复方甲地孕酮注射液、醋酸甲地孕酮和雌二醇的生殖毒理研究

本文用新西兰兔和Sprague Dawley大鼠检测了复方甲地孕酮、醋酸甲地孕酮和雌二醇的胚胎毒性和致畸作用。结果表明,复方甲地孕酮低剂量组和高剂量组(即5倍、20倍临床剂量)以及雌二醇低剂量组的兔和大鼠死胎率均为100%,与对照组比较有非常显著性差异(P<0.01)。醋酸甲地孕酮低剂量组和高剂量组的死胎率:兔分别为24.55%和21.43%;大鼠则分别为7.02%和3.42%,与对照组比较无显著性差异(P>0.05)。醋酸甲地孕酮低剂量组兔共有胎仔84只,其中6只畸形胎仔(颅骨缺失或迟化及胸骨缺失或迟化);大鼠114只胎仔未发现畸形。高剂量组兔70只胎仔中有15只为畸形,多见腹裂和骨胳畸形;大鼠无明显畸形胎仔。     

人参皂苷Rg1对新生鼠缺氧缺血性脑损伤海马神经元凋亡及学习记忆能力的影响

目的探讨人参皂苷Rg1对新生鼠缺氧缺血性脑损伤(HIBD)海马神经元凋亡及学习记忆能力的影响。方法选择15日龄SD乳鼠60只,随机分为HIBD组、人参皂苷Rg1低剂量组和高剂量组各20只。人参皂苷Rg1高、低剂量组术后每天经腹腔注射人参皂苷Rg1 20、10μg/g,HIBD组注射等量生理盐水,各组大鼠均连续注射25d。采用TUNEL法检测海马CA1区神经元凋亡情况,对各组大鼠进行学习能力、记忆力测试,计算其正确反应率。结果 HIBD组海马CA1区TUNEL阳性细胞数高于注射人参皂苷Rg1高、低剂量组,人参皂苷Rg1低剂量组海马CA1区TUNEL阳性细胞数高于高剂量组,差异有统计学意义(P0.05)。HIBD组测试学习能力和记忆力正确反应率低于注射人参皂苷Rg1高、低剂量组,且人参皂苷Rg1低剂量组学习能力及记忆力测试正确反应率低于高剂量组,差异有统计学意义(P0.05)。结论人参皂苷Rg1能减少新生鼠HIBD海马神经元凋亡,有效地改善HIBD新生鼠的学习能力和记忆力。     

低剂量米非司酮应用于子宫肌瘤的效果及对血清激素水平的影响分析

目的探究低剂量米非司酮治疗子宫肌瘤的效果及对血清激素水平的影响。方法将2018年8月~2019年8月期间收治的子宫肌瘤患者42例,按照随机数字表法分成高剂量组和低剂量组,各21例。高剂量组采用高剂量米非司酮治疗,低剂量组采用低剂量米非司酮治疗。治疗8个月后,比较两组间疗效差异及对血清激素水平。结果子宫和子宫肌瘤在低剂量组米非司酮治疗下低于高剂量组,低剂量组治疗后差异有统计学意义(P<0.05);低剂量组治疗后血清孕激素(P)、雌二醇(E_2)、黄体生成素(LH)、卵泡刺激素(FSH)、黄体生成素(LH)水平低于高剂量组,差异有统计学意义(P<0.05)。结论小剂量米非司酮治疗子宫肌瘤的效果显著,可有效缩小子宫肌瘤体积,改善血清激素水平。     

心炎宁颗粒剂对病毒性心肌炎小鼠模型心肌细胞凋亡基因Bcl-2表达的影响

目的观察心炎宁颗粒剂对病毒性心肌炎小鼠心肌细胞保护作用及相关基因Bcl-2表达的影响。方法采用腹腔注射柯萨奇B3病毒诱导BALB/c小鼠心肌炎模型,将心肌炎小鼠随机分为模型组、高剂量组、中剂量组、低剂量组各25只,另设正常组小鼠25只。在病毒感染后第3、5、7、14天动态观察不同剂量的心炎宁颗粒剂对心肌细胞保护作用和对相关调控基因Bcl-2表达的影响。结果各剂量组较模型组心肌细胞病理损伤均减轻,其中高剂量组与模型组的病理积分差异有统计学意义(P0.05);与模型组相比,高、中、低剂量组的Bcl-2表达均上调,其中高剂量组上调明显差异有统计学意义(P0.05)。结论心炎宁颗粒剂对感染柯萨奇病毒的小鼠心肌细胞有保护作用。     

清燥救肺汤抗肺炎支原体感染大鼠作用的实验研究

目的观察清燥救肺汤对肺炎支原体(MP)感染大鼠肺组织病理炎症及肺泡灌洗液(BALF)MP含量的影响,探讨清燥救肺汤的作用机制。方法 90只大鼠随机分正常组、模型组、清燥救肺汤高、中、低剂量组及罗红霉素组,每组各15只。后5组大鼠接种MP,制成大鼠MP感染模型;各组分别给予同容积药物或生理盐水灌胃。感染后第7、10、14天取材,对肺组织炎症程度进行评分,同时检测大鼠BALF中MP阳性率和MP-DNA的含量。结果造模第7天后,模型组肺组织病理改变、BALF中MP的阳性率和MP-DNA含量测定明显高于正常组,说明造模成功;在改善肺部炎症方面,清燥救肺汤高剂量组与罗红霉素组疗效显著,清燥救肺汤中剂量组在造模第10、14天表现较好的疗效,清燥救肺汤低剂量组则作用不明显;在降低BALF中MP-DNA方面,清燥救肺汤高剂量组与罗红霉素组均疗效显著,清燥救肺汤中剂量组在MP感染后第7天作用不明显,而在第10、14天也具有一定作用,且第7天与第14天比较有一定差异;清燥救肺汤低剂量组作用不明显。结论清燥救肺汤具有抗MP作用,可能存在一定的量效关系和时效关系。     

补肾调经方、逍遥丸对小鼠卵母细胞GDF-9表达的比较研究

目的:观察补肾法、疏肝法对小鼠卵母细胞生长分化因子-9(growth differerntiation factor-9,GDF-9)蛋白及mRMA表达的影响。方法:将300只小鼠随机分为6组:补肾高、低剂量组;疏肝高、低剂量组;控制性超促排卵(COH)组和空白对照组,每组50只,应用Western blotting和Real-time PCR方法分别测定卵母细胞中GDF-9蛋白和mRNA的表达,并对比各组小鼠卵母细胞数量及优质卵泡率。结果:各治疗组卵母细胞中GDF-9蛋白及mRNA表达显著高于空白对照组及COH组,其中高剂量组优于低剂量组(P0.05),COH组的GDF-9蛋白及mRNA表达较空白对照组降低(P0.05);各治疗组及COH组卵母细胞数量高于空白对照组(P0.05),治疗组中高剂量组卵母细胞数量高于低剂量组(P0.05);各治疗组及空白对照组优质卵泡率优于COH组(P0.05),治疗组中高剂量组的优质卵泡率优于空白对照组(P0.05)。结论:补肾调经方、逍遥丸在促性腺激素应用的基础上能增加卵母细胞数量及优质卵泡率,其机制可能与调控卵母细胞中GDF-9的蛋白及mRNA表达有关。     

GnRHa低剂量长方案治疗对卵巢型子宫内膜异位症患者术后妊娠的影响CSCD

目的探讨促性腺激素释放激素(GnRHa)低剂量长方案治疗对卵巢型子宫内膜异位症(OEM)患者术后妊娠的影响。方法选取广东省惠州市中心人民医院2015年5月至2020年5月收治的180例OEM患者为研究对象,根据术后GnRHa长方案不同剂量分为低剂量组(n=60,0.40 mg)、中剂量组(n=60,0.80 mg)、高剂量组(n=60,1.0 mg),对比三组体外受精-胚胎移植(IVF-ET)情况。结果高剂量组人绒毛膜促性腺激素(hCG)日促黄体生成素(LH)高于低剂量组与中剂量组(P<0.05),低剂量组hCG日孕酮(P)低于中剂量组与高剂量组(P<0.05);低剂量组可用胚胎率高于中剂量组与高剂量组(P<0.05),中剂量组可用胚胎率高于高剂量组(P<0.05);低剂量组低反应、高反应发生率低于中、高剂量组(P<0.05)。结论GnRHa低剂量长方案可保证OEM患者术后IVF-ET更高的妊娠率,且安全保障性良好。     

氯化镉对大鼠附睾结构及精子的影响

目的:探讨氯化镉(CdCl2)对大鼠附睾组织学和附睾精子参数的影响。方法:20只雄性SD大鼠随机均分为对照组与3个实验组,每组5只动物。实验组分别腹腔注射CdCl2 0.2mg/kg(低剂量组),0.4mg/kg(中剂量组)和0.8mg/kg(高剂量组)×14d,对照组注射等量生理盐水。观察附睾上皮的组织学改变和附睾精子参数变化。结果:低剂量组的附睾上皮未见明显组织学病理改变。随着Cd2+剂量增加,实验组附睾主细胞的胞质疏松明显,胞内空泡化程度加大,核染色质边聚,静纤毛缩短,附睾管腔内的精子明显减少,多见降解的生精细胞。3个剂量组的精子存活率、精子活动率、精子浓度和正常形态精子率均显著低于对照组(P<0.01)。结论:CdCl2染毒可导致大鼠附睾组织学损伤性改变,附睾精子参数显著降低,且损伤呈剂量效应。     

褪黑素抑制氧化应激和铁死亡缓解妊娠糖尿病大鼠病理损伤

目的:探讨褪黑素对妊娠糖尿病(GDM)大鼠的治疗作用及可能作用机制.方法:将24只雌性大鼠分成4组:正常妊娠组、GDM模型组、低剂量褪黑素[5 mg/(kg·d)]治疗组及高剂量褪黑素[10mg/(kg·d)]治疗组,每组6只.不同剂量褪黑素治疗14天后,检测大鼠胰腺组织形态病理变化及细胞凋亡水平,检测血清生化指标、细...     

不同剂量硒染毒对孕鼠胎盘的作用

目的:研究不同剂量的硒对孕鼠胎盘功能和形态的影响。方法:随机将SD大鼠分为4组,自受孕1~20天,实验组(低剂量硒组-A组,中剂量硒组-B组,高剂量硒组-C组)孕鼠分别自由饮用含2、4、8μg/ml亚硒酸钠的双蒸水,对照组自由饮用双蒸水。孕20天时取材,应用亚硝酸盐缓冲液法和免疫组化法分别测定血清碱性磷酸酶水平,并在光镜和电镜下观察胎盘超微结构。结果:低剂量硒组碱性磷酸酶水平较对照组无明显改变(P>0.05),此组镜下超微结构与对照组相比无明显改变。高剂量硒组碱性磷酸酶水平较对照组明显下降(P<0.05),此组镜下超微结构出现明显的毒性改变。结论:高剂量硒会引起胎盘明显的毒性损伤,孕期微量元素硒的补充应谨慎。     

新型长效避孕器——硅橡胶缓释避孕环的研究

用合成硅橡胶材料制成的新型缓释避孕环,内含甲地孕酮200毫克,其外径为40毫米。经体外测试,药物的释放量每天约100微克左右。本环临床试用2470例,共16124妇女月经周期。由于药物能持续、缓慢释放,连续使用一年,仍保持避孕效果。现已有522例连续使用一年以上,受孕率为2.15%(按妇女年计算)。由于部分妇女阴道肌肉松弛,环易脱落,脱落率为2.15%。使用甲地孕酮硅橡胶避孕环一年以上的妇女,经医师检查未发现阴道粘膜刺激及红肿现象。主要副反应为突破性出血,突血率近7%。月经不正常情况主要发生在最初三个月,以后逐步好转。经临床及实验室研究,本环的作用不抑制排卵,而对宫颈粘液有较明显的改变,不利于精子穿透;子宫内膜虽仍属分泌期,但发育较差,不利于孕卵着床;对下丘脑—垂体—卵巢轴影响较小,且又具有较好的避孕效果。     

Contraception by means of a silastic vaginal ring impregnated with medroxyprogesterone acetate

Cylindrical rings, made of silicone rubber impregnated with medroxyprogesterone acetate were placed in the vaginas of 3 regularly menstruating women on the first cycle day. Silastic rings without medication were used in 3 controls. During the 28 days that the rings were in place, there was continuous systemic absorption of the progestogen as evidenced by elevation of the basal body temperature, shift in maturation index, abolition of the midcycle LH peak, and change in the endometrial histology. In the 3 controls, no significant alterations occurred in any of the parameters measured (BBT, vaginal cytology, endometrial biopsies and gonadotrophins) as compared with the cycles before and after insertion of the ring. After removal of the rings in the test group, the advent of withdrawal bleeding and a fall in the basal body temperature indicated a prompt termination of drug activity. Presumptive evidence of ovulation followed shortly thereafter. It is hoped that this method of administering a progestogen may be developed for family planning.     

Low dosage megestrol acetate application as contraceptive

A review of the development of low dose progesterone is presented. Continuous low-dose megestrol acetate therapy data from 43 patients is presented. When short cycle lengths, breakthrough bleeding, and amenorrhea occurred, a lower dose of megestrol acetate was substitute. 78% of the cycles varied between 21 and 38 days a breakthrough bleeding occurred in 19.6% cycles, and average flow was 5.2 days. There were no breakthrough pregnancies in this group. A majority of the cycles with megestrol acetate were ovulatory, but the cervical mucus was hostile and vaginal smears showed a definite progestational effect.     

Ovulation inhibition with sequential therapy. A continuing clinical study of fertility control

A study on sequential ovulation inhibiting pill, 5048-1Z(Oracon), with the following preparation --16 white tablets, each containing .1 mg ethinyl estradiol and 5 colored tablets each with the same does of ethinyl estradiol plus 25 mg dimethisterone--is presented. Another group of patients received a more potent and newer orally effective progestin, megestrol acetate, the tablets being the same except instead of 25 mg dimethisterone in the last 5 tablets there were 5 mg of megestrol acetate. A third group received the megestrol acetate formulation but the dose was reduced to 2.5 mg and then to 2 mg megestrol acetate. The sequential regimen more closely resembles the physiologic hormonal pattern. The Oracon preparation with 25 mg dimethisterone was effective in fertility control. The formulation with megestrol acetate in both dose forms was found to be effective for the inhibition of ovulation and control of conception. Breakthrough bleeding and missed menstrual periods were uncommon with the sequential regimen.     

甲地孕酮阴道避孕药环体外释放量测试研究

本文研究了甲地孕酮避孕药环体外释放,以带磨口的广口瓶作释放池,内放一定体积的1:750氯化[烃基二甲基代苯甲]铵水溶液作为释放介质。甲地孕酮硅橡胶环浸在介质中,在37℃恒温条件下,以一定的频率和振幅振荡,每隔24小时调换介质溶液。用紫外分光光度法,在波长290nm 处测定释放液中甲地孕酮的含量。实验结果表明,甲地孕酮经最初七天的快速释放后,达到稳态释放。     

Effect of contraceptive steroids on serum lipids.

Serum triglycerides, free fatty acids, phospholipids, and cholesterol were estimated in groups of women who were taking either norgestrel, megestrol acetate, daily combination tablet, once-a-month pill, or once-a-month injection as a method of contraception. These estimations were done prior to and during therapy at specific times over a period of 2 years. A significant reduction in serum lipids was observed in women taking norgestrel. The women on megestrol acetate showed practically no changes. All the lipid fractions were significantly elevated in women taking combination pills. Raised serum cholesterol was observed in women receiving once-a-month injection.     

黄体酮阴道环在家兔的药代动力学研究

目的:提供研制可供哺乳期妇女避孕的黄体酮阴道环的药理学依据。方法:将18只去卵巢后2周的新西兰雌兔随机分为3组:阴道环低剂量组(175mg,A组)、高剂量组(350mg,B组)及肌注组(C组),分别在放置阴道环及肌注黄体酮前后不同时点取静脉血,用磁性分离酶联免疫法测定兔血清中黄体酮的浓度,用PK-Graph程序计算药代动力学参数。结果:黄体酮阴道环和黄体酮注射剂在兔体内的药代动力学符合二室开放模型。主要药代动力学参数分别是A组:Tmax:2.23±1.3h,Cmax:47.64±23.58ng/ml,T1/2:818.08±511.77h,AUC:16115.11±8398.88ng·ml·h-1;B组:Tmax:2.03±1.33h,Cmax:74.04±24.57ng/ml,T1/2:730.31±306.49h,AUC:28751.95±7151.95ml·h-1;C组:Tmax:1.54±0.77h,Cmax:138.88±60.96ng/ml,T1/2:2.55±0.89h。其中A组的AUC(56d)明显低于B组,二者有显著性差异(P<0.05);A组和B组的Cmax均低于C组,差异显著(P<0.05);A组和B组的T1/2均明显高于C组(P<0.01),但A、B组间无差异。结论:与传统的黄体酮注射剂相比,黄体酮阴道环的药代动力学参数呈现明显的长效缓释特征。应可成为安全长效且使用方便的哺乳期避孕药具。     

醋炔诺酮肟避孕片对子宫内膜组织学和阴道细胞学的影响

本文报告了38例服醋炔诺酮肟避孕片(其中26例服探亲片、12例服事后片)和3例不服药的健康妇女的子宫内膜活检结果及11名服酮肟探亲片妇女12个周期的阴道细胞学观察结果。所有服药妇女的子宫内膜发育均受不同程度抑制,对在周期早期开始服药者内膜的抑制作用较后期服药者明显。表明药物干扰了内膜的发育和分泌,这可能是该药避孕作用的主要机理。阴道细胞学检查表明,服药后阴道细胞因保持较低的雌激素影响而缺乏正常的周期变化,提示在周期的早期开始服药可能抑制排卵。     

Low-dose follicular-phase cocaine administration disrupts menstrual and ovarian cyclicity in rhesus monkeys

OBJECTIVE: To evaluate the effects of daily low-dose follicular-phase cocaine administration on menstrual cyclicity, ovulation rates, corpus luteum function, and hormone levels in rhesus monkeys. METHOD: Normally cycling, drug-naive, adult rhesus monkeys were randomized to receive either 1 mg/kg of cocaine (n = 7), 2 mg/kg of cocaine (n = 7), or normal saline (n = 7) daily on cycle days 2 to 14. Daily blood samples were obtained through indwelling catheters for measurement of serum gonadotropins and ovarian steroids. Daily vaginal swabs were obtained to determine onset of menses. Laparoscopy was performed 2 days after the midcycle estrogen peak to document ovulation. Daily caloric intakes as well as pretreatment and posttreatment weights were recorded. RESULTS: Two of seven monkeys receiving 1 mg/kg per day and two of seven monkeys receiving 2 mg/kg per day of cocaine had timely ovulation and normal menstrual cycle lengths. One monkey receiving the 2-mg/kg dose ovulated on cycle day 24 and had a short luteal phase (7 days) with a mean progesterone level of 2.4 ng/mL. All seven saline-treated control monkeys ovulated normally; the mean cycle length was 29 days and all had adequate luteal phases. The difference in ovulation rates between cocaine-treated and control monkeys was statistically significant (P = .003). There were no differences in basal levels of LH or FSH between treatment groups. There were no significant differences in weight change or caloric intake among groups. One third of the subsequent menstrual cycles in cocaine-treated monkeys were of abnormal duration. CONCLUSION: Daily low-dose follicular-phase cocaine administration disrupts menstrual cyclicity and folliculogenesis. This effect is independent of weight loss, caloric intake, and basal gonadotropin levels. Cocaine exposure may have a persistent effect on menstrual and ovarian cyclicity in some monkeys.     

Hemostatic effects of high-dose megestrol acetate therapy in patients with advanced gynecological cancer.

Effects of high-dose megestrol acetate on blood coagulation and fibrinolysis were investigated in patients with gynecological (n = 13) and breast (n = 10) cancer. Patients received either 160 mg or 320 mg/day megestrol acetate orally. Blood sampling was performed prior to and after months 1, 3 and 6 of treatment. Pretreatment values of global clotting times, fibrinogen, factor VII, thrombin-antithrombin III complex, anticoagulation, fibrinolysis and antifibrinolysis were found to be within the reference range. Elevated plasma levels were demonstrated for prothrombin fragments 1 and 2, fibrin degradation products and the plasmin-antiplasmin complex. We demonstrated a significant 20-30% reduction of factor VII until the 3rd month of therapy. No further effects were seen within the remaining 3 months of treatment. For the other analyzed parameters of hemostasis, no significant influence of high-dose progestin treatment was found. Furthermore, we observed no clinically relevant differences between the two dosages. Our results do not provide any evidence that there is a thrombogenic effect of high-dosage megestrol acetate with 160 mg or 320 mg per day amongst patients with advanced gynecological malignancies. The observed incidence of thrombosis might be the consequence of other risk factors such as tumor-induced hypercoagulability, simultaneous chemotherapy or other individual thrombosis risk factors.