Alterations of High-Energy Phosphate Compounds in the Skeletal Muscles of Rats Intoxicated with Diisopropylphosphorofluoridate (DFP) and Soman

Alterations of High-Energy Phosphate Compounds in the SkeletalMuscles of Rats Intoxicated with Diisopropylphosphorofluoridate(DFP) and Soman. GUPTA, R. C, and DETTBARN, W.-D. Fundam. Appl.Toxicol. 8, 400–407. The purpose of the present investigationwas to determine the changes in high-energy phosphate compoundsand to establish their relationship with organophosphate-inducednecrotic lesions in skeletal muscles of rats. Following an acutetoxicity signs-producing dose of either diisopropylphosphorofluoridate(DFP) (1.5 mg/kg, sc) or soman (0.1 mg/kg, sc), a significantdecline in phosphocreatine (PC) was seen as early as within1 hr, coinciding with the appearance of necrotic lesions, asreported earlier. The maximum decrease in PC was measured after6 hr. At this time, among the muscles studied, the hemi-diaphragm(the muscle which is known to show the greatest number of necroticlesions with both of the organophosphorus compounds) showedmaximum decrease in PC (57%) with soman treatment. A detailedanalysis of adenine nucleotides indicated a significant decreaseof adenosine triphosphate (ATP) in all three skeletal muscles,with a marked increase in adenosine monophosphate (AMP) andadenosine diphosphate (except in extensor digitorum longus (EDL)).The levels of creatine in all three skeletal muscles remainedunaltered throughout the time-course of study. The observedchanges in PC, ATP, and AMP were reversed toward control baselinevalues after 72 hr. Daily administration of DFP (0.5 mg/kg,sc/day) for 14 days caused only a significant decrease of PCin EDL and soleus during the toxic phase (Day 5), with recoverytoward the normal value during the tolerance phase (Day 14).It is concluded that both DFP and soman reduced the PC in skeletalmuscles, and the time-course for PC reduction correlates wellwith the previously reported time-course for muscle fiber necrosis.It is suggested that the reduction in PC is caused through anincreased demand to meet ATP requirements during severe muscularfasciculations.     

Selective Androgen Receptor Modulator (SARM) Treatment Prevents Bone Loss and Reduces Body Fat in Ovariectomized Rats

Purpose This study was conducted to examine the bone and body composition effects of S-4, an aryl-propionamide derived Selective Androgen Receptor Modulator (SARM) in an ovariectomy induced model of accelerated bone loss. Methods One hundred twenty female Sprague–Dawley rats aged to twenty-three weeks were randomly assigned to twelve treatment groups. Drug treatment was initiated immediately following ovariectomy and continued for one hundred twenty days. Whole body bone mineral density (BMD), body composition, and lumbar vertebrae BMD were measured by dual energy x-ray absorptiometry. More stringent regional pQCT and biomechanical strength testing was performed on excised femurs. Results We found that S-4 treatment maintained whole body and trabecular BMD, cortical content, and increased bone strength while decreasing body fat in these animals. Conclusions The data presented herein show the protective skeletal effects of S-4. Our previous reports have shown the tissue selectivity and muscle anabolic activity of S-4. Together these data suggest that S-4 could reduce the incidence of fracture via two different mechanisms (i.e., via direct effects in bone and reducing the incidence of falls through increased muscle strength). This approach to fracture reduction would be advantageous over current therapies in these patients which are primarily antiresorptive in nature.     

Effect of Beta-Asarone on Impairment of Spatial Working Memory and Apoptosis in the Hippocampus of Rats Exposed to Chronic Corticosterone Administration

β-asarone (BAS) is an active component of Acori graminei rhizoma, a traditional medicine used clinically in treating dementia and chronic stress in Korea. However, the cognitive effects of BAS and its mechanism of action have remained elusive. The purpose of this study was to examine whether BAS improved spatial cognitive impairment induced in rats following chronic corticosterone (CORT) administration. CORT administration (40 mg/kg, i.p., 21 days) resulted in cognitive impairment in the avoidance conditioning test (AAT) and the Morris water maze (MWM) test that was reversed by BAS (200 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and RT-PCR analysis, the administration of BAS significantly alleviated memory-associated decreases in the expression levels of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) proteins and mRNAs in the hippocampus. Also, BAS administration significantly restored the expression of Bax and Bcl-2 mRNAs in the hippocampus. Thus, BAS may be an effective therapeutic for learning and memory disturbances, and its neuroprotective effect was mediated, in part, by normalizing the CORT response, resulting in regulation of BDNF and CREB functions and anti-apoptosis in rats.     

A comparison of the ability of newly-developed bispyridinium oxime K203 and currently available oximes (trimedoxime,obidoxime, HI-6) to counteract the acute neurotoxicity of soman in rats

The neuroprotective effects of newly-developed oxime K203 and currently available oximes (trimedoxime, obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24?h following soman challenge. The results indicate that the potency of a newly-developed oxime K203 to counteract soman-induced neurotoxicity is very low and roughly corresponds to the neuroprotective efficacy of currently available oximes. Among tested oximes, the oxime HI-6 seems to be the most efficacious to counteract acute neurotoxicity of soman, although the differences in neuroprotective efficacy of chosen oximes are not significant. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with soman and the oxime HI-6 should be still considered to be the best oxime for antidotal treatment of acute soman poisonings.     

脂蛋白（a）在动脉粥样硬化患者中的变化及血脂康干预的影响

目的：探讨冠心病（CHD）患者及脑梗死患者血清脂蛋白（a）[Lp(a)]水平及药物干预的影响。方法：151例CHD病人，其中急民生心肌梗死（AMI）20例，陈旧性心肌梗死（OMI）49例，心绞痛（AP）82例；脑梗死患者42例及正常对照组30例，测定其血清Lp(a)浓度。对高Lp(a）水平随机分组用血脂康胶囊及维生素C治疗。结果：CHD及脑梗死组其血清Lp(a)水平明显高于对照组（均P＜0.01)；CHD组高于脑梗死组（P＜0.01)。CHD组中，AMI组＞AP组＞OMI组（P＜0.01或P＜0.05）。用血脂康胶囊4粒/日治疗40例，12周末血清Lp(a)下降19.66%，与治疗前比较差异显著（P＜0.05)。结论：提示Lp(a)有致动脉粥样硬化的作用；血脂康胶囊对高血清Lp(a)水平安全有效。     

氟哌噻吨美利曲辛治疗非小细胞肺癌患者合并抑郁状态的临床研究

目的观察氟哌噻吨美利曲辛治疗非小细胞肺癌（NSCLC）患者合并抑郁状态的临床效果。方法选择NSCLC合并抑郁状态患者76例,随机分为对照组和氟哌噻吨美利曲辛组,各38例,两组均给予NP方案化疗。化疗当日,对照组于早餐后半小时口服维生素C0.2g（2片）;氟哌噻吨美利曲辛组于早餐后半小时口服氟哌噻吨美利曲辛（每片含氟哌噻吨0.5mg,美利曲辛10mg）2片。分别于治疗前及治疗第21、42天应用Zung抑郁自评量表（SDS）、中国癌症患者化学生物治疗生活质量量表（QLQ-CCC）、卡氏功能状态量表（KPS）评定患者抑郁状态及生活质量。结果治疗前两组SDS、QLQ-CCC、KPS评分差异无统计学意义,具有可比性（P〉0.05）。治疗第21、42天,氟哌噻吨美利曲辛组与对照组相比,SDS评分均明显降低（P〈0.01）;治疗第42天,QLQ-CCC各项评分及KPS评分明显升高（P〈0.05）。结论氟哌噻吨美利曲辛可显著改善NSCLC患者的抑郁状态,提高患者的生活质量。     

特拉唑嗪联合强肾片治疗慢性非细菌性前列腺炎／慢性盆腔疼痛综合征效果观察

目的：探讨应用特拉唑嗪联合强肾片治疗慢性非细菌前列腺炎／慢性盆腔痛综合征（CP／CPPS）的临床疗效。方法：183例CP／CPPS患者随机分为特拉唑嗪组48例、强肾片组46例、特拉唑嗪＋强肾片组89例。治疗6周,根据前列腺液情况加用抗生素。观察从开始治疗到6周治疗全部结束后的效果,采用NIH慢性前列腺炎症状评分（CPSI）作为疗效评价指标。结果：治疗6周后特拉唑嗪组有效（CPSI减少≥5分）37例（77．1％）、强肾片组有效32例（69．5％）、特拉唑嗪＋强肾片组有效79例（88．8％）。经统计学分析特拉唑嗪＋强肾片组与特拉唑嗪组、强肾片组比较有统计学意义（P〈0．05）。结论：特拉唑嗪联合强肾片治疗慢性前列腺炎／慢性盆腔痛综合征疗效优于单用强肾片组及特拉唑嗪组。     

血液透析联合血液灌流治疗慢性肾衰竭合并矿物质-骨代谢异常(CKD-MBD)的临床疗效观察

目的:探索血液透析联合血液灌流用于治疗慢性肾衰竭合并矿物质-骨代谢异常的效果。方法:选取在某院于2013年7月~2016年7月间收治的慢性肾衰竭合并矿物质-骨代谢异常患者中随机抽取出82例作为研究对象,将患者随机分为观察组和对照组,其中对照组患者采用血液透析治疗,观察组患者采用血液透析+血液灌流治疗,对比分析两组患者的治疗效果。结果:观察组患者的治疗总有效率92.68%,高于对照组的75.61%,P0.05;在实验室指标上,观察组患者的P3+、iPTH、BALP、FGF-23、OPG指标值均低于对照组,P0.05;两组患者在Ca2+水平上对比差异不明显,P0.05。结论:在慢性肾衰竭合并CKD-MBD治疗中采用血液透析联合血液灌流治疗效果确切,有助于改善患者的矿物质-骨代谢状况,提高患者的生活质量,值得推广应用。     

拉米夫定联合干扰素治疗慢性乙型肝炎的抗病毒疗效与Th细胞因子变化的关系

目的探讨拉米夫定联合干扰素（IFN-α）治疗慢性乙型肝炎（乙肝）抗病毒疗效与Th细胞因子的变化关系。方法以慢性乙肝患者39例作为治疗组，采用拉米夫定联合IFN-α治疗，拉米夫定100 mg·d-1，po;IFN-α 5MU，隔日肌内注射。联合治疗1 a后检测患者外周血HBV-DNA及Th细胞因子IL-2、IFN-γ、IL-4、IL-10;以20例健康献血员作为正常对照组。并根据HBV DNA复制指标及HBeAg/HBeAb转换情况将治疗组分为有效组与无效组。结果治疗组治疗后血清IL-2、IFN-γ均值明显升高（P＜0.05）、HBV-DNA含量均值明显下降（P＜0.05）;治疗有效组与无效组比较，血清IL-2、IFN-γ均值明显升高（P＜0.05），IL-4、HBV-DNA含量均值明显下降（P＜0.05）。结论拉米夫定联合IFN-α治疗慢性乙肝可显著抑制HBV-DNA复制;联合治疗后有效组免疫状态可由以Th2型为主向以Th1型为主转换。     

Comparative Metabolism of Debrisoquine, 7–Ethoxyresorufin and Benzo(a)pyrene in Liver Microsomes from Humans,and from Rats Treated with Cytochrome P–450 Inducers

Abstract: The metabolism of debrisoquine, 7–ethoxyresorufin and benzo(α)pyrene has been studied in human liver microsomes. There was a significant correlation (r = 0.70, P < 0.05) between debrisoquine hydroxylation and 7–ethoxyresorufin 0–deethylation among various livers, and debrisoquine inhibited 7–ethoxyresorufin deethylation competitively. These results suggest that debrisoquine and 7–ethoxyresorufin may be metabolised by a common P–450 form in human liver. The effect of cytochrome P–450 inducers on the metabolism of the three substrates was also examined in rat liver. Debrisoquine hydroxylation was not enhanced by phenobarbitone, β–naphthoflavone or isosafrole     

Chronic progressive external ophthalmoplegia with a novel mitochondrial DNA deletion and a mutation in the tRNALEU(UUR) gene

Large‐scale deletions and point mutations of the mitochondrial DNA are generally accepted as being involved in the pathogenesis of diseases associated with mitochondrial encephalomyopathies such as Kearns‐Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO). We screened suspected patients using polymerase chain reaction techniques, Southern blot analyses, and muscle biopsy specimens. We report on a novel 4,953‐base pair deletion associated with a familial occurrence of a tRNA^Leu(UUR) T3250C point mutation in a young female patient clinically diagnosed with CPEO. This deletion is not flanked by direct repeats, so slip replication and homologous recombination do not seem likely as the mechanism of origin. Here, we point out the possible role of a single base replacement as a promoter of a deleterious event when exceeding an organ‐specific threshold of heteroplasmy. Disturbances of energy metabolism by means of accumulation of reactive oxygen species, thus, may severely interfere in the ATP production of the respiratory chain. Drug Dev. Res. 46:80–85, 1999. © 1999 Wiley‐Liss, Inc.     

The Effectiveness of Botulinum Toxin Type A (BoNT-A) Treatment in Brazilian Patients with Chronic Post-Stroke Spasticity: Results from the Observational,Multicenter, Prospective BCause Study

Botulinum toxin type A (BoNT-A) is an effective treatment for post-stroke spasticity; however, some patients cannot access treatment until ≥1 year post-stroke. This Brazilian post-marketing study ({"type":"clinical-trial","attrs":{"text":"NCT02390206","term_id":"NCT02390206"}}NCT02390206) assessed the achievement of person-centered goals in patients with chronic post-stroke spasticity after a BoNT-A injection. Patients had a last documented stroke ≥1 year before study entry and post-stroke upper limb (UL) spasticity, with or without lower limb (LL) spasticity. Patients received BoNT-A injections at baseline (visit 1) and visit 2 (3–6 months). Primary endpoint was responder rate (achievement of primary goal from Goal Attainment Scaling (GAS)) at visit 2. Overall, 204 patients underwent GAS evaluation at visit 2, mean (SD) age was 56.4 (13.2) years and 90.7% had LL spasticity. Median (range) time between first stroke and onset of spasticity was 3.6 (0−349) months, onset of spasticity and first injection was 22.7 (0−350) months and waiting time for a rehabilitation appointment was 9.0 (1−96) months. At visit 2, 61.3% (95% CI: 54.4, 67.7) of patients were responders, which was similar for UL and LL primary goals (57.8% [95% CI: 49.9, 65.3] vs. 64.1% [95% CI: 48.4, 77.3]). This study provides evidence to support the effectiveness of BoNT-A treatment for chronic post-stroke spasticity.     

Metabolism and Disposition of the HIV-1 Protease Inhibitor Lopinavir (ABT-378) Given in Combination with Ritonavir in Rats, Dogs, and Humans

PURPOSE: The objective of this study was to examine the metabolism and disposition of the HIV protease inhibitor lopinavir in humans and animal models. METHODS: The plasma protein binding of [14C]lopinavir was examined in vitro via equilibrium dialysis technique. The tissue distribution of radioactivity was examined in rats dosed with [14C]lopinavir in combination with ritonavir. The metabolism and disposition of [14C]lopinavir was examined in rats, dogs, and humans given alone (in rats only) or in combination with ritonavir. RESULTS: The plasma protein binding of lopinavir was high in all species (97.4-99.7% in human plasma), with a concentration-dependent decrease in binding. Radioactivity was extensively distributed into tissues, except brain, in rats. On oral dosing to rats, ritonavir was found to increase the exposure of lopinavir-derived radioactivity 13-fold. Radioactivity was primarily cleared via the hepato-biliary route in all species (>82% of radioactive dose excreted via fecal route), with urinary route of elimination being significant only in humans (10.4% of radioactive dose). Oxidative metabolites were the predominant components of excreted radioactivity. The predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety, with subsequent secondary metabolism occurring on the diphenyl core moiety. In all the three species examined, the primary component of plasma radioactivity was unchanged lopinavir (>88%) with small amounts of oxidative metabolites. CONCLUSIONS: Lopinavir was subject to extensive metabolism in vivo. Co-administered ritonavir markedly enhanced the pharmacokinetics of lopinavir-derived radioactivity in rats, probably due to inhibition of presystemic and systemic metabolism, leading to an increased exposure to this potent HIV protease inhibitor.     

彩色多普勒超声心动图在先天性心脏病合并肺动脉高压中的应用及分析

目的利用彩色多普勒超声心动图检测在先天性心脏病合并肺动脉高压中根据连续多普勒三尖瓣反流压差估测肺动脉收缩压的价值。方法对60例左向右分流型先天性心脏病合并肺动脉高压,同时有三尖瓣反流的患者,于术前用上述方法估测肺动脉压／体循环压的比值,与术中所测得肺动脉压／体循环压的比值比较。结果多普勒超声心动图用上述方法估测肺动脉压／体循环压的比值,与术中所测得肺动脉压／体循环压的比值高度相关（r=0．82,P〈0．01）。结论结果表明,多普勒超声心动图测压法可提供可靠的最大三尖瓣跨瓣压,可为患者临床药物治疗及病情分析提供宝贵的血流动力学资料,可用于肺动脉高压的定性和定量诊断,本方法可为外科提供手术时机,并对手术的可行性做出预测。     

头孢哌酮-舒巴坦与两种配方治疗泌尿系统感染的疗效比较

目的 比较头孢哌酮／舒巴坦1：1和2：1两种配方治疗泌尿系统感染的临床疗效。方法将56例泌尿系统感染的患者分别分为A组和B组各28例,分别静脉滴注头孢哌酮／舒巴坦（1：1为A组）4g,Bid和头孢哌酮／舒巴坦（2：1为B组）3g,Bid,共7～14d。结果A组有效率为89．29％;其中治愈率为53．58％;B组有效率为89．29％;其中治愈率为57．15％;A组不良反应发生率为10．72％;B组不良反应发生率为7．15％;结论头孢哌酮／舒巴坦1：1与2：1两种配方治疗泌尿系统感染疗效相似,临床应用2：1配比的头孢哌酮／舒巴坦治疗泌尿系统感染既安全有效又经济实用。     

润降利膈丸联合莫沙必利治疗糖尿病性胃轻瘫(胃阴不足型)的疗效及对胃肠激素、氧化应激反应的影响

目的:探讨润降利膈丸联合莫沙必利治疗糖尿病性胃轻瘫(diabetic gastroparesis,DGP)(胃阴不足型)的疗效及对胃肠激素、氧化应激反应的影响,为临床治疗提供参考。方法:将2018年1月至2019年10月石家庄市中医院内分泌科收治的DGP(胃阴不足型)患者117例纳入研究,采用随机数字表法分为研究组(63例)和对照组(54例)。两组患者均进行常规治疗,在此基础上,对照组患者给予莫沙必利,研究组患者给予润降利膈丸联合莫沙必利,总疗程为2周。比较两组患者治疗前后胃肠激素[胃动素(MOT)、胃泌素(GAS)]、氧化应激指标[超氧化物歧化酶(SOD)、活性氧(ROS)及丙二醛(MDA)]水平及胃排空情况的差异,观察两组患者临床疗效、不良反应发生情况及复发情况。结果:治疗后,两组患者MOT、GAS、SOD水平及胃排空率明显高于治疗前,ROS、MDA水平明显低于治疗前,差异均有统计学意义(P<0.05)。治疗后,研究组患者MOT、GAS、SOD水平及胃排空率明显高于对照组,ROS、MDA水平明显低于对照组,差异均有统计学意义(P<0.05)。研究组患者的总有效率为92.06%(58/63),明显高于对照组的74.07%(40/54),差异有统计学意义(P<0.05)。治疗期间,研究组患者未出现明显不良反应,对照组2例患者出现丙氨酸氨基转移酶水平升高;研究组患者无复发,对照组8例患者复发(复发率为14.81%)。结论:润降利膈丸联合莫沙必利治疗DGP(胃阴不足型)的疗效良好且安全性高,可有效促进胃动力并减轻患者体内氧化应激反应。     

Chronic treatment with polychlorinated biphenyls (PCB) during pregnancy and lactation in the rat: Part 2: Effects on reproductive parameters, on sex behavior, on memory retention and on hypothalamic expression of aromatase and 5alpha-reductases in the offspring

The gender-specific expression pattern of aromatase and 5alpha-reductases (5alpha-R) during brain development provides neurons the right amount of estradiol and DHT to induce a dimorphic organization of the structure. Polychlorinated biphenyls (PCBs) are endocrine disruptive pollutants; exposure to PCBs through placental transfer and breast-feeding may adversely affect the organizational action of sex steroid, resulting in long-term alteration of reproductive neuroendocrinology. The study was aimed at: a) evaluating the hypothalamic expression of aromatase, 5alpha-R1 and 5alpha-R2 in fetuses (GD20), infant (PN12), weaning (PN21) and young adult (PN60) male and female rats exposed to PCBs during development; b) correlating these parameters with the time of testicular descent, puberty onset, estrous cyclicity and copulatory behavior; c) evaluating possible alterations of some non reproductive behaviors (locomotion, learning and memory, depression/anxiety behavior). A reconstituted mixture of four indicator congeners (PCB 126, 138, 153 and 180) was injected subcutaneously to dams at the dose of 10 mg/kg daily from GD15 to GD19 and then twice a week till weanling. The results indicated that developmental PCB exposure produced important changes in the dimorphic hypothalamic expression of both aromatase and the 5alpha-Rs, which were still evident in adult animals. We observed that female puberty onset occurs earlier than in control animals without cycle irregularity, while testicular descent in males was delayed. A slight but significant impairment of sexual behavior and an important alteration in memory retention were also noted specifically in males. We conclude that PCBs might affect the dimorphic neuroendocrine control of reproductive system and of other neurobiological processes.     

Chronic treatment with polychlorinated biphenyls (PCB) during pregnancy and lactation in the rat: Part 2: Effects on reproductive parameters, on sex behavior, on memory retention and on hypothalamic expression of aromatase and 5alpha-reductases in the offspring

The gender-specific expression pattern of aromatase and 5alpha-reductases (5alpha-R) during brain development provides neurons the right amount of estradiol and DHT to induce a dimorphic organization of the structure. Polychlorinated biphenyls (PCBs) are endocrine disruptive pollutants; exposure to PCBs through placental transfer and breast-feeding may adversely affect the organizational action of sex steroid, resulting in long-term alteration of reproductive neuroendocrinology. The study was aimed at: a) evaluating the hypothalamic expression of aromatase, 5alpha-R1 and 5alpha-R2 in fetuses (GD20), infant (PN12), weaning (PN21) and young adult (PN60) male and female rats exposed to PCBs during development; b) correlating these parameters with the time of testicular descent, puberty onset, estrous cyclicity and copulatory behavior; c) evaluating possible alterations of some non reproductive behaviors (locomotion, learning and memory, depression/anxiety behavior). A reconstituted mixture of four indicator congeners (PCB 126, 138, 153 and 180) was injected subcutaneously to dams at the dose of 10 mg/kg daily from GD15 to GD19 and then twice a week till weanling. The results indicated that developmental PCB exposure produced important changes in the dimorphic hypothalamic expression of both aromatase and the 5alpha-Rs, which were still evident in adult animals. We observed that female puberty onset occurs earlier than in control animals without cycle irregularity, while testicular descent in males was delayed. A slight but significant impairment of sexual behavior and an important alteration in memory retention were also noted specifically in males. We conclude that PCBs might affect the dimorphic neuroendocrine control of reproductive system and of other neurobiological processes.