Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative: evaluation of absorption, safety, and effects after intrapulmonary administration in rats

Bisphosphonates are widely used for the treatment of bone diseases, including hypercalcemia and osteoporosis. However, the bioavailability (BA) of orally administered bisphosphonates is low, at approximately 0.9%-1.8%. In addition, the oral administration of bisphosphonates is associated with mucosal damage, including gastritis, gastric ulcer, and erosive esophagitis. Here, to develop a new delivery system for bisphosphonates that improve their BA and safety, we developed polyethylene glycol (PEG)-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative. We evaluated the absorption and safety of PEG-alendronate in rats following intrapulmonary administration. The BA of PEG-alendronate after intrapulmonary administration was approximately 44 ± 10% in rats, which was similar to that of alendronate (54 ± 3.9%). Alendronate significantly increased total protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid, suggesting that pulmonary epithelium was locally damaged by intrapulmonary administration of alendronate. In marked contrast, PEG-alendronate did not significantly increase the markers following intrapulmonary administration. In an osteoporosis model in rats, intrapulmonary administration of PEG-alendronate effectively inhibited decreases in the width of the growth plate to a level similar to that achieved by intrapulmonary administration of alendronate. These results indicate that pulmonary delivery of PEG-alendronate is a promising approach for the treatment of bone diseases.     

Gastric ulcerogenic and healing impairment actions of alendronate, a nitrogen-containing bisphosphonate - prophylactic effects of rebamipide

Alendronate, a nitrogen containing bisphosphonate (BPP), when given p.o., decreases the transmucosal potential difference by direct irritating action, resulting in non-hemorrhagic lesions in both the corpus and antrum of fasted rats, and after re-feeding produces large ulcers in the antrum with increased vascular permeability and submucosal edema. The pathogenesis of these ulcers may be explained by the impairment of the mucosal anti-oxidative system and does not involve acid digestion as well as a deficiency of prostaglandins (PGs). Alendronate, although does not affect cyclooxygenase/ PGE(2) production in the ulcerated mucosa, but impairs the healing of gastric ulcers in rats, and this effect may be related to the down-regulation of vascular endothelial growth factor and basic fibroblast growth factor (bFGF), the important growth factors for the vascularization/granulation as well as the suppression of the stimulatory action of epidermal growth factor on the epithelial proliferation/migration. Rebamipide, a mucosal protective and antiulcer drug, does not affect the direct irritating action of alendronate in the gastric mucosa but prevents the alendronate-induced antral ulceration, probably due to anti-oxidative and anti-inflammatory actions. In addition, this agent also antagonizes the healing impairment action of alendronate by counteracting the down-regulation of bFGF expression in the ulcerated mucosa. It is assumed that rebamipide is a promising drug that can be used as a prophylactic against the adverse effects of BPPs in the stomach.     

Percutaneous penetration of felbinac after application of transdermal patches: relationship with pharmacological effects in rats

We have evaluated the percutaneous penetration of felbinac following application of topical patches using a microdialysis technique, and have examined correlations with pharmacological effects. A linear microdialysis probe with a 20-mm dialysis fibre was inserted into the skin of anaesthetized rats. Probe perfusion was started at 2.0 microL min(-1) with physiological saline and after a 60-min baseline sampling of dialysate, 0.1 mL croton oil was applied to the skin surface at a concentration of 8%, v/v. A felbinac patch was then applied to the same point 60 min thereafter and dialysate was sampled at 60-min intervals up to 300 min after patch application, for determination of concentrations of felbinac and prostaglandin (PG) E2. Analgesic effects of felbinac patches in an iodoacetateinduced osteoarthritis model and an incisional pain model were evaluated using the weight bearing method. After application of patches, felbinac penetration into the skin was rapid, maximum concentrations in the dialysates with 0.07, 0.5 and 3.5% w/w felbinac patches being 0.046+/-0.02, 0.104+/-0.06 and 0.244+/-0.2 microg mL(-1), respectively. Dermal administration of croton oil caused an increment in PGE2 levels, which was significantly decreased by 0.5 and 3.5% felbinac patches 2-5 h after application. In pharmacological studies, 3.5% felbinac patches suppressed pain-associated behaviour induced by iodoacetate injection and plantar incision. These results suggested that the transdermal patch containing 3.5% felbinac may become a useful formulation.     

Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin

The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4 kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully. Both TEWL and TER almost recovered to baseline levels in the microneedle array group, and relatively small pathways created by the microneedles rapidly recovered as compared with those created by a tape stripping treatment. These findings confirmed that the microneedle arrays were quite safe. Furthermore, we found that the transdermal permeability of FD4 using the microneedle arrays was much higher than that of the FD4 solution. Furthermore, we found that the microneedle arrays were much more effective for increasing the amount of FD4 accumulated in the skin.These findings indicated that using novel microneedle arrays fabricated from HA is a very useful and effective strategy to improve the transdermal delivery of drugs, especially relatively high molecular weight drugs without seriously damaging the skin.     

The inhibitory effect of alendronate, a nitrogen-containing bisphosphonate on the PI3K-Akt-NFkappaB pathway in osteosarcoma cells

1 Bisphosphonates are inhibitors of tumor cell growth as well as of bone resorption by inducing cell apoptosis. However, little is known regarding the mechanisms by which the drug induces cell apoptosis. The aim of the present study was to determine the effect of alendronate, one of the nitrogen-containing bisphosphonates on the phoshoinositide 3-kinase (PI3K)-Akt-NFkappaB pathway, the major cell survival pathway. 2 The PI3K-Akt-NFkappaB pathway was activated in the osteosarcoma cell line MG-63 treated with tumor necrosis factor-alpha or insulin. Saos-2 was also used in some experiments. This was assessed by the production of phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)), increased PI3K activity, phosphorylation of Akt at serine 473 and threonine 308, increase in activity of the inhibitor of nuclear factor kappaB (IkappaB) kinase (IKK) and finally phosphorylation of IkappaB and its subsequent degradation. 3 Pretreatment with alendronate at 100 microM for 24 h prior to the stimulation with tumor necrosis factor-alpha or insulin partially inhibited the IkappaB phosphorylation and degradation. These events were more clearly observed in the presence of inhibitors of proteasomes, which are responsible for the degradation of IkappaB. The drug also partially inhibited the activity of IKK, but almost fully inhibited the phosphorylation of Akt and the production of PtdIns(3,4,5)P(3). 4 The inhibitory effect of alendronate on IkappaB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate. 5 The present findings demonstrate that alendronate inhibited the PI3K-Akt-NFkappaB cell survival pathway at the point of PI3K activation, thus indicating the presence of new targets of alendronate.     

Development and biopharmaceutical evaluation of quinupramine-EVA matrix containing penetration enhancer for the enhanced transdermal absorption in rats

To increase the skin permeation of quinupramine through the rat skin, different types of enhancers were added to an ethylene-vinyl acetate (EVA) matrix containing 2% quinupramine. The effects of the enhancers on the level of quinupramine permeation through the skin were evaluated by using Franz diffusion cells that were fitted with the intact excised rat skin. Among the enhancers used, which included fatty acids (saturated and unsaturated), glycerides, pyrrolidones, and nonionic surfactants, polyoxyethylene-2-oleyl ether showed the best enhancement. The pharmacokinetics and bioavailability of quinupramine from an EVA matrix were examined to determine the level of percutaneous absorption in rats. The percutaneous absorption of quinupramine from the EVA matrix with or without an enhancer was investigated. Quinupramine was administered orally or intravenously to compare the pharmacokinetic parameters with that of the transdermal route. The relative bioavailability of quinupramine in the matrix containing polyoxyethylene-2-oleyl ether as an enhancer was approximately 2.81 times higher than the group without an enhancer. Histological examination revealed that the skin pretreated with the EVA matrix containing the enhancers had a loosely layered stratum corneum. These results show that the quinupramine-EVA matrix containing a permeation enhancer could be a good transdermal delivery system for providing sustained plasma concentrations.     

Effects of dose, sex, and age on the disposition of alendronate, a potent antiosteolytic bisphosphonate, in rats.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of a variety of bone disorders. Earlier studies from this laboratory have demonstrated that systemically administered drug was rapidly taken up by bone tissue or excreted by the kidneys. Approximately 60 to 70% of the dose was taken up by the bone, and 30 to 40% was excreted in the urine. The purpose of this study was to determine the effects of dose, sex, and age on the disposition kinetics of alendronate using rats as an animal model. No evidence of saturation of drug uptake by the bone was observed in young rats when small, repetitive doses of alendronate were administered every 3 days for 21 days (total 35 mg/kg iv). However, less than proportional uptake by the bone was observed in young rats when single iv doses exceeded 10 mg/kg. Overall, a 500-fold increase in dose resulted in a 350-fold increase in drug concentration in bone. Nonlinear uptake of alendronate by bone was accompanied by simultaneous accumulation in noncalcified tissues at high doses. Less than 1% of the dose was found in noncalcified tissues at 24 hr after low doses (1 mg/kg iv), and 25% after high doses (30 mg/kg iv). Following iv administration, uptake of alendronate by the bone was lower in senescent rats than in young rats by a factor of 2 to 3. Bone uptake was lower in female rats than in male rats by about 30 to 40%, but this sex difference was only observed at low doses and in young rats.     

Nortriptyline hydrochloride skin absorption: Development of a transdermal patch

The influence of propylen glycol (PG), ethanol, and oleic acid (OA) on nortriptyline hydrochloride (NTH) penetration through human epidermis was studied in vitro at two different pH values (5.5 and 7.4). The influence of lactic acid and polysorbate 80 was studied for a pH of 5.5. Permeation studies through Heat Separated Epidermis, as well as the enhancing effect of the different vehicles, showed a pH dependency. A pH value of 5.5 in the donor solution decreases significantly the permeability coefficient (Kp) with respect to a pH value of 7.4 (0.011+/-0.004 x 10(-6) versus 0.36+/-0.04 x 10(-6)cm/s). The vehicles showed an increasing enhancement effect in the order: polysorbate 80>ethanol/PG/OA>PG>ethanol>ethanol/lactic acid>lactic acid at pH 5.5 while they reduced the permeation of NTH at pH 7.4. Considering the results obtained at pH 5.5, the maximum enhancement ratios were found for polysorbate 80 and the combination ethanol/PG/OA (10.72 and 3.90). Both vehicles were selected for designing a NTH transdermal delivery system (NTH-TDS) using (hydroxypropyl)methyl-cellulose as polymer. The NTH-TDS based on the combination of ethanol/PG/OA showed an enhancement ratio with respect to control of 2.09 and the addition of polysorbate 80 to the matrix, of 5.82.     

Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is currently under investigation as an anti-osteolytic agent in the treatment of a broad range of bone disorders. This study describes the absorption and disposition of the drug in laboratory animals. Following iv administration, alendronate was rapidly cleared from plasma, either taken up and sequestered in the bone or excreted by the kidney. About 30 to 40% of the dose was excreted in the urine in 24 hr, with most of the drug being excreted in the first 3 to 4 hr. There was little or no accumulation of the drug in noncalcified tissues and only a very small fraction of the dose was excreted in the bile. Most of the dose was rapidly taken up by bone tissues: 30% in 5 min, 60% in 1 hr. Absorption of alendronate was very poor. Based on the ratios in bone of the labels from the 14C-labeled oral dose and the 3H-labeled iv dose, absorption was estimated to be about 0.9% for the rat, 1.8% for the dog, and 1.7% for the monkey. Comparison of the concentrations of alendronate in bones of the same rats in fasted (3H-labeled) and fed (14C-labeled) states indicated that food caused a substantial decrease in absorption, by about 6- to 7-fold. The terminal half-life of alendronate in bone was about 200 days for the rat. Based on urinary excretion, the terminal half-life was estimated to be about 1000 days for the dog. The long persistence of alendronate in bone was likely due to its slow dissolution rate from bone tissues.     

Enhanced transdermal absorption and pharmacokinetic evaluation of pranoprofen-ethylene-vinyl acetate matrix containing penetration enhancer in rats

To increase the skin permeation of pranoprofen from the ethylene-vinyl acetate (EVA) matrix, different types of enhancers were added to an EVA matrix containing 2% pranoprofen. The pharmacokinetics and bioavailability of pranoprofen, an anti-inflammatory drug, were examined to determine the feasibility of an enhanced transdermal delivery system for pranoprofen from an EVA matrix containing caprylic acid as the enhancer in rats. The effects of the enhancers on the level of pranoprofen permeation through the skin were evaluated using Franz diffusion cells that were fitted with the intact excised rat skin. Among the enhancers used, including the fatty acids (saturated, unsaturated), the glycols, the glycerides, and the pyrrolidones, caprylic acid showed the best enhancement. A pranoprofen-EVA matrix system was formulated containing caprylic acid as an enhancer. The pranoprofen-EVA matrix system (8 mg/kg) was applied to the abdominal skin of rats. The blood samples were collected through the femoral artery for 24 h and the plasma concentrations of pranoprofen were determined by HPLC. The pharmacokinetic parameters were calculated using the MULTI computer program. The area under the curve (AUC) was significantly higher in the enhancer group (55.49 ± 13.87 ng/mL·h) than in the control group (22.48 ± 5.63 ng/mL·h), which was treated transdermally without the enhancer, showing about 246% increased bioavailability (p<0.05). As the pranoprofen-EVA matrix containing caprylic acid as an enhancer was administered to rats via the transdermal routes, the relative bioavailability increased about 2.46-fold compared to the control group, showing a relatively constant, sustained blood concentration. These results show that a pranoprofen-EVA matrix containing a permeation enhancer could be developed as a transdermal delivery system to provide a sustained plasma concentration.     

Central pharmacological effects of long-term application of piracetam in rats.

Effect of the 14-day administration of piracetam in a dose of 5 g/kg ip upon the behavior of rats and on the content of biogenic amines and their metabolites in different brain areas was studied. It was shown that the treatment by PI for 14 days produced changes in the rat behavior manifested mainly by inhibition of exploratory activity. Long-term PI administration modified the content of NA, DA and 5-HT and their metabolites in different parts of the brain.     

Anti-inflammatory effects by transdermal application of triamcinolone acetonide gel using phonophoresis in rats

The present study was carried out to determine the feasibility of using gel formulations for the transdermal delivery of triamcinolone acetonide (TA), which is one of the synthetic glucocorticoids, in conjunction with phonophoresis, and to develop the carbopol gels of TA. For this purpose, the anti-inflammatory effects of the gel containing TA after the adoption of ultrasound were evaluated by investigating the in vivo change in the serum creatine phosphokinase (CPK) and histological findings. Following a muscle injury, the serum CPK activity decreased significantly in the TA gel group with phonophoresis, comparing with that in the control group and the commercial gel group given ultrasound. In the gross finding, after a muscle injury, the TA gel group with phonophoresis showed rapid moderation of the injury compared with the three other groups. The histological findings showed that the inflammation was relieved within 72 h after the injury from the TA gel group with phonophoresis. These effects were considerably higher in the phonophoresis group than in the other three groups. Overall, a TA gel using phonophoresis might be used as a new transdermal delivery technique providing enhanced anti-inflammatory effects.     

狄诺塞麦和双膦酸盐治疗绝经后妇女骨质疏松症效果及安全性的Meta分析

目的系统评价狄诺塞麦与双膦酸盐治疗绝经后妇女骨质疏松症(osteoporosis,OP)的疗效及安全性的差异。方法在以下几个数据库进行检索:中国生物医学文献数据库CBM、Embase、PubMED、CNKI、维普数据库以及Cochrane临床对照实验中心数据库,获得狄诺塞麦与双膦酸盐对妇女绝经后OP治疗的临床研究,依据纳入与排除标准获得随机对照试验文献,使用Cochrane协作网的偏倚评价标准评估纳入文献质量。获得所需数据,应用RevMan 5.3软件进行Meta分析。结果共获得符合条件的文献9篇,结果显示患有骨质疏松症的绝经后妇女治疗1年后,狄诺塞麦组腰椎、髋部及股骨颈骨密度升高幅度比双膦酸盐组分别高1.42%(95%CI:0.93%~1.90%,P<0.00001)、1.11%(95%CI:0.97%~1.25%,P<0.00001)及1.01%(95%CI:0.81%~1.22%,P<0.00001)。狄诺塞麦组不良反应事件、严重不良反应事件、骨折及死亡的发生率和双膦酸盐组相似,差异无统计学意义;狄诺塞麦组因不良反应导致的患者退出率低于双膦酸盐组,差异具有显著的统计学意义。结论相比双膦酸盐,狄诺塞麦可明显提升绝经后OP妇女的髋部、腰椎、股骨颈等处的骨密度,而安全性,两者相似。     

Bioavailability and absorption kinetics of nicotine following application of a transdermal system.

1. The absolute bioavailability and absorption kinetics of nicotine were investigated in 13 healthy adult male smokers following single and multiple applications of a nicotine transdermal system (NTS), designed to release nicotine at an approximate rate of 1.5 mg h-1 over 24 h. The absorption of nicotine from the single NTS application was calculated with reference to a simultaneous intravenous infusion (i.v.) of deuterium-labelled nicotine. 2. The mean input time (MIT) and mean absorption time (MAT) for nicotine following application of NTS for 24 h were 7.7 and 4.2 h, respectively. 3. Following NTS removal, the mean apparent nicotine elimination half-life was 2.8 h, compared with 2.0 h following i.v. nicotine, reflecting continued absorption of nicotine following NTS removal. 4. The mean amount of nicotine absorbed from the NTS after the 24 h application was 20.9 mg, which represents about 68% of the amount released from the system; the remaining 32% was lost from the system during daily activities. 5. The ratio of AUC values for the metabolite cotinine relative to nicotine was similar whether nicotine was administered transdermally or intravenously. 6. Following i.v. administration, the mean nicotine clearance was 72 l h-1 (coefficient of variation 29%). Since coefficients of variation in AUC values following NTS and i.v. treatments were similar, transdermal administration of nicotine was not associated with increased interindividual variability in plasma nicotine concentrations. 7. No significant changes were seen in the pharmacokinetics of nicotine between single and multiple applications of NTS. 8. As expected from the higher total plasma nicotine concentrations, the incidence of adverse effects was higher following simultaneous intravenous and transdermal administration of nicotine. The most frequently reported systemic side effects were nervousness and headache: mild itching was the most frequent topical effect.     

Preclinical evidence for nitrogen-containing bisphosphonate inhibition of farnesyl diphosphate (FPP) synthase in the kidney: Implications for renal safety

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and play an important role in the treatment of osteoporosis, metastatic bone disease, and Paget disease. However, nephrotoxicity has been reported with some bisphosphonates. Nitrogen-containing bisphosphonates directly inhibit farnesyl diphosphate (FPP) synthase activity (mevalonate pathway) and reduce protein prenylation leading to osteoclast cell death. The aim here was to elucidate if this inhibition also occurs in kidney cells and may directly account for nephrotoxicity. In an exploratory study in rats receiving zoledronate or ibandronate an approximate 2-fold increase in FPP synthase mRNA levels was observed in the kidney. The involvement of the mevalonate pathway was confirmed in subsequent in vitro studies with zoledronate, ibandronate, and pamidronate, using the non-nitrogen containing bisphosphonate clodronate as a comparator. In vitro changes in FPP synthase mRNA expression, enzyme activity, and levels of prenylated proteins were assessed. Using two cell lines (a rat normal kidney cell line, NRK-52E, and a human kidney proximal tubule cell line, HK-2), ibandronate and zoledronate were identified as most cytotoxic (EC₅₀: 23/>1000 μM and 16/82 μM, respectively) and as the most potent inhibitors of FPP synthase (IC₅₀; 1.6/7.4 μM and 0.5/0.7 μM, respectively). In both cell lines, inhibition of FPP synthase activity occurred prior to a decrease in levels of prenylated proteins followed by cytotoxicity. This further supports that the mechanism responsible for osteoclast inhibition (therapeutic effect) might also underlie the mechanism of nephrotoxicity.     

Evaluation of the effects of East Indian sandalwood oil and alpha-santalol on humans after transdermal absorption

The aim of the study was to investigate the effects of East Indian sandalwood oil ( Santalum album, Santalaceae) and alpha-santalol on physiological parameters as well as on mental and emotional conditions in healthy human subjects after transdermal absorption. In order to exclude any olfactory stimulation, the inhalation of the fragrances was prevented by breathing masks. Eight physiological parameters, i. e., blood oxygen saturation, blood pressure, breathing rate, eye-blink rate, pulse rate, skin conductance, skin temperature, and surface electromyogram were recorded. Subjective mental and emotional condition was assessed by means of rating scales. While alpha-santalol caused significant physiological changes which are interpreted in terms of a relaxing/sedative effect, sandalwood oil provoked physiological deactivation but behavioral activation. These findings are likely to represent an uncoupling of physiological and behavioral arousal processes by sandalwood oil.     

Fluoronorepinephrines: further pharmacological evaluation in vitro and in pithed rats

The effect of 6F-, 5F- and 2F-norepinephrine (6F-, 5F- and 2F-NE) in rat vas deferens, guinea-pig ileum and pithed rats was compared to that of norepinephrine (NE). The rank order of potency on postsynaptic alpha 1-adrenoreceptors, determined from the isometric contraction of vas deferens, was 6F-NE = 5F-NE = NE greater than 2F-NE. A similar pattern was found for presynaptic alpha 2-adrenoreceptor activity in both noradrenergic nerve terminals of vas deferens and cholinergic nerve terminals of the ileum, determined from the inhibition of contraction elicited by electrical field stimulation. The only exception was the 5F isomer which was 7 times less active than NE to activate the alpha 2-adrenoreceptors of vas deferens. Thus, ring fluorination markedly alters both alpha 1- and alpha 2-agonist properties of NE. Moreover, alpha 1/alpha 2 selectivity, at least as far as rat vas deferens is concerned, is not significantly influenced by the introduction of a fluorine atom in the NE molecule. 6F-NE was about 3-4 times more active than NE in pithed rats. In turn, NE was equiactive with 5F-NE. 2F-NE was the least active isomer, being 30- and 100-fold less active than NE and 6F-NE, respectively.     

非洛地平-美托洛尔复方经皮给药系统设计及其降压有效性评价

目的:设计制备非洛地平-美托洛尔复方经皮给药系统,评价其对自发性高血压大鼠的降压作用.方法:50只3月龄自发性高血压大鼠随机分为5组进行长期给药治疗试验:空白贴剂对照组、非洛地平(FEL)-美托洛尔(MET)口服混悬液组(FEL 1 mg·kg-1,MET 10 mg·kg-1,qd)及FEL-MET透皮贴剂低、中、高剂量组[剂量分别为:FEL 1 mg·kg-,MET 10 mg·kg-1;FEL 3 mg·kg-1,MET 30 mg·kg-1;FEL 9 mg·kg-1,MET90 mg·kg-,每隔2 d给药1次],共持续44 d.另设同月龄正常血压Wistar大鼠为正常对照组.以无创性尾套法测定给药后大鼠血压和心率,评价经皮给药系统的降压作用.结果:FEL-MET透皮贴剂降压作用起效快、持续时间长,无耐药趋势,强度具有剂量依赖性.FEL-MET透皮贴剂低、中、高剂量分别使收缩压下降27.3-39.2mmHg(14.78%～21.22%),34.2～49.7 mmHg(18.59%～27.01%)和50.8～68.6 mmHg(27.34%～36.92%);使舒张压下降19.8～32.6 mmHg(12.90%～21.24%),22.7～34.9 mmHg(15.30%～23.52%)和33.7～52.8mmHg(22.74%～35.63%);降压效果显著优于FEL和MET长期口服联用(P＜0.05).结论:FEL-MET经皮给药系统降压效果确切,作用平稳,持效时间长,使用方便,安全性高,适于高血压的长期药物治疗.