创面灵抗过敏止痒作用及毒理学试验研究

目的：观察创面灵的抗过敏、止痒作用及其对皮肤的刺激性和皮肤用药急性毒性。方法：2,4－二硝基氯苯（DNCB）所致迟发型皮肤过敏反应观察其抗过敏作用,采用豚鼠皮肤过敏试验评分法研究其皮肤过敏作用,磷酸组织胺致痒法观察其止痒作用。结果：创面灵不同剂量均对DNCB所致小鼠迟发型过敏反应有一定抑制作用,并可显著提高磷酸组织胺致痒阈;外用后豚鼠皮肤无红斑及水肿发生,对皮肤刺激强度分值显著低于刺激强度评价标准;体外给药未见毒副反应。结论：创面灵具有抗过敏、止痒作用,对皮肤无过敏反应,无刺激性,体外使用无毒副作用。     

创面灵抗过敏止痒作用及毒理学试验研究

目的观察创面灵的抗过敏、止痒作用及其对皮肤的刺激性和皮肤用药急性毒性。方法2,4-二硝基氯苯(DNCB)所致迟发型皮肤过敏反应观察其抗过敏作用,采用豚鼠皮肤过敏试验评分法研究其皮肤过敏作用,磷酸组织胺致痒法观察其止痒作用。结果创面灵不同剂量均对DNCB所致小鼠迟发型过敏反应有一定抑制作用,并可显著提高磷酸组织胺致痒阈;外用后豚鼠皮肤无红斑及水肿发生,对皮肤刺激强度分值显著低于刺激强度评价标准;体外给药未见毒副反应。结论创面灵具有抗过敏、止痒作用,对皮肤无过敏反应、无刺激性,体外使用无毒副作用。     

祛风止痒酊对实验动物的抗过敏和止痒作用

目的 研究祛风止痒酊的抗过敏与止痒作用.方法 采用过敏与瘙痒模型,观察不同剂量祛风止痒酊对实验动物过敏反应和全身与局部皮肤搔痒的影响.结果 抗过敏试验显示,祛风止痒酊能不同程度地抑制抗血清诱发的大鼠同种被动皮肤过敏和2,4-二硝基氯苯所致的小鼠迟发性超敏反应;大剂量时还可增加小鼠的胸腺指数及脾指数;止痒试验显示,祛风止痒酊能明显降低右旋糖酐诱导的小鼠搔痒发作次数及搔痒持续时间,并能增加豚鼠耐受磷酸组胺的致痒阈.结论 祛风止痒酊具有良好的抗过敏、止痒作用.     

风热汤的抗过敏、抗炎和止痒作用研究

目的探讨风热汤对大鼠被动皮肤过敏反应的影响及其抗炎、止痒作用。方法制备大鼠被动皮肤过敏反应模型,观察风热汤的抗过敏作用。采用炎症模型,观察给药后对二甲苯致小鼠耳廓肿胀和角叉菜胶致大鼠足趾肿胀的影响。采用瘙痒模型,观察给药后对葡聚糖-40致小鼠瘙痒和磷酸组胺致豚鼠瘙痒的影响。结果风热汤对血清抗原有抗过敏作用,对二甲苯所致小鼠耳廓肿胀和角叉菜胶所致的大鼠足趾肿胀有显著抗炎作用,能延长葡聚糖-40所致的小鼠瘙痒的潜伏期和减少瘙痒次数,对磷酸组胺致痒有止痒作用。结论风热汤具有抗过敏及抗炎、止痒的作用。     

辛芩口服液抗过敏作用的实验研究

目的研究辛芩口服液的抗过敏作用。方法利用动物模型进行评价。采用卵蛋白（OA）致大鼠同种被动皮肤过敏和豚鼠鼻黏膜过敏,测定其吸光度值（OD）,观察药物过敏抑制率;采用磷酸组胺致豚鼠过敏反应,计算过敏反应的致敏阈及持续时间;采用2,4-二硝基氯苯（DNCB）诱发的DTH小鼠迟发性超敏反应模型,计算肿胀度与脾指数、胸腺指数,观察辛芩口服液对迟发性超敏反应的影响。结果与空白对照组比较,辛芩口服液能显著抑制大鼠同种被动皮肤过敏和豚鼠鼻黏膜过敏反应,提高豚鼠对磷酸组胺的致敏阈并缩短过敏反应的持续时间,抑制DTH小鼠迟发性超敏反应,大剂量时还可增加小鼠的胸腺指数及脾指数。结论辛芩口服液具有一定的抗过敏作用。     

盐酸多塞平乳膏的止痒和抗过敏作用

目的研究盐酸多塞平乳膏(Doxepinhydrochloridecream)的止痒、抗过敏作用。方法观察对4氨基吡啶(4AP)所致小鼠和磷酸组胺所致豚鼠皮肤瘙痒的影响;并观察对醋酸致小鼠腹腔毛细血管通透性及组胺所致大鼠皮肤血管扩张的抑制作用;以2,4-二硝基氯苯(DNCB)致小鼠迟发性过敏反应(DTH)和大鼠同种皮肤被动过敏反应,探讨抗过敏作用。结果小鼠皮肤涂抹盐酸多塞平乳膏(50、125、250mg·kg-1),对4AP所致皮肤的瘙痒有抑制作用;豚鼠皮肤涂抹盐酸多塞平乳膏(10、25、50mg·kg-1),对磷酸组胺所致皮肤瘙痒也有抑制作用。皮肤涂抹盐酸多塞平乳膏(10、25、50mg·kg-1和50、125、250mg·kg-1)可抑制磷酸组胺致大鼠皮肤毛细血管通透性增加和醋酸致小鼠腹腔毛细血管通透性增加。皮肤涂抹盐酸多塞平乳膏(50、125、250mg·kg-1和10、25、50mg·kg-1)可抑制2,4二硝基氯苯致小鼠迟发性变态反应和大鼠同种皮肤过敏反应。结论盐酸多塞平乳膏具有止痒、抑制致炎性物质所致毛细血管通透性增加和对Ⅰ、Ⅳ型变态反应有抑制作用。     

消疹乳膏的药效学研究

目的 考察消疹乳膏的药效作用. 方法 观察消疹乳膏高、中、低剂量对二甲苯所致小鼠耳肿胀、磷酸组胺所致豚鼠致痒阈、2,4-二硝基氯苯(DNCB)诱发过敏性接触性皮炎的影响. 结果消疹乳膏高、中、低剂量对二甲苯所致小鼠耳肿胀均有显著的抑制作用(P<0.05或P<0.01);能显著提高磷酸组胺所致豚鼠致痒阈(P<0.05或P<0.01);对DNCB诱发豚鼠过敏性接触性皮炎有显著的抑制作用(P<0.05或P<0.01),且能下调血清中的白细胞介素(IL)-4水平. 结论 消疹乳膏具有抗炎、止痒及抗迟发型变态反应的功效.     

湿疹特灵软膏主要药效学研究

目的:考察湿疹特灵软膏的药效作用。方法:观察湿疹特灵软膏高、中、低剂量对巴豆油所致小鼠耳肿胀、透明质酸酶所致大鼠足跖肿胀、组织胺所致小鼠毛细血管渗透性增高、DNCB诱发豚鼠过敏性接触性皮炎的作用和对磷酸组胺致痒阈的影响以及对32株常见病原菌的体外抑菌情况。结果:湿疹特灵软膏高、中、低剂量对巴豆油所致小鼠耳肿胀、透明质酸酶所致大鼠足肿胀均有显著的抑制作用(P<0.05、P<0.01),对组织胺所致小鼠毛细血管渗透性增高以及DNCB诱发豚鼠过敏性接触性皮炎均有非常显著的抑制作用(P<0.01),能显著提高磷酸组胺致痒阈(P<0.05、P<0.01),对常见病原菌有一定的抑制作用。结论:湿疹特灵软膏具有抗炎、止痒及抗菌的功效。     

苦参碱止痒乳药效学研究

目的：观察苦参碱止痒乳对动物模型的主要药效学。方法：以豚鼠为模型，右后足背剃毛并用粗砂纸擦伤，涂药后在创面处滴磷酸组织胺溶液，至出现豚鼠回头舔右后足止，统计致痒阈值的改变；采用小鼠耳廓二甲苯致炎试验以及大鼠蛋清足跖肿胀法观察其抗炎作用；给大鼠皮肤外用苦参碱止痒乳，连用10d，采用生物组化方法测定动物皮肤P-物质的改变。结果：苦参碱止痒乳局部应用，可以提高动物的致痒阈；明显抑制致炎动物部位的肿胀度；有效降低皮肤P-物质的的含量。结论：苦参碱止痒乳具有抗炎、止痒作用。     

聚维酮碘溶液皮肤刺激性和致敏性实验研究

目的评价聚维酮碘溶液的安全性。方法采用家兔皮肤刺激试验和豚鼠皮肤过敏试验观察聚维酮碘溶液的安全性。结果家兔皮肤刺激试验，聚维酮碘溶液对家兔完整皮肤无刺激性，破损皮肤组1只家兔出现轻度红斑，停药48h后恢复正常．豚鼠皮肤过敏试验，聚维酮碘溶液未出现过敏反应。结论聚维酮碘溶液对家免皮肤无明显刺激性作用，对豚鼠皮肤无明显致变态反应作用。     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Arsenic induced changes in growth development and apoptosis in neonatal and adult brain cells in vivo and in tissue culture

Arsenic at a nonlethal level in drinking water consumed over a period of time has been reported to produce chronic toxicity and various types of health problems ranging from skin cancer to disturbance in memory. Neurotoxic effects have been reported in clinical cases with chronic exposure to arsenic. Physiological detoxication of arsenic occurs partially through methylation. Arsenic and its methylated derivatives are distributed in different organs and systems. The present study examined the possible interference in the neuronal development and differentiation due to the exposure to arsenic during gestation. The experiments were carried out to examine short and long term effects of arsenic on brain explants and cells grown and maintained in tissue culture system. The effects of arsenic exposure showed changes in brain cell membrane function indicated by generation and release of reactive oxygen-nitrogen intermediates. On the morphological aspect the explants' growth was reduced, ground matrix was lost and neural networking was inhibited. Cells showed signs of apoptotic changes. Arsenic toxicity may induce damage to brain cells prior to more visible clinical conditions. The deleterious effects also pass from the maternal to fetal tissue across the transplacental barrier.     

Metabolic interaction between imipramine and carbamazepine in vivo and in vitro in rats

Summary The pharmacokinetic consequences of the combination of carbamazepine with imipramine in male Wistar rats have been investigated. It was found that a 2-week treatment with the combination resulted in the increase of the concentrations of the parent compounds and a simultaneous decrease in their metabolites in blood plasma i.e. carbamazepine inhibited imipramine demethylation in the side chain while imipramine inhibited carbamazepine 10,11-epoxidation. The velocity of imipramine 2-hydroxylation and 10,11-epoxy-carbamazepine hydration did not seem to be changed by the combination. On the basis of studies in vitro it is concluded that the observed metabolic interaction between carbamazepine and imipramine is due to the competition of the drugs for the active centre of cytochrome P 450 and to a certain qualitative alteration of the enzyme by imipramine as can be deducted from the decrease of carbamazepine binding to the cytochrome. Send offprint requests to K. J. Netter     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85-100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.     

Nicotine metabolism and urinary elimination in mouse: in vitro and in vivo

This study aimed at elucidating the in vivo metabolism of nicotine both with and without inhibitors of nicotine metabolism. Second, the role of mouse CYP2A5 in nicotine oxidation in vitro was studied as such information is needed to assess whether the mouse is a suitable model for studying chemical inhibitors of the human CYP2A6. The oxidation of nicotine to cotinine was measured and the ability of various inhibitors to modify this reaction was determined. Nicotine and various inhibitors were co-administered to CD2F1 mice, and nicotine and urinary levels of nicotine and four metabolites were determined. In mouse liver microsomes anti-CYP2A5 antibody and known chemical inhibitors of the CYP2A5 enzyme blocked cotinine formation by 85–100%, depending on the pre-treatment of the mice. The amount of trans-3-hydroxycotine was five times higher than cotinine N-oxide, and ten times higher than nicotine N-1-oxide and cotinine. Methoxsalen, an irreversible inhibitor of CYP2A5, significantly reduced the metabolic elimination of nicotine in vivo, but the reversible inhibitors had no effect. It is concluded that the metabolism of nicotine in mouse is very similar to that in man and, therefore, that the mouse is a suitable model for testing novel chemical inhibitors of human CYP2A6.     

Penetration and action of edoxudine in vitro and in vivo

The penetration of 5-ethyl-2'-deoxyuridine (edoxudine, Aedurid) from gel base with and without the addition of urea and other adjuvant has been studied in an in vitro model using guinea pig skin. The formulation of 3% edoxudine gel with 5% urea showed the best results. In vivo experiments on hairless mice infected intracutaneously with herpes simplex virus type 1 also showed this formulation's good efficacy as compared to other formulations.     

Buprenorphine and naloxone alone and in combination in opioid-dependent humans

Subjective, physiological and behavioral effects of subcutaneously administered hydromorphone (6 mg), naloxone (0.2 mg), buprenorphine (0.2 and 0.3 mg), and two buprenorphine-naloxone combinations (buprenorphine 0.2 mg plus naloxone 0.2 mg and buprenorphine 0.3 mg plus naloxone 0.2 mg) were assessed under double-blind conditions in six opioid-dependent volunteers. Physiologic measures and subject- and observer-rated behavioral responses were measured before dosing and for 120 min after drug administration. Hydromorphone decreased pupil diameter and respiration, increased blood pressure and increased scores on subjective measures indicating opioid-like effects. Buprenorphine given alone had no significant effect on any variable measured. Naloxone given alone produced opioid abstinence-like effects which were measurable on subject- and observer-rated behavioral measures and physiological measures. Buprenorphine in combination with naloxone somewhat attenuated the naloxone-precipitated withdrawal response. Overall, the naloxone-buprenorphine combinations produced effects which were qualitatively similar to the effects of naloxone alone, suggesting a low potential for abuse of the combination product by opioid-dependent individuals.Supported by a grant from Reckitt and Colman Pharmaceutical Division and USPHS Grants DA-00050 and DA-04089 from the National Institute on Drug Abuse     

Cadmium in milk and mammary gland in rats and mice

The purpose of the present investigation was to study the uptake of cadmium in mammary tissue, effects on milk secretion and composition, and lactational transport of cadmium to the sucklings. Cadmium exposure during lactation resulted in retention of cadmium in the mammary tissue in mice and rats. The uptake of cadmium in the mammary tissue was rapid, as shown in lactating mice by whole-body autoradiography 4 h after an intravenous injection of a tracer dose of (109)CdCl(2). Retention of cadmium in kidneys of suckling pups was observed in the autoradiograms at 7 days after exposure of the dams. Lactating rats were intravenously infused with (109)CdCl(2) in 0.9% saline via osmotic minipumps from day 3 to day 16 after parturition. The cadmium dose given was 0, 8.8, 62 and 300 microg Cd/kg body wt. per day. Plasma and milk were collected at day 10 and 16 after parturition. Plasma cadmium levels in dams increased from day 10 to day 16. Cadmium levels were higher in milk than in plasma, with milk/plasma ratios varying from 2 to 6. Zinc levels in milk were positively correlated to cadmium levels in milk (r(2)=0.26; P=0. 03). In milk, (109)Cd was distributed in fat (46-52%), casein fraction (40-46%), and whey fraction (6-8%). There was a high correlation between cadmium concentrations in pups' kidney and cadmium concentrations in dam's milk (r(2)=0.98; P < 0.001). Of the cadmium dose given to the dams <0.05% was retained in the litters on day 16 of lactation. No effects were observed due to cadmium exposure on body weight in pups or dams. Cadmium treatment did not cause any effect on the lactose or protein concentration in milk, the concentrations of DNA, RNA or the ratio RNA/DNA in the mammary gland. Histological evaluation of mammary tissue did not reveal any abnormalities at any dose level. (109)Cd was bound to metallothionein in mammary tissue. The fraction of radiolabelled cadmium bound to metallothionein increased in a dose-dependent manner in both the liver (88-98%) and mammary tissue (57-80%). The present results indicate a low transfer of cadmium to the suckling pup, which might be due to binding of cadmium to metallothionein in the mammary tissue. However, during the susceptible developmental period even a low cadmium exposure may be of concern.     

Circulating nucleic acids in plasma and serum: roles in diagnosis and prognosis in diabetes and cancer

The presence of DNA and RNA circulating in human plasma and serum is described. The possible sources of the DNA/RNA in blood, their ability to enter other cells and to express in the recipient cells are discussed and the relationship with metastases considered. The possible role(s) of the DNA/RNA in clinical diagnosis, in monitoring treatment and in prognosis are considered for diabetes and oncology.