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Inhibition of CYP2D6 by quinidine and its effects on the metabolism of cilostazol

CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 41-51页

作者： Bramer, SL Suri, A Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: In vitro results are inconclusive as to whether cilostazol is metabolised by cytochrome P450 isoenzyme 2D6 (CYP2D6). The goals of this study were (1) to assure the dose of quinidine and timing relative to cilostazol used in this study were adequate to cause inhibition of CYP2D6, (2) to evaluate carryover effects of quinidine administration, and (3) to evaluate the effect of CYP2D6 deficiency and administration of quinidine (a CYP2D6 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, randomised sequence, 2-period, crossover pharmacokinetic trial. Water alone (treatment without quinidine) or two 200mg oral doses of quinidine sulfate with water were administered 25 hours and 1 hour prior to a single 100mg dose of cilostazol in period 1. Study participants were crossed over to opposite treatment in period 2. Metoprolol 25mg, used as a positive control, was administered 1 hour after quinidine sulfate with water or using water alone to assess the magnitude of CYP2D6 inhibition by quinidine. Study Participants: 22 healthy nonsmoking Caucasian (14 male and 8 female) volunteers participated in the study. Main Outcome Measures: Serial blood and urine samples were collected at predose and after cilostazol administration to characterise cilostazol and its metabolite pharmacokinetics. Additional plasma samples were taken to assess the pharmacokinetics of quinidine. Urine samples were collected to measure metoprolol and hydroxymetoprolol. Results: Administration of metoprolol with quinidine caused a significant (p < 0.001) decrease in the urinary 4-hydroxymetoprolol/metoprolol ratio compared with administration of metoprolol alone (42-fold decrease, 0.065 vs 2.707). Hence, quinidine effectively converted extensive metabolisers of CYP2D6 to poor metabolisers of CYP2D6. The 21-day washout period was adequate to have complete recovery from quinidine inhibition of CYP2D6. The analys

关键词：投药口服肾上腺素能β受体拮抗剂/代谢肾上腺素能β受体拮抗剂/尿方差分析曲线下面积交叉研究细胞色素P450CYP2D6/拮抗剂和抑制剂药物相互作用酶抑制剂/药代动力学酶抑制剂/药理学半衰期代谢清除率美托洛尔/代谢美托洛尔/尿奎尼丁/药代动力学奎尼丁/药理学四唑类/投药和剂量四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/代谢血管舒张药/药代动力学成年人女(雌)性人类男(雄)性中年人

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Relative bioavailability and effects of a high fat meal on single dose cilostazol pharmacokinetics

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 13-23页

作者： Bramer, SL Forbes, WP Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objectives: The objectives of this research were to (1) assess the relative bioavailability following administration of a 100mg cilostazol suspension versus 100mg tablet;(2) assess dosage form equivalency (2 x 50mg compared with 1 x 100mg);(3) compare the relative bioavailability following a single 50mg dose of cilostazol administered as an ethanolic solution versus a 50mg tablet;and (4) determine the effects of high fat diet on the pharmacokinetics of cilostazol following a single dose of 100mg cilostazol in the fed or fasted state. Results were compiled from 3 separate studies to address these objectives. Design: All studies involved healthy adult males receiving single oral doses of cilostazol in the fed or fasted state. The fed state consisted of administering cilostazol after ingestion of a high fat meal. One study compared the relative bioavailability of 100mg suspension and 2 x 50mg tablet versus 100mg tablet in a randomised crossover design. The study involving administration of a 50mg cilostazol ethanolic solution was a single treatment study. The effects of food on the pharmacokinetics of cilostazol after administration of 100mg cilostazol in the fed or fasted state as well as the pharmacokinetic profile following administration of a single 50mg oral dose of cilostazol were assessed in a randomised crossover design. Study Participants: All participants were healthy nonsmoking males aged between 19 and 48 years whose bodyweight was within 15% of ideal bodyweight. Main Outcome Measures: Noncompartmental pharmacokinetic parameters: were determined for each study participant. Results: The area under the plasma concentration-time curve (AUC) parameters were within the 80 to 125% criterion for bioequivalence for the cilostazol and its primary metabolite, OPC-13015. The maximum observed plasma concentrations (C-max) for these formulations were not equivalent and indicated that the absorption of cilostazol from a suspension is more rapid than from a tablet. The ap

关键词：投药口服曲线下面积生物利用度交叉研究膳食脂肪类/药理学禁食/代谢悬液片剂四唑类/投药和剂量四唑类/血液四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/代谢血管舒张药/药代动力学成年人人类男(雄)性中年人

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Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 578-585页

作者： Ratz, JD Fraser, AB Rees-Milton, KJ Adams, MA Bennett, BM Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC50 value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.

关键词：主动脉胸/药物作用主动脉胸/代谢主动脉胸/生理学结合竞争性生物转化血压/药物作用环GMP/代谢药物耐受性/生理学内皮缩血管肽1/拮抗剂和抑制剂内皮缩血管肽1/代谢内皮缩血管肽1/生理学肌收缩/药物作用肌松弛/药物作用硝酸甘油/药代动力学硝酸甘油/药理学吡嗪类/药理学大鼠 Sprague-Dawley 受体内皮素A 受体内皮缩血管肽/拮抗剂和抑制剂受体内皮缩血管肽/代谢磺胺类/药理学血管舒张药/药代动力学血管舒张药/药理学动物男(雄)性大鼠

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4-(3-chloro-4-methoxybenzyl) aminophthalazines: Synthesis and inhibitory activity toward phosphodiesterase 5

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第13期43卷 2523-2529页

作者： Watanabe, N Adachi, H Takase, Y Ozaki, H Matsukura, M Miyazaki, K Ishibashi, K Ishihara, H Kodama, K Nishino, M Kakiki, M Kabasawa, Y Eisai & Co Ltd Tsukuba Res Labs Tsukuba Ibaraki 3002635 Japan

We synthesized various 4-(3-chloro-4-methoxybenzyl)aminophthalazines substituted at the 1- and 6-positions and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) and their vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F2 alpha (10(-5) M). The preferred substituents at the 1-position of the phthalazine were 4-hydroxypiperidino, 4-hydroxymethylpiperidino, 4-(2-hydroxyethyl)piperidino, and 4-oxopiperidino. Among these compounds, [4-(3-chloro-4-methoxybenzyl)amino-1-(4-hydroxy)piperidino]-6-phthalazinecarbonitrile monohydrochloride (13) exhibited potent PDE5 inhibitory activity (IC50 = 0.56 nM) with > 1700-fold high selectivity over other PDE isozymes (PDE1-4). Compound 13 exhibited the most potent vasorelaxant action (EC50 = 13 nM) in this series of compounds. Compound 13 reduced mean pulmonary arterial pressure by 29.9 +/- 3.1% when administered intravenously at 30 mu g/kg to the chronically hypoxic rats and had an apparent oral bioavailability of about 19.5% in rats and was selected for further biological evaluation.

关键词： 3' 5'-环GMP磷酸二酯酶类抗高血压药/化学合成抗高血压药/化学抗高血压药/药代动力学抗高血压药/药理学生物利用度血压/药物作用冠状血管/药物作用冠状血管/生理学环核苷酸磷酸二酯酶类 5型地诺前列素/药理学高血压肺性/药物疗法高血压肺性/病理生理学肌松弛/药物作用肌平滑血管/药物作用肌平滑血管/生理学磷酸二酯酶抑制剂/化学合成磷酸二酯酶抑制剂/化学磷酸二酯酶抑制剂/药代动力学磷酸二酯酶抑制剂/药理学磷酸二酯水解酶类/代谢酞嗪类/化学合成酞嗪类/化学酞嗪类/药代动力学酞嗪类/药理学哌啶类/化学合成哌啶类/化学哌啶类/药代动力学哌啶类/药理学喹唑啉类/药理学大鼠 Sprague-Dawley 构效关系猪血管舒张药/化学合成血管舒张药/化学血管舒张药/药代动力学血管舒张药/药理学动物男(雄)性大鼠

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Effect of omeprazole on the metabolism of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 53-59页

作者： Suri, A Bramer, SL Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40mg every day) was administered on days 7 to 18. Study Participants: 20 healthy nonsmoking male and female volunteers. Main Outcome Measures: Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites. Results: Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (C-max) and area under the plasma concentration-time curve at time t (AUC(t)) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 C-max and AUC(t) increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUC(t) decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole. Conclusions: Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.

关键词：投药口服曲线下面积血蛋白质类/代谢色谱法高压液相交叉研究药物相互作用酶抑制剂/药理学半衰期奥美拉唑/药理学四唑类/投药和剂量四唑类/血液四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/代谢血管舒张药/药代动力学成年人女(雌)性人类男(雄)性中年人

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Effect of hepatic impairment on the pharmacokinetics of a single dose of cilostazol

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 25-32页

作者： Bramer, SL Forbes, WP Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: The pharmacokinetic profiles of cilostazol and its metabolites following a single oral dose of cilostazol 100mg were compared between individuals with impaired and normal liver function. Design: The study was conducted as a single-centre, open-label, single dose pharmacokinetic and tolerability trial. Study Participants: 12 patients with impaired and compensated liver function were compared with 12 volunteers with normal liver function. Participants in each group were matched for gender, age and weight. Of the 12 patients with hepatic impairment examined in this study, 10 had mild impairment (Child-Pugh class A) and 2 had moderate impairment (Child-Pugh class B). Main Outcome Measures: Blood and urine were collected up to 144 hours after drug administration. Pharmacokinetics were determined by noncompartmental methods. Results: Protein binding did not differ between the groups (95.2% healthy volunteers, 94.6% hepatically impaired patients). Mean +/- SD unbound oral clearance of cilostazol decreased by 8.6% because of hepatic impairment (3380 +/- 1400 ml/min in healthy volunteers, 3260 +/- 2030 ml/min in hepatically impaired patients). Total urinary excretion of metabolites was significantly higher in healthy volunteers (26 vs 17% of dose). Overall, the pharmacokinetics of cilostazol and its metabolites, OPC-13213 and OPC-13015, were not substantially different in those with mild and moderate hepatic disease compared with values in healthy volunteers. Except for terminal-phase disposition half-life and apparent terminal-phase volume of distribution for cilostazol, the ratios of geometric means of pharmacokinetic parameters for plasma cilostazol, OPC-13213 and OPC-13015 in those with hepatic impairment versus healthy volunteers were close to 100%. Conclusions: Based on The results of the pharmacokinetic analysis, dose adjust ment in patients with mild hepatic impairment is not necessary. However, caution should be exercised when cilostazol is administered t

关键词：投药口服曲线下面积半衰期肝疾病/分类肝疾病/代谢参考值疾病严重程度指数四唑类/代谢四唑类/药代动力学血管舒张药/代谢血管舒张药/药代动力学成年人人类男(雄)性中年人

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Effect of renal impairment on the pharmacokinetics of cilostazol and its metabolites

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 33-40页

作者： Mallikaarjun, S Forbes, WP Bramer, SL Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: The pharmacokinetics of cilostazol were studied in patients with mild, moderate and severe renal impairment and in healthy volunteers after administration of 50mg single and multiple doses of cilostazol. Design: This was an open-label, single and multiple dose study administering 50mg cilostazol every 12 hours to healthy volunteers and patients with varying degrees of renal impairment. Participants: 6 normal volunteers [creatinine clearance (CLCR) greater than or equal to 90 ml/min];6 patients with mild (CLCR 50 to 89 ml/min), 5 with moderate (CLCR 26 to 49 ml/min) and 6 with severe (CLCR 5 to 25 ml/min) renal impairment. Outcome Measures: Noncompartmental pharmacokinetic parameters were determined for each study participant. Results: At steady state, in the severe renal disease group, cilostazol and OPC-13015 peak concentrations (C-max) were 24 and 41% lower and the areas under the concentration-time curve over the dosage interval (AUC(tau)) 39 and 47% lower than in the healthy volunteers. C-max and AUC(tau) of OPC-13213 were significantly higher, 173 and 209%, respectively, than those in the healthy volunteers. The accumulation ratios were not significantly different between the various renal function groups for cilostazol and its metabolites. The estimated pharmacological activity of cilostazol and its metabolites was similar between the normal volunteers and those with severe renal impairment. Conclusions: A dosage reduction in renally impaired patients is not supported by the pharmacokinetics of cilostazol and its metabolites in this patient group.

关键词：投药口服方差分析曲线下面积色谱法高压液相肌酸酐/代谢用药计划表半衰期代谢清除率参考值肾功能不全/分类肾功能不全/代谢疾病严重程度指数四唑类/投药和剂量四唑类/血液四唑类/代谢四唑类/药代动力学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/代谢血管舒张药/药代动力学女(雌)性人类男(雄)性中年人

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Effect of multiple cilostazol doses on single dose lovastatin pharmacokinetics in healthy volunteers

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 69-77页

作者： Bramer, SL Brisson, J Corey, AE Mallikaarjun, S Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80mg on days 1, 7 and 9, as well as oral cilostazol 100mg twice daily on days 2 to 8, followed by a single oral 150mg cilostazol dose on day 9. Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. Results: The maximum observed plasma concentration (C-max) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(t)) for lovastatin coadministered with 100mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUC(t) ratios for lovastatin given with 150mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150mg of cilostazol. Maximum steady-state plasma drug concentration (C(ss)max) and AUC during a dosage interval (AUC(tau)) for cilostazol 100mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilos

关键词：方差分析抗胆固醇血症药/血液抗胆固醇血症药/代谢抗胆固醇血症药/药代动力学曲线下面积色谱法高压液相剂量效应关系药物用药计划表药物相互作用半衰期肠吸收/药物作用洛伐他汀/血液洛伐他汀/代谢洛伐他汀/药代动力学参考值四唑类/投药和剂量四唑类/血液四唑类/药代动力学四唑类/药理学血管舒张药/投药和剂量血管舒张药/血液血管舒张药/药代动力学血管舒张药/药理学成年人女(雌)性人类男(雄)性中年人

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Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease

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CLINICAL PHARMACOKINETICS 1999年第2-Sup期37卷 1-11页

作者： Bramer, SL Forbes, WP Mallikaarjun, S Otsuka Amer Pharmaceut Inc Dept Clin Pharmacokinet Pharmacodynam & Metab Rockville MD 20850 USA

Objective: To study the pharmacokinetics of cilostazol following single oral administration of 50 to 200mg in healthy young males, and after repeated oral administration of 100mg every 12 hours to patients with peripheral arterial disease (PAD). Design: The healthy male single dose study was a single-centre, randomised sequence, open-label, incomplete block, 3-period, 4-treatment, crossover design. The patient study was a single-centre, multiple dose, open-label study. Study Participants: 20 healthy nonsmoking male volunteers were enrolled and successfully completed the single dose study. 26 patients (21 males, 5 females) with intermittent claudication resulting from PAD were enrolled and completed the single/multiple dose study. Main Outcome Measures: Noncompartmental pharmacokinetic parameters, the area under the plasma concentration-time curve from zero to the time of last measurable plasma concentration, and maximum plasma concentration. Results: Peak plasma concentrations of cilostazol occurred about 3 hours after drug administration and then declined biexponentially with concentrations detectable (>20 mu g/L) in the plasma for at least 36 hours postdose. The apparent elimination half-life of cilostazol (approximately 11 hours) was similar after a single dose or after multiple doses, with steady state being reached within 4 days. Cilostazol accumulated 1.7-fold following multiple dose administration. The apparent volume of distribution (V-2/F;2.76 L/kg) suggested extensive distribution of cilostazol in the tissues. The oral clearance of cilostazol (CL/F;0.18 L/h/kg) was much lower than liver blood flow, indicating a low extraction ratio drug, and hence low probability of a significant first-pass effect. None of the administered doses were recovered in the urine as unchanged cilostazol, suggesting that metabolism, rather than urinary excretion, is the major elimination route. Following single oral doses of 50 to 200mg, the plasma concentrations of cilostazol and

关键词：投药口服方差分析曲线下面积交叉研究用药计划表间歇性跛行/药物疗法间歇性跛行/病因学代谢清除率外周血管疾病/并发症外周血管疾病/药物疗法四唑类/投药和剂量四唑类/血液四唑类/药代动力学四唑类/治疗应用组织分布血管舒张药/投药和剂量血管舒张药/血液血管舒张药/药代动力学血管舒张药/治疗应用女(雌)性人类男(雄)性

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Dypiridamole, a cGMP phosphodiesterase inhibitor, transiently improves the response to inhaled nitric oxide in two newborns with congenital diaphragmatic hernia

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INTENSIVE CARE MEDICINE 1999年第3期25卷 300-303页

作者： Thébaud, B Saizou, C Farnoux, C Hartman, JF Mercier, JC Univ Paris 07 Fac Med Xavier Bichat Hop Robert Debre Serv Pediat Reanimat F-75019 Paris France

Introduction: Congenital diaphragmatic hernia (CDH) remains a frusta;ling cause of respiratory failure associated with persistent pulmonary hypertension of the newborn (PPHN). Although inhaled nitric oxide (iNO) is effective in many infants with PPHN, it often fails to improve oxygenation in infants with CDH. As the increase in vascular smooth muscle cyclic guanosine monophosphate (cGMP) in response to iNO may be impeded by increased phosphodiesterase type-V (PDE-V) activity, it has been suggested that: PDE-V blockade potentiates the efficiency of iNO. Case reports: We used dypiridamole (Persantine), a specific PDE-V inhibitor, in two patients with CDH. Prenatal diagnosis showed a left-sided CDH at 23 weeks of gestation (GA) with intrathoracic stomach and left heart underdevelopment in the one infant and a right-sided CDH at 26 weeks GA with intrathoracic liver in the other. After antenatal corticoids, planned delivery was performed by the vaginal route at 38 weeks GA. Preoperative stabilization was achieved by high frequency oscillation, iNO and inotropic support over 24 h. Both had early pneumothorax drained by a chest tube. Despite optimization of ventilatory and hemodynamic support with surfactant replacement, iNO and adrenaline, oxygenation worsened progressively. Dypiridamole was introduced intravenously at 27 and 40 h, respectively, and improved oxygenation over the next 12 h. However, oxygenation again deteriorated and both patients died. Conclusion: Dypiridamole enhanced the response to iNO in PPHN associated with CDH, although this effect was transient. Combined therapy of iNO with PDE-V inhibitors may improve pulmonary vasodilation in some forms of PPHN which do not respond to iNO, thereby reducing the need for extracorporeal membrane oxygenation (ECMO) and improving outcome.

关键词：投药吸入双嘧达莫/药理学致命性结局疝横膈/治疗一氧化氮/投药和剂量一氧化氮/药代动力学氧/代谢磷酸二酯酶抑制剂/药理学血管舒张药/投药和剂量血管舒张药/药代动力学人类婴儿新生

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