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.
【Abstract】 Objective To introduce a new method using calcium phosphate cement/Danshen drug del ivery systemfor avascular necrosis of femoral head and to evaluate its cl inical outcome. Methods From May 2000 to June 2005, 48 patients (54 hips) with avascular necrosis of femoral head were treated with calcium phosphate cement/Danshen drug del ivery system implantation in the involved femoral head. There were 32 males(36 hips) and 16 females(18 hips) with an average age of 38.7 years (26-62 years). Twenty-one cases had the history of drinking or smoking, 15 cases had the history of receiving hormonotherapy and 2 had the history of injury in hip joint. The disease course was 2-32 months. According to standard of Association Research Circulation Osseous (ARCO) staging, 9 hips were classified as stage I, 31 as stage II and 14 as stage III. The operation consisted of removal of necrotic bone under weight-loading cartilage and the implantation of calcium phosphate cement/Danshen drug del ivery system, all mani pulations were done through a bone tunnel in trochanter. The function of hi p joint were evaluated and X-ray films were taken pre- and post-operatively. Results No phlebothrombosis of leg and foreign body action occurred in all cases, and incision healed by first intention. The postoperative follow-up averaged 42.5 months, ranging from 22 to 73 months. According to the evaluation criterion of Dandong 1995 for adult avascular necrosis of femoral head, the results were excellent in 33 hi ps, good in 17, fair in 3 and poor in 1, the excellent and good rate was92.6 %. Conclusion This method is relatively simple with less invasion, it not only improves the microcirculation of femoral head by local appl ication of traditional Chinese medicine, but also provide mechanic buttress in the weight-loaded area, which is beneficial to repair and reconstruction of femoral head. It may be a choice of minimally invasion surgery for femoral head necrosis.
Objective To investigate the physicochemicalproperties of the calcium phosphate cement (CPC) containing Danshen composite injection and its drug release rate. Methods This experiment included 4 groups and each group contained 6 specimens. CPC (2 g) was mixed with the setting solution that served as thecontrol group; 0.1,0.5 and 1.0 ml of Danshen composites injection (concentration, 1 000 mg/ml; pH, 7.35) were respectively added to CPC (2 g), which were used as the experimental groups 1, 2 and 3. The resulting specimens were investigated by the X-ray diffraction (XRD), the fourier transformed infrared spectroscopy(FTIR), and the scanning electron microscope (SEM).ResultsThe XRD analysis showed that the control group had a typical diffraction pattern of the hydroxypatite (HAP), which was consistent with the standard patternof HAP. When more Danshen was added in the experimental groups, the diffractionpeaks of HAP gradually decreased; when the diffraction angle 2θ was about 25.92°, the HAP peaks disappeared. Based on the FTIR analysis, with an increase of the drug concentration, the absorption peak of the hydroxy groups decreased. The SEM showed that the size of the CPC particle was related to the drug concentration; with an increase of the drug concentration, the CPC particle increased in number, resulting in an increasing trend of coacervation. The elution test showed that the drugrelease rate and capacity varied with the different concentrationsof Danshen. The initial release rate was relatively great, but after 96 hours the rate slowed down, lasting for a long time. Conclusion The physicochemical properties of CPC do not change when a proper dose (0.1 ml/2 g) of Danshen isadded to CPC. The Danshen composite can be effectively released from CPC, and so CPCcan be used as an ideal drugdelivery carrier for Danshen composite.
Objective To study the potential of a bioderived material combined with Pluronic F-127 in vitro as a delivery vehicle for WO-1 in the bone repair therapy. Methods Bio-derived materials were fabricated and loaded with WO-1 by Pluronic F-127. Micromorphology and porosity were detected by the scanning electron microscope and the digital image analysis system respectively. The WO-1 release from the system in vitro was studied by the high performance liquid chromatography. Results Bio-derived material-WO-1 drug delivery systems were created with the interconnected pore network. Theporosity and pore size of the system were 55% and 522.43±16.75 μm respectively, compared with those of bio-derived materials, which were 75% and 623.67±12.31 μm respectively. And the main composition of the system was HA. The in vitrorelease kinetics of WO-1 revealedthat an effective therapeutic concentration(0.2-0.8 μg/ml) of WO-1 was maintained for 6 days after a high initial burst release. Conclusion The bio-derived material-WO-1 drug delivery system can be used in the bone repair therapy. However, the in vivostudy on it is still needed.
Objective To develop the plastic nano-hydroxyapatite (nano-HA)/poly (3-hydroxybutyrate-hydroxyvalerate) polyethylene glycol(PHBV-PEG) gentamicin (GM) drug delivery system(DDS)(nano-HA/PHBV-PEG-GM-DDS) for treating osteomyelitis and find its releasing character in vivo. Methods The plastic nano-HA/PHBV- PEG-GM-DDS was prepared using nanoHAas the core carrier of GM, nano-HA with PHBV and PEG as coating and plastic fibrin glue(FG) as microsphere scaffold. The morphological features of nano-HA,drug loaded nano-HA and drug loaded nano-HA/PHBVPEG microsphere were examined by electron microscope.The GM concentration in blood, cortex bone and cancellousbone was detected at 12 different time points by the method of K-B after the plastic nano-HA/PHBV-PEGGM-DDS was implanted into the femora of 36 rabbits. Its GM releasing character was assayed in vivo. Results Nano-HA was similar to a blackjack, and its length was less than 60 nm. Drug loaded nano-HA appeared natural crystal condensate, of which surface adsorbed massive GM. The average grain diameter was 200.5 nm. Drug loaded nanoHA/PHBV-PEG microsphere had a shrinkable porous structure, of which surface configuration was consistent. The average grain diameter was 34.5 μm. The GM concentration and the antibacterial annulus was in the linear correlation. The correlation coefficient was 0.998. In cortex and cancellous bone tissue, the GM concentration was about 95.50±16.50 μg/ml and 80.20±13.80 μg/ml from the plastic nano-HA/PHBV-PEG-GM-DDS on the 1st day, then decreased gradually. After 56 days of operation, the GM concentration still exceeded the minimum inhibitory concentrationfor the staphylococcus aureus, but the peak level of serum GM concentration wasunder the nephrotoxicity concentration. Conclusion Plastic nano-HA/PHBV-PEG-GM-DDS was a good drug delivery system with sustained antibiotic effect in vivo. It was an effective method for the treatment of osteomyelitis.
Objective To find out an effective technique torepair large segmental infected bony defect.Methods Calcium phosphate cement(CPC) incorporated with bone morphogenetic protein and gentamycin was embedded in the massive reconstituted bovine xenograft(MRBX), then CPC-MRBX was obtained after CPC’s solidification. In vivo test was applied to test the drug delivery capability of CPC-MRBX, in which it was implanted in the dorsal muscle pouch of 18 rabbits. The drug concentration of animal blood and surrounding soft tissue of the CPC-MRBX in the muscle pouch was measured 1, 2, 5, 10, 15, 20, 25, 30 and 35 d after operation, 2 rabbits each time. Large segmental infected femur defect in the rabbit model was created to test the repairing capability of CPC-MRBX. External fixation was done 1.5~2.0 cm above the knee, the most adjacent nail to fracture site was 0.5～0.8 cm away, and proper pressure was applied to the graft. In experimental group(n=25), the bony defect was replaced by CPC-MRBX, while in the control group(n=15) dissected bone block was re-implanted in original position. The animal was subjected to radiographic, histological examination at 4, 8, 16 and 24 weeks. The general condition was observed after the operation.Results CPC-MRBX was easily made under normal temperature and pressure. In viro drug delivery test showed that the drug concentration of the tissue remainedabove the minimal inhibitory concentration of staphylococcus 30 d after operation and no significant increase of blood drug concentration was observed. In experimental group, no adverse influence was observed. Four weeks after operation, the animal could bear load, bony callus around the graft was observed by X-ray, and abundant chondral tissues that grew into CPC-MRBX were observed by histological method. Eight weeks after operation, progressively increasing bony callus around the graft was observed, external fixation could be removed, normal function was restored, and CPC was degenerated dramatically while new bone tissues were growing. Sixteen weeks after the operation, more new bone tissues grew and CPC was degenerated furtherly while marrow tissues were taking shape. Twenty-four weeks after the operation, femur healed completely and CPC was degenerated completely. In the control group, the autograft remained unhealedon X-ray at 4 weeks, and osteomyelitis manifestation such as inflammatory cells infiltration and osteolysis was detected at 4 weeks. All the animals in the control group died before the 8th week, 4 of which showed positive hemoculture. Conclusion CPC-MRBX is readily available and can be applied to repairing large segmental infected bony defect.30 d after operation and no significant increase of blood drug concentration was observed. In experimental group, no adverse influence was observed. Four weeks after operation, the animal could bear load, bony callus around the graft was observed by X-ray, and abundant chondral tissues that grew into CPCMRBX were observed by histological method. Eight weeks after operation, progressively increasing bony callus around the graft was observed, external fixation could be removed, normal function was restored, and CPC was degenerated dramatically while new bone tissues were growing. Sixteen weeks after the operation, more new bone tissues grew and CPC was degenerated furtherly while marrow tissues were taking shape. Twenty-four weeks after the operation, femur healed completely and CPC was degenerated completely. In the control group, the autograft remained unhealedon X-ray at 4 weeks, and osteomyelitis manifestation such as inflammatory cells infiltration and osteolysis was detected at 4 weeks. All the animals in the control group died before the 8th week, 4 of which showed positive hemoculture.Conclusion CPC-MRBX is readily available and can be applied to repairing large segmental infected bony defect.
OBJECTIVE To manufacture adriamycin-porous tricalcium phosphate (A-PTCP) ceramic drug delivery system (DDS) as a possible method for bone defect treatment after bone tumor operation. METHODS A-PTCP DDS was made from putting adriamycin into PTCP. Thirty rabbits were divided randomly into group A(24 rabbits) and group B(6 rabbits). A-PTCP was implanted in the greater trochanter of the right femur in group A. Adriamycin were injected into veins in group B. Muscle around A-PTCP and plasma were taken out at different period. Adriamycin concentrations in muscle and plasma were measured by high performance liquid chromatography (HPLC). RESULTS A-PTCP could gradually release adriamycin over 10 weeks. Adriamycin concentrations in the muscle were higher than that in plasma. CONCLUSION A-PTCP may be a new method for repairing bone defects after bone tumor operation.
An clinical and pharmacokinetic study for a drug delivery system (DDS) of gentamycin-loaded chitosan bar were carried out with the purpose to evaluate its efficacy and giving further data for its clinical applications. Eighteen cases of chronic osteomyelitis were treated by surgical necrectomy with implantation of gentamycin-load chitosan bar in the prepared bone cavity. After operation, the concentration of gentamycin in serum and wound drainage fluid were examined at different times and blood urea nitrogen (BUN) and serum creatinine (Cr) as well. The clinical results were evaluated by the conditions of wound healing and clinical and roentgenographic manifestations. The results showed that the serum gentamycin concentration reached its peak level (0.86 microgram/ml) at 24 hours after operation and lasted for 4 days. No increase in the concentrations of BUN and Cr were observed after implantation. The gentamycin concentration in wound drainage fluid was several hundred times higher than the minimum inhibitory concentration (MIC) for staphylococcus aureus. All of the 18 cases were followed up for 24.8 months (in an range of 6-34 months) 16 patients received initial cure and without any recurrence. So, it could be concluded that the gentamycin-loaded chitosan DDS was a simple and effective method for the treatment of chronic osteomylitis without the necessity to carry out a second operation to remove the drug carrier, and it was sound to popularize its clinical application.
Objective To observe the distribution and concentration of 125I-nerve growth factor (NGF) in rabbitsprime; eyes after intravitreal injection and posterior juxtascleral injection.Methods Intravitreal injection(group A) and posterior juxtascleral injection (group B) were performed with the dosage of 30mu;g/100mu;l 125I-NGF on left and right eyes in 45 white rabbits respectively. The gamma;-counts and the concentration of 125I-NGF (％ID/g) of each ocular tissue was determined 15 and 30 minutes, and 1,3,6,12,24,and 48 hours after injection. Results The 125I-NGF diffusion in group A was faster in ocular content and ocular inner wall. The vitreous content of 125I-NGF decreased gradually in group A, the curve changes in other eye tissues were normal. The concentration of 125I-NGF reached the peak 3 hours after injection in aqueous humor, iris and ciliary body, retina, and choroids, but 6 hours after injection in sclera and 8 hours in cornea. The changes of concentration of 125I-NGF in group B showed normal curve change. The peak time in group B were all 6 hours in all the tissues except aqueous humor (3 hours). Except the high concentration in vitreous body caused by intravitreal injection, the concentration of 125I-NGF in retina was the highest in group A. Conclusion Intravitreal injection of 125I-NGF can gain higher concentration in each ocular tissue than posterior juxtascleral injection, especially in retina. So intravitreal injection of NGF is a better ocular delivery method to treat the ocular fundus diseases.
Objective To explore the correlation between adverse pregnancy outcomes and previous bearing status. Methods The related information of pregnant and postnatal women was extracted from 6825 hospitalized records in two general hospitals and one special hospital, which were selected by the method of cluster sampling, and the related rate and correlation analyses were calculated. Results Women who had abortion history were much easier to cause adverse pregnancy outcomes compared to those who had no abortion history, with the incidence rates of 16.83% and 13.31%, respectively; the incidence rates of adverse pregnancy outcomes of women who ever had zero, one, and two or more than twice of delivery were 14.14%, 16.34% and 22.78%, respectively; the rates of women on their third or more than third, second, first or zero pregnancy were 49.14%, 18.05%, 14.22% and 12.88%, respectively; and the rates of adverse pregnancy outcomes of women with abnormal and normal gestation history were 31.06% and 14.21%, respectively. Conclusion The previous abortion, delivery times and abnormal gestation history are highly related to adverse pregnancy outcomes. Therefore, in order to reduce adverse pregnancy outcomes, it is necessary to make an effective family planning and decrease abortion and pregnancy.