CYP1A1 and CYP1B1 genetic polymorphisms and uterine leiomyoma risk in Chinese women

Purpose  The aim of the study was to evaluate the association of CYP1A1 and CYP1B1 polymorphisms with uterine leiomyoma in Chinese women. Methods  We investigated 100 women with clinically diagnosed uterine leiomyoma and 110 healthy normal subjects from Chinese women. The genetic distribution of two CYP1A1 polymorphisms at MspI, Ile462Val and four CYP1B1 polymorphisms at Arg48Gly, Ala119Ser, Leu432Val, Asp449Asp were analyzed by polymerase chain reaction–restriction fragment length polymorphism and DNA sequencing method. Results  All the SNPs showed polymorphisms in Chinese women. The genotype A/G and the allele G on Ile462Val was significantly different between uterine leiomyoma patients and controls (P < 0.05). Conclusion  These results suggest that the genotype of CYP1A1 Ile462Val was associated with the increased risk of uterine leiomyomas in Chinese women. Capsule This is the first report that demonstrates the polymorphism at Ile462Val of CYP1A1 to be associated with uterine leiomyoma in Chinese women.     

Multimodal Dispersion of Nanoparticles: A Comprehensive Evaluation of Size Distribution with 9 Size Measurement Methods

Purpose

Evaluation of particle size distribution (PSD) of multimodal dispersion of nanoparticles is a difficult task due to inherent limitations of size measurement methods. The present work reports the evaluation of PSD of a dispersion of poly(isobutylcyanoacrylate) nanoparticles decorated with dextran known as multimodal and developed as nanomedecine.

Methods

The nine methods used were classified as batch particle i.e. Static Light Scattering (SLS) and Dynamic Light Scattering (DLS), single particle i.e. Electron Microscopy (EM), Atomic Force Microscopy (AFM), Tunable Resistive Pulse Sensing (TRPS) and Nanoparticle Tracking Analysis (NTA) and separative particle i.e. Asymmetrical Flow Field-Flow Fractionation coupled with DLS (AsFlFFF) size measurement methods.

Results

The multimodal dispersion was identified using AFM, TRPS and NTA and results were consistent with those provided with the method based on a separation step prior to on-line size measurements. None of the light scattering batch methods could reveal the complexity of the PSD of the dispersion.

Conclusions

Difference between PSD obtained from all size measurement methods tested suggested that study of the PSD of multimodal dispersion required to analyze samples by at least one of the single size particle measurement method or a method that uses a separation step prior PSD measurement.

     

Metabolite profiling of 14C-omacetaxine mepesuccinate in plasma and excreta of cancer patients

1. Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors.

2. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72?h after a single 1.25-mg/m² subcutaneous dose of ¹⁴C-omacetaxine in cancer patients.

3. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification.

4. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4′-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4′-desmethyl homoharringtonine (4′-DMHHT) was the most abundant metabolites.

5. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.

     

Cocaine self-administration on a hold-down schedule of reinforcement in rats

Rationale and objective  Although many contingencies operating in the natural environment include continuous dimensions of responses and reinforcers, previous studies of drug self-administration have almost exclusively used discrete dimensions of responses (e.g., a lever press) and reinforcers (e.g., 1.0 mg/kg/injection cocaine). Therefore, the present study provides an initial examination under experimental conditions with both responses and reinforcers measured along continuous dimensions. Materials and methods  Cocaine-maintained responding was studied in rats under a novel, hold-down schedule of reinforcement wherein the duration of the response was directly related to the magnitude of the reinforcer. These conditions were established by activating the syringe pump when the lever was pressed down and turning the pump off when the lever was released. The concentration of cocaine available in the syringe was varied across sessions. Results  Cocaine self-administration was readily maintained under these conditions and remained stable across sessions. Responding was concentration dependent, with the number of responses and total duration of the response inversely related to concentration, and overall session intake of cocaine was stable across concentrations. In general, the duration of the responses were less than 0.5 s and did not vary as a function of concentration. Conclusions  Stability of responding under these schedule conditions was acquired quickly. This schedule of reinforcement may be useful for comparing across drug classes, can be extended for use with other types of responses and reinforcers, and may be more representative of the natural world where response-reinforcer contingencies are more likely to be experienced along continuous, rather than discrete, dimensions. Drake Morgan and Yu Liu contributed equally to this publication.     

Liquid chromatography–tandem mass spectrometric assay for the quantitation in human plasma of the novel indenoisoquinoline topoisomerase I inhibitors,NSC 743400 and NSC 725776

Topoisomerase I (Topo I) is a recognized target for ovarian, lung, and colorectal cancer therapy. The FDA-approved camptothecin (CPT) Topo I inhibitors, topotecan and irinotecan are labile and their effects are rapidly reversible. The indenoisoquinoline topoisomerase I inhibitors, NSC 743400 and NSC 725776, have been developed as a new generation of Topo I inhibitors and are being advanced to clinical evaluation. To support the clinical development of NSC 743400 and NSC 725776, we developed and validated, according to FDA guidelines, LC–MS/MS assays for the sensitive, accurate and precise quantitation of NSC 743400 and NSC 725776 in 0.2 mL human plasma. After ethyl acetate extraction, separation was achieved with a Synergi Polar RP column and a gradient of 0.1% formic acid in acetonitrile:water. NSC 743400 and NSC 725776 eluted at approximately 3 min, and the total run time was 14 min. Detection consisted of electrospray, positive-mode ionization mass spectrometry. Between 3 and 1000 ng/mL, accuracy was 96.9–108.2% for NSC 743400 and 95.1–106.7% for NSC 725776, and precision was <11.4% for NSC 743400 and <5.9% for NSC 725776. Extraction recovery was >80% for both analytes, and ion suppression ranged from −46.7 to 5.7%. The use of isotopically labeled internal standards and a wash phase at the end of the run were necessary to achieve adequate assay performance. Protein binding in human plasma as assessed by equilibrium dialysis showed both indenoisoquinolines to be more than 98% protein bound.     

Effects of point application on celiac mast cell degranulation in mice with allergic rhinitis: An experimental study

目的：研究不同处理方法对卵白蛋白（Ovum Albumin,OVA）变应性鼻炎小鼠模型腹腔肥大细胞脱颗粒的影响。方法：将60只雌性小鼠随机分为5组,每组12只,分别按不同方法处理后分离各组小鼠的腹腔肥大细胞,中性红染色后计算腹腔肥大细胞脱颗粒率。结果：正常对照组、OVA变应性鼻炎组、穴位敷贴组、激素对照组、磷酸盐缓冲液（Phosphate Buffer Saline,PBS）阴性对照组小鼠腹腔肥大细胞脱颗粒率分别为（15±6）％、（53±11）％、（37±13）％、（31±15）％、（47±14）％。OVA变应性鼻炎小鼠的腹腔肥大细胞有明显的脱颗粒现象：与OVA变应性鼻炎小鼠相比,穴位敷贴组及激素对照组小鼠的腹腔肥大细胞脱颗粒现象显著减轻;PBS对照组小鼠的腹腔肥大细胞脱颗粒现象没有明显变化。结论：推测穴位敷贴抗过敏机制为稳定肥大细胞膜,抑制肥大细胞脱颗粒,减少致炎介质产生。     

Clinical trial on the role of tuina in rehabilitation therapy following total hip replacement

目的：观察推拿在全髋关节置换术后康复治疗中的临床疗效。方法：将60例患者随机分成治疗组和对照组。治疗组30例进行推拿结合康复治疗,对照组30例进行单纯康复治疗。两组均治疗2星期。分别观察两组患者术后7天、术后2星期、术后6星期的改良人工髋关节Harris量表及汉密尔顿焦虑量表（Hamilton Anxiety Rating Scale,HAMA）。结果：Harris量表评分总分,两组组内患者不同时间点多重比较差异有统计学意义（P〈0．05）;术后1天、术后7天及术后6星期两组间比较,差畀均无统计学意义（A,0．05）;术后2星期两组间比较差异有统计学意义（P〈0．05）。HAMA量表两组组内患者不同时间点多重比较差异有统计学意义（P〈0．05）;术后1天两纽间评分无显著性差异（P〉0．05）;术后7天、术后2星期、术后6星期两组间评分均有显著性差异（P〈0．05）。结论：单位时间内,推拿结合康复治疗对全髋关节置换术后患者的疼痛、关节活动范围及焦虑等方面的改善作用优于单纯康复治疗。