摘要:眼部的局部给药方式影响着药物作用的强度,速率及持续时间和不良反应。视网膜,脉络膜,玻璃体及视神经的疾病则对眼后节的局部给药治疗提出了挑战,以局部给药的方式通过解剖学的膜屏障及泪液排泄,并达到在特定部位起治疗作用的药物浓度是其中的重要课题。全身给药则难以在眼组织积蓄足够的药物浓度,且易引起全身性的不良反应。眼表局部应用滴眼剂在泪液循环及角膜,结膜的屏障作用下易发生流失,而有创的给药方式包括玻璃体内注射,结膜下注射等变得越来越普遍的同时,除对病人造成疼痛不适外,甚至也可导致多种严重于疾病本身的并发症。本文综述了近几年来随着各种眼科疾病分子机制的研究和解明,眼部局部给药方式及新剂型的药代动力学及安全性的研究进展。Abstract: The ocular drug delivery system affects the drug’s efficacy,rate of speed,velocity and adverse reaction.How to deliver the drug with therapeutic local concentrations to the posterior segment remains a challenge. Many invasive methods such as intravitreal injection,subconjunctival injection are generally used,noninvasive method like eye drop can not pass through the barrier of the eye although it is convenient.The recent progress in safty and pharmacokinetic of ocular drug delivery system is reviewed in this article.
Objective To evaluate the legitimate of regional artery infusion chemotherapy in the treatment of gastric carcinoma. MethodsThe pharmacokinetics of 5-Fu after different route of administration was studied. Results High concentration of 5-Fu found in portal vein via left-gastric intra-artetial administration were 4-40 folds higher than the group via intravenous administration.The time of high concentrations of 5-Fu via left-gastric intra-arterial administration maintained significantly longer than by intravenous administraion. The concentration of 5-Fu in tumor tissues and paratumorous lymph tissues by intra-arterial administration were 19 times and 23 times of the group by intravenous administration. Conclusion Regional arterial infusion chemotherapy can significantly increase the concentration of chemotherapeutic drugs in the tumorous region.
Objective To compare the systematic and lung pharmacokinetic parameters of moxifloxacin hydrochloride and explore a feasible tool to monitor drug concentration and evaluate therapeutic efficacy of respiratory fluoroquinolones. Methods Ten adult patients with community-acquired pneumonia or acute exacerbation of chronic bronchitis were enrolled.The subjects received a single dose of oral moxifloxacin hydrochloride 400 mg. Serum specimens were sampled at 0，1，2，3，4，8，24 h and sputum specimens were collected 0，1，2，4，8，20，24 h after administration，respectively.The serum and sputum concentrations of moxifloxacin hydrochloride were assayed by means of high-performance liquid chromatography. Standard pharmacokinetic parameters including peak concentrations(Cmax) and area under the concentration-time curve (AUC0-24 h) were assessed. Results Serum C(max) was（5.95±1.35）mg/L at 2 hours and serum AUC0-24 h was (58.72±8.11）mg·h-1·L-1 while sputum Cmax and AUC0-24 h were （16.18±6.47）mg/L at 3 hours and （138.04±78.29）mg·h-1·L-1 respectively，which were significantly higher than those in serum. Conclusion Oral administration of moxifloxacin hydrochloride to patients with respiratory infections results in rapid penetration into lung and maintain a one-fold drug concentration compared to blood concentration within 24 hours.Sputum drug concentration analysis demonstrates a superior pharmacokinetic profile of moxifloxacin in respiratory tract.
OBJECTIVE To study the character of cefazolin (CEZ) pharmacokinetics on Neijiang pig and human. METHODS The serum concentration of CEZ in 8 normal Chinese adult men, 9 of 8-month male Neijiang pigs and 5 of 4-month male Neijiang pigs were detected by high-performance liquid chromatography (HPLC). RESULTS The pharmacokinetic parameters suggested that two-compartment model was found in all groups after intramuscular injection of CEZ. In normal men, 8-month pigs and 4-month pigs, the peak time (Tmax) was (58.8 +/- 13.0), (19.7 +/- 9.9) and (18.2 +/- 8.6) min respectively, T1/2 alpha was (42.3 +/- 19.7), (19.0 +/- 7.7) and (9.3 +/- 1.9) min, the peak concentration (Cmax) was (101.6 +/- 14.6), (28.7 +/- 9.0) and (23.5 +/- 4.6) mg/L; Vd was (0.096 +/- 0.016), (0.374 +/- 0.184) and (0.386 +/- 0.211) L/kg; T1/2ka was (22.5 +/- 6.8), (8.6 +/- 4.8) and (10.6 +/- 10.2) min; T1/2 beta was (117.3 +/- 8.6), (84.2 +/- 9.8) and (45.1 +/- 11.5) min; clean rate of plasma Cl was (0.8 +/- 0.1), (6.8 +/- 1.2) and (11.0 +/- 3.0) ml/kg.min; AUC was (21,803 +/- 4,145), (2,407 +/- 443) and (1,636 +/- 685) mg.min/L. CONCLUSION It could conclude that the Neijiang pigs could eliminate CEZ effectively, but the absorption, distribution and elimination of CEZ in pigs were quicker than that of in human while the absorption from muscle in both pig groups were lower than that in human.
Objectives To explore intraocular drug concentration changes and the pharmacokinetics after topically applied of bevacizumab with annexin A5-associated liposome on rabbit eyes. Methods A total of 105 healthy New Zealand white rabbits were selected and divided randomly into 3 groups (group A, B and C), and each group had 35 rats. Bevacizumab with annexin A5-associated liposome, bevacizumab liposome and bevacizumab were topically applied 50 μl respectively on right eyes of rabbits in group A, B and C, respectively. Aqueous, vitreous body and retina/choroid were obtained at 5, 15, 30 minutes and 1, 2, 4, 8 hours and the free bevacizumab concentrations in these ocular tissues were measured by ELISA (enzyme linked immunosorbent assay). DAS 2.1.1 software was used to fit the pharmacokinetic parameters. Results The peak drug concentrations in aqueous humor of the eyes in group A, B, C were at 15 minutes after topical administration and the difference was statistically significant (F=301.061,P＜0.01). The peak drug concentrations in vitreous of the eyes in the group A, B, C were at 2 hours after topical administration and the difference was statistically significant (F=885.997,P＜0.01). The peak drug concentrations in retina/choroid of the eyes in the group A, B, C were at 1 hour after topical administration and the difference was statistically significant (F=644.908,P＜0.01). Least significant difference pair-wise test found that the drug concentrations in aqueous humor, vitreous and retina/choroid of group A was higher than that of the group B and C respectively (P＜0.05), while that of the group B and C had no significant different (P＞0.05). Pharmacokinetic fitting analysis found that the half-life (t½) of bevacizumab in aqueous humor were 1.14, 1.29, 1.29 hours, the distribution t½ were 1.40, 1.50, 1.42 hours and the eliminated t½ were 2.62, 2.84, 2.73 hours in vitreous, the distribution t½ were 2.61, 2.99, 2.70 hours and the eliminated t½ were 2.61, 2.99, 2.70 hours in retina/choroid respectively for the 3 groups. Changes of bevacizumab concentration in aqueous humor of rabbit eyes for 3 groups was complied with one compartment model, and that in vitreous body and retina/choroid complied with two compartment model. Conclusions Topically applied annexin A5-associated liposome has higher ocular concentrations of bevacizumab than those of controls. Changes of bevacizumab concentration in aqueous humor of rabbit eyes was complied with one compartment model, and that in vitreous body and retina/choroid complied with two compartment model.
Paclitaxel (PTX)-loaded self-assembling nano-micelles (PTX/NMs) were prepared based on amphiphilic cholesterol-bearing γ-polyglutamic acid (γ-PGA-graft-CH). The properties of PTX/NMs in vitro and in vivo were investigated. The results indicated that PTX could be entrapped in γ-PGA-graft-CH NMs. PTX/NMs was characterized with a size of (343.5 ± 7.3) nm, drug loading content of 26.9% ± 0.8% and entrapment efficiency of 88.6% ± 1.7% at the optimized drug/carrier ratio of 1/10, and showed a pH-sensitive sustainable drug-release and less cytotoxicity in vitro. In vivo release and the pharmacokinetics study in mice showed that the elimination half-life (t1/2β) and area under curve (AUC) of PTX/NMs were significantly higher than those of PTX/polyoxyethylene castor oil (PTX/PCO), and less clearance (CL) of PTX/NMs was also observed. PTX/NMs were distributed higher in liver and tumor than PTX/PCO, and showed a good tumor-inhibiting activity in tumor-bearing mice. This study would lay a foundation on the potential application of γ-PGA-graft-CH NMs were the antitumor drug-delivery.
Population pharmacokinetics is a research technique based on computer simulation and data analysis, and it has been employed to investigate the dynamic behavior of drug metabolism in different populations. This approach could address practical challenges such as prolonged clinical trial durations, high costs, and increased difficulty in traditional clinical trials. By comprehensively analyzing differences in the internal drug metabolism processes across populations with varying physiological and pathological conditions, population pharmacokinetics has emerged as an effective method to optimize drug development and clinical applications. This article provides a preliminary overview of the essence of population pharmacokinetics, its application in clinical trials, and potential future trends. We hope to serve as a reference and guidance for the application of new technologies and methods in clinical trials.