伯氏疟原虫K173株对喹哌抗药性的实验研究

用小剂量递增法培育伯氏疟原虫对喹哌的抗药性,起始剂量7 mg/kg×1,每传三代递增3.5 mg/kg,至20代,历时5个多月,培育出对喹哌有110倍以上抗性的虫系。抗喹哌伯氏疟原虫系对羟基喹哌、甲氟喹、青蒿酯、青蒿素都有明显的交叉抗性,对咯萘啶、氯喹和伯喹仅有微弱交叉抗性;对乙胺嘧啶和硝喹显示高敏效应。但该虫系的抗性尚不稳定,停药后连续血传12代,抗性水平由110多倍降至8倍.     

伯氏疟原虫对青蒿素抗药性的研究

仿Peters剂量递增法用伯氏疟原虫ANKA株及N株对QHS进行了抗药性的研究。经14个月的培育至第58代,QHS im注射“4日抑制性实验”的ED₅₀在RQ/ANKA系及RQ/N系分别为其亲代系的53.4及54.6倍,但经蚊传未获成功。在第40代(I₅₀=25)时,其50%的治愈剂量为其亲代系的5.4倍。停药传代其抗性会逐渐消失。该虫系对青蒿酯钠及蒿甲醚有明显的交叉抗性,其ED₅₀分别为其亲代系的13.1及11.7倍,对伯喹的抗性为2.9倍,对氯喹未见明显交叉抗性。     

伯氏疟原虫对青蒿素抗药性的研究

仿Peters剂量递增法用伯氏疟原虫ANKA株及N株对QHS进行了抗药性的研究。经14个月的培育至第58代,QHS im注射“4日抑制性实验”的ED_(50)在RQ/ANKA系及RQ/N系分别为其亲代系的53.4及54.6倍,但经蚊传未获成功。在第40代(I_(50)=25)时,其50%的治愈剂量为其亲代系的5.4倍。停药传代其抗性会逐渐消失。该虫系对青蒿酯钠及蒿甲醚有明显的交叉抗性,其ED_(50)分别为其亲代系的13.1及11.7倍,对伯喹的抗性为2.9倍,对氯喹未见明显交叉抗性。     

伯氏鼠疟原虫(Plasmodium berghei)对咯萘啶抗药性的研究

用本所传代已二十余年、对药物敏感的伯氏鼠疟原虫作种源,每转种一代给小白鼠口服单次量咯萘啶。第1代剂量为8 mg/kg,其后剂量每代增加2 mg/kg。转种至第23代,剂量达2,400mg/kg时,虽部分小鼠死亡,存活小鼠的原虫血症仍不转阴,此时原虫的抗药性为亲代原虫的300倍以上。抗咯萘啶鼠疟原虫(RPB_2)对氯喹、喹哌、吡咯喹、M-6407、阿的平与青蒿素等有一定程度的交叉抗药性。用对亲代原虫有效量的3～10倍治疗RPB_2原虫时,不能使原虫血症转阴。如不再用药,连续转种5代,RPB_2可恢复对咯萘啶的敏感性。     

伯氏鼠疟原虫(Plasmodium berghei)对咯萘啶抗药性的研究

用本所传代已二十余年、对药物敏感的伯氏鼠疟原虫作种源,每转种一代给小白鼠口服单次量咯萘啶。第1代剂量为8 mg/kg,其后剂量每代增加2 mg/kg。转种至第23代,剂量达2,400mg/kg时,虽部分小鼠死亡,存活小鼠的原虫血症仍不转阴,此时原虫的抗药性为亲代原虫的300倍以上。抗咯萘啶鼠疟原虫(RPB₂)对氯喹、喹哌、吡咯喹、M-6407、阿的平与青蒿素等有一定程度的交叉抗药性。用对亲代原虫有效量的3～10倍治疗RPB₂原虫时,不能使原虫血症转阴。如不再用药,连续转种5代,RPB₂可恢复对咯萘啶的敏感性。     

胍丁胺对伯氏疟原虫K173株的抗疟作用(英文)

AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.     

口服青蒿琥酯对伯氏鼠疟和诺氏猴疟的杀灭效果

目的:研究青蒿琥酯口服对伯氏鼠疟和诺氏猴疟的血液裂殖体杀灭效果。方法:分别在鼠疟和猴疟模型上采用“4-day试验法”、“28-day试验法”和“7-day试验法”检测了青蒿琥酯和氯喹的药效。结果:口服青蒿琥酯对伯氏鼠疟民K_(173)株的抑制效果低于氯喹,但其原虫血症下降50％、90％和转阴的时间比氯喹快10-15h,对抗株RC/K_(173)的疗效优于氯喹,无交叉抗性,I_(90)仅为1.4。青蒿琥酯和氯喹对诺氏猴疟在31.6,10.0和3.16mg·kg~(-1)剂量组的试验猴全部治愈。结论:口服青蒿琥酯在鼠、猴疟模型上的药效研究为临床研究提供有益参考。     

青蒿素哌喹片治疗无并发症恶性疟的剂量探索试验

目的探索青蒿素哌喹片治疗无并发症恶性疟的安全有效的适宜剂量。方法收治7～65岁男性和女性病人共100例,按区组随机化方案分成2组,成人总量1400 mg组年龄(22±s12)岁,1750 mg组年龄(21±12)岁。分别于0h和24h给药一次,比较2组的平均原虫转阴和退热时间、28d治愈率及原虫复燃率。结果2组的平均原虫转阴时间分别是(61±19)h和(57±21)h,平均退热时间为(20±15)h和(18±10)h,P>0.05;28 d治愈率是80%和96%,原虫复燃率为20%和4%,总量1750 mg组显著优于1400 mg组(P<0.05)。2组耐受性均良好,未发现明显的不良反应。结论推荐青蒿素哌喹片的临床治疗剂量为总量1750 mg,每日1次,分2d服完为1个疗程。     

疟原虫组织期裂殖体杀灭剂4-甲基-5-(对-氟苯氧基)伯氨喹类似物的合成

A series of. analogues of 4-methyl-5-(p-fluorophenoxy)-primaquine have been prepared for evaluating of tissue schizonticidal actiyity of Plasmodium yoelii in mice. 2-Bromo-4-acetamino-5-nitroanisole was reacted with pfluorophenol in the presence of potassium hydroxide to give 2-(p-fluorophenoxy) 4-acetamino-5-nitroanisole, which was subsequently hydrolyzed to yield corresponding amino compound. Cyclization of the amino compound with methyl vinyl ketone afforded 4-methyl-5-(p-fluorophenoxy)-6-methoxy-8-nitroquinoline. This product was reduced by iron and acetic acid to give corresponding 8-aminoquinoline. The latter was condensed with bromoalkylphthalimides to yield 4-methyl-5-(pfluorophenoxy)-6-methony-8- (1-phthalimidoalkyl) aminoquinolines (Ⅳ₁～Ⅳ₇). These compounds were heated with hydrazine hydrate to form 4-methyl-5-(p-fluorophenoxy)-6-methoxy-8-(1-aminoalkyl)aminoquinolines(Ⅳ₈～Ⅳ₁₃), and 4-methyl-5-(p-fluorophenoxy) primaquine (Ⅱ).Compound Ⅱ synthesized was radical curative at 10 mg/kg×1, while the analogues Ⅳ₉ and Ⅳ₁₀ were radical curative at 100 mg/kg×1 against P. yoelii in mice.     

红曲菌发酵黄精渣审查monacolin K的探索性研究

目的 开展以紫色红曲菌固体发酵黄精渣生产重要降血脂肪成分monacolin K的探索研究。方法 系统考察了红曲菌发酵过程中黄精渣加入量、辅料黄豆粉与米粉的配比、含水量、发酵时间等因素对monacolin K产量的影响。结果 在紫色红曲菌（Monascus purpureus）发酵黄精渣生产monacolin K的过程中，当含水量为40%、黄精加入量为70%，米粉与黄豆粉加入量为1:1，在25 ℃下发酵30 d，monacolin K的产量可以达到16.21 mg·g^-1。结论 这一新固体发酵方式既能充分利用黄精深加工废弃物，又能高效产生降血脂生物活性组分，是中药材深加工的一个切实可行的开发方向。     

Interaction between saquinavir and antimycotic drugs on C. albicans and C. neoformans strains

Candidiasis and cryptococcosis are the most common fungal diseases among patients suffering from HIV infection. In the present work we assess whether the combined therapies, proteinase inhibitors and antimycotic drugs, could modify the therapeutic effect of antimycotics. An in vitro study to evaluate the antifungal effect of saquinavir and antimycotic drugs combination on yeast growth was performed. Strains of C. albicans and C. neoformans from HIV-seropositive patients were used. Susceptibility tests of yeasts to amphotericin B, 5-fluorocytosine, miconazole and fluconazole, singly and in combination with saquinavir, were performed in two different media. In the combinations the antimycotic agents and saquinavir were tested at sub-inhibitory concentrations: 0.1-10 microg ml(-1) and 12.50 microg ml(-1), respectively. The fractionary inhibitory concentration (FIC) index was also calculated. The results show that the interaction between saquinavir and all the antimycotic drugs never resulted in antagonism. Fluconazole acts in more synergistic way, no matter which medium is used. The combined therapy miconazole/saquinavir results in synergism, especially in Sabouraud. The total absence of antagonism and the presence of synergism suggest that a combined therapy could be proposed in the treatment of HIV-seropositive patients to reduce side effects, thanks to the use of lower doses of antimycotic drugs.     

曲茎石斛及其近似种鉴别的形态和DNA分子证据

目的　探讨曲茎石斛(南阳居群)与同属近似种:细茎石斛(南阳居群)、霍山石斛(霍山居群)、铁皮石斛(天台居群)药材鉴别的形态及DNA分子证据。方法　对曲茎石斛(南阳居群)及其近似种的药材进行了外部形态和rDNA ITS序列比较。结果　曲茎石斛及其近似种药材的外部形态虽无明显区别,但在rDNA ITS序列上却存在着显著而稳定的差异。曲茎石斛(南阳居群)与铁皮石斛(天台居群)的rDNA ITS序列的差异最小,绝对遗传距离为7;但与细茎石斛(南阳居群)及霍山石斛(霍山居群)rDNA ITS区的差异较大,绝对遗传距离分别为40和42。在rDNA ITS区域中,作者共挑选了7个碱基位点用作鉴别曲茎石斛(南阳居群)及其近似种的DNA证据。结论　根据药材的形态特征及rDNA ITS区碱基序列差异,可准确鉴别曲茎石斛及其近似种药材。     

Update on antifungal drug resistance mechanisms of Aspergillus fumigatus

Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis (IA) remains unacceptably high. Aspergillus fumigatus still accounts for the majority of cases of IA; however less susceptible to antifungals non-fumigatus aspergilli began to emerge. Antifungal drug resistance of Aspergillus might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, has brought resistance testing to the forefront of clinical mycology. In addition, molecular biology has started to shed light on the mechanisms of resistance of A. fumigatus to azoles and the echinocandins, while genome-based assays show promise for high-throughput screening for genotypic antifungal resistance. Several problems remain, however, in the study of this complex area. Large multicenter clinical studies--point prevalence or longitudinal--to capture the incidence and prevalence of antifungal resistance in A. fumigatus isolates are lacking. Correlation of in vitro susceptibility with clinical outcome and susceptibility breakpoints has not been established. In addition, the issue of cross-resistance between the newer triazoles is of concern. Furthermore, in vitro resistance testing for polyenes and echinocandins is difficult, and their mechanisms of resistance are largely unknown. This review examines challenges in the diagnosis, epidemiology, and mechanisms of antifungal drug resistance in A. fumigatus.