肉桂提取物醇质体凝胶经皮给药研究

目的 制备肉桂提取物醇质体凝胶,考察肉桂提取物醇质体凝胶的透皮速率影响因素。方法 采用注入法制备肉桂提取物醇质体,将醇质体与羟丙基甲基纤维素（HPMC）凝胶混合制备肉桂提取物凝胶,采用♂SD大鼠皮肤和Franz单室扩散池作体外经皮研究,HPLC测定不同时间点接受池的肉桂酸含量,考察不同HPMC浓度、不同促渗剂和促渗剂浓度对肉桂提取物醇质体凝胶渗透速率的影响。结果 不同HPMC浓度作为肉桂提取物醇质体基质时经皮渗透速率：2%HPMC〉3%HPMC〉4%HPMC〉5%HPMC≈醇质体。2%氮酮-丙二醇（1∶1）处理显示最好的促渗效果,渗透速率与醇质体相比：（4.38±0.47）μg·h1·cm2vs（1.53±0.31）μg·h1·cm2。结论 2%HPMC制备的肉桂提取物醇质体凝胶,能提高肉桂透皮速率,醇质体凝胶有望开发为肉桂提取物经皮给药剂型。     

纳洛酮醇质体的经皮渗透研究

目的 考察以醇质体为载体的纳洛酮经皮给药的可行性以及醇浓度、药物含量对药物渗透速率的影响.方法 采用注入法制醇质体,以SD雄性大鼠皮肤为媒介,Franz单室扩散池为体外模型,用HPLC法测定透过皮肤的纳洛酮含量.求算累积渗透量稳态透皮速率和皮肤中的滞留量,考察醇浓度和药物含量对渗透速率的影响.结果 纳洛酮为5 mg·mL-1时,含醇20%、30%、40%和50%的醇质体稳态透皮速率分别为(54.3±3.6),(92.0±8.8),(111.4±22.6)和(139.8±7.6)μg·h-1·cm-2,与纳洛酮水溶液(30.9±3.4)μg·h-1·cm-2相比,其增渗倍数分别为1.76,2.98,3.61和4.52倍;在皮肤中的滞留量和时滞的顺序一致50%醇质体＞40%醇质体＞30%醇质体＞20%醇质体＞药物水溶液.含纳洛酮0.625,1.25,2.5,5,7.5和10 mg·mL-1的30%的醇质体,其渗透速率分别为(2.8±1.3),(15.1±2.4),(43.8±5.0),(92.0±8.8),(145.2±4.6)和(193.8±5.7)μg·h-1·cm-2.结论 醇质体能显著地促进渗透,增加药物在皮肤中的滞留量.随着醇质体内醇的含量增加,其渗透速率增加.醇质体内药物含量增加,渗透速率也增加.     

酮洛芬醇质体体外经皮渗透研究

目的:考察酮洛芬醇质体的体外经皮渗透特性。方法:乙醇注入法制备酮洛芬醇质体,采用Franz扩散池,以离体小鼠皮为皮肤屏障,对酮洛芬醇质体的体外经皮渗透量、稳态透皮速率进行研究,并测定24 h时皮肤中的滞留量。结果:酮洛芬醇质体体外24 h累积渗透量Q为(720.88±2.04)μg.cm-2,稳态透皮速率J为(28.15±0.20)μg.cm-2.h-1,24 h皮肤中的滞留量(50.86±1.44)μg.cm-2,与同剂量酮洛芬脂质体及其30%醇溶液相比,均有明显提高(P<0.05)。结论:醇质体可显著增加酮洛芬的体外经皮渗透,值得进一步研发。     

姜黄二酮醇质体凝胶的制备与经皮渗透性研究

摘要：目的:采用醇质体凝胶装载药物改善姜黄二酮透皮性能。方法:分别制备姜黄二酮醇质体凝胶、普通凝胶、乳膏选取小鼠腹部皮肤进行Franz体外扩散试验用HPLC法测定姜黄二酮的浓度。以透皮量、皮肤储滞留量和透皮速率为指标,评价三者透皮性能。结果:姜黄二酮醇质体凝胶中姜黄二酮的稳态透皮速率为64.24μg·cm-2·h-1,分别达普通凝胶的3.29倍、乳膏的1.21倍;皮肤滞留量为369.35μg·cm-2,分别为普通凝胶的5.11倍、乳膏的3.36倍。结论:姜黄二酮醇质体凝胶的透皮性能良好具有新药开发的前景。     

尼美舒利醇质体的体外经皮渗透特性及皮肤刺激性

目的:考察醇质体作为尼美舒利经皮给药载体的体外渗透性及刺激性。方法:采用注入法制备尼美舒利醇质体,采用Franz扩散池和鼠皮进行体外渗透实验,HPLC测定药物浓度并计算药物稳态透皮速率、12 h累积释放量及皮内滞留量;采用小鼠皮肤红斑平均积分考察尼美舒利醇质体刺激性。结果:测得尼美舒利醇质体的稳态经皮渗透速率和12 h累积释放量分别是(16.28±1.68)μg.(cm2.h)-1,(195.38±19.89)μg/cm2,与脂质体相比提高了1.9倍(P<0.05);而醇质体的皮内滞留量为(318.67±38.57)μg/cm2,仅是脂质体的1.07倍(P>0.05)。皮肤刺激性实验显示,NIM醇质体的红斑指数与生理盐水的差异并不明显(P>0.05)。结论:尼美舒利醇质体的经皮渗透性和皮肤刺激性都优于脂质体,是一种有效的经皮给药制剂。     

不同基质及促渗剂对姜黄素脂质体凝胶经皮渗透的影响

考察了凝胶基质种类及浓度和促渗剂对姜黄素脂质体凝胶经小鼠离体皮肤的累积渗透量及皮肤滞留量的影响.所得优化处方为:以1％卡波姆为凝胶基质,加入2％月桂氮草酮和2％薄荷醇为复合促渗剂.所得制品的24h累积渗透量、稳态渗透速率及皮肤滞留量均显著高于姜黄素脂质体.     

姜黄素醇质体体外透皮及其稳定性研究

目的：对姜黄素醇质体体外透皮及其稳定性进行考察方法：采用透皮扩散仪进行体外透皮实验,比较姜黄素醇质体、溶液、脂质体经小鼠离体皮肤的累积渗透量及皮肤滞留量;并将姜黄素醇质体4℃条件下冷藏,考察其稳定性。结果：姜黄素醇质体12h内单位面积皮肤的累计渗透量和皮肤滞留量是其溶液（含0．5％吐温-80）的2．71倍和2．81倍;但与其脂质体无显著差异。姜黄素醇质体4℃条件下冷藏1个月,其外观、包封率、粒径及多分散指数（PDI）变化较小。结论：醇质体作为透皮给药载体能促进姜黄素的透皮吸收,并能增加皮肤中的滞留量;姜黄素醇质体具有一定的稳定性。     

促渗剂对贴剂中双氯芬酸二乙胺的经皮促渗作用

目的 制备双氯芬酸二乙胺(DDEA)水凝用胶贴剂,研究不同促渗剂对水凝胶贴剂中DDEA体外透皮吸收的影响.方法 以具有良好生物相容性的亲水性高分子材料为基质材料制备DDEA水凝胶贴剂;用离体大鼠腹部皮肤为模型,采用改良Franz扩散池装置进行经皮渗透实验.HPLC法测定不同时间点接收池中DDEA的浓度,计算药物的累积渗透量和经皮渗透动力学参数.结果 不同促渗剂对DDEA的经皮渗透有不同程度的促进作用,其中薄荷脑的促渗作用最为显著.薄荷脑对DDEA的促渗在1%～5%,呈正相关剂量效应关系,薄荷脑用量为5%时,药物的稳态透皮速率可达18.121 μg·cm-2·h-1,与空白对照组相比增渗倍数为5.45.结论 薄荷脑可作为DDEA水凝胶贴剂的促渗剂,并可开发此新型水凝胶贴剂.     

甲氨蝶呤柔性纳米脂质体凝胶的构建及体外经皮渗透性研究

目的 制备甲氨蝶呤(methotrexate,MTX)柔性纳米脂质体凝胶,并研究其体外经皮渗透行为.方法 采用逆向蒸发法制备MTX柔性纳米脂质体,以卡波姆940为基质制成脂质体凝胶,并考察其初步稳定性;Franz扩散池研究MTX柔性纳米脂质体凝胶与普通凝胶的经皮渗透规律.结果 脂质体凝胶4℃下稳定性良好;体外透皮试验表明,MTX柔性纳米脂质体凝胶的累积透过量明显＜MTX普通凝胶(P＜0.05),皮肤滞留量＞MTX普通凝胶(P＜0.05).结论 MTX柔性纳米脂质体凝胶可显著提高药物的皮肤滞留量,而不增加药物进入血液循环的量,能有效降低药物潜在的全身毒性,有望成为MTX局部治疗的新剂型.     

甘草酸二铵脂质囊泡的体外经皮渗透研究

目的 考察不同种类的甘草酸二铵(DG)脂质囊泡的体外经皮渗透情况,并制备脂质囊泡凝胶剂。方法 分别采用非质子传递溶剂法制备磷脂复合物,薄膜分散法制备柔性脂质体,注入法制备醇质体,并测定粒径;采用改良的Franz扩散池,以离体人皮进行经皮渗透实验;HPLC测定接收液和皮肤组织中药物含量。最后,将皮肤渗透性较好的囊泡处方制备成凝胶剂,考察凝胶的经皮渗透情况。结果 DG磷脂复合物24 h累计透过量为(8.07±5.42)μg·cm^-2,其余处方透过液中均未检测到药物。24 h药物在皮肤中的累积量大小顺序为磷脂复合物>醇质体>柔性脂质体>水溶液。DG磷脂复合物凝胶透皮效果与卡波姆浓度有关,0.5%卡波姆处方的皮肤中药物滞留量为1%卡波姆处方的2.2倍,降低卡波姆的浓度不但能提高DG在表皮层的含量,而且还能使药物进一步渗透至真皮层。结论 磷脂复合物能显著促进DG在皮肤中的渗透,并增加药物在皮肤中的蓄积。采用0.5%卡波姆制备磷脂复合物凝胶具有较好的经皮渗透性。     

The effect of naloxone on C-fiber reflex in cats

The specific opiate antagonist naloxone rapidly reverses hypotension caused by endotoxin, hypovolemia and spinal transection. The fact that naloxone appears to act as a causative level to improve shock pathophysiology, as well as its extensive clinical use for opiate overdose, makes this drug a particularly clinical use for opiate overdose, makes this drug a particularly attractive potential therapeutic agent for the treatment of shock in humans. The electrophysiological effects of naloxone were studied on c-fiber reflex in spinal and intact cats. The drugs were injected in to the right cephalic vein. Results can be summarized as follows: Naloxone in the intact cat had a more pronounced facilitating effect than in the spinal cat. Naloxone given as a one shot injection was more potentiating than naloxone given as a 5 minute injection. Naloxone antagonized the facilitation of a small dose of ketamine-HCL in the intact cat and also the depression of a large dose ketamine-HCL. Naloxone antagonized capsaicin on c-fiber reflex. This result supports that naloxone has the antagonizable inhibitory effect of substance-P. Naloxone for the first injection had an effective response but additional naloxone did not facilitate the c-fiber reflex.     

纳络酮抢救重度有机氟灭鼠药中毒的临床观察

目的:进一步观察纳络酮对重度有机氟灭鼠药中毒的治疗作用.方法:治疗组在综合治疗的基础上,早期辅以纳络酮0.01mg/(kg·次),每小时静推一次,每天应用4~6次,至临床症状改善后停药;对照组采用综合治疗.结果:治疗组在意识恢复时间、肺水肿消失、止痉、纠正呼吸衰竭及临床治愈率、平均住院天数及病死率等方面均显著优于对照组.结论:纳络酮可显著提高有机氟灭鼠药中毒的抢救效果.     

Opioid pathways exert a tonic restraint in the guinea-pig isolated colon: changes after chronic sympathetic denervation

Abstract— We have studied the effects of naloxone on acetylcholine and noradrenaline release in the guinea-pig isolated distal colon, and have assessed the effect of naloxone on electrically-induced contractions of the longitudinal muscle and non-adrenergic, non-cholinergic (NANC) relaxations of the circular muscle coat. Naloxone dose-dependently increased resting and electrically-evoked acetylcholine release and electrically-evoked noradrenaline release. Naloxone was more potent in increasing resting acetylcholine release in colonic specimens obtained after chronic sympathetic denervation. Naloxone (1 μm ) did not affect electrically-induced contractions of the longitudinal muscle, while it enhanced NANC relaxations of the circular muscle. The effects observed with naloxone in the present experiments suggest that opioid pathways exert a tonic restraint on neurotransmission in the guinea-pig colon. After suppression of the adrenergic inhibitory tone, the functional relevance of opioid pathways seems to be increased.     

Effect of naloxone on blood pressure and survival in different shock models in rats

The effect of naloxone on a number of experimental shock models, using the anaesthetized rat, was studied with special emphasis on mean arterial blood pressure (MABP) and chance of survival. Only a slight increase in MABP was noted in haemorrhagic shock models whereas survival was not affected. Naloxone was without effect in endotoxin shock (i.p. administration of endotoxin). In endotoxin shock (i.v. administration) naloxone increased MABP especially at a high dose of endotoxin. Although survival time was prolonged, the chance of permanent survival was not improved. Naloxone had practically no effect in anaphylactic shock and intestinal ischaemia shock. It is concluded that if naloxone has any effect it is relatively slight. However, this does not exclude the possibility that naloxone might still be considered as an adjunct to other forms of shock treatment at least in certain types of shock.     

Effects of naloxone and its quarternary analogue on stimulation-induced feeding

Feeding was induced in rats by electrical stimulation in the lateral hypothalamus. Naloxone (0.2 and 1.0 mg/kg) produced a dose-related elevation of the frequency threshold for stimulation-induced feeding while quarternary naloxone (2.0 and 10.0 mg/kg) had no effect. Since quarternary naloxone does not readily penetrate the blood-brain barrier, we conclude that the opiate receptors at which naloxone exerts its anorectic action are located in the brain rather than in potential peripheral tissues such as gastrointestinal tract, pancreas or adrenal medulla. The threshold-elevating effect of naloxone only became marked after rats had engaged in one or two 5-sec bouts of feeding. The effect continued to increase following each subsequent bout of feeding. Naloxone therefore appears to inhibit feeding by interacting with post-ingestive factors.     

Antiarrhythmic properties of naloxone: an electrophysiological study on sheep cardiac Purkinje fibers

Recent data suggest that the opioid antagonist naloxone may exert an antiarrhythmic action on arrhythmias caused by coronary artery occlusion and reperfusion in experimental animals. We used intracellular microelectrodes to study the direct electrophysiological properties of naloxone. Experiments were carried out on sheep cardiac Purkinje fibers, the electrical and mechanical activity of which were recorded simultaneously. Naloxone (10(-7)-10(-4) M) caused a prolongation of the action potential duration, a decrease in the maximum rate of depolarization, a flattening of the slope of diastolic depolarization and a decrease in contractility. Naloxone at 10(-6) M significantly reduced the rate of spontaneously beating Purkinje fibers and at 10(-5) M completely blocked normal automaticity. Naloxone had, however, intriguing effect on the oscillatory afterpotentials, which is a relevant arrhythmogenic mechanism. While naloxone (10(-7)-10(-4) M) did not affect the digitalis-induced oscillatory afterpotentials, it increased the amplitude of the barium-induced oscillatory afterpotentials at lower concentrations (10(-7) M) and decreased the amplitude of these potentials at high concentrations (10(-6)-10(-4) M). It is concluded that naloxone exerts a direct electrophysiological effect on cardiac cells and that this effect is probably important for explaining the antiarrhythmic action of naloxone.     

Suppression of deprivation-induced food and water intake in rats and mice by naloxone

Naloxone, an opiate antagonist, was administered to male and female rats and male mice after periods of food or water deprivation ranging from 12 to 48 hr. Naloxone (0.01-10 mg/kg) reduced postdeprivational water intake in most groups of rats and mice in a dose-related manner. Naloxone suppression of water consumption appeared to be independent of sexual differences in rats, and phase of the diurnal cycle, and length of the deprivation interval in both rats and mice. Postdeprivational food intake in male rats and mice was also reduced by naloxone in a dose-dependent fashion. This naloxone effect was less pronounced than actions observed with water intake, and tended to diminish with lengthening food deprivation periods. In general, mice appeared to be less sensitive than rats to naloxone suppression of food and water intake. Naloxone appears to markedly reduce appetitive behavior, particularly water intake, following deprivation in both rats and mice. The fact that low doses of naloxone can elicit these effects suggests that the drug is acting at specific tissue sites, possibly endorphine recpetors.     

Peripheral antinociceptive effects of low doses of naloxone in an in vivo and in vitro model of trigeminal nociception

Naloxone has been used to antagonize opioid effects for many years, even though at low doses it can exert antinociceptive effects. This ‘paradoxical’ analgesia has been detected after systemic administration of naloxone given alone or in combination with opioid drugs. In the present study, we investigated possible peripheral antinociceptive effects of low doses of naloxone using both an in vivo and in vitro model of trigeminal nociception. Low doses of naloxone injected locally into the rat wiskerpad elicited antinociceptive activity in the rat orofacial formalin test. The block of primary afferents with local administration of capsaicin suggested that naloxone acts both directly on sensory neurons and indirectly, by modulating the inflammatory component of the second phase of formalin test. Naloxone analgesia is maintained in rats made tolerant to the μ-receptor agonist DAMGO, suggesting the involvement of δ- and κ-opioid receptors. Subsequently, the effects of very low doses of naloxone were tested in primary cultures of rat trigeminal neurons activated with bradykinin, in order to elucidate the mechanisms of action underlying naloxone antinociceptive effects. Naloxone inhibited bradykinin-evoked CGRP release in two different experimental paradigms, i.e. primed and unprimed cultures, acting at the level of δ- and κ-opioids receptors. These results suggest that low doses of naloxone can directly modulate the activation of the trigeminal neurons by modulating the activity of specific opioid receptors, and this effect may be clinically relevant in combined therapies where an increased analgesic effect is sought through the potentiation of peripheral mechanisms.     

Morphine metabolism in isolated rat hepatocytes and its implications for hepatotoxicity

Isolated rat hepatocytes metabolized morphine to its glucuronide conjugate, morphinone-glutathione conjugate, normorphine and morphinone. Addition of morphine to the isolated hepatocytes induced a marked decrease in the level of glutathione in the cells and resulted in cell death. The formation of glutathione conjugate was correlated well with the loss of intracellular glutathione. The cytotoxicity of morphinone was higher than that of morphine. Naloxone and normorphine showed no cytotoxic effect on the cells. Naloxone inhibited the formation of morphinone-glutathione conjugate and prevented the morphine-induced cytotoxicity. Naloxone also blocked morphine-induced liver damage in vivo. In contrast, the morphinone-induced hepatotoxicity was not prevented by naloxone. It is concluded that morphine has a hepatotoxic effect, that the morphine-induced hepatotoxicity is due to its metabolic activation, and that naloxone acts as an inhibitor of an enzyme converting morphine to morphinone.