纳米羟基磷灰石急性毒性试验研究

对纳米羟幕磷灰石(nano-HAP)进行急性毒性试验研究,为长期毒性试验和其他毒理学试验提供参考依据,并初步了解nano-HAP进入血液循环系统后,是否会迁移到其它器官和组织.实验选用清洁级的110～130g Wistar大鼠70只,分为7组,实验组各组剂量分别为21.66mg/kg、29.97 mg/kg、41.49 mg/kg、57.42 mg/kg、79.48 mg/kg、110.39 mg/kg,以生理盐水为对照组.单次尾静脉注射,14d内观察动物的毒性症状,记录动物死亡情况.将死亡动物解剖,对动物主要脏器进行病理组织学检查.结果显示nano-HAP在Wistar大鼠身上尾静脉注射时LD50为51.79 mg/kg,由病理结果推测实验动物的死亡原因是由血管栓塞所致.在一只最低剂量组死亡动物肝的汇管区及附近肝内有占位性蓝染无定型物,肝内灶性炎细胞浸润.说明nano-HAP颗粒在充分分散的情况下会通过血液循环进入到身体其它器官,因此有必要对nano-HAP的生物安全性进行进一步研究.     

Steady-state pharmacokinetics of twice-daily dosing of saquinavir plus ritonavir in HIV-1-infected individuals

OBJECTIVE: To compare the steady state plasma pharmacokinetics of 1000 mg of saquinavir (SQV) in a soft-gel capsule (SGC) formulation in combination with 100 mg of ritonavir (RTV) (capsules) in a twice-daily dosing regimen in HIV-1-infected individuals with historical controls who used 400 mg of SQV in a hard-gel capsule (HGC) formulation in combination with 400 mg of RTV and to investigate the plasma pharmacokinetics of the 1000 mg/100 mg regimen after normal and high-fat breakfasts. DESIGN: Open-label, crossover, steady-state pharmacokinetic study. METHODS: Six HIV-1-infected individuals who used either 1200 mg of SQV (SGC or HGC) three times daily or 400 mg twice daily in combination with 400 mg of RTV twice daily were included. Each patient was switched to 1000 mg of SQV SGC twice daily in combination with 100 mg of RTV twice daily. After 14 days, the patients came to the hospital for assessment of a pharmacokinetic profile during 12 hours. Patients were randomized to receive a high-fat (+/-45 g of fat) or normal (+/-20 g of fat) breakfast. After 7 days, a second pharmacokinetic profile was assessed after ingestion of the drugs with the alternate breakfast. A noncompartmental pharmacokinetic method was used to calculate the area under the plasma concentration versus time curve (AUC0-12h), the maximum plasma concentration (Cmax), the plasma trough concentration (C12h), and the elimination half-life in plasma (t1/2). The obtained pharmacokinetic parameters were compared with those of 12 patients using SQV HGC (400 mg twice daily) in combination with RTV (400 mg twice daily). RESULTS: The median values of the pharmacokinetic parameters for SQV SGC (1000 mg twice daily, normal breakfast) were: AUC0-12h, 18.84 h*mg/L; Cmax, 3.66 mg/L; C12h, 0.40 mg/L; and t1/2, 3.0 hours. The median values of the pharmacokinetic parameters for SQV HGC (400 mg twice daily, normal breakfast) were: AUC0-12h, 6.99 h*mg/L; Cmax, 1.28 mg/L; C12h, 0.23 mg/L; and t1/2, 3.9 hours. The exposure to SQV in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily was significantly higher than the exposure to SQV in a dosing regimen of 400 mg twice daily in combination with 400 mg of RTV twice daily. The pharmacokinetic parameters of SQV SGC in the dosing regimen of 1000 mg twice daily in combination with 100 mg of RTV twice daily were not significantly different after ingestion of a high-fat or normal breakfast (p >.35). CONCLUSIONS: The combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily resulted in a higher exposure to SQV compared with the exposure to SQV obtained when SQV is used in the 400 mg/400 mg twice-daily combination with RTV. In this small number of patients, no significant differences in exposure were seen after ingestion of either a normal or high-fat breakfast. From a pharmacokinetic perspective, the combination of 1000 mg of SQV SGC twice daily and 100 mg of RTV twice daily seems to be a good option for further clinical evaluation.     

杂色曲霉素对小鼠脾细胞IL-4 mRNA表达和蛋白分泌的影响

目的：探讨杂色曲霉素（ST）对体外培养的小鼠脾细胞IL-4 mRNA表达及其蛋白分泌的影响。 方法： 分别采用半定量RT-PCR及ELISA方法，研究5种不同剂量ST（0.125 mg/L、0.25 mg/L、0.5 mg/L、1 mg/L、2 mg/L）预处理2 h、12 h对小鼠脾细胞IL-4 mRNA表达及其蛋白分泌的影响，观察ST对IL-4影响的时效及量效关系。 结果： ST预处理2 h，较小剂量ST（0.125、0.25、0.5 mg/L）处理组小鼠脾细胞IL-4 mRNA的表达高于对照组，以0.5 mg/L组表达最高；当ST预处理达到12 h时，较小剂量ST处理组IL-4 mRNA表达均低于对照组，其中以ST 0.125、0.25 mg/L组降低最明显。而大剂量ST（1 mg/L、2 mg/L）处理2 h及12 h对小鼠脾细胞IL-4 mRNA表达均低于对照组。在蛋白水平上的改变与mRNA水平变化相似。 结论： ST对小鼠脾细胞IL-4 mRNA表达的影响与其剂量和作用时间有关，既可表现为抑制作用，也可表现诱导作用。     

Pharmacokinetic studies of amoxicillin,potassium clavulanate and their combination

Pharmacokinetic parameters after oral administration of 500 mg amoxicillin, 125 mg potassium clavulanate and 625 mg of their combination (augmentin) were determined in a randomized crossover study in ten healthy volunteers. The absolute bioavailability of amoxicillin (AUC_oral/AUC_i.v.) was 0.70±0.12. The mean maximum serum concentration of amoxicillin was 6.5±1.6 mg/l after administration alone and 6.5±1.4 mg/l after administration in combination. The respective values for potassium clavulanate were 3.4±1.4 mg/l and 2.8±1.1 mg/l. With both substances there was no significant difference between the pharmacokinetic parameters after administration alone and in combination. The AUC for amoxicillin was 19.5±5.4 h×mg/l after administration alone and 23.2±10.6 h×mg/l after administration in combination. The respective values for potassium clavulanate were 7.8±3.2 h×mg/l and 7.3±2.0 h×mg/l.     

Metabolic and cardiovascular effects of carbuterol and metaproterenol.

Metabolic and cardiovascular responses to selective beta-adrenergic bronchodilators, carbuterol and metaproterenol, were studied during an asymptomatic period in 8 male subjects with bronchial asthma diagnosed as mile to moderate. On separate days each individual received either placebo, carbuterol 2 mg, carbuterol 4 mg, or metaproterenol 20 mg orally in a double-blind fashion. Subsequently, metabolic and cardiovascular responses were measured periodically for 5 hr. Carbuterol 2 mg was indistinguishable from placebo except for small elevations of glucose at 3 and 4 hr. Carbuterol 4 mg produced significant increases in glucose, insulin, lactate, and free fatty acids as well as in pulse rate and arterial pulse pressure. Metaproterenol produced increases only in plasma glucose and insulin. The majority of patients reported drug-related side effects which were all mild, after taking either carbuterol 4 mg or metaproterenol 20 mg. Fewer subjective side effects were noted with carbuterol 2 mg. These findings indicate that a 2-mg dose of carbuterol can be administered to typical asthmatic subjects without significant subjective or objective side effects. The larger dose (4 mg) may be accompanied by a greater frequency of side effects.     

Effect of various doses of palm vitamin E and tocopherol on aspirin-induced gastric lesions in rats

This study examined the effects of vitamin E on the prevention of aspirin-induced gastric lesions. The study was divided into two phases. Phase 1 determined the effects of various doses of palm vitamin E on the factors affecting mucosal integrity. Thirty-two male rats of the Sprague-Dawley strain (200-250 g) were randomly divided into four groups. Group I was fed a normal diet (control), Groups II, III and IV were fed a diet supplemented with palm vitamin E in a dose of 60 mg/kg food, 100 mg/kg food and 150 mg/kg food, respectively. The rats were killed after 4 weeks of feeding for the determination of gastric malondialdehyde (MDA), acid and mucus content. There was a significant decrease in gastric MDA and gastric acid in all the palm vitamin E supplemented groups compared to control. However, these doses of palm vitamin E had no significant effect on gastric mucus. The phase 2 study determined the effect of multiple doses of palm vitamin E and tocopherol on the prevention of aspirin-induced gastric lesions. Fifty rats of the same weight and strain were randomized into seven groups. Group I was fed a normal diet; groups II to IV were fed with a palm vitamin E enriched diet in doses of 60 mg, 100 mg and 150 mg/kg food, respectively; groups V to VII were fed with a tocopherol-enriched diet in doses of 20 mg, 30 mg and 50 mg/kg food, respectively. After 4 weeks of feeding with the respective diets the rats were challenged with a single intra-gastric dose of 400 mg/kg body weight aspirin suspended in propylene glycol. The rats were killed 6 h post-aspirin exposure for the determination of gastric lesion index and gastric parameters as mentioned in the phase I study. The gastric lesions index was significantly lower in all the vitamin E groups compared to control. The lowest ulcer index was observed in the groups that received 100 mg of palm vitamin E and 30 mg tocopherol in the diet. However, there was no significant difference in ulcer indices between palm vitamin E and tocopherol-treated groups. The lower ulcer index was only accompanied by lower gastric MDA content. We conclude that both palm vitamin E in doses of 60 mg, 100 mg and 150 mg/kg food as well as tocopherol in doses of 20 mg, 30 mg and 50 mg/kg food are equally effective in preventing aspirin-induced gastric lesions. The most probable mechanism is through their ability in limiting the lipid peroxidation that is involved in aspirin-induced gastric lesions.     

不同镉离子浓度诱导饲养对参环毛蚓体腔细胞溶酶体膜的影响

目的 观察不同浓度镉离子诱导饲养对参环毛蚓体腔细胞溶酶体膜的毒性效应.方法 选取健康参环毛蚓70只,按照饲养土壤镉离子浓度的不同随机分为7组,每组10只.各组土壤镉离子浓度分别为0.28(对照组)、3.28、6.28、12.28、18.28、24.28和30.28 mg/kg,采用不同浓度镉离子诱导参环毛蚓染毒并饲养14 d.诱导饲养7 d和14 d时观察参环毛蚓体腔细胞的形态变化,测定其体腔细胞溶酶体中性红保留时间.结果 高浓度镉离子诱导参环毛蚓体腔细胞溶酶体的损害明显.诱导饲养7 d,对照组、3.28、6.28、12.28、18.28、24.28和30.28 mg/kg镉离子浓度组参环毛蚓体腔细胞溶酶体中性红保留时间随着镉离子浓度的增加而逐渐缩短,分别为(71.3±2.4)、(60.5±1.6)、(55.1±2.9)、(51.9±3.6)、(46.0±2.5)、(38.8±1.8)、(34.2±2.0)min.与对照组比较,诱导饲养7 d、14d时各实验组参环毛蚓溶酶体中性红保留时间明显缩短(均P＜0.05).结论 体腔细胞溶酶体中性红保留时间可用于评价土壤中重金属镉对参环毛蚓的毒性效应.     

Combined solution of ketamine and chloral hydrate as an anesthetic

The use of ketamine and chloral hydrate as anesthetics in rats is hampered by potentially deleterious side-effects. Ketamine in effective doses (50–90 mg/kg, IP) stimulates mucosal secretion from the nostrils and can interfere with breathing, while chloral hydrate in effective doses (200–400 mg/kg, IP) can cause intestinal distention and possibly death in rats. In order to reduce these side-effects, mixtures of the two drugs were tested in male and female rats to determine effectiveness of anesthesia with the mixed solutions without apparent side-effects. For females weighing 150–300 g, effective combinations of the drugs were found for mixtures with combined doses of 30 mg/kg ketamine-150 mg/kg chloral hydrate (IP); with females greater than 300 g the effective combined dose was 15 mg/kg ketamine-75 mg/kg chloral hydrate (IP). For males weighing 200–400 g, effective combinations of the drugs were found for mixtures with combined doses of 50 mg/kg ketamine-150 mg/kg chloral hydrate (IP); for males weighing more than 400 g, the effective combined dose was 30 mg/kg ketamine-150 mg/kg chloral hydrate (IP). All effective doses resulted in a loss of withdrawal reflexes within 5 minutes, and an absence of the reflexes continuing for 25 min. The combination of the anesthetics offers a safe and inexpensive alternative to the barbiturate anesthetics for use in rats.     

Effects of four different regimens of hormone replacement therapy on hemostatic parameters: a prospective randomized study

OBJECTIVE: To compare the effects of four different regimens including oral and transdermal formulations with or without progestins on the hemostatic system in a prospective randomized fashion. METHODS: Eighty-eight women were randomized to four groups receiving continuous transdermal estradiol 50 microg/day (tE2), oral conjugated equine estrogen 0.625 mg/day (CEE 0.625 mg), oral conjugated equine estrogen 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day (CEE 0.625 mg/MPA 2.5 mg), or oral 2 mg 17-beta estradiol combined with 1 mg norethistrone acetate (E2/norethistrone). The hysterectomized patients received only estrogen, and the remaining women received the estrogen plus progesterone combination regimens. As a marker of hemostatic system fibrinogen, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) levels were measured initially, and after 1 and 6 months of therapy. RESULTS: The treatment groups were well matched for baseline characteristics including age, height, weight, body mass index, and systolic and diastolic blood pressures. During the study period fibrinogen levels were below the baseline values in all groups. However, the decrease was only statistically significant in patients treated with oral 0.625 mg/day CEE. tPA levels were decreased significantly by tE2, CEE 0.625 mg, and CEE 0.625 mg/MPA 2.5 mg. PAI-1 levels were decreased significantly by CEE 0.625 mg, and CEE 0.625 mg/MPA 2.5 mg. When the effects of the four different regimens were compared using percentage changes from the baseline, no significant difference was found among the treatment groups. CONCLUSION: One of the treatment regimens resulted in a more coagulable state. Oral therapy with CEE decreased the levels of all parameters, and MPA did not impair this beneficial effect, except for in fibrinogen. Transdermal therapy had a minimal effect. No significant difference was noted among the four regimens.     

坐骨神经损伤后雏菊叶龙胆的修复作用实验研究

目的观察雏菊叶龙胆是否对坐骨神经损伤后有促进功能恢复的作用,其中是否有睫状神经营养因子的参与。方法雄性Wistar大鼠225只,右侧坐骨神经离断后显微镜下缝合。造模后随机分为对照组、雏菊叶龙胆25 mg组、50 mg组、75 mg组和甲钴胺组5组。对照组生理盐水注射,其他组相应剂量的雏菊叶龙胆及甲钴胺注射,1、3、5周测定神经传导速度及腓肠肌肌细胞截面积,免疫组化分析睫状神经营养因子(CNTF)阳性细胞比率。结果雏菊叶龙胆50 mg、75 mg组与对照组、甲钴胺组神经传导速度相比有明显差异,雏菊叶龙胆25 mg组与75 mg、50 mg组相比有明显差异(P=0.025)。3周时对照组、甲钴胺组、雏菊叶龙胆25 mg、50 mg、75 mg组腓肠肌肌细胞截面积分别为:(455.06±29.38)μm2、(679.03±81.48)μm2、(465.31±71.55)μm2、(670.24±91.26)μm2、(669.28±78.54)μm2,对照组、雏菊叶龙胆25 mg组与其他组比较有显著差异(P0.05)。3周时各组睫状神经营养因子免疫组化可见雏菊叶龙胆25 mg组和对照组与雏菊叶龙胆50 mg、75 mg组比较结果有统计学差异。结论雏菊叶龙胆可促进坐骨神经损伤后功能恢复,可促进神经功能恢复中有睫状神经营养因子参与。     

The contribution of pharmacokinetic–pharmacodynamic modelling with Monte Carlo simulation to the development of susceptibility breakpoints for Neisseria meningitidis

This study used pharmacokinetic-pharmacodynamic (PK-PD) modelling and MICs of 15 antimicrobial agents, derived from testing a large international culture collection, to assist in the development of interpretative criteria, i.e., breakpoints, for Neisseria meningitidis. PK parameters, protein binding, percentage penetration into cerebrospinal fluid (CSF), and the variability of these values, were extracted from the published literature for the 15 agents. PK-PD parameters have not been developed specifically for N. meningitidis in animal or human studies. Thus, it was necessary to invoke PK-PD targets from other organisms that cause infections at similar sites. The PK-PD targets utilised were: time above the MIC for at least 50% of the dosing interval for all beta-lactams, chloramphenicol, sulphafurazole and trimethoprim-sulphamethoxazole; an AUC/MIC ratio of >or=25 for the tetracyclines and macrolides; and an AUC/MIC ratio of >or=125 for the fluoroquinolones. A 10 000-subject Monte Carlo simulation was designed with the usual dosing regimens of each antimicrobial agent at MIC values of 0.03-64 mg/L in both serum and CSF. The PK-PD breakpoint was defined as the MIC at which the calculated target attainment was >or=95%. Using these assumptions, the proposed PK-PD breakpoints were: azithromycin, 0.125 mg/L; doxycycline, 0.25 mg/L; cefotaxime, ciprofloxacin and levofloxacin, 0.5 mg/L; penicillin G, meropenem, rifampicin, tetracycline and minocycline, 1 mg/L; chloramphenicol and sulphafurazole, 2 mg/L; and ampicillin, ceftriaxone and trimethoprim-sulphamethoxazole, 4 mg/L. Proposed PK-PD breakpoints applicable to CSF were: penicillin and cefotaxime, 0.06 mg/L; rifampicin, 0.125 mg/L; ceftriaxone, meropenem and trimethoprim-sulphamethoxazole, 0.25 mg/L; ampicillin, 0.5 mg/L; and chloramphenicol, 1 mg/L.     

Comparison of a triphasic oestradiol/norethisterone acetate preparation with and without an oestriol component in the treatment of climacteric complaints

This study was undertaken to evaluate the effects of oestriol in combination with oestradiol in the treatment of women with climacteric complaints. Forty-three post-menopausal women were randomly allocated to two groups on a double-blind basis. Over a 28-day cycle 23 of the women were treated sequentially for 12 days with 1 tablet containing 17β-oestradiol 2 mg plus oestriol 1 mg, then for 10 days with 1 tablet containing the same oestrogens plus norethisterone acetate 1 mg, thereafter for 6 days with 1 tablet containing 17β-oestradiol 1 mg plus oestriol 0.5 mg. The other 20 women received the same treatment but without the oestriol. No clinical, laboratory or histological differences were seen between the two groups. Both treatments were found to be equally effective in alleviating climacteric symptoms, with few side effects. It may be stated in conclusion that, on the basis of routine clinical and laboratory parameters no differences were found between the two preparations.     

吉西他滨对CD34+CD38-髓系白血病干细胞的增殖抑制和凋亡诱导作用

 目的：探讨与阿糖胞苷(Ara-C)结构相似的新型脱氧胞苷相似物和核苷还原酶抑制剂--吉西他滨(gemeitabine,GEM)对CD34+CD38-KG1a髓系白血病干细胞(LSCs)增殖抑制和诱导凋亡的影响。方法：流式细胞术检测急性髓系白血病KG1a细胞表面CD34和CD38的表达; 24 h和持续用药软琼脂克隆形成实验观察不同浓度GEM对KG1a细胞增殖的影响,流式细胞术检测不同浓度GEM对KG1a细胞周期的影响,Annexin V/PI双染法检测不同浓度GEM对KG1a细胞凋亡的影响。结果：急性髓系白血病KG1a细胞中CD34+ CD38-占(98.02±0.72)%。0.05 mg/L、0.1 mg/L和0.5 mg/L的GEM分别作用KG1a细胞24 h、48 h和72 h后, 0.5 mg/L GEM作用KG1a细胞24 h后,G0/G1期细胞高于盐水对照组 (P<0.05),而0.05 mg/L 和0.1 mg/L GEM作用KG1a细胞24 h后,G0/G1期细胞与盐水对照组相比,差异无统计学意义(P>0.05)。0.05 mg/L、0.1 mg/L和0.5 mg/L GEM作用KG1a细胞24 h后,软琼脂培养第14 d和21d后, 0.1 mg/L和0.5 mg/L组形成的克隆数,低于盐水对照组 (P<0.05), 0.05 mg/L GEM组14 d、21 d的克隆数与对照组相比,差异无统计学意义(P>0.05)。0.05 mg/L、0.1 mg/L、0.5 mg/L GEM和Ara-C持续作用组,软琼脂培养14 d和21d均未见集落生长,与对照组相比差异显著(P<0.05)。0.05 mg/L、0.1 mg/L GEM作用KG1a细胞后其凋亡率与盐水对照组相比,差异无统计学意义(P>0.05）,而0.5 mg/L GEM作用24 h后KG1a细胞凋亡率显著高于盐水对照组（P<0.05）。结论：GEM能抑制CD34+CD38-髓系白血病干细胞增殖和克隆形成,并将CD34+CD38-KG1a细胞阻滞在G0/G1期和诱导其凋亡。     

不同剂量氯胺酮对其所诱发梦幻性质的影响

目的观察使用不同剂量氯胺酮辅助来增强镇痛作用时是否存在产生不同性质的梦幻的现象。方法 80例拟实施四肢体表手术的患者按双盲试验设计原则随机分为每组20人的4组。在麻醉手术期间4组患者分别使用0.25、0.50、1.00、2.00mg/kg剂量的氯胺酮辅助增强镇痛。于术后第1日晨随访患者,记录患者不良梦幻和非不良梦幻的发生率以及总的梦幻的发生率并进行相应的统计学分析。结果各组患者不良梦幻和非不良梦幻的发生率以及总体的梦幻的发生率都有显著差异,而且梦魇的总体发生率、不良梦幻的发生率与氯胺酮剂量呈正相关。与此相反,非不良梦幻的发生率与氯胺酮的剂量呈负相关。结论不同剂量的氯胺酮会给患者带来不同性质的梦幻体验。大剂量的氯胺酮更可能给患者带来令人不愉快的不良梦幻体验,而小剂量氯胺酮更可能给患者带来令人愉快的非不良梦幻体验。使用氯胺酮增强镇痛作用时,应使用小剂量方案以避免导致更多的不良梦幻以及不良梦幻带来的不良影响。     

Minimum effective dose of trimethoprim for urinary tract infection

Non-pregnant women with urinary tract infection attending a health centre were treated with single doses of 400 mg, 200 mg or 100 mg of trimethoprim. The cure rates for these doses were 100%, 93% and 90%, respectively. In general practice the expected cure rate for this infection treated conventionally over five to seven days is 85-90%. Therefore, 100 mg of trimethoprim is the minimum effective dose for the treatment of urinary tract infection in general practice.     

The effect of varying low-dose combinations of norethindrone acetate and ethinyl estradiol (femhrt) on the frequency and intensity of vasomotor symptoms

OBJECTIVE: To determine whether there is a significant reduction in frequency and severity of hot flashes in symptomatic postmenopausal women who are administered continuously different dose combinations of norethindrone acetate and ethinyl estradiol. DESIGN: Two randomized clinical trials (Study 1 and Study 2) were conducted in which study participants recorded in daily diaries the frequency of their hot flashes. Study 2 participants also recorded the number of mild, moderate, or severe hot flashes they experienced. In Study 1, a total of 219 postmenopausal women reporting vasomotor symptoms were placed randomly into groups to receive either a placebo or 1 of 4 treatments (0.2 mg/1 microg; 0.5 mg/2.5 microg; 1 mg/5 microg; or 1 mg/10 microg norethindrone acetate/ethinyl estradiol). In Study 2, a total of 266 highly symptomatic postmenopausal women were placed randomly to receive either a placebo or 1 of 3 treatment groups [0.5 mg/2.5 microg; 1 mg/5 microg; or 1 mg/10 microg norethindrone acetate (NA)/ethinyl estradiol (EE)]. Total duration of treatment was 16 weeks in Study 1 and 12 weeks in Study 2. Study 1 subjects had to have at least 10 hot flashes during the week before randomization. Study 2 subjects had to have at least 56 moderate to severe hot flashes during the week before randomization. RESULTS: In both studies, there was a dose-related decrease in hot flash frequency with the highest dose (1 mg NA/10 microg EE) group that had the greatest response. Significant differences from placebo (p < 0.05, Dunnett's test) occurred within 4 weeks in Study 1 for hot flash frequency with a percent reduction in frequency ranging from 33% for placebo to 84% for both the 1 mg NA/10 microg EE and 1 mg NA/5 microg EE dose groups. Likewise, Study 2 significant reductions in hot flash frequency occurred by Week 2 for 1 mg NA/10 microg EE, Week 3 for 1 mg NA/5 microg EE, and Week 5 for 0.5 mg NA/2.5 microg EE (p < 0.05, Dunnett's test). This dose effect was also apparent with regard to severity. In addition, more subjects had clinically meaningful reductions in hot flash frequency or elimination as the dose combinations increased. CONCLUSION: There were significant reductions in hot flash frequency and severity with continuous treatment with norethindrone acetate and ethinyl estradiol combinations. The time at which significant reductions were observed, as well as the magnitude of the response, were dose dependent. The opportunity for lower-dose options of a new continuous-combined hormone replacement therapy provides therapeutic flexibility for women who are recently menopausal.     

Can fosfomycin reduce the nephrotoxicity of aminoglycosides?

Fosfomycin is an active antibiotic on Gram positive and Gram negative bacteria with a low toxicity in animals. To treat severe infections, it is recommended to associate fosfomycin with gentamicin. Wistar rats were given one of the following regimens for eight days : 100, 500 or 1 000 mg/kg fosfomycin, 50 mg/kg gentamicin or dibekacin, association of 100, 500, or 1 000 mg/kg fosfomycin and 50 mg/kg gentamicin or dibekacin. Control rats were given a saline solution. No renal histological alterations were identified with fosfomycin 100 mg/kg. Tubular dilatation and brush border rarefaction were observed with fosfomycin 500 and 1 000 mg/kg. These abnormalities did not seem related to fosfomycin itself but rather to the sodium load induced by fosfomycin treatment. A decrease in alanine aminopeptidase activity was noted for all doses of fosfomycin. Renal concentrations of gentamicin and dibekacin were not decreased by concomitant administration of fosfomycin. Fosfomycin, 100 mg/kg, did not change the nephrotoxic potential of gentamicin or dibekacin. Fosfomycin, 500 mg/kg, protected the kidney from the action of gentamicin or dibekacin. This effect seemed to be more pronounced for dibekacin than for gentamicin. Fosfomycin, 1 000 mg/kg, did not induce a more protective effect against the nephrotoxicity of these two aminoglycosides. Thus, we observed that fosfomycin combined with gentamicin or dibekacin reduced the degree of proximal tubular cell alterations, induced less modifications in alanine aminopeptidase, less lysosomal alterations, and a minor modification in sphingomyelinase activity.     

Proliferation of the superficial epithelium of ovaries in senile female rats following oral administration of conjugated equine estrogens

OBJECTIVE: To evaluate the effect of different concentrations of estrogen on the ovarian superficial epithelium in senile female rats. Design: Fifty female rats at 15 months of age and with irregular estrous cycles were selected and randomly divided into five experimental groups containing equal numbers of animals in each: GPROP, control group receiving vehicle only; GE0.05mg, group receiving conjugated equine estrogens (CEE) at a dose of 50 microg/kg; GE0.5mg, group receiving CEE at 500 microg/kg; GE1mg, group receiving CEE at 1 mg/kg; and GE2mg, receiving CEE at 2 mg/kg. The length of treatment was 21 days. After this period, the animals were anesthetized and the ovaries were fixed in 10% formaldehyde and processed for routine histology. Histomorphology was analyzed by light microscopy, and histomorphometrics were evaluated using the Imagelab program. RESULTS: In the GPROP and GE0.05mg groups, the superficial epithelium of the ovary had a simple cuboidal shape, and as the estrogen dose increased, the epithelium thickened, with pseudo-stratified or stratified epithelium appearing in the GE2mg group. The animals in the group given the highest estrogen dose (GE2mg) showed the thickest ovarian epithelium and the largest perimeter and surface area of the surface ovarian epithelium (P < 0.01). However, the difference in epithelium thickness between the GE0.5mg and GE1mg groups was only slight. CONCLUSION: Our data suggest that CEE at a dose of 2 mg/kg may induce marked proliferation of rat ovarian epithelium.     

Trovafloxacin versus amoxicillin/clavulanic acid in the treatment of acute exacerbations of chronic obstructive bronchitis

Treatments with once-daily trovafloxacin (200 or 100 mg) and amoxicillin/ clavulanic acid (500/125 mg three times daily) were compared in adults with acute exacerbations of chronic obstructive bronchitis. At end of treatment, 95% (113/119) of clinically evaluable patients receiving trovafloxacin 200 mg, 98% (113/115) of patients treated with trovafloxacin 100 mg and 97% (113/117) of patients receiving amoxicillin/clavulanic acid were cured or improved. At study end, 91%, 87% and 88%, respectively, were cured or improved. At end of treatment, trovafloxacin 200 mg eradicatedHaemophilus influenzae in 97% of patients,Streptococcus pneumoniae in 90% andChlamydia pneumoniae in 100%. The respective eradication rates for trovafloxacin 100 mg were 84%, 100% and 100%; those for amoxicillin/ clavulanic acid were 92%, 100% and 100%. At study end, trovafloxacin 200 mg totally eradicated all three pathogens. Trovafloxacin 100 mg eradicatedHaemophilus influenzae in 91% of patients,Streptococcus pneumoniae in 100% andChlamydia pneumoniae in 80%. Respective eradication rates for amoxicillin/clavulanic acid were 78%, 100% and 80%. Only 7% (10/144) of patients receiving trovafloxacin 200 mg reported treatment-related adverse events, as did 7% (10/135) of patients given trovafloxacin 100 mg and 12% (17/140) of patients given amoxicillin/clavulanic acid.     

Clinical trial of benidipine in mild to moderate hypertension

Thirty four patients with mild to moderate hypertension, were put on benidipine 4 mg/day after two weeks of placebo therapy. Twenty five patients completed the trial successfully for 4 mg benidipine. The blood pressure of 20 patients was controlled with benidipine 4 mg/day (effective rate 80%). Five patients with unsatisfactory control on 4 mg/day benidipine were put on 8 mg/day. Four of them were controlled and one was considered as failure (effective rate 80%). Most of the patients tolerated the drug well. Three patients had mild side effects like headache and heaviness in the head. One of them also had puffiness of face and body (on benidipine 8 mg/day) and was withdrawn from the study. One patient had mild constipation. We conclude that benidipine is well tolerated in the dose of 4-8 mg/day and is an effective antihypertensive agent for treatment of patients with mild to moderate hypertension.