匹多莫德的临床应用

匹多莫德为广谱免疫促进剂,可增强机体免疫反应,用于治疗细菌感染及病毒性感染,也可用于急慢性感染和反复发作性感染的控制,匹多莫德不良反应少,安全性好,在临床应用广泛.     

匹多莫德的合成

L-半胱氨酸盐酸盐与甲醛反应生成L-4-噻唑烷羧酸(4).另用L-焦谷氨酸与氯化亚砜反应制得L-焦谷氨酰氯(5).4和5在三乙胺作缚酸剂的条件下反应制得免疫调节剂匹多莫德,总收率约55%(以三L-半胱氨酸盐酸盐计).     

匹多莫德的合成工艺改进

目的:改进匹多莫德的合成工艺。方法:在文献方法的基础上设计出新的方法,即取L-半胱氨酸与甲醛反应生成L-4-噻唑烷甲酸,然后与L-焦谷氨酸在强酸性阳离子交换树脂的催化作用下反应得到目标化合物,并经质谱和核磁共振氢谱确证其化学结构。结果:目标化合物经确证为匹多莫德,其产率达到55.48%,含量大于98.5%。与文献方法比较,新方法路线反应步骤少,反应条件较温和,原料易得,产物结晶性好。结论:改进方法为匹多莫德的工业化生产提供了一条新型的、较为合理的工艺路线。     

新型免疫调节剂匹多莫德

匹多莫德(pidotimod)是一种新型的可刺激机体免疫活性的生物反应调节剂.临床试验显示有良好的治疗和预防感染的作用;可提高受抑制的或老龄化免疫系统的活性;不良反应低,安全性和耐受性好.     

新型合成免疫调节剂--匹多莫德

匹多莫德(pidotimod)是一种新型的化学合成免疫调节剂，可以促进机体的特异和非特异免疫反应。主要用于小儿反复呼吸道和泌尿系统感染、慢性支气管炎急性发作及肿瘤患者伴发感染的治疗和预防。与传统的免疫调节剂相比，匹多莫德具有安全、使用方便和耐受性好的优点。现对匹多莫德的免疫调节作用、药动学、临床应用、安全性及用法用量等作一概述。     

免疫促进剂匹多莫德的合成

目的：合成免疫促进剂（Ｒ）－３－［（Ｓ）－（５－氧－吡咯烷基）羰基］－噻唑烷基－４－甲酸（匹多莫德）。方法：以Ｌ－半胱氨酸及Ｌ－焦谷氨酸为起始原料,经成环、酯化及缩合３步反应,合成该化合物。结果：合成产物经元素分析、红外光谱、核磁共振谱、质谱等确证,ＨＰＬＣ法测定其纯度在９９％以上,结论：此合成路线是完全可行的。     

匹多莫德颗粒剂的生物等效性研究

目的 :研究匹多莫德颗粒剂和片剂的生物等效性。方法 :18例健康男性志愿者 ,随机分为两个序列 ,交叉单剂量口服 80 0mg匹多莫德颗粒剂和片剂 ,给药前及给药后不同时间定时采取血样 ;以HPLC UV法测定血浆样本中匹多莫德的浓度 ,并对两种制剂进行生物等效性评价。结果 :口服匹多莫德颗粒剂或片剂 80 0mg后 ,匹多莫德的Cmax分别为 (4 .37± 1.6 6 )和 (4 .83± 1.5 5 ) μg·mL-1,Tmax分别为 (2 .4 2± 1.0 9)和 (2 .6 1± 1.0 9)h ,AUC0～∞分别为 (2 1.17± 8.4 3)和 (2 1.89± 9.0 2 ) μg·h·mL-1;t1/ 2 分别为 (2 .2 1± 0 .4 6 )和 (2 .2 3± 0 .36 )h。结论 :匹多莫德颗粒剂和片剂生物等效。     

匹多莫德治疗儿童支气管哮喘41例疗效观察

目的 观察匹多莫德治疗儿童支气管哮喘的临床疗效.方法 将支气管哮喘患儿82例随机分为观察组和对照组,各41例.对照组应用2006年GINA方案中的常规治疗方案;观察组在对照组的基础上给予匹多莫德400mg口服,每天1次,连用60d.治疗后比较2组临床疗效及不良反应.结果 观察组总有效率为95.1%显著高于对照组的75.6%,差异有统计学意义(P<0.05);观察组出现不良反应3例,均未影响治疗.结论 匹多莫德能够显著改善支气管哮喘患儿临床症状和体征,提高患儿免疫功能,具有良好的辅助治疗效果,值得临床推广应用.     

匹多莫德治疗儿童支气管哮喘41例疗效观察

目的观察匹多莫德治疗儿童支气管哮喘的临床疗效。方法将支气管哮喘患儿82例随机分为观察组和对照组,各41例。对照组应用2006年GINA方案中的常规治疗方案;观察组在对照组的基础上给予匹多莫德400mg口服,每天1次,连用60d。治疗后比较2组临床疗效及不良反应。结果观察组总有效率为95.1%显著高于对照组的75.6%,差异有统计学意义（P〈0.05）;观察组出现不良反应3例,均未影响治疗。结论匹多莫德能够显著改善支气管哮喘患儿临床症状和体征,提高患儿免疫功能,具有良好的辅助治疗效果,值得临床推广应用。     

匹多莫德佐治小儿手足口病疗效观察

本院2008年6月至2009年9月,应用匹多莫德佐治103例手足口病患儿取得较好疗效。报告如下。1资料与方法1.1一般资料收集2008年6月至2009年9月本院入院时有发热且无并发症的手足口病住院患儿210例为研究对象,均符合卫生部制定的《肠道病毒（EV71）感染诊疗指南（2008年版）》[1]中的临床诊断标准。     

One-generation reproductive toxicity study of 2-methylbutane in Sprague-Dawley rats

This study investigated the potential reproductive toxicity of 2-methylbutane in a one-generation reproductive toxicity study using Sprague-Dawley rats. A total of 24 male and female rats per group were given 2-methylbutane by gavage at 0, 100, 300, and 1000 mg/kg/day. Males were dosed for 10 weeks prior to mating and during mating. Females were dosed from 2 weeks before mating to day 21 of lactation. At 1000 mg/kg/day, both genders exhibited an increase in adrenal gland weight, however, a decrease in body weight gain and food intake, an increase in kidney weight, and an increased incidence of histopathological changes of the kidney were also observed in male rats. No treatment-related effects of 2-methylbutane were found in relation to the reproductive capacity of parental animals or the pre- and post-natal development of the F1 generation. There were no treatment-related effects in either gender at ≤ 300 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level of 2-methylbutane was 300 mg/kg/day for general toxicity and 1000 mg/kg/day for reproductive capacity and pup development in rats.     

龙葵素的生殖毒性研究进展

龙葵素广泛存在于马铃薯、番茄及茄子等茄科植物中。因其具有抗肿瘤和潜在的毒性作用而引起广泛关注。本文主要介绍了龙葵素在生殖毒性方面的研究进展。     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat. I. Reproductive toxicity

The reproductive toxicity of toluene was evaluated in a 2-generation test in which male and female Sprague–Dawley rats, parental (F0) and first generation (F1), were exposed to toluene via whole body inhalation, 6 h/day, 7 days/week for 80 days premating and 15 days of mating at concentrations of 0, 100, 500 and 2000 ppm (0, 375, 1875 and 7500 mg/m³). Toluene was administered at 2000 ppm to both sexes, or to females or males only to be mated with untreated partners. Pregnant females at all dose levels were exposed from gestation day (GD) 1–20 and lactation day (LD) 5–21. At LD5, females were removed from their litters for daily exposure and returned when 6 h of exposure was completed. F1 pups selected to produce the F2 generation were treated for 80 days beginning immediately after weaning (LD21) and initially mated at a minimum of 100 days of age. F2 pups were not exposed to toluene by inhalation.

Toluene exposure did not induce adverse effects on fertility, reproductive performance, or maternal/pup behaviors during the lactation period in males and females of the parental or first generation, but did inhibit growth in F1 and F2 offspring in the 2000 ppm (both sexes treated) and 2000 ppm (females only treated) groups. Caesarean section of selected 2000 ppm (both sexes treated) dams at GD20 showed reduced fetal body weight and skeletal variations. Exposure to toluene caused decreased pup weights throughout lactation in F1 and F2 2000 ppm (both sexes treated), and 2000 ppm (females only treated) groups. Exposure at 2000 ppm to male parents only did not induce similar weight inhibition in offspring. The toluene offspring NOAEL is 500 ppm in groups in which maternal animals were exposed, and 2000 ppm for male only treated groups.     

An evaluation of the male reproductive toxicity of cathinone

(−)-Cathinone is the major psychoactive component of khat plant (Catha edulis Forssk.). Khat has been shown to produce reproductive toxicity in human beings and experimental animals. However, the chemical constituents of khat leaves responsible for sexual dysfunction are not known. In the present study cathinone enantiomers have been investigated for their reproductive toxicity in rats. Cathinone produced a dose-dependent decrease in food consumption and suppressed the gain in body weight. There was a significant decrease in sperm count and motility and increase in the number of abnormal sperms in cathinone treated animals. Histopathological examination of testes revealed degeneration of interstitial tissue, cellular infiltration and atrophy of Sertoli and Leydig's cells in cathinone treated animals. Cathinone also produced a significant decrease in plasma testosterone levels of the rats. Although both enantiomers of cathinone produced deleterious effects on male reproductive system, (−)-cathinone was found to be more toxic. From this study it may be concluded that the cathinone content in khat may be partially or totally responsible for the reproductive toxicity in khat chewers.     

依替米星一般生殖毒性研究

依替米星 10 0、2 0 0和 40 0 mg/(kg· d) ,sc给于 SD雄、雌性大鼠分别连续 9周和 2周后合笼 ,雄鼠给药至 11周 ,雌鼠给药至妊娠第 15天。实验结果表明 ,40 0 mg/(kg·d)对雄鼠、雌鼠及胎仔均有毒性 ,表现为雄鼠从给药第 4周起体重增长受到抑制 (给药 4、5、周 P<0 .0 5 ,P<0 .0 1) ,雌鼠交配前和交配后体重增长也受到抑制 (交配前给药第 11、14天 ,P<0 .0 5 ,P<0 .0 1,交配后怀孕第 7、11～ 15天 ,P<0 .0 5 ) ,且孕鼠的黄体数减少 (P<0 .0 1) ,胎仔骨骼检查见胸骨节第一中心及耻骨未骨化 ,剑突和指 ,趾骨化点减少。 2 0 mg/(kg·d)对雄、雌大鼠的体重、交配率、妊娠率 ,孕鼠的黄体数 ,着床数 ,活胎、死胎数及胎仔体重、外形、内脏组织 ,骨骼均无影响。因此依替米星是不具有一般生殖毒性的药物。     

Food and drug administration guidelines for reproductive toxicity testing

The Food and Drug Administration generally requires reproductive toxicity testing of all new drugs to be used by pregnant women or women or men of reproductive potential. These requirements may vary among the centers within the FDA. Reproductive and developmental toxicity is usually tested in one or two animal species and is divided into three segments to represent treatment throughout the reproductive process. The FDA monitors adverse drug effects on human reproduction through postmarketing surveillance.     

附子提取物的大鼠生殖毒性研究

目的：探讨附子提取物对雌性大鼠生殖毒性的影响。方法附子提取物给大鼠连续灌胃30 d,考察脏器指数、动情期观察、生殖激素含量变化。结果附子提取物造成雌性大鼠动情周期紊乱,脏器指数明显下降,性激素：卵泡刺激素（FSH）、黄体生成素（LH）、雌二醇（E2）、孕酮（P）含量较阴性对照组均显著下降。结论附子提取物的生殖毒性作用可能与FSH、LH、E2、P含量下降有关,提示提高性激素水平,可有助于降低附子提取物的生殖毒性。     

Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid

The industrial chemical melamine was used in 2007 and 2008 to raise the apparent protein content in pet feed and watered down milk, respectively. Because humans may be exposed to melamine via several different routes into the human diet as well as deliberate contamination, this study was designed to characterize the effect of high dose melamine or cyanuric acid oral exposure on the pregnant animal and developing fetus, including placental transfer. Clear rectangular crystals formed following a single triazine exposure which is a different morphology from the golden spherulites caused by combined exposure or the calculi formed when melamine combines with endogenous uric acid. Crystal nephropathy, regardless of cause, induces renal failure which in turn has reproductive sequelae. Specifically, melamine alone-treated dams had increased numbers of early and late fetal deaths compared to controls or cyanuric acid-treated dams. As melamine was found in the amniotic fluid, this study confirms transfer of melamine from mammalian mother to fetus and our study provides evidence that cyanuric acid also appears in the amniotic fluid if mothers are exposed to high doses.     

Developmental toxicity of copaiba tree (Copaifera reticulata Ducke, Fabaceae) oleoresin in rat

The oleoresin of the copaiba tree (Copaifera sp., Fabaceae) is traditionally used in Brazilian herbal medicine to treat a variety of illnesses and symptoms. This study, conducted according to the OECD Guideline 414, provides data on the developmental toxicity of oleoresin from C. reticulata (COPA-R) in rats. Pregnant Wistar rats (25 per dose group) were treated by gavage with COPA-R (0, 500, 1000 and 1250 mg/kg bw/day) on gestation days (GD) 6-19 and Caesarean sections performed on GD20. Implantations, living and dead fetuses and resorptions were recorded. Half of the fetuses from each litter were examined for visceral abnormalities and the remaining were cleared and stained for skeleton evaluation. COPA-R was maternally toxic (reduced food intake and weight gain) and embryotoxic (lower fetal body weight and increased occurrence of fetal skeleton variations) at the two highest doses, but did not cause embryo deaths or fetal malformations at any dose level. The study derived an oral no-observed-adverse-effect-level (NOAEL) for maternal and developmental toxicity induced by COPA-R of 500 mg/kg bw/day. The results suggest that copaiba oleoresin does not pose a health risk to pregnant women when used according to the recommended doses (up to five drops, three times a day).     

Association of methamidophos and sleep loss on reproductive toxicity of male mice

This study investigated the effects of organophosphate exposure on the male reproductive system of mice submitted to chronic sleep loss condition. Adult Swiss mice were distributed into 4 groups: control; methamidophos (MTP); sleep restriction (SR); and MTP + SR. The dose of methamidophos was 0.002 mg kg⁻¹ day⁻¹ (half of the Acceptable Daily Intake). Sleep restriction condition was 21 h day⁻¹ during 15 days. In relation to control group, MTP treatment induced a significant reduction of 12% on morphologically normal spermatozoa in both MTP and MTP + SR groups. In addition, the absolute and relative weights of the seminal vesicles were decreased (MTP, −34%; MTP + SR, −45%). Epididymal fat was reduced in SR groups (SR, −64%; MTP + SR, −58%). Plasma testosterone levels were significantly decreased in MTP and SR groups, and progesterone levels were increased 8 times in MTP + SR in comparison with the control group. The corticosterone levels were unaffected by MTP or SR conditions. Thus, low dose MTP exposure resulted in deleterious effects on the male reproductive system. Sleep loss associated with MTP potentiated the effect on steroidogenesis, mainly in terms of progesterone levels.