Tissue penetration of cefpodoxime into the skeletal muscle and lung in rats

PURPOSE: The aim of this study was to investigate the pharmacokinetics of cefpodoxime in interstitial tissue fluids (skeletal muscle and lung) in rats by microdialysis, and to examine the relationship between free drug levels in plasma and in tissues. METHODS: Cefpodoxime was administered to anesthetized male Wistar rats as single intravenous bolus of 10 or 20 mg/kg and constant infusion of 260 microg/h with a loading dose. The protein binding of cefpodoxime in rat plasma was determined using ultrafiltration. RESULTS: The average protein binding of cefpodoxime in rat plasma was 38%. The half-lives in plasma, muscle and lung were similar (approximately 5 h). After constant rate infusion, the free concentrations in the muscle and the lung were almost identical, but lower than total and free plasma concentrations. The data were modeled simultaneously using a two-compartmental body model. CONCLUSIONS: Free interstitial levels of cefpodoxime in muscle and lung tissue are very similar. Since muscle is more accessible than lung, free muscle concentrations may serve as a good surrogate for unbound concentrations in lung.     

Perioperative penetration of metronidazole into muscle tissue: a microdialysis study

Objective To evaluate the concentration of metronidazole in muscle tissue using microdialysis and to compare it with plasma concentration and in vitro-defined MIC₉₀ (minimal inhibiting concentration) for the most frequent anaerobic bacteria isolated in our hospital.Materials and methods Six female patients scheduled for elective gynaecological surgery were included. Exclusion criteria were active inflammatory process and being overweight (BMI more than 30). Microdialysis catheters (CMA 60 catheters with 20 kDa cut-off membrane) were placed into the m. vastus lateralis. The microdialysis perfusion rate was 2 l/min. To assess in vivo recovery of the drug, retrodialysis with a 5-mg/l solution of metronidazole was performed. Microdialysis and blood samples were collected simultaneously 10 h after metronidazole administration. MIC₉₀ data were obtained from the database of the microbiology laboratory of the local hospital.Results Data from five patients were included in analysis. The metronidazole concentration in blood achieved a value of 16.5±4.6 mg/l at 30 min (first available data), while in muscle a maximum level of 7.8±1.5 mg/l was achieved at 114 min. The mean MIC₉₀ for the Bacteroides fragilis group was 0.25±0.26 mg/l. Data from mean plasma concentrations were fitted into the two-compartmental model and time over MIC₉₀ and time over four times MIC₉₀ were calculated, which were 52.1±13.5 h and 33.2±8.7 h, respectively. The C_max/MIC₉₀ ratio was 65.8±18.5 for plasma and 31.1±6.2 for muscle.Conclusion The present data demonstrate that metronidazole penetrates well into muscle tissue. Muscle tissue concentrations reach values far greater than MIC₉₀ for the Bacteroides fragilis group and persist at such high levels for at least 10 h.     

Determination of norfloxacin free interstitial levels in skeletal muscle by microdialysis

Tissue penetration and distribution of antibiotics are important issues when establishing antibiotic therapies. Free concentrations of antibiotics at the infection site are responsible for bacteria killing effect. The knowledge of the correlation between blood levels and tissue concentrations can be helpful for adequate dosing of these drugs. It was the aim of this study to investigate norfloxacin pharmacokinetics in rats to predict free interstitial levels of the drug, determined by microdialysis, using pharmacokinetic parameters derived from total plasma data. Norfloxacin free tissue and total plasma levels were determined in Wistar rats after administering 5 and 10 mg/kg i.v. bolus doses. Plasma and microdialysis samples were analyzed by high-performance liquid chromatography. Norfloxacin plasma pharmacokinetics was consistent with a two compartments model. A simultaneous fitting of plasma and tissue concentrations was performed using a proportionality factor because norfloxacin free tissue levels determined by microdialysis were lower than those predicted using plasma data. A similar proportionality (f(T)) factor was calculated by the computer program Scientist((R)) for both doses (0.25 +/- 0.08). It can be concluded that it is possible to predict concentration time profiles of norfloxacin in the peripheral compartment based on plasma data using the adequate tissue penetration factor.     

Evaluation of ofloxacin penetration into the skin after a single oral dose assessed by cutaneous microdialysis

An antibacterial drug can exert its therapeutic action if it is present in target tissue at proper concentration. Cutaneous microdialysis is a relatively new technique, which allows to determine drug concentration in the skin. The aim of the study was to evaluate the ofloxacin concentrations in plasma and skin following a single oral dose of 0.4 g. Drug concentration in the skin was assessed by applying cutaneous microdialysis. The penetration of the studied agent into dermal microdialysate was compared with its penetration into theoretical peripheral compartment. Maximum ofloxacin concentration in plasma was 9.26 micromol/l on average and was achieved after about 1.7 h. Mean peak concentrations in cutaneous microdialysate and in theoretical peripheral compartment were comparable (4.16 versus 4.50 micromol/l), but time to peak concentration in theoretical peripheral compartment was significantly longer than in microdialysates (5.8 and 2.0 h, respectively). Degree of penetration into cutaneous microdialysate was about 0.54. Cutaneous microdialysis seems to be a valuable technique to evaluate drug penetration into the skin.     

COX-2 inhibition attenuates lung injury induced by skeletal muscle ischemia reperfusion in rats

BackgroundSkeletal muscle ischemia reperfusion accounts for high morbidity and mortality, and cyclooxygenase (COX)-2 is implicated in causing muscle damage. Downregulation of aquaporin-1 (AQP-1) transmembrane protein is implicated in skeletal muscle ischemia reperfusion induced remote lung injury. The expression of COX-2 in lung tissue and the effect of COX-2 inhibition on AQP-1 expression and lung injury during skeletal muscle ischemia reperfusion are not known. We investigated the role of COX-2 in lung injury induced by skeletal muscle ischemia reperfusion in rats and evaluated the effects of NS-398, a specific COX-2 inhibitor.MethodsTwenty-four Sprague Dawley rats were randomized into 4 groups: sham group (SM group), sham + NS-398 group (SN group), ischemia reperfusion group (IR group) and ischemia reperfusion + NS-398 group (IN group). Rats in the IR and IN groups were subjected to 3 h of bilateral ischemia followed by 6 h of reperfusion in hindlimbs, and intravenous NS-398 8 mg/kg was administered in the IN group. In the SM and SN groups, rubber bands were in place without inflation. At the end of reperfusion, myeloperoxidase (MPO) activity, COX-2 and AQP-1 protein expression in lung tissue, PGE₂ metabolite (PGEM), tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels in bronchoalveolar lavage (BAL) fluid were assessed. Histological changes in lung and muscle tissues and wet/dry (W/D) ratio were also evaluated.ResultsMPO activity, COX-2 expression, W/D ratio in lung tissue, and PGEM, TNF-α and IL-1β levels in BAL fluid were significantly increased, while AQP-1 protein expression downregulated in the IR group as compared to that in the SM group (P < 0.05). These changes were remarkably mitigated in the IN group (P < 0.05). NS-398 treatment also alleviated histological signs of lung and skeletal muscle injury.ConclusionCOX-2 protein expression was upregulated in lung tissue in response to skeletal muscle ischemia reperfusion. COX-2 inhibition may modulate pulmonary AQP-1 expression and attenuate lung injury.     

Pharmacologic modulation of skeletal muscle metabolism: a microdialysis study

Microdialysis is a valuable tool to measure tissue responses. We hypothesized that skeletal muscle metabolism can be modulated by microdialysis applied drugs which alter cytosolic calcium concentration. With approval of the local animal care committee, the hind limbs of sacrificed male Sprague Dawley rats were perfused either with Ringer's solution or with dantrolene 1 microM at 30 ml hr(-1) and 21 degrees. Microdialysis probes in both hind limbs were perfused at 1 microl min(-1) either with sorbitol 80 mM, calcium 20 mM, 40 mM, 80 mM, caffeine 40 mM, 80 mM, and halothane 10 vol% respectively, and at the contralateral adductor muscle with Ringer as control. Lactate was measured spectrophotometrically in the dialysate at 15 min. intervals. Lactate levels as measured by intramuscular microdialysis were not influenced by intramuscular application of sorbitol 80 mM compared to control measurements with Ringer's solution. Local application of calcium 20 mM, 40 mM, 80 mM, caffeine 40 mM, 80 mM, and halothane 10 vol% via microdialysis increased lactate concentrations, while organ perfusion by dantrolene 1 microM reduced the caffeine-induced lactate increase. Modulation of intramuscular lactate metabolism by exogenous compounds via microdialysis probes generates new insights in skeletal muscle metabolism.     

Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis.

The purpose was to investigate the in vivo skin penetration of four 14C-salicylic compounds using microdialysis and to relate dermal concentrations to structural features. Furthermore, to compare two in vivo retrodialysis recovery methods for estimation of true unbound extracellular concentrations. Microdialysis probes were inserted in the dermis of hairless rats. Equimolal 14C-salicylic formulations were applied topically and dialysate sampled consecutively for 4h. True extracellular concentrations were estimated by retrodialysis by drug method (the 14C-salicylic compounds themselves) and by retrodialysis by calibrator method (3H-salicylic acid as internal standard). Probe depth was measured by ultrasound scanning. High dermal concentrations were found after application of 14C-salicylamide (low protein-binding) and the lipophilic ester 14C-butyl salicylate, which was completely hydrolysed to 14C-salicylic acid during skin diffusion. Protein binding and dissociation may explain the lower dermal concentrations of 14C-salicylic acid and 14C-diethylamine salicylate, respectively. Probe depth did not significantly influence dialysate concentrations. The two in vivo recovery correction methods did not reduce the variation in concentration-time curves. In conclusion, differentiated penetration kinetics was found ranking: 14C-salicylamide >/= 14C-butyl salicylate > 14C-salicylic acid > 14C-diethylamine salicylate. Dermal concentrations were related to structural features of the model compounds. The two correction methods performed alike; however, the calibrator method has the advantage of serving as a quality control during experiments.     

甲磺酸加替沙星与加替沙星的药物代谢动力学比较

目的甲磺酸加替沙星(GATM)和加替沙星(GAT)是喹诺酮类抗感染药物的新型制剂,对改变酸根的甲磺酸加替沙星在大鼠体内的药物代谢动力学规律和特点进行了考察并和加替沙星进行比较。方法以SD大鼠为研究对象,单剂量口服等克分子剂量(0.0497 mmol.kg-1)GATM和GAT后,采用高效液相色谱法(HPLC)检测血清中GAT的含量,采用3p97程序软件计算二者在大鼠体内的药代动力学参数。结果大鼠单次口服GATM(23.43 mg.kg-1)和GAT(20 mg.kg-1)后,二者的血药浓度经时变化符合一级消除动力学特征,药时曲线拟合为二房室模型,其中GATM的药代动力学参数为:血浆消除半衰期(T12β)9.13 h,药时曲线下面积(AUC)15.05 mg.L-1.h,血药峰浓度(Cm ax)4.41mg.L-1,达峰时间(Tm ax)0.5 h;而GAT的药代参数分别为:T12β10.70 h,AUC 13.84 mg.L-1.h,Cm ax4.25 mg.L-1,Tm ax0.5 h。结论在上述剂量条件下GATM与GAT的吸收(Tm ax、Cm ax、AUC)、分布(V/F)和消除(T12β、CL)参数差异未见显著性,二者的血药浓度经时变化相似,药代动力学规律基本一致。     

用微透析法研究肺炎大鼠灌胃左氧氟沙星的肺部药动学

目的：观察肺炎大鼠模型灌胃左氧氟沙星后在肺组织中的药动学特点.方法：以肺炎链球菌诱导肺炎大鼠模型,之后灌胃左氧氟沙星42 mg/kg.采用微透析技术对大鼠血液和肺组织同步取样,以HPLC法测定血液和肺组织中的药物浓度,计算左氧氟沙星的主要药动学参数和肺组织穿透率.结果：血液和肺组织中的药物浓度变化趋势一致.从第20 min开始,肺组织中的药物浓度始终高于血药浓度.左氧氟沙星的肺组织穿透率为（1.17±0.06）.在血液和肺组织的主要药动学参数分别为：tmax（46.67±20.82）和（43.33±23.09） min,cmax（1.29±0.41）和（1.56±0.70） μg/ml,t12（534.38±381.64）和（591.38±416.08） min,AUCinf（920.33±473.56）和（1196.23±992.35） μg·min·ml-1,在肺组织的分布系数为（1.22±0.56）.结论：肺炎大鼠模型灌胃左氧氟沙星后具有良好的肺组织穿透率和分布系数.     

Penetration of piperacillin and tazobactam into pneumonic human lung tissue measured by in vivo microdialysis

OBJECTIVES: The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma. PATIENTS AND METHODS: The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam. RESULTS: The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed. CONCLUSION: This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.     

Effect of glycyrrhizic acid on rhein renal penetration: a microdialysis study in rats

Abstract

1.?Rhein (RH), a primary active component isolated from rhubarb, is effective in protecting against the progression of diabetic nephropathy (DN) progression. Glycyrrhizic acid (GA), an active constituent of liquorice, is also considered to be a protective agent against DN. Here, we evaluated the effect of GA on the renal penetration of RH in rats.

2.?Plasma and renal pharmacokinetics were profiled to estimate kidney penetration. After rats were anesthetized, the carotid artery was used for blood collection and a microdialysis probe was inserted into the kidney cortex to collect dialysate samples.

3.?When co-administered with GA, the V_ss and CL values of RH in plasma increased by 25% and 34%, respectively. The C_max in kidney dialysates significantly increased 1.3-fold (p?<?0.05). There was no change in AUC_0–∞ in kidney dialysates, but a significant decrease (2?×?fold) in the plasma was observed. The AUC_{0–∞kidney}/AUC_{0–∞plasma} ratio of RH, representing kidney penetration, increased by 1.4-fold in the group pre-treated with GA compared to the RH alone group.

4.?These results demonstrate that GA increases the renal penetration of RH efficiently and may exert a synergistic effect, although the molecular mechanism of interaction requires further investigation.     

Capillary neoformation in skeletal muscle of dipyridamole-treated rats

Rats were given 0.3 mg dipyridamole i.p. twice a day, 5 days/week for 3 weeks. Morphometric determinations of the hindlimb skeletal muscle of these animals showed that they had a higher degree of capillary vascular supply than the muscles of sham-injected control rats. The number of capillaries per muscle fiber was increased by 24%, the number of capillaries/mm2 by 22% and the number of capillaries in contact with each muscle fiber by 22%.     

Contracture induction by snake venom cardiotoxin in skeletal muscle from humans and rats

Contracture responses to cardiotoxin (CTX) from Naja naja kaouthia venom were investigated in rat and human skeletal muscle of similar fiber type distribution to determine species differences in mechanism of action. Rat diaphragm strips and human vastus lateralis preparations were directly stimulated in a tissue bath. The calcium dependence of toxin action, synergism between CTX and phospholipase A2 (PLA2) activity and roles of Na+ + K+-ATPase activity and the sarcoplasmic reticulum Ca2+ stores in contracture induction were examined. The threshold of contracture to CTX was decreased in human and rat muscle when Sr2+ was substituted for Ca2+ in the bathing medium. In rat, but not in human muscle the threshold of contracture to CTX was decreased in a medium in which Ca2+ had been omitted. The decrease in contracture threshold may relate to toxin binding. The maximum height of contracture for preparations from humans, but not for those from rats was considerably depressed in a medium in which Ca2+ had been omitted. Exogenously added bee venom PLA2 acts synergistically with CTX in skeletal muscle in a manner similar to that in erythrocytes. Ouabain (100 microM) did not elicit contractures in any of the media tested nor affect CTX-induced contractures in Sr2+-containing medium. Dantrolene antagonized CTX-induced contractures, suggesting a role for Ca2+ derived from the sarcoplasmic reticulum in CTX action. The species difference in CTX action may reflect differences in the relative contribution of Ca2+ from the sarcolemma and sarcoplasmic reticulum to the contracture.     

Cyclosporin A attenuates skeletal muscle damage induced by crotoxin in rats.

This work was undertaken to determine the role of the calcineurin pathway on the necrosis of skeletal muscle induced by crotoxin, the major component of the venom of Crotalus durissus terrificus. Rats were treated with cyclosporin A (CsA), a calcineurin inhibitor, for 5 days and, in the 6th day, received an intramuscular injection of crotoxin into the tibialis anterior muscle. Rats were also treated with diclofenac, a non-steroidal anti-inflammatory drug, for 5 days and, on the 6th day, injected with crotoxin. All treated groups were sacrificed 24 h after injection of crotoxin. Tibialis anterior and soleus muscles were removed, frozen and stored in liquid nitrogen. Histological sections were stained with Toluidine Blue and assayed for acid phosphatase. The results show that CsA, but not diclofenac, is able to significantly minimize myonecrosis promoted by crotoxin. In conclusion, CsA attenuates skeletal muscle necrosis induced by crotoxin, indicating that the calcineurin pathway is essential for crotoxin myotoxic activity. The myoprotective effect of CsA is not related to its anti-inflammatory effect since diclofenac, a cyclo-oxygenase inhibitor, was not able to produce myoprotection.     

Evaluation of skeletal muscle relaxant activity of aqueous extract of Nerium oleander flowers in Albino rats

Objectives:

Nerium oleander is traditionally used in various diseases because of its medicinal properties. One of its uses is in musculoskeletal disorder. The aim of the study was to evaluate the skeletal muscle relaxant activity of the aqueous extract of Nerium oleander flowers (AENOF) in albino rats in comparison with diazepam.

Materials and Methods:

A total of 20 Swiss albino rats aged 6–7 weeks, of either sex, weighing about 100–150 g, were taken, and after acute toxicity studies two different doses were selected. The animals were divided into four different groups. The first group was kept as the control (normal saline), second as the standard (diazepam) and the remaining two groups as Test I and Test II, and given different doses of the AENOF. Skeletal muscle relaxant activity (motor coordination) on Rotarod and locomotor activity on photoactometer was performed. Statistical analysis was carried out by using analysis of variance, followed by Dunnett''s multiple comparison tests.

Results:

The result from the Actophotometer test and Rotarod test showed that the extract of AENOF significantly reduced (P < 0.05) the motor coordination of the tested animals.

Conclusions:

Our data indicates that AENOF possesses skeletal muscle relaxant activities.KEY WORDS: Actophotometer, muscle relaxant, Nerium oleander, rotarod, soxhlet apparatus     

Cultured myotubes from skeletal muscle of adult rats

Summary Mononucleated myogenic cells (satellite cells) were isolated from skeletal muscle of adult rats and grown in culture. These cells replicated and, beginning with the 6th day in culture, they fused and differentiated into multinucleated myotubes, which accumulated creatine kinase and developed cross striation and spontaneous contractions. The differentiation of the excitable membrane and the action of sea anemone toxin ATX II were investigated with microelectrode techniques. Mature myotubes reached a stable membrane potential of –47.3 mV (±6.5 mV) with the IIth day in culture. Action potentials could be generated in all myotubes. During maturation they became faster (increasing rate of rise) and shorter in duration. In spontaneously contracting myotubes spontaneous action potentials were recorded, which were often associated with subthreshold oscillations of membrane potential. ATX II reduced the membrane potential and prolonged the action potential duration with the lowest effective concentrations being 1 nmol/l and 0.5 nmol/l, respectively. Furthermore, ATX II induced electrical activity in quiescent myotubes. After fusion the development of the membrane electrical properties of satellite cell derived muscle cells followed essentially the same pattern as in primary cultures of embryonic myotubes. Electrophysiologically and with respect to their sensitivity to ATX II the mature myotubes resemble denervated muscle fibres. Send offprint requests to I. Tesseraux at the above address     

Evaluation of brain targeting in rats of Salvianolic acid B nasal delivery by the microdialysis technique

The purpose of this study was to investigate the biodistribution of Salvianolic acid B in rats blood and brain after intranasal administration and explore its feasibility and evaluate its brain targeting effect. The concentration of Salvianolic acid B in blood and brain following nasal administration (32?mg?kg^?1) was measured combining with microdialysis sampling and liquid chromatograph-mass spectrometer/MS detection technology. After the microdialysis samples were corrected with in vivo recoveries, the pharmacokinetic parameters were obtained by using non-compartment model and the brain targeting evaluated by the value of drug targeting index (DTI). The C_max in blood and brain by intravenous injection were higher than intranasal administration, but the intranasal administration of MRT_0-∞ significantly prolonged and increased by nearly 2.03 and 1.86 times, respectively. The DTI value of Salvianolic acid B was 5.54 and bioavailability (F) was 43.98%. After nasal administration of Salvianolic acid B, it has a certain brain targeting, which could become a new drug system for the treatment of brain diseases.     

Evaluation of brain-targeting for the nasal delivery of ergoloid mesylate by the microdialysis method in rats.

The aim of this study was to quantify the nasal delivery of ergoloid mesylate (EM) to the brain by comparing cerebrospinal fluid (CSF) and plasma EM levels after nasal administration at a dose of 4 mg/kg with those after intravenous administration. Following nasal delivery, EM reached a Cmax value (mean+/-SD) in plasma of 348.41+/-19.47 ng/ml and in CSF of 87.35+/-6.37 ng/ml after 107 and 20 min, respectively, while after intravenous injection, EM reached a Cmax value (mean+/-S.D.) in CSF of 54.81+/-4.92 ng/ml at 60 min and the Cmax in plasma was 1255.51+/-133.59 ng/ml. The AUC(CSF)/AUC plasma ratio (0.48+/-0.05) after intranasal delivery differed greatly from the ratio (0.14+/-0.04) observed after intravenous injection (P<0.05). The further analyzed data demonstrated a statistically significant distribution advantage of EM to the brain via the nasal route, and further suggesting that nasal administration can be a promising alternative for EM that undergoes first-pass metabolism following oral administration.     

梓醇对尘肺大鼠运动能力及骨骼肌功能改善作用研究

目的 探讨梓醇对尘肺模型大鼠运动能力及骨骼肌功能的改善作用。方法 通过气管注射石英粉尘建立大鼠慢性尘肺模型,造模3个月后,取造模大鼠30只随机分为3组：模型组、梓醇100mg·kg^-1组、梓醇50mg·kg^-1组,每组10只,另取10只正常大鼠作为对照组。大鼠ig给药,每天1次,每周给药6d,连续给药8周。观察大鼠一般状况及体质量变化;采用小动物跑台检测大鼠的1次力竭运动时间;采用抓力测定仪进行大鼠骨骼肌力量检测;解剖大鼠取同一位置肺叶,HE染色用于观察肺组织基本结构及炎症反应等状态,Masson染色用于观察肺组织胶原沉积和纤维化情况;取双侧后肢的腓肠肌和比目鱼肌,称质量,计算质量指数（肌肉质量/体质量）;试剂盒法检测腓肠肌组织线粒体膜电位（△φ_m）和腺嘌呤核苷三磷酸（ATP）水平;试剂盒法检测腓肠肌组织超氧化物歧化酶（SOD）活性、丙二醛（MDA）水平及琥珀酸脱氢酶（SDH）活性;实时荧光定量PCR（qRT-PCR）法检测过线粒体生物发生相关基因——氧化物酶体增殖物激活受体γ辅激活因子1α（Pgc-1α）、核呼吸因子1（Nrf1）、线粒体转录因子A（Tfam）的mRNA表达水平。结果 与模型组比较,梓醇100、50mg·kg^-1对尘肺大鼠肺部炎症和纤维未见显著改善;梓醇100、50mg·kg^-1均能显著延长尘肺大鼠跑动力竭时间（P＜0.05、0.01）;梓醇可显著增加尘肺大鼠的肌肉抓力,其中100mg·kg^-1组差异显著（P＜0.05）;梓醇100mg·kg^-1组尘肺大鼠的腓肠肌和比目鱼肌质量指数显著增加（P＜0.05、0.01）,50mg·kg^-1组的比目鱼肌质量指数显著增加（P＜0.05）;梓醇可明显升高尘肺大鼠腓肠肌ATP水平和△φ_m,其中100mg·kg^-1组差异显著（P＜0.05）;梓醇100mg·kg^-1显著增加腓肠肌SDH和SOD活力、同时降低MDA水平（P＜0.05、0.01）,梓醇50mg·kg^-1显著增加腓肠肌SDH活力、同时降低MDA水平（P＜0.05、0.01）;梓醇100、50mg·kg^-1显著上调腓肠肌中线粒体生物发生相关基因表达（P＜0.05、0.01）。结论 梓醇可以调节尘肺模型大鼠骨骼肌线粒体功能,减轻肌肉萎缩并增强运动能力,此作用可能通过PGC-1α/NRF1、TFAM途径促进线粒体生物发生而介导。     

Viral and non-viral methods for gene transfer into skeletal muscle

Skeletal muscle is an important target for genetic manipulation and its stable post-mitotic nature allows the use of both integrating and non-integrating viral and non-viral vectors. Adeno-associated viral vectors and naked plasmid DNA are currently the vectors of choice for gene transfer into muscle. The last couple of years have seen major breakthroughs in the field of vector delivery systems, particularly those using the vascular route, such that gene therapy of muscular dystrophies and the use of muscle as a platform for the production of secreted proteins has become a clinical possibility.