A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Analysis of Chlamydomonas thiamin metabolism in vivo reveals riboswitch plasticity

Thiamin (vitamin B₁) is an essential micronutrient needed as a cofactor for many central metabolic enzymes. Animals must have thiamin in their diet, whereas bacteria, fungi, and plants can biosynthesize it de novo from the condensation of a thiazole and a pyrimidine moiety. Although the routes to biosynthesize these two heterocycles are not conserved in different organisms, in all cases exogenous thiamin represses expression of one or more of the biosynthetic pathway genes. One important mechanism for this control is via thiamin-pyrophosphate (TPP) riboswitches, regions of the mRNA to which TPP can bind directly, thus facilitating fine-tuning to maintain homeostasis. However, there is little information on how modulation of riboswitches affects thiamin metabolism in vivo. Here we use the green alga, Chlamydomonas reinhardtii, which regulates both thiazole and pyrimidine biosynthesis with riboswitches in the THI4 (Thiamin 4) and THIC (Thiamin C) genes, respectively, to investigate this question. Our study reveals that regulation of thiamin metabolism is not the simple dogma of negative feedback control. Specifically, balancing the provision of both of the heterocycles of TPP appears to be an important requirement. Furthermore, we show that the Chlamydomonas THIC riboswitch is controlled by hydroxymethylpyrimidine pyrophosphate, as well as TPP, but with an identical alternative splicing mechanism. Similarly, the THI4 gene is responsive to thiazole. The study not only provides insight into the plasticity of the TPP riboswitches but also shows that their maintenance is likely to be a consequence of evolutionary need as a function of the organisms’ environment and the particular pathway used.     

Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension

Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.     

动态监测血清相关指标对重型颅脑损伤术后肺部感染的预测价值

目的分析动态监测重型颅脑损伤术后患者血清降钙素原(PCT)、可溶性髓样细胞表达的激发受体-1(sTREM-1)及C反应蛋白与白蛋白比值(CRP/ALB)的变化对肺部感染的早期预测价值。方法选取手术治疗的196例重型颅脑损伤患者,监测并记录术后1、3、5 d的血清PCT、CRP、ALB、sTREM-1及CRP/ALB水平,记录患者术后肺部感染情况。分析重型颅脑损伤术后肺部感染的危险因素,通过绘制受试者工作特征(ROC)曲线分析相关指标对肺部感染的早期预测价值。结果重型颅脑损伤术后发生肺部感染者76例(38.78%),感染发生时间为术后6~13 d,中位数为7 d。无肺部感染组术后3、5 d血清PCT、sTREM-1及CRP/ALB低于肺部感染组,差异有统计学意义(P0.05);肺部感染组术后5 d血清ALB低于无肺部感染组,差异有统计学意义(P0.05)。机械通气时间、术后格拉斯哥昏迷量表(GCS)评分、术后急性生理与慢性健康评分Ⅱ(APACHEⅡ)以及术后5 d血清PCT、sTREM-1及CRP/ALB是术后肺部感染的独立危险因素(P0.05)。ROC曲线显示,单独检测时,术后5 d血清CRP/ALB预测肺部感染的曲线下面积(AUC)值、约登指数、特异度最高,sTREM-1预测的敏感度最高;联合检测的AUC、约登指数、灵敏度、特异度均高于单独检测。肺部感染诊断时临床肺部感染评分(CPIS)、全身炎症反应综合征修正(ASS)评分均与术后5 d PCT、sTREM-1、CRP/ALB水平呈显著正相关(P0.05)。结论术后5 d血清PCT、sTREM-1及CRP/ALB水平均可作为重型颅脑损伤术后肺部感染早期预测的有效依据,而联合检测的预测价值更高,更有利于早期对肺部感染程度及病情进展的评估。     

22例皮质醇增多症的临床研究

目的：探讨皮质醇增多症的临床表现和内分泌检查等辅助检查的意义.方法：从年龄、性别、病程及实验室检查等方面,观察22例不同原因所致皮质醇增多症患者不同的临床表现和测定实验室检查指标.结果：22例中诊断库欣病（增生型）14例[63.6％,其中13例（92.9％）得到MRI检查证实],肾上腺腺瘤6例[27.3％,均得到MRI检查证实（100％）],另有肾上腺结节样增生1例（4.5％）,异位ACTH综合征1例（4.5％）.临床表现：按出现的频率前4位依次为,库欣病：高血压（100％）、满月脸（92.9％）、向心性肥胖（85.7％）、多血质（85.7％）,肾上腺腺瘤：高血压（100％）、满月脸（100％）、向心性肥胖（100％）、多血质（83.3％）.实验室检查：小剂量地塞米松不能抑制：库欣病与肾上腺腺瘤均为100％.结论：根据高血压、满月脸、向心性肥胖,小剂量地塞米松抑制试验和MRI检查可诊断绝大多数皮质醇增多症.     

Patient‐reported convenience of once‐daily versus three‐times‐daily dosing during long‐term studies of pramipexole in early and advanced Parkinson’s disease

Background and purpose: In chronic diseases including Parkinson’s disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less‐effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical‐trial designs preclude direct comparisons of adherence to various schedules. Methods: In two double‐blind (DB) studies of early PD and one of advanced PD, subjects received three‐times‐daily (t.i.d.) pramipexole or placebo. In open‐label (OL) extensions, subjects took extended‐release, once‐daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. Results: Of 590 DB‐trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it ‘very much more convenient’ and 27.8%‘more convenient’), 2.7% preferred t.i.d., and 2.9% chose ‘no difference’. Of 465 DB‐trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it ‘very much more convenient’ and 40.1%‘more convenient’), 5.7% preferred t.i.d., and 5.4% chose ‘no difference’. Results excluding DB‐placebo recipients were highly similar. Conclusions: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine‐agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced‐PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.     

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.