Improving the direct penetration into tissues underneath the skin with iontophoresis delivery of a ketoprofen cationic prodrug

Current topical nonsteroidal anti-inflammatory drugs (NSAIDs) showed marginal efficacy in treatment of musculoskeletal disorders due to their fast clearance by skin blood flow and thus little direct penetration into the underlying muscle and joint tissues. Using ketoprofen (Kt) as a model NSAID and converting it to a cationic ester prodrug ketoprofen choline chloride (KCC), this study was to investigate the iontophoresis delivery of the prodrug KCC for improving the drug retention in the skin and the direct penetration into underlying tissues. From in vitro flux study, anodal iontophoresis of KCC showed 5 times higher flux than cathodal iontophoresis of Kt across human epidermis skin, and also 1.5 times higher across full thickness rat skin. From in situ dual agar gel model rat study, anodal iontophoresis of KCC showed 35 times more drug penetrating across the live skin into underlying agar gel and 22 times more drug retained in the skin than those from cathodal iontophoresis of Kt. Co-iontophoresis of a vasoconstrictor phenylephrine with KCC did not show better result than the iontophoresis of KCC alone. Overall, iontophoresis delivery of the cationic prodrug KCC showed great potential for direct penetration into local tissues underneath the skin.     

Distribution of fentanyl in rats: an autoradiographic study

Summary Unexpected respiratory depression reported to have occurred up to 2 h after neurolept analgesia with fentanyl has been proposed to be a redistribution phenomenon due to a gastro-entero systemic recirculation of fentanyl sequestered in the stomach. In the study presented here, this redistribution hypothesis was tested by employing whole-body autoradiography (WBAR) in two series of time-course experiments, designated to further elucidate the distribution of intravenously administered fentanyl which was radiolabelled in different parts of the molecule respectively. However, there was no evidence of a secondary accumulation of radioactivity in the brain. The possibility that fentanyl trapped in the stomach may be reabsorbed as it passes throgh the small intestines was investigated by intragastric administration of the drug. Its oral bioavailability was found to be only 1.5%. Also, evidence of a strong metabolic effect was obtained by analysis employing high performance thin-layer chromatography (HPTLC). In conclusion, the results obtained from this work do not support the hypothesis that the fentanyl rebound effect is due to a secondary rise in brain levels of the parent drug and its major metabolites, an event which could be brought about by reabsorption of fentanyl sequestered in the stomach.     

Trials and tribulations of skin iontophoresis in therapeutics

Iontophoresis is a method of non-invasive transdermal drug delivery based on the transfer of charged molecules using a low-intensity electric current. Both local and systemic administration are possible; however, the skin pharmacokinetics of iontophoretically delivered drugs is complex and difficult to anticipate. The unquestionable theoretical advantages of the technique make it attractive in several potential applications. After a brief review of the factors influencing iontophoresis, we detail the current applications of iontophoresis in therapeutics and the main potential applications under investigation, including systemic and topical drugs and focusing on the treatment of scleroderma-related ulcerations. Finally, we address the issue of safety, which could be a limitation to the routine clinical use of iontophoresis.     

An in vivo investigation of the rabbit skin responses to transdermal iontophoresis

To optimize the benefits of transdermal iontophoresis, it is necessary to develop a suitable animal model that would allow for extensive assessments of the biological effects associated with electro-transport. Rabbit skin responses to iontophoresis treatments were evaluated by visual scoring and by non-invasive bioengineering parameters and compared with available human data. In the current density range 0.1–1.0 mA/cm² applied for 1 h using 0.9% w/v NaCl and 0.5 mA/cm² for up to 4 h, no significant irritation was observed. 2 mA/cm² applied through an area of 1 cm² for 1 h resulted in slight erythema at both active electrode sites but without significant changes in transepidermal water loss (TEWL) and laser Doppler velocimetry (LDV). A value of 4 mA/cm² under similar conditions caused moderate erythema at the anode and cathode with TEWL and LDV being significantly elevated at both sites; 1 mA/cm² current applied for 4 h, caused moderate erythema at both anode and cathode; and 1 mA/cm² applied for 1 h caused no irritation when the area of exposure was increased from 1 to 4.5 cm². When significant irritation and barrier impairment occurred, the erythema was resolved within 24 h with barrier recovery complete 3–5 days post-treatment. Rabbit skin thus shows promise as an acceptable model for iontophoresis experiments.     

A novel electronic skin patch for delivery and pharmacokinetic evaluation of donepezil following transdermal iontophoresis

The nature of Alzheimer's disease limits the effectiveness of available oral treatments. The aim of this study was to assess the feasibility of transdermal iontophoretic delivery of donepezil in a hairless rat model as a potential treatment modality in Alzheimer's and to evaluate the effect of current densities on its pharmacokinetics. Donepezil loaded integrated Wearable Electronic Drug Delivery (WEDD^®) patches supplied current levels of 0, 0.13, 0.26 and 0.39 mA. Plasma extracted donepezil was analyzed by HPLC. Noncompartmental analysis was used to characterize disposition of the drug. The amount delivered across hairless rat skin and areas under the curve (AUC) were found to rise in proportion to the current levels. Peak plasma levels of 0.094, 0.237 and 0.336 μg/ml were achieved at 0.13, 0.26 and 0.39 mA respectively. Time to peak plasma concentrations was after termination of current and same for all current levels. Transdermal elimination half-life was significantly increased from the true value of 3.2 h due to depot formation, prolonging complete absorption of the drug. Donepezil was successfully delivered iontophoretically at levels sufficient to produce pharmacodymanic effect. Pharmacokinetic analysis demonstrated linear kinetics at the current levels used and flip flop kinetics following iontophoretic administration.     

Effect of iontophoresis and fatty acids on permeation of Arginine Vasopressin through rat skin

The aim of this study was to assess the effects of fatty acids and iontophoretic mode of penetration enhancement on transdermal delivery of Arginine Vasopressin (AVP). Sprague-Dawley (SD) rat skin was pretreated with fatty acids (e.g. 5% w/v, lauric acid, oleic acid, and linoleic acid in ethanol:water (EtOH:W, 2:1 system) for 2h and iontophoresis in vitro, separately or together. The results indicate that all fatty acids studied increased (P<0.05) the flux of AVP in comparison to control (not pretreated with enhancer) and their effectiveness in flux enhancement was comparable. Further, oleic acid in combination with iontophoresis significantly increased the permeation of AVP both in comparison to pretreatment with fatty acids and iontophoresis alone. However, iontophoresis did not further increase the permeation of AVP through linoleic acid pretreated skin. Fourier transform infrared (FT-IR) spectroscopic studies revealed that EtOH:W (2:1) system is not effective in lipid extraction. The shift to higher wavenumbers of the symmetric and asymmetric stretching peaks at 2850 and 2920cm(-1) revealed that at the concentration used, oleic acid and linoleic acid caused fluidization of stratum corneum (SC) lipids. This study provides direct evidence that oleic acid in EtOH:W (2:1) system causes disruption of the SC lipid lamellae and that a combination of oleic acid with iontophoresis further enhances the effects of oleic acid in a synergistic manner.     

渗透促进剂对胰岛素体外经皮离子导入渗透性的影响

本文考察了某些渗透促进剂如月桂氮Zhuo酮（AZ）、油酸（OA）、泊洛沙姆（POL）和丙二醇（PG）等对胰岛素体外经皮离子导入渗透性的影响。结果表明AZ对离子导入具有协同作用，PG能够增强这种作用，三者并用对胰岛素的经皮渗透具有特别显著的促渗效果。5％AZ／PG与离子导入并用后，较单独离子导入处理组的促渗因子为2.75。OA不能增强离子导入的作用，离子导入与某些渗透促进剂并用为胰岛素等大分子多肽类药物的透皮给药提供了新的思路和可能。     

正清风痛宁注射液离子导入治疗类风湿性关节炎

目的：观察正清风痛宁注射液离子导入治疗类风湿性关节炎的临床疗效。方法：将78例类风湿性关节炎患者随机分为两组,对照组给予非甾体类抗炎药和改善风湿病情抗风湿药物等一般常规治疗,治疗组在此基础上加用正清风痛宁注射液离子导入方法治疗3个疗程。观察治疗前后压痛关节数及程度、肿胀关节数及程度、晨僵时间、类风湿因子（RF）、血沉（ESR）、C-反应蛋白（CRP）。结果：在改善RA临床症状和炎性指标方面,治疗组明显优于对照组,差异有统计学意义。结论：正清风痛宁注射液离子导入治疗类风湿性关节炎疗效好。     

Pharmacokinetics of fentanyl in man and the rabbit

Summary Plasma levels and urinary excretion of³H-fentanyl were studied in 5 human subjects after intravenous injection of this drug. After an initial rapid decline, the plasma level of fentanyl decreased slowly and approximately exponentially. The plasma concentration of metabolites remained almost steady from 1–3 h after injection. More than 60% of the administered radioactivity was excreted through the kidneys within 4 days. Only a small proportion of it was unchanged fentanyl. The rates of fall of plasma concentration and of urinary excretion were slower in man than in rabbits. — The time courses of plasma concentrations and of urinary excretion were simulated on an analogue computer. The results support the assumption that the different time courses of concentrations in man and rabbits are caused by slower metabolism in man. It seems likely that redistribution plays a dominant part in the short duration of action of fentanyl in man.     

RP-HPLC测定缓释膜剂中芬太尼的含量

目的　建立测定膜剂中枸橼酸芬太尼含量的方法。方法　采用RP -HPLC ,样品经超声处理过滤后采用C1 8Diamonsil色谱柱(4.6mm×2 5 0mm ,5 μm) ,以乙腈-pH 2 .5 0 .0 33mol·L-1 磷酸盐缓冲液(35∶6 5 )为流动相,检测波长2 2 0nm ,柱温为30℃。结果　枸橼酸芬太尼浓度在4 .0～4 0 .0 μg·ml-1 范围内线性关系良好(r =0 .9999,n =5 ) ,平均回收率为99.1 2 %,RSD =0 .6 6 %(n =3)。结论　该方法简便快速,结果准确,专属性强,可用于该制剂的质量控制。     

A comparison of the skin irritation potential of transdermal fentanyl versus transdermal buprenorphine in middle-aged to elderly healthy volunteers

ABSTRACT

Objective: Establishing local tolerability of transdermal opioid systems is important as more systems become available for use in a range of indications. We compared the skin irritation potential of a single application of transdermal fentanyl (Durogesic D-trans; DDTDF) and transdermal buprenorphine (Transtec; TDB) patches in healthy volunteers.

Methods: 46 healthy males and females (mean age [range]: 59.6 [50–69] years) with healthy skin received a single dose of both the DDTDF 25?μg/h patch and the TDB 35?μg/h patch in a randomised order under naltrexone cover. The incidence and severity of erythema was assessed at various timepoints after patch removal.

Results: There was a non-significant trend towards a higher incidence of erythema 60?min after patch removal with TDB compared with DDTDF. The severity of erythema at 60?min and the incidence of erythema at 72?h after patch removal were significantly higher with TDB than with DDTDF (?p = 0.01 and 22% versus 4.9%, p = 0.04, respectively). In general, the results from the chromametric assessment of treated skin were in agreement. The incidence of topical adverse events (AEs) was lower with DDTDF than with TDB (one versus six events) and subjects preferred the DDTDF patch and felt it was less noticeable on the skin. The DDTDF patch was considered less painful to remove, and, consistent with that, the TDB patch was judged to have better adhesion. Twenty-one subjects reported systemic AEs with DDTDF plus naltrexone and 22 with TDB plus naltrexone, most of which were considered treatment-related, 34 and 60 AEs, respectively.

Conclusions: Local tolerability of transdermal opioid systems should be considered when making a therapeutic choice. Even after a single application in healthy volunteers, differences in local tolerability, assessed both clinically and by chromametry, and patch comfort were shown between DDTDF and TDB, in favour of DDTDF.     

HPLC-MS-MS法测定人血浆中芬太尼浓度及其生物等效性研究

目的:建立液相色谱-串联质谱法(HPLC-MS-MS)测定人血浆中芬太尼的浓度。方法:以D5-芬太尼为内标,采用正己烷处理血浆样品。色谱柱为Thermo Hypurity C18(150mm×2.1mm,5μm),流动相为甲醇∶水(含0.1%甲酸)=(85∶15,V/V),流速为0.3mL/min,柱温40℃;质谱条件为电喷雾电离源(ESI),检测方式为正离子方式、多离子反应监测(MRM),用于定量分析的离子为芬太尼m/z 337.1→188.1,D5-芬太尼m/z 341.9→187.9。结果:芬太尼血药浓度在19.53～5000pg/mL范围内线性关系良好,定量下限为19.53pg/mL,日内和日间变异均小于5.16%,提取回收率均在90%以上;应用此方法研究了24名健康男性受试者使用两种芬太尼透皮贴剂的药代动力学特点,受试制剂对参比制剂的相对生物利用度为(94.0±19.5)%。结论:本法具有快速、简便、灵敏、准确等特点,适合人血浆中芬太尼浓度测定。两种制剂生物等效。     

干扰电联合药物离子导入治疗退行性膝关节炎

目的观察应用干扰电加直流电药物离子导入治疗退行性膝关节炎的疗效并进行分析。方法185例退行性膝关节炎患者随机分为治疗组92例,对照组93例。治疗组采用干扰电加直流电药物离子导入疗法;对照组采用调制中频电加直流电药物离子导入疗法,两组均行2个疗程治疗。结果治疗组各项症状如疼痛、肿胀、屈曲程度、行走能力及上下楼能力等综合评分均优于照组（P〈0．01）。讨论干扰电疗法治疗以疼痛为主要表现的关节炎、软组织病安全、有效。     

丙泊酚联合芬太尼麻醉在无痛人工流产术中的应用

目的探讨丙泊酚联合芬太尼麻醉在无痛人工流产术中的应用效果。方法 130例患者随机分为观察组和对照组各65例,对照组以丙泊酚麻醉诱导,观察组在对照组基础上联合芬太尼麻醉。观察2组丙泊酚用量、苏醒时间及镇痛效果。结果观察组丙泊酚用量少于对照组,苏醒时间短于对照组,差异均有统计学意义(P<0.05)。观察组优良率为98.5%高于对照组的92.3%,差异有统计学意义(P<0.05)。结论丙泊酚联合芬太尼用于无痛人工流产术中可产生较好的镇静和镇痛作用,值得临床推广应用。     

Effects of fentanyl dose and exposure duration on the affective and somatic signs of fentanyl withdrawal in rats

Fentanyl is a potent mu-opioid receptor agonist that is widely used for the treatment of chronic pain. The aim of the present study was to investigate the effect of the dose of fentanyl and the exposure duration on the affective and somatic signs of fentanyl withdrawal in rats. Fentanyl and saline were chronically administered via osmotic minipumps. A discrete-trial intracranial self-stimulation procedure was used to provide a measure of brain reward function and somatic signs were recorded from a checklist of opioid abstinence signs. The opioid receptor antagonist naloxone elevated the brain reward thresholds of the rats chronically treated with high doses of fentanyl (0.3 and 0.6mg/kg/day), but not those of rats treated with low doses of fentanyl (0.006 and 0.06mg/kg/day). Fentanyl had a dose-dependent effect on the naloxone-induced elevations in brain reward thresholds. On a similar note, the discontinuation of the administration of high doses of fentanyl was associated with elevations in brain reward thresholds and the discontinuation of the administration of low doses of fentanyl did not lead to an elevation in brain reward thresholds. The results also demonstrated that the duration of fentanyl administration does not affect naloxone-induced elevation in brain reward thresholds. In contrast, the somatic withdrawal syndrome gradually developed over time; maximum somatic signs were observed 120h after pump implantation. These studies suggest that the magnitude and duration of the negative affective signs of fentanyl withdrawal depend on the dose of fentanyl administered and not on the duration of fentanyl administration.     

药学监护在芬太尼联合丙泊酚麻醉中的临床价值

目的：分析药学监护在芬太尼联合丙泊酚麻醉中的临床价值。方法将120例手术者随机分为研究组和对照组各60例。患者均使用芬太尼联合丙泊酚进行局麻或全麻,在此基础上研究组由临床药师进行麻醉监控,观察2组中局麻手术患者的疼痛分级,全麻手术患者睁眼时间和问答切题用时,以及不良反应发生率。结果2组局麻手术患者疼痛同一等级比较差异有统计学意义（P＜0．05）。研究组睁眼时间和问答切题时间均短于对照组,差异均有统计学意义（P＜0．05）,研究组不良反应发生率为3．3％低于对照组的13．3％,差异有统计学意义（P＜0．05）。结论药学监护在芬太尼联合丙泊酚麻醉中效果明显,值得临床推广使用。     

利多卡因在全麻诱导中预防芬太尼诱发呛咳反应的临床观察

目的观察利多卡因在全麻诱导中能否抑制芬太尼诱发的呛咳反应。方法选择100例ASAI—II级全麻择期手术患者,随机分为利多卡因组和对照组,每组50例。组I为对照组,实验药物为生理盐水5ml,组Ⅱ为利多卡因1．5mg／kg,两组药物分别在全麻诱导中静脉给予芬太尼前1min时给予。观察芬太尼诱发呛咳的发生率及诱导期血流动力学的变化。结果两组呛咳的发生率分别为：组I26％,组II6％,组Ⅱ呛咳发生率明显降低（P〈0．05）,但诱导前后血流动力学的变化一致。结论应用利多卡因在全麻诱导中能安全有效地预防芬太尼诱发的呛咳反应。     

雷米芬太尼与芬太尼在小儿扁桃体摘除手术中的临床观察

目的:探讨雷米芬太尼在小儿扁桃体摘除术中的有效性和安全性.方法:将30例患儿随机分为雷米芬太尼组(R组)和芬太尼组(F组).R组给药:氯胺酮2 mg·kg-1、丙泊酚1 mg·kg-1、雷米芬太尼1 μg·kg-1和岁库溴铵0.5 μg·kg-1诱导插管,维持以输液泵泵入丙泊酚4～10 mg·kg-1·h-1和雷米芬太尼0.25～0.5 μg·kg-1·min-1;F组给药:氯胺酮2 mg·kg-1、丙泊酚1 mg·kg-1、芬太尼3 μg·kg-1和罗库溴铵0.5 mg·kg-1静脉推注诱导插管维持以输液泵泵入丙泊酚4～10 mg·kg-1·h-1,间断静脉推入芬太尼1 μg·k-1·h-1.分别记录患儿麻醉前、插管前1 min、插管后1 min的SBP、DBP、HR;术毕停药后患儿自主呼吸恢复时间、呼唤睁眼时间、拔管时间;术后24 h恶心、呕吐情况.结果:R组患儿术后呼吸恢复时间、呼唤睁眼时间、拔管时间与F组相比差异有统计学意义(P<0.05);麻醉诱导前两组血流动力学相似,插管前1 min R组HR慢于F组(P<0.05);插管后1 min R组SBP低于F组(P<0.05);术后恶心、呕吐的发生率及患儿年龄、性别、体重、手术时间等一般情况无统计学意义.结论:雷米芬太尼对血压、心率等血流动力学有良好的可控性,其麻醉镇痛效果好,诱导和苏醒迅速,术中平稳,不良反应小,值得临床推广.     

芬太尼和瑞芬太尼对老年患者依托咪酯肌阵挛的预防作用

目的研究芬太尼和瑞芬太尼预处理在老年患者依托咪酯气管插管全麻诱导中对肌阵挛发生及血流动力学参数剧烈波动的预防作用。方法选取择期行全麻气管插管手术患者90例,年龄>65岁,ASAⅠ~Ⅱ级,按随机数字法分为芬太尼组(F组)、瑞芬太尼组(R组)和生理盐水组(C组),每组30例。麻醉诱导开始静脉注射0.2 mg/kg依托咪酯前,C组注射生理盐水10 mL,F组注射芬太尼3.0μg/kg,R组给予瑞芬太尼2.0μg/kg,注射时间至少30s,随后R组0.3μg/(kg·min)持续泵注,记录肌阵挛的发生情况和严重程度。待患者意识消失,睫毛反射消失,BIS值低于50,注射顺式阿曲库铵0.2 mg/kg后2 min进行气管插管。记录基础值(T_0)、诱导即刻(T_1)、插管即刻(T_2)及插管后1 min(T_3)、3 min(T_4)的MAP、HR。结果 F组、R组及C组的肌阵挛发生率分别为10%、3.3%、50%。F组、R组发生肌阵挛的频率和严重程度均显著低于C组(P<0.05),而F组与R组比较差异无统计学意义(P>0.05)。气管插管后,R组血流动力学的稳定性优于其他两组(P<0.05)。结论 3.0μg/kg芬太尼和2.0μg/kg瑞芬太尼均可降低老年患者依托咪酯全麻诱导期引起的肌阵挛发生率和严重程度,而2.0μg/kg瑞芬太尼预处理在麻醉诱导期可起到更好的血流动力学作用。     

芬太尼及其联合氯诺昔康用于妇科患者术后静脉镇痛的效果观察

目的评价芬太尼及其联合氯诺昔康用于妇科下腹部手术患者术后静脉镇痛的效应。方法30例全身麻醉下行妇科下腹部手术患者，以术后静脉镇痛用药不同，随机分为3组，每组10例。A组：负荷量：芬太尼1μg／kg，持续静脉输注15μg／h；B组：负荷量：氯诺昔康8mg，持续静脉输注氯诺昔康0．4mg／h＋芬太尼5μg／h；C组：负荷量：氯诺昔康8mg，持续静脉输注氯诺昔康0．32mg／h＋芬太尼5μg／h。分别记录3组术后2、6、24、48小时的视觉模拟评分（VAS），患者对镇痛效果的总体满意度及不良反应发生情况。结果A、B、C3组术后各时间点VAS评分差异无显著性（P〉0．05）。镇痛效果的总体满意度B组高于A、C组，但3组之间差异无显著性（P〉0．05）。A组恶心、呕吐的发生率显著高于B、C组（P〈0．05或P〈0．01）。结论芬太尼复合氯诺昔康用于妇科下腹部手术患者术后静脉镇痛效果可靠，与单纯芬太尼相比不良反应明显减少。