A simple and sensitive high performance liquid chromatography method using fluorescence detection （HPLC- FLD） and a one-step single solvent extraction for the determination of prazosin（PZS） in dog plasma is develo...A simple and sensitive high performance liquid chromatography method using fluorescence detection （HPLC- FLD） and a one-step single solvent extraction for the determination of prazosin（PZS） in dog plasma is developed and validated. After extraction with ether, the chromatographic separation of PZS is carried out using a reverse phase C18 column （ 150 mm ×4.6 mm, 5 μm） with a mobile phase of 30% acetonitrile and 70% acetic acid-sodium acetate buffer solution （pH = 3.6） and quantified by fluorescence detection operated with an excitation wavelength of 258 nm and an emission wavelength of 387 nm. The flow rate of the mobile phase is 1.0 mL/min and the retention time of PZS and the internal standard is found to be 4. 4 and 5. 8 rain, respectively. The calibration curve is linear within a concentration range from 1.0 to 1 000.0 ng/mL （ P 〉 0. 998）. The limit of detection is 0.4 ng/mL. The inter-day coefficient of variation （COV） of the calibration standards is below 5.0% and the mean accuracy is in the range from 92. 7% to 104. 2%. Moreover, by analyzing quality control plasma samples for three days, the results show that the method is precise and accurate, for the intra- and inter- day COV within 10% and the accuracy from 95.9% to 112.7%. The developed and validated method is successfully applied to phannacokinetic study for the preclinical evaluation of a new peroral PZS-sulfobutyl ether beta-cyclodextrin （PZS-SBE-β-CD） inclusion complex tablets （test preparation）, which demonstrates that the test preparation released PZS is conducted in a slow and controlled way, and the relative bioavailability of the test preparation is found to be 105.0%.展开更多
Prazosin（PRZ） and levonorgestrel（LNG） are widely used as an anti-disease drugs due to their biological activity in the human body. The frequent detection of these compounds in water samples requires alternative te...Prazosin（PRZ） and levonorgestrel（LNG） are widely used as an anti-disease drugs due to their biological activity in the human body. The frequent detection of these compounds in water samples requires alternative technologies for the removal of both compounds. After electrochemical degradation of PRZ and LNG, the parent compounds could be completely removed after treatment, but the identification and characterization of by-products are necessary as well. In this study, the effects of NaCl concentration and applied voltage were investigated during the electrochemical degradation process. The results revealed that the increase of NaCl concentration and applied voltage could promote the generation of hypochlorite OCl-and then enhance the degradation of PRZ and LNG. After initial study, 6 V and 0.2 g NaCl were selected for further experiments（96% and 99% removal of PRZ and LNG after 40 min, respectively）. Energy consumption was also evaluated and calculated for PRZ and LNG at 3, 6 and 8 V. Solid phase extraction（SPE） method plays an important role in enhancing the detection limit of by-products. Furthermore, characterization and identification of chlorinated and non-chlorinated by-products were conducted using an accurate liquid chromatography-time of flight/mass spectrometry LC-TOF/MS instrument. The monitoring of products during the electrochemical degradation process was performed at6 V and 0.2 g NaCl in a 50 m L solution. The results indicated that two chlorinated products were formed during the electrochemical process. The toxicity of by-products toward E. coli bacteria was investigated at 37°C and 20 hr incubation time.展开更多
Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral ro...Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.展开更多
Spinal cord injury （SCI） is a devastating condition that not only results in a loss of motor functions but also severe autonomic dysfunctions （Krassioukov and Claydon, 2006）. Autonomic dysreflexia （AD） is a life...Spinal cord injury （SCI） is a devastating condition that not only results in a loss of motor functions but also severe autonomic dysfunctions （Krassioukov and Claydon, 2006）. Autonomic dysreflexia （AD） is a life threatening episode of tran- sient hypertension that occurs up to 30x/day （1 Ix/day on average） in those with cervical or high thoracic SCI （Hubli et al., 2015）. Most common triggers of AD are from stimuli such as a full bowel and/or bladder, or sexual arousal （Teasell et al., 2000）. Penile vibrostimulation （PVS） is a clinical pro- cedure for sperm retrieval used for the purpose of family planning or fertility assessment that unfortunately iatrogenically induces episodes of AD （Elliott, 2006）. Recently, we published a clinical trial highlighting that prazosin may be a viable option for treating AD secondary to PVS （Phillips et al., 2014）.展开更多
In this study, a new naphthalene-prazosin derivative (compound 5) was synthetized with the objective of evaluating its activity on ischemia/reperfusion injury. The Langendorff technique was used to evaluate the effect...In this study, a new naphthalene-prazosin derivative (compound 5) was synthetized with the objective of evaluating its activity on ischemia/reperfusion injury. The Langendorff technique was used to evaluate the effect of the compound 5 on ischemia/reperfusion injury. Additionally, the mechanism of action involved in the activity exerted by the compound 5 on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in absence or presence of following compounds;prazosin, metoprolol, indomethacin and nifedipine. The results showed that the compound 5 reduced infarct size compared with the control conditions. Other results showed that the compound 5 significantly increases (p = 0.05) the perfusion pressure and coronary resistance in isolated rat heart. In addition, other data indicate that the compound 5 increases left ventricular pressure in a dose-dependent manner (0.001 to 100 nM);however, this phenomenon was significantly inhibited by nifedipine at a dose of 1 nM (p = 0.05) and this effect was independent of cAMP levels. In conclusion, these data suggest that the naphthalene-prazosin derivative exerts a cardio protective effect via the calcium channels activation and consequently induces changes in the left ventricular pressure levels. This phenomenon results in a decrease of myocardial necrosis after ischemia and reperfusion.展开更多
Purpose: To investigate the effects of topical prazosin and pilocarpine on uveoscleral outflow(Fu) in rabbits.Methods: Sixteen rabbits were randomly divided into the control group (5 rabbits, only topical application ...Purpose: To investigate the effects of topical prazosin and pilocarpine on uveoscleral outflow(Fu) in rabbits.Methods: Sixteen rabbits were randomly divided into the control group (5 rabbits, only topical application of normal saline in the right eye of each rabbit), Prazosin (PZ) treated group (6 rabbits, only 0.1% Prazosin eyedrop 0.1% in the right eye of each one) and Pilocarpine (PC) treated group (5 rabbits, 1% Pilocarpine eye drop in each right eye).Intraocular pressure (IOP)of bilateral eyes of each rabbit was measured before and 1 h after topical application of the eye drop.And the bilateral eyes were perfused with Fluorescein-isothiocyanate bovine serum albumin (FITC-BSA) as the tracer into the anterior chamber of each rabbit for 30 min at 90 min after topical treatment. Then the rabbits were killed for Fu measurement.Results: IOP of PZ-treated eyes decreased [ (0.71 +0.07)kPa ] in 1 hour after PZ application.IOP of PC-treated eyes decreased [(0.70+0.08)kPa] in 1 hour after PC application. The average value of Fu was (0.176+0.048)μl/min in control eyes. The average value of Fu in PZ-treated eyes was (0.339+0.018)μl/min. The average value of Fu in PC-treated eye was(0.123+0.022) μl/min.Conclusion: Both of PZ and PC can decrease IOP in rabbits following topical application.Topical PZ can increase Fu in rabbits and this is one of the mechanisms of PZ-induced IOP decrease.Topical PC can prevent Fu. PC decreases IOP not through uveoscleral pathway.This study demonstrates that uveoscleral pathway plays an important role in aqueous humor drainage. PZ may be a novel drug for decreasing IOP. FITC-BSA is an effective tracer for studying uveoscleral pathway.展开更多
基金Pre-Research Foundation for the National Natural Science Foundation of Southeast University(No.9225000007)Suzhou Science and Technology Development Projects(No.YJS0948)
文摘A simple and sensitive high performance liquid chromatography method using fluorescence detection （HPLC- FLD） and a one-step single solvent extraction for the determination of prazosin（PZS） in dog plasma is developed and validated. After extraction with ether, the chromatographic separation of PZS is carried out using a reverse phase C18 column （ 150 mm ×4.6 mm, 5 μm） with a mobile phase of 30% acetonitrile and 70% acetic acid-sodium acetate buffer solution （pH = 3.6） and quantified by fluorescence detection operated with an excitation wavelength of 258 nm and an emission wavelength of 387 nm. The flow rate of the mobile phase is 1.0 mL/min and the retention time of PZS and the internal standard is found to be 4. 4 and 5. 8 rain, respectively. The calibration curve is linear within a concentration range from 1.0 to 1 000.0 ng/mL （ P 〉 0. 998）. The limit of detection is 0.4 ng/mL. The inter-day coefficient of variation （COV） of the calibration standards is below 5.0% and the mean accuracy is in the range from 92. 7% to 104. 2%. Moreover, by analyzing quality control plasma samples for three days, the results show that the method is precise and accurate, for the intra- and inter- day COV within 10% and the accuracy from 95.9% to 112.7%. The developed and validated method is successfully applied to phannacokinetic study for the preclinical evaluation of a new peroral PZS-sulfobutyl ether beta-cyclodextrin （PZS-SBE-β-CD） inclusion complex tablets （test preparation）, which demonstrates that the test preparation released PZS is conducted in a slow and controlled way, and the relative bioavailability of the test preparation is found to be 105.0%.
基金Universiti Kebangsaan Malaysia for the scholarship of Z. H. Mussa (matric No. p69014)
文摘Prazosin（PRZ） and levonorgestrel（LNG） are widely used as an anti-disease drugs due to their biological activity in the human body. The frequent detection of these compounds in water samples requires alternative technologies for the removal of both compounds. After electrochemical degradation of PRZ and LNG, the parent compounds could be completely removed after treatment, but the identification and characterization of by-products are necessary as well. In this study, the effects of NaCl concentration and applied voltage were investigated during the electrochemical degradation process. The results revealed that the increase of NaCl concentration and applied voltage could promote the generation of hypochlorite OCl-and then enhance the degradation of PRZ and LNG. After initial study, 6 V and 0.2 g NaCl were selected for further experiments（96% and 99% removal of PRZ and LNG after 40 min, respectively）. Energy consumption was also evaluated and calculated for PRZ and LNG at 3, 6 and 8 V. Solid phase extraction（SPE） method plays an important role in enhancing the detection limit of by-products. Furthermore, characterization and identification of chlorinated and non-chlorinated by-products were conducted using an accurate liquid chromatography-time of flight/mass spectrometry LC-TOF/MS instrument. The monitoring of products during the electrochemical degradation process was performed at6 V and 0.2 g NaCl in a 50 m L solution. The results indicated that two chlorinated products were formed during the electrochemical process. The toxicity of by-products toward E. coli bacteria was investigated at 37°C and 20 hr incubation time.
文摘Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.
基金AAP is supported by the Heart and Stroke Foundation of Canadathe Michael Smith Foundation for Health Research+3 种基金AVK is supported by the Paralyzed Veterans of Americathe Craig Neilson Foundationthe Canadian Institute of Health Researchthe Heart and Stroke Foundation of Canada
文摘Spinal cord injury （SCI） is a devastating condition that not only results in a loss of motor functions but also severe autonomic dysfunctions （Krassioukov and Claydon, 2006）. Autonomic dysreflexia （AD） is a life threatening episode of tran- sient hypertension that occurs up to 30x/day （1 Ix/day on average） in those with cervical or high thoracic SCI （Hubli et al., 2015）. Most common triggers of AD are from stimuli such as a full bowel and/or bladder, or sexual arousal （Teasell et al., 2000）. Penile vibrostimulation （PVS） is a clinical pro- cedure for sperm retrieval used for the purpose of family planning or fertility assessment that unfortunately iatrogenically induces episodes of AD （Elliott, 2006）. Recently, we published a clinical trial highlighting that prazosin may be a viable option for treating AD secondary to PVS （Phillips et al., 2014）.
文摘In this study, a new naphthalene-prazosin derivative (compound 5) was synthetized with the objective of evaluating its activity on ischemia/reperfusion injury. The Langendorff technique was used to evaluate the effect of the compound 5 on ischemia/reperfusion injury. Additionally, the mechanism of action involved in the activity exerted by the compound 5 on perfusion pressure and coronary resistance was evaluated by measuring left ventricular pressure in absence or presence of following compounds;prazosin, metoprolol, indomethacin and nifedipine. The results showed that the compound 5 reduced infarct size compared with the control conditions. Other results showed that the compound 5 significantly increases (p = 0.05) the perfusion pressure and coronary resistance in isolated rat heart. In addition, other data indicate that the compound 5 increases left ventricular pressure in a dose-dependent manner (0.001 to 100 nM);however, this phenomenon was significantly inhibited by nifedipine at a dose of 1 nM (p = 0.05) and this effect was independent of cAMP levels. In conclusion, these data suggest that the naphthalene-prazosin derivative exerts a cardio protective effect via the calcium channels activation and consequently induces changes in the left ventricular pressure levels. This phenomenon results in a decrease of myocardial necrosis after ischemia and reperfusion.
基金This study is supported by Chinese Natural Science Foundation (No.39370724)
文摘Purpose: To investigate the effects of topical prazosin and pilocarpine on uveoscleral outflow(Fu) in rabbits.Methods: Sixteen rabbits were randomly divided into the control group (5 rabbits, only topical application of normal saline in the right eye of each rabbit), Prazosin (PZ) treated group (6 rabbits, only 0.1% Prazosin eyedrop 0.1% in the right eye of each one) and Pilocarpine (PC) treated group (5 rabbits, 1% Pilocarpine eye drop in each right eye).Intraocular pressure (IOP)of bilateral eyes of each rabbit was measured before and 1 h after topical application of the eye drop.And the bilateral eyes were perfused with Fluorescein-isothiocyanate bovine serum albumin (FITC-BSA) as the tracer into the anterior chamber of each rabbit for 30 min at 90 min after topical treatment. Then the rabbits were killed for Fu measurement.Results: IOP of PZ-treated eyes decreased [ (0.71 +0.07)kPa ] in 1 hour after PZ application.IOP of PC-treated eyes decreased [(0.70+0.08)kPa] in 1 hour after PC application. The average value of Fu was (0.176+0.048)μl/min in control eyes. The average value of Fu in PZ-treated eyes was (0.339+0.018)μl/min. The average value of Fu in PC-treated eye was(0.123+0.022) μl/min.Conclusion: Both of PZ and PC can decrease IOP in rabbits following topical application.Topical PZ can increase Fu in rabbits and this is one of the mechanisms of PZ-induced IOP decrease.Topical PC can prevent Fu. PC decreases IOP not through uveoscleral pathway.This study demonstrates that uveoscleral pathway plays an important role in aqueous humor drainage. PZ may be a novel drug for decreasing IOP. FITC-BSA is an effective tracer for studying uveoscleral pathway.
基金supported by the National Natural Science Foundation of China (No. 30393130, No. 30572086)the National Basic Research Development Program of China (No. 2006CB504100)the Special Foundation for Doctoral Point in High Educational Institute of China (No. 20060089009)
文摘本研究通过肌肉收缩描记方法,应用α1肾上腺素能受体激动剂——苯肾上腺素(phenylephrine,PE)和α1受体阻断剂——哌唑嗪(prazosin,PRA)探讨慢性间歇性低压低氧(chronic intermittent hypobaric hypoxia,CIHH)大鼠心室乳头状肌α1受体的变化以及α1受体在心脏保护中的作用。雄性Sprague-Dawley大鼠66只,随机分为4组:对照组(control,Con)、CIHH处理14天组(CIHH14)、CIHH处理28天组(CIHH28)和CIHH处理42天组(CIHH42)。CIHH处理动物置于低压氧舱内,分别接受14、28、42天相当于5000m高原(pB=404mmHg,pO2=84mmHg)低氧处理,每天6h。对照组动物除不接受低氧处理外,其余条件同CIHH处理动物。大鼠以戊巴比妥钠(3.0～3.5mL/kg体重)腹腔注射麻醉后立即取出心脏,分离右室乳头状肌,用氧饱和的改良台氏液恒温(37oC)、恒速(12mL/min)灌流,电刺激诱发乳头状肌收缩。通过累加给药法,观察不同浓度(1×10-7、1×10-6和1×10-5mol/L)PE对大鼠乳头状肌收缩的影响;用模拟缺血液以及加入PRA(1×10-6mol/L)的模拟缺血液灌流,观察各组乳头状肌收缩的变化。结果如下:(1)PE增加各组乳头状肌的最大收缩力(maximal isometric tension,Pmax)和最大张力上升速率(maximal velocity of tension development,PdT/dt),作用呈剂量依赖性(P<0.05);CIHH28、CIHH42处理组乳头状肌对PE反应性增强(P<0.05)。最大浓度PE(1×10-5mol/L)作用下,CIHH28组的Pmax和PdT/dt分别较基础值增加51.2%和44.5%,CIHH42组的Pmax和PdT/dt分别增加48.6%和44.5%,较对照组(28.7%和24.5%)明显增加(P<0.05);(2)CIHH处理可以对抗模拟缺血液对乳头状肌收缩的抑制。CIHH28和CIHH42组的Pmax和PdT/dt降低幅度分别为59.6%,53.6%和60.4%,49.9%,明显小于对照组(74.4%,64.7%)(P<0.05);(3)α1受体阻断剂PRA(1×10-6mol/L)可取消CIHH对抗缺血的保护作用。以上结果表明,CIHH处理增强大鼠心肌α1肾上腺素能受体活动,此作用可能是CIHH处理对抗心肌缺血/再灌注损伤的机制之一。
