1.14 +/- 0.04 after St John's wort and Asian ginseng pretreatment, respectively. Other pharmacokinetic and pharmacodynamic parameters were unaffected. Coadministration of St John's wort significantly increased S-warfarin CL/F, whereas treatment with Asian ginseng produced only a moderate increase in CL/F. Ginkgo and ginger did not affect the pharmacokinetics of warfarin in healthy subjects. None of the herbs studied had a direct effect on warfarin pharmacodynamics. Studies in anticoagulated patients are warranted to assess the clinical significance of these herb-drug interactions.


Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/farmacocinética , Interações Ervas-Drogas/fisiologia , Medicina Herbária , Modelos Biológicos , Varfarina/farmacologia , Varfarina/farmacocinética , Adulto , Zingiber officinale , Ginkgo biloba , Saúde , Humanos , Hypericum , Masculino , Panax , Extratos Vegetais/farmacologia
13.
J Clin Pharmacol ; 56(12): 1516-1527, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27119439

RESUMO

The characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) properties in pediatric patients is essential in supporting the recommended dosage of canakinumab in the relevant population. Here the PK and PD properties of canakinumab-a monoclonal antibody-in pediatric patients with systemic juvenile idiopathic arthritis (SJIA) are presented. Blood samples were obtained from 4 phase 2/3 clinical studies in patients with SJIA. Canakinumab PK properties and total interleukin (IL)-1ß kinetic properties were characterized by a population-based PK-binding model. On administration, canakinumab increased total IL-1ß complex in SJIA patients. Canakinumab clearance and volume of distribution were not impacted by age in pediatric patients after correction for the patient's body weight. The estimated serum clearance of canakinumab was 0.106 ± 0.00689 L/day, with a corresponding volume of distribution at steady state of 3.2 L and an estimated half-life of 22 days, based on a model typical body weight of 33 kg. Body-weight-based dosing provided comparable canakinumab exposure across the age groups in patients 2 to <20 years with SJIA. In younger children, a modest increase in the turnover rate of IL-1ß was observed. Compared to other indications, IL-1ß production rate was higher and clearance was slower in patients with SJIA. Low immunogenicity incidence of 3.1% was observed, and none of the patients had neutralizing antibodies. In conclusion, the PK/PD findings further support dose selection of canakinumab in patients with SJIA.


Assuntos
Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Interleucina-1beta/sangue , Interleucina-1beta/uso terapêutico , Adolescente , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Interleucina-1beta/farmacocinética , Masculino , Adulto Jovem
14.
Clin Pharmacol Drug Dev ; 5(1): 27-39, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27119576

RESUMO

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 µg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.


Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Tetrazóis/administração & dosagem , Adolescente , Adulto , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Área Sob a Curva , Compostos de Bifenilo , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacocinética , Feminino , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Masculino , Metformina/administração & dosagem , Metformina/farmacocinética , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Tetrazóis/farmacocinética , Valsartana , Adulto Jovem
15.
Clin Pharmacol Drug Dev ; 3(6): 487-92, 2014 11.
Artigo em Inglês | MEDLINE | ID: mdl-27129123

RESUMO

A double fixed dose combination of amlodipine/valsartan and triple fixed dose combination of amlodipine/valsartan/HCTZ tablets have been developed to treat patients with moderate-to-severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/valsartan (10/160 mg) and amlodipine/valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, valsartan, and/or HCTZ using non-compartmental analysis. Following amlodipine/valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0-∞ and Cmax were 1.09 (1.05-1.13) and 1.03 (0.97-1.09) for amlodipine, and 0.94 (0.81-1.10) and 0.86 (0.73-1.02) for valsartan, respectively. Following amlodipine/valsartan/HCTZ administration, the GMRs (90%CI) of AUC0-∞ and Cmax were 1.09 (1.04-1.15) and 1.11 (1.05-1.08) for amlodipine, 1.14 (0.99-1.31) and 1.12 (0.98-1.29) for valsartan, and 1.09 (1.02-1.16) and 0.86 (0.79-0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.


Assuntos
Combinação Anlodipino e Valsartana/administração & dosagem , Combinação Anlodipino e Valsartana/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Interações Alimento-Droga , Hidroclorotiazida/administração & dosagem , Hidroclorotiazida/farmacocinética , Administração Oral , Adolescente , Adulto , Combinação Anlodipino e Valsartana/efeitos adversos , Combinação Anlodipino e Valsartana/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Área Sob a Curva , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/sangue , Estudos Cross-Over , Gorduras na Dieta/administração & dosagem , Combinação de Medicamentos , Monitoramento de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Hidroclorotiazida/efeitos adversos , Hidroclorotiazida/sangue , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Comprimidos , Adulto Jovem
16.
J Clin Oncol ; 26(7): 1119-27, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18309947

RESUMO

PURPOSE: To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. PATIENTS AND METHODS: A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5 were genotyped, and their effects on pharmacokinetics and toxicities were evaluated. RESULTS: A novel diplotype of two polymorphic loci in the ABCG2 promoter involving -15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration. CONCLUSION: Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.


Assuntos
Receptores ErbB/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias Pulmonares/genética , Neoplasias Ovarianas/genética , Farmacogenética , Polimorfismo Genético , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Diarreia/induzido quimicamente , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Exantema/induzido quimicamente , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/metabolismo , Neoplasias Ovarianas/metabolismo , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos
17.
Br J Clin Pharmacol ; 59(4): 425-32, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15801937

RESUMO

AIM: The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status. METHODS: This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported. RESULTS: INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167-210) ml h(-1), 200 (173-227) ml h(-1) and 201 (171-231) ml h(-1), respectively. The respective apparent clearances of R-warfarin were 127 (106-149) ml h(-1), 126 (111-141) ml h(-1) and 131 (106-156) ml h(-1). The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.98-1.21) and for R-warfarin was 1.00 (0.93-1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC(0-168) of INR was 0.93 (0.81-1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.97-1.13) and for R-warfarin was 1.02 (0.95-1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC(0-168) of INR was 1.01 (0.93-1.15) when coadministered with ginger. The mean ratio (90% CI) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85-1.32) for ginkgo treatment, and 1.00 (0.81-1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin. CONCLUSIONS: Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.


Assuntos
Anticoagulantes/farmacocinética , Ginkgo biloba/metabolismo , Interações Ervas-Drogas , Varfarina/farmacocinética , Zingiber officinale/metabolismo , Administração Oral , Adulto , Anticoagulantes/farmacologia , Área Sob a Curva , Estudos Cross-Over , Humanos , Coeficiente Internacional Normatizado , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Varfarina/farmacologia
18.
Br J Clin Pharmacol ; 57(5): 592-9, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15089812

RESUMO

UNLABELLED: M: The aim of this study was to investigate the effect of St John's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: This was an open-label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25-mg dose of warfarin alone or after 14 days' pretreatment with St John's wort, or 7 days' pretreatment with ginseng. Dosing with St John's wort or ginseng was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and 90% confidence intervals are reported. RESULTS: INR and platelet aggregation were not affected by treatment with St John's wort or ginseng. The apparent clearances of S-warfarin after warfarin alone or with St John's wort or ginseng were, respectively, 198 +/- 38 ml h(-1), 270 +/- 44 ml h(-1) and 220 +/- 29 ml h(-1). The respective apparent clearances of R-warfarin were 110 +/- 25 ml h(-1), 142 +/- 29 ml h(-1) and 119 +/- 20 ml h(-1) [corrected]. The mean ratio and 90% confidence interval (CI) of apparent clearance for S-warfarin was 1.29 (1.16, 1.46) and for R-warfarin it was 1.23 (1.11, 1.37) when St John's wort was coadministered. The mean ratio and 90% CI of AUC(0-168) of INR was 0.79 (0.70, 0.95) when St John's wort was coadministered. St John's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers. CONCLUSIONS: St John's wort significantly induced the apparent clearance of both S-warfarin and R-warfarin, which in turn resulted in a significant reduction in the pharmacological effect of rac-warfarin. Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin.


Assuntos
Anticoagulantes/farmacocinética , Hypericum , Panax , Extratos Vegetais/farmacologia , Varfarina/análogos & derivados , Varfarina/farmacocinética , Análise de Variância , Anticoagulantes/sangue , Anticoagulantes/farmacologia , Área Sob a Curva , Estudos Cross-Over , Interações Ervas-Drogas , Humanos , Coeficiente Internacional Normatizado , Masculino , Agregação Plaquetária/efeitos dos fármacos , Tempo de Protrombina , Varfarina/sangue , Varfarina/farmacologia , Varfarina/urina
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