丹参注射液在大鼠体内的药动学研究

目的 :检测丹参注射液静脉用药在大鼠体内的药动学。方法 :大鼠iv丹参注射液 ,以丹参酸甲为检测指标 ,用高效液相色谱 (HPLC)测定不同时间血浆药物浓度。计算丹参酸甲在大鼠体内的药动学参数。结果 :大鼠iv丹参注射液 (相当于丹参酸甲4 0mg·kg-1) ,药动学参数 :T1 2α0 .2 9± 0 .2 3h ,T1 2 β1.75± 0 .99h ,Vd0 .83± 0 .70L·kg-1,Cl 0 .33±0 .16L·h-1·kg-1,AUC(0 -inf) 148± 66mg·h-1·L-1。结论 :大鼠iv丹参注射液 ,血药浓度 时间曲线呈二室开放模型     

十一酸睾酮自微乳制剂的大鼠体内药代动力学研究

目的制备十一酸睾酮自微乳化制剂,并对其大鼠体内药代动力学进行研究。方法采用血清睾酮放免法测定给药后大鼠体内血清睾酮水平的变化,并计算药代动力学参数。结果十一酸睾酮原料药混悬液基本没吸收,而自微乳制剂和市售Andriol药物的吸收大大提高。以Andriol为参比制剂,自微乳制剂的相对生物利用度为96.4%。结论自微乳化给药系统能提高脂溶性药物十一酸睾酮的吸收。     

家兔体内环孢素A微囊栓剂的药动学

目的 :制备环孢素A微囊栓 ,考察其药动学性质。方法 :利用复凝聚法制备环孢素A微囊 ,并用于环孢素A微囊栓的研制 ;利用家兔进行药动学实验 ,用荧光偏振免疫分析仪测定血药浓度 ,以 3P97药动学软件按二室模型拟合 ,并对所得药动学参数进行统计学分析。结果 :环孢素A微囊栓的生物半衰期显著延长 (P <0 .0 5 ) ,AUC有增加的趋势。结论 :与环孢素A口服液和普通栓剂相比 ,环孢素A微囊栓具有一定缓释作用。     

布洛芬与拉呋替丁在大鼠体内药动学相互作用

目的:本文研究了布洛芬和拉呋替丁联合用药前后在大鼠体内的药动学变化规律。方法:用LC-MS/MS测定两者的血药浓度,用DAS 2.0统计软件计算药动学参数。结果:联合用药前后两者的药动学参数无显著性差异。结论:两者不存在药动学相互作用,合用时不需要调整给药剂量和给药间隔。     

联苯双酯对狗体内环孢素A的药动学影响

目的:考察联苯双酯(DDB)与环孢素A(CsA)在比格犬(beagle dog)体内合用后联苯双酯对CsA动力学过程的影响。方法:采用安慰剂、随机交叉试验方法。用放射免疫分析法测定6只比格犬单用CsA及合用DDB后CsA的血药浓度,并进行动力学参数的计算与比较。结果:CsA与DDB合用后,CsA在比格犬体内的血药浓度普遍降低,相对清除率(CL/F)显著增大[(1.1±0.8)mL.h-1.kg-1,(1.9±1.4)mL.h-1.kg-1,P<0.05],生物半衰期(t1/2)显著缩短[(14.3±3.4)h,(10.3±2.5)h,P<0.05],AUC明显变小[(11.1±4.1)mg.L-1.h,(7.4±3.7)mg.L-1.h,P<0.05],其余的参数无统计学差异(P>0.05)。结论:DDB可明显降低CsA的血药浓度。临床上合用DDB和CsA时必须监测CsA的血药浓度,随时调整给药剂量,保证安全有效的治疗。     

肝肾移植受者环孢素稳态药动学比较

目的比较肝肾移植受者环孢素（CsA）临床药动学差异。方法采用荧光偏振免疫法测定16例肝肾移植受者服用CsA后不同时间点的血药浓度，计算药动学参数。结果CsA代谢呈二房室开放模型。肝移植受者较肾移植β显著减小，T1／2日、T1／2a延长，tmax和达平均稳态血药浓度的时间（tcos）后移。结论CsA药动学参数个体差异大。肝移植受者的CsA分布和消除较肾移植显著减慢，易发生蓄积。     

利福布汀与依非韦伦在大鼠体内药动学的相互作用研究

目的:研究利福布汀(RBT)与依非韦伦(EFV)在大鼠体内药动学的相互影响。方法:将大鼠随机分为EFV单用组(54mg·kg-1)、RBT单用组(40.5mg·kg-1)及其联用组,每组6只,灌胃给药后,液质联用法检测给药后0、0.25、0.5、1、2、3、4、6、9、12、24、48、72h的血药浓度,计算药动学参数。结果:单用时,EFV、RBT的药动学参数分别为:cmax:(4.36±1.23)、(5.62±2.33)mg·L-1,AUC0～72h:(27.37±8.10)、(117.00±50.45)mg·h·L-1,CLZ/F:(2.15±0.77)、(0.36±0.15)L·h-1·kg-1,VZ/F:(8.33±2.49)、(12.06±7.64)L·kg-1;联用组二者的药动学参数分别为cmax:(1.68±0.82)、(3.05±1.66)mg·L-1,AUC0～72h:(13.13±9.95)、(89.60±55.75)mg·h·L-1,CLZ/F:(5.12±2.17)、(0.54±0.24)L·h-1·kg-1,VZ/F:(23.53±11.43)、(13.06±4.75)L·kg-1。与单用时比较,联用组EFV的cmax、AUC0～72h显著减小,CLZ/F、VZ/F显著增加(P<0.05),而RBT药动学各参数未见显著变化。结论:RBT能加快大鼠体内EFV的消除,降低其生物利用度。     

酮咯酸氨丁三醇在大鼠体内药动学

目的:比较研究大鼠尾静脉注射与局部皮肤给予酮咯酸氨丁三醇的药动学行为。方法:采用HPLC法,色谱柱:Dia-monsil C18柱(200mm×4.6mm,5μm);流动相:甲醇-水-三乙胺-冰醋酸(80∶19.9∶0.02∶0.08);流速:1.0mL.min-1;柱温:30℃;检测波长:313nm。结果:酮咯酸氨丁三醇在0.2~100mg.L-1范围内与峰面积呈良好的线性关系(r=0.999 0),日内RSD为2.3%~5.1%,日间RSD为2.2%~12.2%,萃取回收率为86.8%~96.2%,注射剂和凝胶剂的T1/2α分别为(0.4±0.3)h,(2.9±2.6)h;T1/2β分别为(2.7±2.0)h,(9.0±8.5)h。结论:本试验建立的方法操作简单,方法灵敏、特异,结果准确。酮咯酸在大鼠体内药动学行为符合二房室模型;外用给药透皮吸收良好。     

托莫西汀与氟西汀在大鼠体内药动学的相互作用

目的:考察托莫西汀和氟西汀在大鼠体内的药动学特性及合用时的相互作用.方法:采用柱前衍生-高效液相色谱法测定大鼠给药后不同时间的托莫西汀和氟西汀的血浆浓度.血浆浓度-时间数据用3P97程序拟合,求得药动学参数.结果:托莫西汀与氟西汀均符合二室模型特征,两药合用时,托莫西汀的t1/2、Cmax、AUC均明显增加,而氟西汀的药动学参数无统计学差异.结论:两药合用时,氟西汀会对托莫西汀的体内药代动力学产生显著影响,临床上应对托莫西汀的剂量以及给药间隔做相应的调整,必要时进行血药浓度监测.     

氧化苦参碱在乙肝患者体内的药动学

目的:研究氧化苦参碱注射液在乙型肝炎患者体内的药动学。方法:8例乙型肝炎患者和10名健康志愿者分别予氧化苦参碱注射液400mg,im,用HPLC分析法测定人血浆中的氧化苦参碱浓度。结果:肌注氧化苦参碱后其体内过程符合药动学二室模型,乙型肝炎患者和健康受试者的主要药动学参数分别为:T_((1/2)(K_a))(7.2±4.0),(4.6±2.0)min;T_((1/2)(α))(24.9±13.3),(29.8±13.8)min; T_((1/2)(β))(141.8±22.5),(133.3±19.1)min;t_(max)(23.8±12.2).(19.0±5.4)min;c_(max)(6.80±1.48),(7.09±0.88)mg·L~(-1);F(c)(41.96±11.00),(43.64±12.40)L;AUC(847.18±137.89),(934.49±159.06)mg·L~(-1)·min;CL_((s))(0.48±0.07),(0.44±0.07)L·min~(-1)。经统计学处理,2组药动学参数均无显著差异(P均>0.05)。结论:氧化苦参碱在乙型肝炎患者和健康人体内的药动学过程无显著性差异。     

Injectable testosterone undecanoate for the treatment of hypogonadism

Introduction: Injectable testosterone undecanoate (TU) is a long-acting testosterone (T) formulation available for the treatment of male hypogonadism (HG) since 2003.

Areas covered: The efficacy and safety of injectable TU are assessed, as obtained by meta-analyzing available evidence. An extensive Medline, Embase and Cochrane search was performed. All uncontrolled and placebo-controlled randomized clinical trials (RCTs), evaluating the effect of injectable TU on different outcomes, were included. Of the 98 retrieved articles, 33 were included in the study. Among those, 11 were placebo-controlled RCTs. Injectable TU was significantly associated with a reduction of fat mass and HbA1c in both controlled and uncontrolled trials, in particular when hypogonadal subjects were enrolled. Similar results were observed for the improvement of erectile function. In addition, TU ameliorated several other outcomes, including blood pressure, lipid profile, waist circumference and body mass index in uncontrolled studies, but these data were not confirmed in placebo-controlled trials. The treatment was well tolerated and no risk of prostate cancer or cardiovascular disease was observed.

Expert opinion: Injectable TU is a safe and effective treatment for male HG. The possibility of a therapeutic intervention just four to five times per year frees the patient, at least partially, from having a chronic condition, thus maintaining a positive, active role in self-caring.     

Pharmacokinetic interaction between fluvastatin and diltiazem in rats

The present study aimed to investigate the effect of fluvastatin on the pharmacokinetics of diltiazem in rats. Pharmacokinetic parameters of diltiazem were determined in rats following an oral administration of diltiazem (15 mg/kg) in the presence and absence of fluvastatin (0.6 and 2.0 mg/kg). Compared with the control given diltiazem alone, the C(max) and AUC of diltiazem increased by 30-70% in rats with the concurrent use of fluvastatin, while there was no significant change in T(max) and the plasma half-life (T(1/2)) of diltiazem. Consequently, absolute and relative bioavailability values of diltiazem in the presence of fluvastatin were significantly higher (p<0.05) than those from the control group, implying that fluvastatin could reduce the presystemic extraction of diltiazem. In conclusion, the concurrent use of fluvastatin significantly enhanced the oral exposure of diltiazem in rats.     

伐地那非、十一酸睾酮合用与单用伐地那非治疗糖尿病患者勃起功能障碍的疗效比较

目的比较联合应用伐地那非和十一酸睾酮与单用伐地那非治疗糖尿病患者勃起功能障碍的疗效及不良反应。方法该院男科门诊患有糖尿病的勃起功能障碍患者58例,随机分成A、B组,每组29例,A组口服伐地那非20mg,性生活前30min服用;B组除了同样服用伐地那非外,每日早晚饭后服用十一酸睾酮40mg,共观察12周。比较两组治疗前后的国际勃起功能指数-5(IIEF-5)问卷中的评分、每周性交频率以及治疗期间的不良反应,并评估在疗程结束时,患者及其配偶对性生活的满意程度。结果 A、B两组患者IIEF-5评分在治疗后均显著增加,而B组较A组增加更显著(P<0.05);治疗后每周性交频率两组均显著增多,两组之间比较B组增加更明显(P<0.05)。治疗结束时,A组患者对性生活感到满意的有15例(51.7%),B组有21例(72.4%),B组满意比例较A组更高(P<0.05)。在不良反应方面,B组患者共有6例(20.7%)发生不良反应,较A组的5例(17.2%)无统计学意义(P>0.05)。结论在对糖尿病患者勃起功能障碍的治疗上,联合应用伐地那非和十一酸睾酮比单用伐地那非治疗糖尿病患者勃起功能障碍疗效要好,同时引起的不良反应却无明显增加。     

Testosterone undecanoate in the treatment of male hypogonadism

Importance of the field: Testosterone undecanoate (TU) represents an exciting new testosterone replacement therapy for hypogonadal men due to its convenient dosing schedule and favorable pharmacokinetic and safety profiles.

Areas covered in this review: Clinical, pharmacokinetic and safety characteristics of TU will be reviewed. The characteristics of currently approved testosterone therapies will be reviewed and compared with those of TU in order to determine which therapy most appropriately meets the clinical objective of properly matching a patient with a therapy that is best able to deliver physiological levels of testosterone for prolonged periods of time, while at the same time being safe, effective, inexpensive, simple to use, and with few side effects.

What the reader will gain: TU represents the first long-acting injectable with an excellent safety profile that can be administered only four times annually to produce stable levels of testosterone. Long-term studies have validated the clinical efficacy of TU in maintaining therapeutic levels of testosterone. Patient preference for the convenient dosing schedule might also lead to better compliance and therapeutic benefit. No serious side effects have been noted with the use of TU, including long-term data on patients treated with TU over 8 years.

Take home message: TU is both a desirable and safe option for the treatment of hypogonadal men. Patients will benefit from the stable testosterone levels and fewer required injections, while achieving the desired benefits of androgen replacement.     

国产和进口十一酸睾酮雄激素活性的比较

目的 :观察国产十一酸睾酮 (TU)灌胃给药后的雄激素活性 ,并与进口TU (Andriol)比较。方法 :未成年雄性大鼠 ( 161只 ) ,去势 17d后分别灌胃给予国产TU或进口TU油溶液 5,10 ,2 0mg·kg- 1,对照组用油酸 4mL·kg- 1灌胃 ,bid× 7d ,停药 2d和 12d后各处死一半动物 ,称取前列腺和精液囊的重量。结果 :国产TU和进口TU均剂量依赖性增加去势大鼠前列腺和精液囊的重量 ,此作用在停药后可维持 10d以上 ,由六点法平行线检定得到国产TU与进口TU的相对效价 ,前列腺为1.0 7∶1;精液囊为 1∶1。结论 :国产TU的雄激素活性与进口TU相等     

高效液相色谱法测定十一酸睾酮在不同介质中的平衡溶解度和表观油水分配系数

目的测定十一酸睾酮在水和表面活性剂溶液中的平衡溶解度以及在正辛醇-缓冲液体系中的表观油水分配系数。方法采用高效液相色谱法测定十一酸睾酮在水和表面活性剂溶液中的浓度,采用摇瓶法测定十一酸睾酮的表观油水分配系数。结果 37℃下十一酸睾酮在水中不溶,Cremophor EL-35对十一酸睾酮有较强的增溶能力;十一酸睾酮的表观油水分配系数为12.21。结论十一酸睾酮的水溶性差,提高其制剂的溶出度可能会提高其生物利用度。     

云南地区男性避孕针可接受性研究

目的探讨十一酸睾酮酯男性避孕针在云南地区的可接受性。方法对注射男性避孕针对象及妻子、管理服务人员等进行问卷调查、访谈调查和心理测试。结果多数使用者是因为女方身体不好、不适合放环而采用男性避孕针；打针后约29％的人自觉身体无变化，26．2％的人感觉较好，部分人反应打针时性欲增强，停针时性欲减弱；使用者认为打针比安全套方便，比男性结扎容易接受，还有人认为注射部位疼痛和使用不方便（需每月打针1次有点麻烦），部分人对长期使用药物的安全和使用价格比较关心。心理测试注射者和未注射者的抑郁和焦虑状况无明显差异（P〉0．05）。结论十一酸睾酮酯避孕针作为一种男性避孕方法，可供育龄夫妇知情选择，有利促进男性参与计划生育。对该方法的长期使用安全性、满意程度和服务提供的有关问题还需作进一步研究.     

Pharmacokinetic interaction between efavirenz and ketoconazole in rats

1. It is well known that efavirenz and ketoconazole act as an inducer and inhibitor of CYP3A4, respectively. As a result of these actions, co-administration of these drugs may result in changes in the pharmacokinetic parameters of one or both of them.

2. Duodenum-cannulated rats have been used to compare the effect of intraduodenal (KC_i.d.) and intravenous administration of ketoconazole (KC_i.v.) on the pharmacokinetics of efavirenz after intraduodenal administration, as well as the potential effect of efavirenz as a CYP450 inducer on ketoconazole pharmacokinetic profile.

3. While KC_i.v. did not show any significant effect on efavirenz pharmacokinetic profile, KC_i.d. increased significantly (p < 0.05) the peak concentration (C_max) and the area under the plasma concentration–time curve (AUC) of efavirenz by 25.5% and 44.5%, respectively. In addition, the time necessary to reach peak concentration (T_max) increased markedly by 71%. However, the mean total clearance (CL/F) of efavirenz was significantly decreased by 45%. Efavirenz did not produce any alteration in ketoconazole pharmacokinetics.

4. These findings suggest that when the treatment starts with enteral administration of ketoconazole, the inhibitor effect on CYP450 prevails over the inducer effect of efavirenz.

     

Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men

AIMS: The influence of ageing on the pharmacokinetics of zolpidem, an extensively prescribed hypnotic medication, was evaluated in healthy human volunteers. METHODS: A series of 16 elderly (age: 61-85 years) and 24 young (age: 22-42 years) volunteers received single 5 mg oral doses of zolpidem tartrate. Serum zolpidem concentrations were determined by HPLC with fluorescence detection in samples drawn during 8 h after dosage. The effect of testosterone on zolpidem biotransformation was evaluated in vitro using human liver microsomes. Possible induction of CYP3A protein expression and function was studied in cultured human hepatocytes. RESULTS: Among men, apparent oral clearance of zolpidem was decreased in elderly compared to young subjects (3.8 vs 11.0 ml min-1 kg-1, P < 0.01), Cmax was increased (93 vs 40 ng ml-1, P < 0.01), and half-life increased (2.7 vs 1.5 h, P < 0.03). Among women, zolpidem oral clearance was decreased in the elderly (3.0 vs 5.8 ml min-1 kg-1, P < 0.02), Cmax increased (108 vs 60 ng ml-1, P < 0.001), with no difference in t1/2 (2.3 vs 2.4 h). Among male subjects, free serum testosterone concentrations were lower in the elderly (10.5 vs 19.0 pg ml-1, P < 0.01), and were significantly correlated with zolpidem clearance (r2 = 0.46, P < 0.001). Multiple regression analysis indicated a greater relative contribution of serum testosterone than age to the oral clearance of zolpidem among men. In human liver microsomes, co-incubation of zolpidem (10 micro m) with varying concentrations of testosterone produced activation of biotransformation of zolpidem to its principal hydroxylated metabolite. Maximum activation was achieved at equimolar concentrations of testosterone (10 micro m). However, testosterone did not induce immunoactive CYP3A4 expression or catalytic function in cultured human hepatocytes. CONCLUSIONS: The increased Cmax and lower oral clearance of zolpidem in the elderly are consistent with recommendations of lower clinical doses of zolpidem in the elderly. Our clinical and in vitro data both suggest that reduced free serum testosterone may have a modulatory role in age-dependent changes in zolpidem pharmacokinetics in men.     

Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism

Over the last six decades, tremendous strides have been made in the development of safe, efficacious and ‘patient-friendly’ modalities of testosterone replacement therapy in men. The most recent forms of androgen replacement that are in widespread use include testosterone patch and gel. These preparations are convenient in their use and deliver a physiological amount of testosterone. Although these transdermal preparations are gaining popularity, many hypogonadal men still receive treatment with intramuscular esters. Testosterone enanthate remains the most commonly prescribed ester. Although testosterone esters are efficacious in terms of improving bone and muscle mass, they possess unfavourable pharmacokinetics that result in fluctuations in the mood, energy and sexual function of patients. Furthermore, these esters need to be injected every 2 – 4 weeks. Hence, there has been a need to develop long-acting esters that can be administered infrequently and deliver a physiological amount of testosterone without major fluctuations. Recently, injectable testosterone undecanoate (Nebido^®) has become available in Europe and will soon be marketed in south America, Asia and Australia. In this paper, the structure, pharmacokinetics, efficacy and side-effect profile of testosterone undecanoate will be reviewed and also compared with other existing testosterone esters.