Effects of the antimigraine compound zolmitriptan ('Zomig') on psychomotor performance alone and in combination with diazepam in healthy volunteers

Zolmitriptan (Zomig^TM) is a 5HT_1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following "treatments" as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg+diazepam 10 mg, zolmitriptan 5 mg+diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination.     

Indapamide inhibits endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat

Summary— Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium-dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate-β-S in the presence of a nitric oxide synthase inhibitor, caused endothelium-dependent contractions, which were inhibited by indapamide. The compound (10⁻⁴M) also slightly reduced the contractions of rings without endothelium evoked by U-46,619, which activates thromboxane-endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium-dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle.     

Determination of Chemical Antioxidants and Phenolic Compounds in the Brazilian Mushroom Agaricus sylvaticus

Agaricus sylvaticus mushroom has been widely studied because of its high nutritional value and medicinal properties. The objective of this study was to evaluate the antioxidant potential of both alcoholic and aqueous extracts of Agaricus sylvaticus and quantify their total polyphenol content. The antioxidant activity was performed by the 2,2-diphenyl-1-picrylhydrazyl radical scavenging capacity and total polyphenol content was assessed by colorimetric method. Observation also noted the great antioxidant potential of aqueous, alcoholic and ethereal extracts (14.6%, 75.6% and 14.6%, respectively) of the Agaricus sylvaticus mushroom, highlighting the alcoholic extract, which demonstrates the extraordinary benefits of this mushroom in the diet, since antioxidants prevent premature ageing and various types of cancer.     

Targeted Tissue and Cell-Free Tumor DNA Sequencing of Advanced Lung Squamous-Cell Carcinoma Reveals Clinically Significant Prevalence of Actionable Alterations

Background

Major guidelines do not recommend routine molecular profiling of lung squamous-cell carcinoma (LUSC) because the prevalence of actionable alterations is thought to be low. Increased utilization of next-generation sequencing (NGS), particularly with cell-free circulating tumor DNA, facilitates reevaluation of this premise.

Effect of 2'-deoxycoformycin on erythroid, granulocytic, and T- lymphocyte colony growth

The finding of elevated intracellular levels of adenosine deaminase (ADA) in some patients with acute lymphoblastic leukemia has led to attempts to control this disease with the adenosine deaminase inhibitor 2'-deoxycoformycin (dCF). Because of clinical reports indicating its relative freedom from myelotoxicity, we have tested the effects of this drug on erythroid, granulocytic, and T-lymphocyte colony formation by normal marrow and peripheral blood cells. While clinically the drug has been found to be active at serum concentrations of approximately 10 microM, we have tested it at concentrations up to and including 1 mM. It was found that both erythroid and granulocytic colony growth was completely unaffected by 1 mM dCF, a concentration at least 2 magnitudes higher than that necessary to totally ablate intracellular ADA levels. T-lymphocyte colony growth was unaffected by 100 microM dCF, but at 1 mM some inhibition was observed. These findings therefore indicate that dCF, while able to cause leukemic cell lysis in vivo, has no inhibitory effect on the proliferative capacity of normal hematopoietic cells.     

Diaphragmatic Hernia Masquerading as a Pulmonary Metastasis

Iatrogenic injury accounts for the second most common cause of acquired diaphragmatic hernias after penetrating trauma. An increased incidence of these hernias has been observed with the widespread use of laparoscopic surgery. We present the case of a 65-year-old woman who initially underwent sigmoid resection for an adenocarcinoma and a subsequent liver resection for metastasis. She was noted to have a left lower lobe pulmonary nodule on surveillance computed tomography, for which she underwent a mini-thoracotomy for a planned resection. At the time of surgery, the pulmonary nodule was discovered to be a diaphragmatic hernia, most probably of iatrogenic origin. We discuss the difficulty in diagnosis given her history and the location of such a lesion.     

Copy number variants in patients with short stature

Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents'' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.     

Osimertinib,Surgery, and Radiation Therapy in Treating Patients with Stage IIIB or IV Non-Small Cell Lung Cancer with EGFR Mutations (NORTHSTAR)

Annals of Surgical Oncology -     

基于CYP3A4酶探讨灯盏花素对洛伐他汀的药动学的影响及机制

目的 探究灯盏花素与洛伐他汀联用对大鼠体内药动学的影响,从代谢酶的角度揭示灯盏花素对洛伐他汀药动学产生影响的机制。方法 采用探针药物法及RT-HPLC法测定咪达唑仑在肝微粒体孵育体系中的浓度,评价灯盏花素与洛伐他汀联用对CYP3A4酶活性的影响。通过RT-PCR反应来检测CYP3A4酶mRNA基因表达,采用Western blot法,从蛋白翻译水平上分析灯盏花素与洛伐他汀联用对大鼠肝脏CYP3A4蛋白表达的影响。结果 洛伐他汀与灯盏花素联合用药后,洛伐他汀在大鼠体内的血药浓度显著升高,从0.39 mg?L-1 上升到1.08 mg?L-1 ,清除率从3.36L?h-1?kg-1降低到1.08L?h-1?kg-1,药物半衰期从5.0h延长到6.2h,联合给药后洛伐他汀的AUC从2.42mg?L-1?h-1上升到4.22mg?L-1?h-1。洛伐他汀组与空白组比较CYP3A4酶活性均没有明显变化;灯盏花素组及灯盏花素联合洛伐他汀组与空白组比较发现均抑制CYP3A4酶活性;灯盏花素与灯盏花素联合洛伐他汀组CYP3A4酶mRNA 表达量均较空白组显著降低;CYP3A4酶蛋白含量结果表明,洛伐他汀组与灯盏花素联合洛伐他汀组与空白组比较CYP3A4酶蛋白含量均没有明显变化。结论 洛伐他汀与灯盏花素联用,灯盏花素通过抑制其基因转录水平抑制CYP3A4的活性,使大鼠体内药动学过程发生变化,洛伐他汀药物的代谢减慢。     

山奈酚通过抑制NLRP3炎症小体介导的脂肪组织炎症改善db/db小鼠胰岛素抵抗发生

目的：探讨山奈酚能否通过调控肥胖小鼠脂肪组织炎症改善胰岛素抵抗发生并研究作用机制。方法：db/m小鼠作为对照组,db/db雄性小鼠随机分为模型组、二甲双胍组(0.15 g·kg^-1·d^-1)和山奈酚组(50 mg·kg^-1·d^-1)。连续灌胃给药6周,每周记录小鼠体重,6周后进行葡萄糖耐量试验、胰岛素耐量试验、皮下和附睾白色脂肪组织质量测定;HE染色观察脂肪组织形态学变化,免疫组化法观察巨噬细胞向脂肪组织的浸润程度及巨噬细胞标志物F4/80的表达,实时荧光定量PCR检测TNF-α和IL-18以及Arg-1和IL-10的mRNA表达,蛋白质免疫印迹试验检测NLRP3、pro-caspase1、cle-caspase1和IL-1β表达。结果：与模型组相比,山奈酚能够显著抑制db/db小鼠脂肪质量增加,抑制脂肪细胞肥大。山奈酚组小鼠脂肪组织巨噬细胞浸润减少,TNF-α和IL-18 mRNA表达减少,Arg-1和IL-10 mRNA表达增加;山奈酚治疗能够抑制小鼠附睾脂肪组织NLRP3、caspase1以及...