Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
AAPS J ; 22(1): 15, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858313

RESUMO

Bioanalysis in biosimilar biological product development (BPD) plays a critical role in demonstrating pharmacokinetic (PK) similarity across products. The 2018 FDA Bioanalytical Method Validation guidance for industry provides general principles in the development, validation, and conduct of bioanalytical assays. Given that the PK similarity assessment in BPD programs involves two or more non-identical products, there are additional considerations for bioanalytical methods. Here in, we provide our perspectives on the definition of (1) a single bioanalytical method in the context of BPD in supporting a PK similarity study, (2) bioanalytical method comparability during accuracy and precision experiments to determine the potential bias difference prior to assessing other validation parameters, and (3) bioanalytical method validations that support PK similarity assessments.


Assuntos
Produtos Biológicos/metabolismo , Medicamentos Biossimilares/metabolismo , Proteínas Sanguíneas/metabolismo , Desenvolvimento de Medicamentos/métodos , Bioensaio/métodos , Bioensaio/normas , Produtos Biológicos/análise , Medicamentos Biossimilares/análise , Proteínas Sanguíneas/análise , Desenvolvimento de Medicamentos/normas , Humanos , Ligantes , Reprodutibilidade dos Testes
2.
Ann Oncol ; 30(4): 644-651, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30715147

RESUMO

BACKGROUND: A nivolumab dosage regimen of 480 mg intravenously (i.v.) every 4 weeks (Q4W) was approved by FDA for the majority of the approved indications for nivolumab. METHODS: The proposed new dosage regimen was supported by pharmacokinetic modeling and simulation, dose/exposure-response relationships for efficacy and safety in the indicated patient populations, and the clinical safety data with the 480 mg Q4W dosage regimen. Pharmacokinetic exposures achieved with 480 mg Q4W were predicted for 4166 patients in 21 clinical studies with various types of solid and hematological tumors. Exposure-response analyses were conducted to predict 480 mg Q4W safety and efficacy across all FDA-approved indications for nivolumab. RESULTS: For the overall population, the geometric mean exposure achieved with 480 mg i.v. Q4W was 5.2% higher for steady state Cavg and 15.6% lower for Ctrough than those with 3 mg/kg i.v. Q2W, the approved dosage regimen. The simulated concentration-time course achieved with 480 mg Q4W regimen was below the median concentration achieved with 10 mg/kg i.v. Q2W that was also studied in clinical trials. The predicted probability of adverse events was similar between 480 mg Q4W and that observed with the 3 mg/kg Q2W regimen. Efficacy results were found to be similar between Q2W and Q3W dosage regimens in patients with renal cell carcinoma. The predicted efficacy for each indication suggested that the efficacy with 480 mg Q4W is unlikely to be compromised compared with that observed with 3 mg/kg Q2W. CONCLUSIONS: The model-informed analyses of predicted exposure, efficacy and safety based on data from extensive clinical experience with nivolumab suggest that the benefit-risk profile of 480 mg Q4W regimen is comparable to the approved 3 mg/kg Q2W regimen, thus providing the regulatory basis for the approval of 480 mg Q4W regimen in the absence of clinical efficacy data with this new dosage regimen.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Aprovação de Drogas/legislação & jurisprudência , Modelos Biológicos , Neoplasias/tratamento farmacológico , Nivolumabe/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Infusões Intravenosas , Nivolumabe/efeitos adversos , Nivolumabe/farmacocinética , Medição de Risco , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência
3.
Clin Pharmacol Ther ; 101(5): 657-666, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28182273

RESUMO

Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2. Nivolumab demonstrated efficacy in clinical trials for various types of cancer. A time-varying clearance was identified for nivolumab. We show that the change of clearance over time is associated with the post-treatment effects: clearance decreases when disease status improves. This interaction between posttreatment effects and drug exposure may lead to a biased steep estimate of the exposure-response (E-R) relationship for efficacy. Under this scenario, simulations were performed to develop a proposed methodology to assess the causal effect of drug exposure upon clinical response. Data from nivolumab trials were subsequently used to verify the proposed methodology for E-R analysis. The results showed that E-R analysis results based on pharmacokinetic (PK) metrics derived from the first dose are more consistent with the true E-R or dose-response relationship than the steady-state PK metrics.


Assuntos
Anticorpos Monoclonais/farmacocinética , Antineoplásicos/farmacocinética , Algoritmos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Simulação por Computador , Relação Dose-Resposta a Droga , Humanos , Modelos Estatísticos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Nivolumabe , População , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resultado do Tratamento
4.
Clin Pharmacol Ther ; 89(2): 259-67, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21191381

RESUMO

Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ dysfunction, age, genetics) and extrinsic (e.g., drug-drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision-making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.


Assuntos
Aprovação de Drogas , Modelos Biológicos , Farmacocinética , Simulação por Computador , Controle de Medicamentos e Entorpecentes , Humanos , Aplicação de Novas Drogas em Teste , Fisiologia , Estados Unidos , United States Food and Drug Administration
5.
Clin Pharmacol Ther ; 86(2): 167-74, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19440187

RESUMO

Four non-small-cell lung cancer (NSCLC) registration trials were utilized to develop models linking survival to risk factors and changes in tumor size during treatment. The purpose was to leverage existing quantitative knowledge to facilitate future development of anti-NSCLC drugs. Eleven risk factors were screened using a Cox model. A mixed exponential decay and linear growth model was utilized for modeling tumor size. Survival times were described in a parametric model. Eastern Cooperative Oncology Group (ECOG) score and baseline tumor size were consistent prognostic factors of survival. Tumor size was well described by the mixed model. The parametric survival model includes ECOG score, baseline tumor size, and week 8 tumor size change as predictors of survival duration. The change in tumor size at week 8 allows early assessment of the activity of an experimental regimen. The survival model and the tumor model will be beneficial for early screening of candidate drugs, simulating NSCLC trials, and optimizing trial designs.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Tomada de Decisões , Desenho de Fármacos , Drogas em Investigação , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Modelos Estatísticos , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida , Fatores de Tempo
6.
Bioorg Med Chem Lett ; 10(10): 1077-80, 2000 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-10843221

RESUMO

L-N5-(1-Hydroxyiminoethyl)-ornithine (L-NHIO) and L-N6-(1-hydroxyiminoethyl)-lysine (L-NHIL) were synthesized and tested as potential intermediates in the mechanism-based inactivation of nitric oxide synthase (NOS) by L-N5-iminoethylornithine (L-NIO) and L-N6-iminoethyllysine (L-NIL). Although these compounds were determined to be competitive inhibitors, mechanism-based inactivation was not observed.


Assuntos
Lisina/análogos & derivados , Óxido Nítrico Sintase/metabolismo , Ornitina/análogos & derivados , Ligação Competitiva , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Hidroxilação , Lisina/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/química , Ornitina/farmacologia
7.
Biochem Pharmacol ; 59(12): 1603-9, 2000 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-10799659

RESUMO

We investigated the involvement of calcitonin gene-related peptide (CGRP) in the vasodilatory mechanism of action of nitric oxide (NO) donors. The functional role of CGRP in NO donor-induced vasodilation of isolated rat aortic rings was determined by incubating these drugs with and without CGRP(8-37), a selective CGRP receptor antagonist. CGRP(8-37) (0.63 microM) induced rightward shifts in the vasodilatory concentration-response curves for nitroglycerin (NTG), Piloty's acid (PA), and SIN-1 (linsidomine). The EC(50) values for NTG, PA, and SIN-1 were increased by 8.3-, 5.2-, and 2.3-fold, respectively (P < 0.05). The release of CGRP from rat aorta in response to NTG and PA was measured specifically by radioimmunoassay. Thirty-minute incubations of NTG or PA with rat aorta induced 189.5 and 214.6% increases, respectively, in CGRP release when compared with the control (P < 0.05). The concentration-response curves of sodium nitroprusside (SNP), S-nitroso-acetylpenicillamine (SNAP), tetranitromethane (TNM), diethylamine NO complex (DEA-NO), and diethylenetriamine/nitric oxide adduct (DETA NONOate) were not inhibited significantly by CGRP(8-37) co-incubation (P 0.05). NO donors also were incubated with aortic strips, and NTG and PA alone induced significant formation of hydroxylamine, a NO(-) metabolite (232.4 and 364.9%, respectively, P < 0.05). These results indicate that only NTG and PA, and to a lesser extent SIN-1, stimulate the release of CGRP from the rat aorta, which subsequently contributes to the vasodilatory activity of these agents. The hydroxylamine formation suggests a possible link between NO(-) generation and CGRP release from the vascular wall.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Doadores de Óxido Nítrico/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Aorta , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Hidroxilamina/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
9.
J Cardiovasc Pharmacol ; 32(1): 129-33, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9676732

RESUMO

We tested whether or not platelet inhibition by sodium nitroprusside (SNP) was enhanced by vascular tissue production of nitric oxide (NO) and calcitonin gene-related peptide (CGRP) release. Platelet aggregation was determined with whole blood impedance aggregometry after incubations of SNP in the presence or absence of rat aortic tissue (AT) or AT + CGRPS(8-37) (a specific CGRP antagonist). SNP alone had no effect on platelet aggregation until 100 microM was used (2.3 + 1.5 omega vs. control aggregation of 9.9 +/- 2.0 omega; p < 0.001). Co-incubation of AT with SNP significantly enhanced platelet inhibition at 1 (1.6 +/- 1.3 omega; p < 0.001), 10 (0.7 +/- 0.4 omega; p < 0.001), and 100 microM (0.3 +/- 0.3 omega; p < 0.001). CGRP(8-37) did not significantly antagonize aggregation by SNP + AT (p > 0.05). The inhibition of platelet aggregation by 10 microM SNP was inhibited by methylene blue (MB) (9.0 +/- 1.7 omega at 10 microM; 11.7 +/- 2.4 omega at 100 microM; p < 0.001) but not by 30 microM L-N(upsilon)-monomethyl-L-arginine (L-NMMA; 2.9 +/- 1.8 omega; p > 0.05). These results indicate that vascular tissue significantly contributes to the ability of SNP to inhibit platelet aggregation, probably through greater vascular enzymatic production of NO, but not by releasing CGRP, in contrast to nitroglycerin.


Assuntos
Vasos Sanguíneos/fisiologia , Nitroprussiato/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Vasodilatadores/farmacologia , Animais , Vasos Sanguíneos/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Inibidores Enzimáticos/farmacologia , Masculino , Azul de Metileno/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo III , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , ômega-N-Metilarginina/farmacologia
10.
Can J Physiol Pharmacol ; 76(7-8): 811-3, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-10030464

RESUMO

The purpose of these experiments was to determine whether calcitonin gene related peptide (CGRP) mediates physiological control of platelet function in vivo. Rat blood pressure was continuously monitored via a femoral arterial cannula, and whole blood aggregation was assessed periodically ex vivo with an impedance aggregometer before and following a 1.4 nmol/kg bolus dose of CGRP8-37, a specific receptor antagonist of CGRP. Mean arterial blood pressure was not significantly affected by CGRP8-37 over a 30-min period (p>0.05). However, whole blood aggregation increased by 38.4+/-18.0% (p<0.01) and 32.0+/-11.2% (p<0.05), at 5 and 15 min post CGRP8-37, respectively, when compared with control. Whole blood aggregation was not significantly different from control at 30 min (p>0.05), suggesting a relatively short duration of action for in vivo CGRP8-37. These data suggest that CGRP contributes to the maintenance of hemostasis, and that this function may be more important than the better known vasodilatatory effects of this neuropeptide.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
11.
Br J Pharmacol ; 122(3): 577-83, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9351518

RESUMO

1. The role of the vasculature and calcitonin gene-related peptide (CGRP) in nitroglycerin (NTG)-mediated platelet inhibition was studied. 2. In vitro incubations of CGRP in whole blood induced a dose-dependent inhibition of platelet aggregation with an IC50 of 62.1 nM. 3. The platelet inhibition induced by CGRP was blocked by co-incubation of 0.53 microM CGRP8-37, as well as 30 microM N(G)-nitro-monomethyl-L-arginine (L-NMMA). 4. In a separate group of experiments, 100 nM NTG in rat whole blood (WB) induced platelet inhibition of 6.0 +/- 1.3% (mean +/- s.d.), which was enhanced to 77.6+/-3.5% by the addition of rat aortic tissue (AT) (P<0.001). The inclusion of CGRP8-37 with NTG and AT in WB reduced platelet inhibition to 31.6+6.8% (P<0.01). Incubation of WB and AT with 30 microM L-NMMA reduced NTG-induced inhibition of platelet aggregation to 26.4+/-4.2% (P<0.001). 5. It is concluded that vascular tissue contributes to the antiplatelet mechanism of action of NTG. Furthermore, NTG apparently evokes the release of CGRP from vascular tissue and this neuropeptide contributes to the antiplatelet actions of NTG. 6. The antiplatelet activity of CGRP in whole blood is mediated primarily through the activation of nitric oxide synthase.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Neurotransmissores/fisiologia , Nitroglicerina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Difosfato de Adenosina/farmacologia , Animais , Aorta/fisiologia , Impedância Elétrica , Técnicas In Vitro , Masculino , Ratos , Ratos Sprague-Dawley , ômega-N-Metilarginina/farmacologia
12.
J Cardiovasc Pharmacol ; 28(3): 432-8, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8877591

RESUMO

Organic nitrates possess important antiplatelet actions that are useful in the treatment of unstable angina and myocardial infarction, but the susceptibility of platelets to nitrate tolerance has not been extensively studied. In normal conscious rats, we showed that continuous infusion of nitroglycerin (NTG) at 10 micrograms/min had no significant effect on mean arterial pressure (MAP) as compared with control, but hemodynamic tolerance could be demonstrated by MAP response to a bolus intravenous (i.v.) NTG challenge. By this criterion, continuous 8-h NTG infusion produced hemodynamic tolerance (a decrease in MAP response of 45.7 +/- 19.9%, p < 0.05), whereas D5W control and S-nitroso-N-acetylpenicillamine (SNAP) infusions did not. During NTG infusion, platelet-rich plasma (PRP) cyclic GMP was increased by 41.4 +/- 13.6% as compared with control and remained increased throughout the infusion (p < 0.05). Bleeding time during a 2-h infusion of NTG was 8.9 +/- 1.2 min as compared to 3.8 +/- 0.4 min in controls (p < 0.05). After 8-h of NTG infusion, the bleeding time was 10.2 +/- 1.4 min versus 4.4 +/- 0.4 min in controls (p < 0.05). NTG also decreased the PRP platelet concentration by 30% in 8 h, whereas D5W had no effect. In vitro experiments showed that platelets in themselves do not produce significant amounts of cyclic GMP. These data indicate that the biochemical and antiaggregation effects of NTG on platelets are not diminished during hemodynamic tolerance and that these effects may be dependent on extraplatelet production of nitric oxide (NO).


Assuntos
Plaquetas/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Nitroglicerina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Vasodilatadores/farmacologia , Animais , Plaquetas/metabolismo , GMP Cíclico/biossíntese , Tolerância a Medicamentos , Hematócrito , Masculino , Contagem de Plaquetas , Ratos , Ratos Sprague-Dawley
13.
Adv Pharmacol ; 34: 361-81, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8562446

RESUMO

The NO donors are a diverse group of agents with unique chemical structures and biochemical requirements for generation of NO. The differences in biochemistry and metabolism may, in turn, cause differences in their pharmacology and therapeutic actions. A thorough understanding of the biochemical pharmacology of NO donors and factors controlling their therapeutic activity would facilitate the optimal use of these agents as chemical carriers of NO, and the development of newer agents than can selectively modulate the many physiological actions of NO.


Assuntos
Óxido Nítrico/fisiologia , Animais , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Humanos , Óxido Nítrico/química , Óxido Nítrico/metabolismo
14.
Anesth Analg ; 78(5): 848-56, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-8160981

RESUMO

Glyceryl trinitrate (GTN) is used to control arterial blood pressure during cardiopulmonary bypass (CPB) procedures, but its effects are often decreased during the period of extracorporeal support. The plasma and urine concentrations of GTN and glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN) for male and female patients who received GTN during hypothermic CPB, and male and female patients who were given GTN during normothermic CPB, were measured by gas-liquid chromatography. During hypothermic CPB, the male and female subjects experienced significant decreases in GTN clearance (P < 0.05), 66% and 52%, respectively. Neither the males nor the females who underwent normothermic CPB experienced any significant change in GTN clearance. These results suggest that the lower core temperature during hypothermic CPB may decrease the biotransformation of GTN to GDNs and nitric oxide, thereby resulting in less dilation of blood vessels. Furthermore, the males in the hypothermic CPB group had significantly greater urinary concentrations of 1,3-GDN and 1,2-GDN than the females (P < 0.05), and the normothermic CPB males had a significantly greater urinary concentration of 1,2-GDN than the females in that group. The normothermic CPB males also had significantly higher plasma concentration of GTN at two time points, and 1,3-GDN at one time point, than the females. These data suggest that there may be a gender difference in GTN biotransformation.


Assuntos
Ponte Cardiopulmonar/métodos , Hipotermia Induzida , Nitroglicerina/sangue , Nitroglicerina/urina , Idoso , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitroglicerina/análogos & derivados , Vasodilatadores/sangue , Vasodilatadores/urina
15.
Can J Physiol Pharmacol ; 71(8): 629-32, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8306203

RESUMO

It has previously been shown that the vasodilatory response to glyceryl trinitrate (GTN) was decreased during hypothermic cardiopulmonary bypass. The purpose of these experiments was to determine the effect of temperature on GTN-induced relaxation and on GTN biotransformation in rabbit aorta. It was determined that the EC50 of GTN on rabbit aortic rings (RARs) was increased significantly from 1.8 x 10(-8) M at 37 degrees C to 3.4 x 10(-8) M at 27 degrees C (p < 0.05). The production of NO by rabbit aortic strips (RASs) was significantly less at 27 degrees C compared with 37 degrees C after 80 min, being 9.62 x 10(-11) +/- 13.2 x 10(-11) mol NO/g wet wt. RASs compared with 5.71 x 10(-10) +/- 9.43 x 10(-11) mol NO/g wet wt. RASs, respectively (p < 0.05), after 80 min incubation. There was no difference in the amount of glyceryl-1,2-dinitrate (1,2-GDN) produced from GTN at the two temperatures. The ED20 for NO-induced relaxation of RARs increased from 3.46 x 10(-10) +/- 2.24 x 10(-10) mol at 37 degrees C to 1.01 x 10(-9) +/- 4.51 x 10(-10) mol at 27 degrees C (p < 0.05). These data indicate that the biotransformation of GTN and the release of NO were impaired by hypothermia, and that this, as well as a decrease in the tissue response to NO at 27 degrees C, explains the decrease in GTN activity at reduced body temperatures.


Assuntos
Temperatura Alta , Óxido Nítrico/metabolismo , Nitroglicerina/farmacocinética , Vasodilatação/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Biotransformação/fisiologia , Meios de Cultura , Técnicas In Vitro , Masculino , Nitroglicerina/análogos & derivados , Nitroglicerina/metabolismo , Coelhos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/metabolismo
16.
Can J Physiol Pharmacol ; 69(6): 889-92, 1991 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-1913335

RESUMO

The current proposed mechanism of action of nitrovasodilator drugs involves biotransformation to nitric oxide, which is postulated to be the active vasodilator substance. Our objective was to determine whether nitric oxide was formed from two prototype nitrovasodilator drugs, glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), after incubation with bovine pulmonary vein (BPV) preparations. GTN or SNP was incubated in an argon atmosphere with phosphate buffer, BPV homogenate, or the 10,000 x g supernatant fraction of the homogenate. Nitric oxide formation, as determined by a chemiluminescence-headspace gas method, was measurable following the incubation of SNP with BPV homogenate and 10,000 x g supernatant. There was no detectable formation of nitric oxide from the incubation of GTN with the two BPV preparations, although GTN was biotransformed to glyceryl dinitrate, as determined by gas-liquid chromatography. There was decreased recovery of nitric oxide during the incubation of authentic nitric oxide with the two BPV preparations as compared with buffer. In conclusion, formation of nitric oxide was measured for the interaction of SNP, but not GTN, with BPV preparations. However, the data do not exclude the possible formation of nitric oxide from GTN, as nitric oxide was shown to be sequestered or transformed by the BPV preparations.


Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Nitroglicerina/farmacologia , Nitroprussiato/farmacologia , Animais , Biotransformação , Bovinos , Cromatografia Gasosa , Técnicas In Vitro , Medições Luminescentes , Veias Pulmonares/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo
17.
Anesth Analg ; 72(4): 493-7, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1900982

RESUMO

The effectiveness of glyceryl trinitrate (nitroglycerin) in controlling myocardial ischemia and blood pressure during coronary artery bypass graft surgery is frequently lost during surgery, possibly as a result of drug sequestration by the cardiopulmonary bypass circuit. The objective of this study was to utilize a gas-liquid chromatographic assay to determine the extent of removal of glyceryl trinitrate from the priming fluid by the bubble and membrane oxygenators. The apparatus was maintained at either 25 or 37 degrees C, the two extreme temperatures experienced by the patient during bypass surgery. At apparent steady state, the circulating glyceryl trinitrate concentration was decreased by 20.6%, 46.6%, and 67.3% with the Maxima membrane oxygenator, Cobe membrane oxygenator, and Bentley bubble oxygenator, respectively. The three-layer defoaming filters that are used in the Bentley bubble oxygenator were studied by immersing each of the three filters in fluid containing 60 nM glyceryl trinitrate and monitoring the drug concentration in Plasmalyte. The filters sequestered approximately 90% of the glyceryl trinitrate from the bathing solution of which 31% was recovered with a single methanol wash of the polyurethane filter. These data demonstrate that the different oxygenators used in the cardiopulmonary bypass circuit remove glyceryl trinitrate to varying degrees from the circulating fluid.


Assuntos
Ponte Cardiopulmonar/instrumentação , Nitroglicerina/análise , Oxigenadores de Membrana , Cromatografia Gasosa , Humanos
18.
Biopharm Drug Dispos ; 11(8): 663-77, 1990 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2125512

RESUMO

Two large-bore capillary columns, one with dimethyl polysiloxane (HP-1) as the stationary phase and the other with phenyl (50 per cent) methyl (50 per cent) polysiloxane (DB-17), were used to develop gas-liquid chromatographic (GLC) assays for measuring isosorbide dinitrate (ISDN), glyceryl trinitrate (GTN), and their metabolites. ISDN, isosorbide-2-mononitrate (2-ISMN), and isosorbide-5-mononitrate (5-ISMN) in plasma, ranging in concentration from 1 to 300 nM, and GTN, glyceryl-1,2-dinitrate (1,2-GDN), and glyceryl-1,3-dinitrate (1,3-GDN), ranging in concentration from 3 to 60 nM in plasma, were analysed on both columns. GLC analysis yielded baseline resolution of the analytes. The method using the dimethyl polysiloxane column gave a lower limit of detectability for GTN of 0.75 nM (signal/noise (s/n) = 2), and the procedure using the phenyl-methyl column provided a lower limit of detectability for ISDN of 81 pM (s/n = 2). The large-bore column GLC procedures exhibited shorter retention times for both ISDN and GTN than those previously reported for capillary-column assays. The chromatographic resolution of analytes and column efficiency of the large-bore capillary columns were comparable to the results previously found using capillary-column GC. The assays for ISDN and GTN have been shown to be appropriate for pharmacokinetic studies in volunteers and patients. We determined that the HP-1 column is appropriate for the analysis of GTN and metabolites, and the DB-17 column is suitable for analysis of ISDN and its metabolites. We conclude that the use of large-bore capillary columns provides rapid and reliable GLC assays for organic nitrates.


Assuntos
Dinitrato de Isossorbida/sangue , Nitroglicerina/sangue , Cromatografia Gasosa , Humanos , Dinitrato de Isossorbida/análogos & derivados
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...