Seasonal variation in the content of a febrifugine and isofebrifugine alkaloid mixture in aerial parts of <Emphasis Type="Italic">Hydrangea macrophylla</Emphasis> var. <Emphasis Type="Italic">Otaksa</Emphasis>, with special reference to its antimalarial activity

Febrifugine and isofebrifugine alkaloid mixtures extracted from the leaves and buds of Hydrangea macrophylla var. Otaksa, collected during different months, in Japan, were quantified using high-performance liquid chromatography. Leaves collected during the flowering season, namely from June to August, contained 0.16–0.31 mg/g of the alkaloid mixture, whereas those collected from September to December had less than 0.03 mg/g of the mixture. However, extracts of buds harvested from October to February contained a consistently larger amount (more than 0.49 mg/g) of the alkaloids. Hot-water extracts from the leaves and buds collected during different seasons were evaluated for antimalarial activity against Plasmodium yoelii 17XL in mice. The extract of leaves collected in August demonstrated high antimalarial activity, and all mice that received the extract survived the infection. In contrast, the extract of leaves collected in December showed little activity. The extract of buds collected in December cleared parasites, but with subsequent mortality to mouse. The present results show that the amount of antimalarial agent—febrifugine and isofebrifugine mixture—in H. macrophylla var. Otaksa is both part- and season-dependent, suggesting that the choice of plant parts and their harvesting season are important factors worth considering in the pharmacological use of medicinal plants.     

GNAS gene mutations affecting XLαs and bone health: A long neglected relationship

The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.     

Long-term,open-label,safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease

Long-term safety of once-daily ropinirole extended/prolonged release (ropinirole XL/PR) was evaluated in subjects with early and advanced Parkinson's disease (PD) in this study, 101468/248. Subjects (n = 419) who completed one of three prior studies evaluating ropinirole XL/PR for the treatment of PD were enrolled in this open-label, multicenter, extension study, and were to be followed for up to 73 months. Ropinirole XL/PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/d). Levodopa (L-dopa) and other nondopamine agonist PD medications were permitted. Safety outcomes that were investigated included frequency of adverse events (AEs). Subjects’ preference regarding once daily versus three times daily study medication regimens was also investigated in a subset of the study population. The median duration of ropinirole XL/PR exposure was 1275 d. Most subjects (87%) reported at least one AE, with the most common (≥ 10%) AEs being, back pain (14%), hallucinations (13%), somnolence (11%) and peripheral edema (11%). Twenty-five percent of subjects discontinued the study prematurely due to an AE during the treatment period. Long-term treatment with ropinirole XL/PR was not associated with any new or unexpected safety concerns in patients with early and advanced PD, and a majority of subjects preferred the once-daily dosing regimen.     

HPLC-ELSD法测定葛兰心宁软胶囊中绞股蓝皂苷 XL IL 的含量

目的：建立以HPLC-ELSD法测定葛兰心宁软胶囊中绞股蓝皂苷XL IX含量的方法。方法色谱柱为Kromasil C18（250 mm ×4．6 mm,5μm）,流动相为乙腈—水（35∶65）,检测器为蒸发光散射检测器,流速2．8 L· min－1,漂移管温度105℃。结果绞股蓝皂苷XL IL的线性良好,Y（峰面积）＝1．56X＋5．25,r＝0．999,平均回收率（ n＝6）为101．56％,绞股蓝皂苷XL IX在0．513～10．254μg范围内线性关系良好。。结论该方法专属性强、重复性良好,可用于葛兰心宁软胶囊的质量控制。     

糖尿病强化治疗对大动脉硬化的影响

目的　观察瑞易宁联合络活喜强化治疗糖尿病对大动脉硬化的影响。　方法　糖尿病合并高血压6 3例 ,男 32例 ,女 31例 ,年龄 4 6岁～ 75岁 ,病情为慢性稳定期 ,除外心脑血管和糖尿病急症 ,随机分为A、B组。A组瑞易宁 5mg～ 2 0mgqd(餐前 )、络活喜 5mg～ 15mgqd联合治疗 ;B组美吡哒 5mg～ 10mgtid(餐前 )、长效心痛定 2 0mg～ 4 0mgq 12h联合治疗。两组根据病情可加用阿卡波糖、卡托普利和调脂药。疗程 6个月。观察治疗前和治疗后 3个月、6个月血糖、血脂、血压、主动脉内径和振幅的变化。　结果　A、B组在治疗前各项指标无差异 (P >0 0 5 )具有可比性。治疗后 6个月两组 :①空腹血糖≤ 6 1mmol L ,A、B组分别为 87 5 %对 73 3% (P <0 0 5 ) ;②非空腹血糖≤ 8 0mmol L ,为 81 3%对 6 6 7% (P <0 0 1) ;③血压≤ 130mmHg 80mmHg ,为 90 6 %对 73 3% (P <0 0 1) ;④血脂LDL C <2 6 0mmol L ,为 6 8 8%对 6 6 7% (P >0 0 5 ) ;⑤血压、脉压、主动脉内径和振幅的改善A组均优于B组。　结论　瑞易宁联合络活喜强化治疗能够平稳降糖、控压和改善糖尿病大动脉的硬化。     

BCL-2 family proteins in peripheral T-cell lymphomas: correlation with tumour apoptosis and proliferation

The present study investigated expression levels of the anti-apoptotic proteins BCL-2, BCL-XL and MCL-1 and the pro-apoptotic proteins BAX and BCL-XS in a series of 112 peripheral T-cell lymphomas (PTCLs) classified according to the WHO classification. Using immunohistochemical methods and a 10% cut-off, each protein was detected in a subset of PTCLs: BCL-2 in 46%, BCL-XS in 49%, BAX in 57%, BCL-XL in 57%, and MCL-1 in 65%. The mean percentage of positive cells for these proteins varied significantly among the PTCL types. Only two types of PTCL, ALK-positive anaplastic large cell lymphoma (ALCL) and enteropathy-type T-cell lymphoma, had a distinctive pattern of expression; all were BCL-2-negative and MCL-1-positive. The mean percentage of BAX-positive and BCL-XS-positive tumour cells was higher in ALK-positive ALCL than in ALK-negative ALCL or other types of PTCL (p = 0.06 and p = 0.01, respectively, Kruskal-Wallis test). MCL-1 was detected significantly more frequently (p = 0.01, chi-square test) and at higher levels (p = 0.0001, Kruskal-Wallis test) in ALK-positive ALCL and ALK-negative ALCL than in other PTCL types. The apoptotic rate, evaluated by the TUNEL assay, correlated inversely with BCL-2 expression (p = 0.035). The proliferation index, assessed by the MIB-1 antibody, correlated with expression levels of MCL-1 (R = 0.42, p = 0.003), BCL-2 (R = 0.32, p = 0.027), BAX (R = 0.33, p = 0.014), and BCL-XL (R = 0.34, p = 0.015) (Spearman rank). In conclusion, BCL-2 family proteins are expressed by a subset of PTCLs and their levels correlate with some histological types, apoptotic rate, and proliferation index. Expression of these proteins may explain the poor response of many types of PTCL to standard chemotherapy. These proteins may also provide novel targets for experimental therapy.     

Comparison of antimalarial activity of the alkaloidal fraction of Hydrangea macrophylla var. Otaksa leaves with the hot-water extract in ICR mice infected with Plasmodium yoelii 17 XL

The antimalarial activity of the fractions isolated from the leaves of Hydrangea macrophylla Seringe var. Otaksa Makino was evaluated against Plasmodium yoelii 17 XL in mice. Four different fractions were prepared in the usual manner to obtain an alkaloid fraction. All mice treated with the fraction containing febrifugine and isofebrifugine mixture at 1 mg/kg twice a day for 5 consecutive days survived during the experiment, and the change of mean parasitemia level showed almost the same pattern as that from mice treated with the hot-water extract of the same plant leaves. Activity of this fraction, however, was markedly reduced compared with the hot-water extract. Furthermore, no antimalarial activity was shown in the hotwater extract from H. macrophylla var. Otaksa roots or Dichroa febrifuga Lour. leaves.     

可多华与达克罗宁联合应用治疗早泄的临床研究

目的 探索、研究联合应用口服可多华（多沙唑嗪控释片）和局部涂抹达克罗宁药液治疗早泄的效果。方法 36例早泄病例，在性生活前6～8h服用可多华4mg，性生活前20min和10min各在阴茎皮肤和阴茎头涂抹一次达克罗宁。用药治疗后，射精潜伏时间延长≥4min者为有效；射精潜伏时间延长至34min者为改善；射精潜伏时间延长，但不到3min者为无效。结果 36例联合应用口服可多华和局部涂抹达克罗宁药液治疗后，总的有效率为50％，总的改善率为27．8％。结论 联合应用口服可多华和局部涂抹达克罗宁药液于阴茎皮肤及头治疗早泄，能够达到满意的效果。     

C5a/C5aR通路对约氏疟原虫增殖和小鼠生存的影响

目的观察C5a/C5aR通路对约氏疟原虫17XL（P.y17XL）的增殖及其对BALB/c小鼠致死率的影响。结论将实验小鼠分为正常BALB/c组和C5aR-/-BALB/c组,每组5只,相同剂量的P.y17XL（2×105）分别感染正常BALB/c组小鼠和C5aR-/-BALB/c组小鼠,于感染后0、2、4和6d观察两组小鼠原虫血症和存活率的变化,并且采用ELISA检测感染P.y17XLBALB/c小鼠血清中C5a的水平。结果与正常组小鼠相比,C5aR-/-组小鼠生存期缩短,P.y17XL在C5aR-/-组小鼠的原虫血症较野生株小鼠高（P〈0.05）,而P.y17XL感染小鼠的血清中C5a含量低于未感染的小鼠。结论 C5a/C5aR能够抑制P.y17XL的增殖,并能延长感染小鼠的生存期。     

Pinocembrin triggers Bax-dependent mitochondrial apoptosis in colon cancer cells

Bioflavanoids are the major pigments in plants with multitude of biological activities including inhibition of proliferation or induction of apoptosis in tumor cells. Even though the safety records of most flavanoids are exceptional, its therapeutic use is still in its infancy. We have isolated pinocembrin (5,7-dihydroxyflavanone) from Alpinia galanga that showed cytotoxicity against a variety of cancer cells including normal lung fibroblasts with relative nontoxicity to human umbilical cord endothelial cells. The compound induced loss of mitochondrial membrane potential with subsequent release of cytochrome c and processing of caspase-9 and -3 in colon cancer cell line HCT 116. Processing of caspase-8 was minimal. The initial trigger for mitochondrial apoptosis appears to be by the translocation of cytosolic Bax protein to mitochondria. Overexpression of proapoptotic Bax protein sensitized the colon cancer cells to pinocembrin-induced apoptosis and Bax knockout cells were resistant to pinocembrin-induced apoptosis. Antiapoptotic protein Bcl-X(L) only partially prevented apoptosis induced by this compound. The Bax-dependent cell death involving classical cytochrome c release and processing of caspase-9 and -3 suggests that pinocembrin is a classical mitochondrial apoptosis inducer. But the failure of Bcl-X(L) overexpression to completely prevent apoptosis induced by this compound suggests that pinocembrin is capable of triggering mitochondrial-independent cell death that needs to be clarified. The existence of cell death upon Bcl-X(L) overexpression is a promising feature of this compound that can be exploited against drug resistant forms of cancer cells either alone or in combination with other drugs.