树脂法提取发酵液中利福霉素SV的研究

主要研究了树脂法提取发酵液中的利福霉素SV。结果表明，抚顺市鑫泰参茸保健品有限公司精细化工分公司生产的大孔吸附树脂DAl01A、DA201A，在水溶液中对利福霉素SV的最大吸附量分别为28．31mg／ml和25．19mg／ml。吸附后的DAl01A、DA201A树脂洗脱利福霉素SV的最佳洗脱剂为甲醇、乙醇70％（v／v）水溶液．发酵液经过滤后上柱吸附．洗脱后的利福霉素SV的收率分别高于85％和90％。     

利福平(Rifampicin)

利福霉素是1957年意大利从链丝菌Streptomyces mediterranei中得到的抗革兰氏阳性细菌和结核杆菌的抗菌素。链丝菌培养液中有利福霉素A、B、C、D、E五种物质。其中A、C、D、E为碱性,不稳定,较难分离,称为利福霉素混合体,仅利福霉素B是结晶,为一比较稳定的化合物。利福霉素B易转变成为其他衍生物,如经氧化、酸水解及还原,可转变为利福霉素O、S及SV。利福霉素SV是一高效的抗革兰氏阳性菌及结核分枝杆菌的抗菌素。据报导,利福霉素SV不仅可通过利福霉素B转化,而且可以用利福霉素B的产生菌经诱变剂处理,获得突变菌种,直接生产利福霉素SV及其他组份。科学工作者试制了利福霉素B的酯、酰胺及酰肼衍生物,从中选出了Rifamide。     

国产力复霉素注射剂的毒性与药理研究

力复霉素即利福霉素SV(Rifamycin SV),是一种新抗菌素。Sensi等首先发现从地中海链霉菌(S.mediterranei)产生利福霉素B。国外利福霉素SV生产初期主要是通过利福霉素B化学转化而得。我国四川抗菌素工业研究所1972年从桂林池塘泥土中分离得到了新的利福霉素产生菌——小单孢菌S—190(MicromonsporaS—190),它直     

利用均匀实验优化利福霉素SV发酵培养基氮源配比

应用均匀设计的方法对利福霉素SV发酵培养基中的氮源配比进行优化。研究了氮源中各成分对发酵效价的影响。确定各成分的最佳配比并用实验验证，使摇瓶发酵效价提高了10％以上。并对利福霉素SV产生菌在新、老培养基中的代谢特性进行了比较。     

利福霉素和利福平

1957年意大利米兰的莱佩蒂研究所Sensi等氏在链丝菌属Streptomyces Me-ditterranei发酵的培养基肉汤中发现一组天然抗菌素(利福霉素Rifamycin),其中利福霉素B活性最强,以后用人工方法改变其化学结构,先后获得O、S、SV三种衍化物,利福霉素S和SV的制菌力比利福霉素B和O强,而利福霉素SV的毒性又比利福霉素S小,故利福霉素SV在1962年就开始应用于临床。1962-1964年中已有很多学者报告了关于利福霉素实验研究和临床研究的结果,1965年Bergamin和Fowst两氏系统地报告了它们的化学结构,试管内的活性,药理及临床应用价值。利福霉素SV在试管内能抑制革兰氏阳性菌和抗酸菌的生长,尤其对结核菌和麻风杆菌显示有极强的制菌力,但口服疗效很不理想。1966年Maggi等氏又从几百个半合成的利福霉素衍化物中找到了利福平,它口服吸收很好,治疗结核病相当理想。     

利福平的临床应用——探讨对肺结核的治疗问题

利福霉素SV,利福霉素B二乙胺及利福平是利福霉素类抗菌素中评价最高的抗结核新药,也是抗菌、抗麻风新药,主要用于肺结核复治。1957年,意大利首先从法国土壤中分离出地中海链丝菌,在培养发酵液中发现利福霉素。后来,又从各国土壤中分离的链丝菌,选出产生菌,在发酵液中获得利福霉素A、B、C、D、E五种新抗菌素,从利福霉素B氧化获得利福霉素O,水解获得利福霉素S,再还原获得利福霉素SV(Rifamy     

力复霉素SV(钠)针剂的试制

1957年意大利发现利福霉素后,直到1962年利福素霉SV针剂才大量使用于临床,它对革兰氏阳性菌感染和结核菌感染有显著效果。国外利福霉素SV针剂(含利福霉素SV250mg)以高达人民币5元/支的价格向我国出售。在毛主席革命路线的指引下,通过批林批孔运动,我国也试制成功了这一抗菌素,名为力复霉素,粉碎了资本主义     

利福霉素族的薄层色层分离

本文报导了利福霉素 B 衍生物:利福霉素 O(Ⅰ),S(Ⅱ),3-特丁胺利福霉素S(Ⅲ),3-特丁胺利福霉素 SV(Ⅳ),3-甲酰利福霉素 SV(Ⅴ)硅胶薄层色层分离。在探讨薄层分离条件中,主要采用了作者本国 KCK№2,颗粒性硅胶。将硅胶置球形研磨器中研磨四小时,经0.1mm 筛孔过筛。取1.5克硅胶,0.06克石膏和6毫升 pH     

硝酸钾浓度对发酵法生产利福平-SV的效价影响的研究

利福霉素-SV(Rifanmycin)是广谱抗生素之一，也是合成利福平、利福定等抗结核药的中间体，它是由地中海诺卡氏菌经液体发酵提取纯化而制得，在发酵中的培养基中，硝酸钾对地中海诺卡氏菌生物合成利福霉素SV有刺激作用。培养基中加入定量的硝酸钾有利于提高利福霉素SV的产量。过去我厂50m^3发酵罐培养基配方中硝酸钾的浓度是6g／100ml。在生产中发现120小时以后出现了利福霉素SV的发酵单位增长缓慢甚至下降的情况。     

利福霉素SV生物合成的代谢调节的研究

利福霉素作为一类抗生素,由地中海链霉菌(Streptomyces mediterranei)(现在称为地中海诺卡氏菌(Nocardia mediterranei)产生,它首先在1959年为Sensi等报道。有关利福霉素的生产、生物合成和发酵方面的综述已经发表。我们对于利福霉素SV的研究工作几年前就开始,主要集中在它的生物合成的调节机制方面。本文主要侧重报道了近来的进展。一、硝酸盐和无机磷的调节影响 (一)硝酸盐的影响在丰富培养基中,硝酸盐明显促进地中海诺卡氏菌NG12-4产生利福霉素SV(增加     

The interaction of rifamycin SV with hepatic transport of taurocholic acid in the isolated perfused rat liver

Summary The effect of rifamycin SV on hepatic transport of taurocholic acid was investigated using isolated perfused rat liver technique. In all experiments, the perfused liver was maintained at taurocholic acid steady state by infusing constant amount of taurocholic acid.Infusion of rifamycin SV at various rates decreased biliary secretion of bile acids in a dose-dependent manner. Replacement of rifamycin SV by perfusion medium reversed this effect.To determine the site of action of rifamycin SV, kinetic experiments with ¹⁴C-taurocholic acid were undertaken. Rifamycin SV elevated the half-life of the medium disappearance of ¹⁴C-taurocholic acid. Furthermore, the antibiotic delayed the biliary appearance of ¹⁴C-taurocholic acid.The analysis of the results gave indications that the antibiotic interferred with hepatic uptake as well as biliary secretion of taurocholic acid.Part of this publication was presented in the 18. Frühjahrstagung der Deutschen Pharmakologischen Gesellschaft (1977)     

Oxygen radical damage to DNA by rifamycin SV and copper ions

The hydroquinone moiety of the antibiotic rifamycin SV reacts with molecular oxygen to form reduced oxygen intermediates such as superoxide (O2-.) and hydrogen peroxide (H2O2). The antibiotic semiquinone is also formed. Rifamycin SV in the presence of iron and copper salts can lead to the formation of the highly reactive hydroxyl radical (OH) which degrades the sugar deoxyribose. This damage is substantially inhibited by the enzyme catalase and scavengers of the hydroxyl radical such as formate, mannitol and thiourea. When linear duplex DNA is substituted for deoxyribose only rifamycin SV and copper ions substantially degrade DNA with release from the DNA molecule of thiobarbituric acid-reactive products. Damage to DNA by rifamycin and copper ions is significantly inhibited by catalase but poorly inhibited by scavengers of the hydroxyl radical consistent with a site-specific radical reaction of the DNA molecule. Several biological properties of rifamycin SV are known to resemble those of the metal chelating agent 1,10-phenanthroline. Here, we show that similarities extend to an unusual chemical property whereby thiobarbituric acid-reactive material is released from DNA in the presence of a copper salt.     

含利福霉素钠注射液方案治疗肺结核的有效性和安全性评价

目的 :评价含利福霉素钠注射液 (SV)方案治疗肺结核的疗效和安全性。方法 :按随机配对法将44例肺结核患者分为利福霉素钠组 2 1例和常规治疗组 2 3例。化疗方案 :治疗组 2 1例采用 2HZE +SV 7HR方案治疗 ,对照组采用 2HRZE 7HR方案治疗。结果 :疗程结束时 ,治疗组痰菌转阴率 85 .7% ,病灶吸收好转率 90 .5 % ,对照组痰菌阴转率60 .9% ,病灶吸收好转率 60 .9% ,两组比较有统计学意义 (P <0 .0 5 )。结论 :含利福霉素钠注射液方案治疗肺结核有助于痰菌转阴和病灶吸收 ,疗效满意     

The effect of rifamycin SV on the wound-healing process.

The influence of rifamycin SV on the healing process of a wound was studied in animal experiments. Measurement of the degree of cicatrization, determination of the free hydroxyproline in serum, and histological findings helped to demonstrate that local application of rifamycin SV leads to an increased fibrinous conglutination of the lips of the wound at an early phase of the healing process and the subsequent formation of fibres in the regenerative tissue is not impaired.     

Rifamycins as inhibitors of collagenase activity: Their possible pharmacological role in collagen degradative diseases

The interaction of commercial rifamycin SV, rifamycin B, rifampicin and some other semi-synthetic analogous with collagenase in vitro was studied by using the fluorogenic substrate Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH₂. Increased fluorescence, due to the removal of the NH₂-terminal dinitrophenyl group, after cleavage of the probe by collagenase was monitored and related to the enzyme activity. The peptide was an efficient substrate for collagenase with a K_m of 0.83 µM at 20°C in the presence of 10 µM Ca^{2 +}, pH= 7.5. In the same conditions, in the presence of rifamycin SV, rifampicin and rifamycin B or their semi-synthetic analogues AM₄₁, MC₁₁ and MC₃₀, a marked inhibition of the enzyme activity was observed and an IC₅₀ ranging from 13.1 to 20.7 µM was calculated. The inhibitory effect was reversible as demonstrated by restoration of enzyme activity by dialysis. These results may support the hypothesis that drugs based upon inhibitors of collagenase activity will provide a therapeutical tool for the underlying pathological destruction of extracellular matrix observed for instance in rheumatoid arthritis as reported by several authors.     

Electrochemical behavior and differential pulse polarographic determination of rifampicin in the pharmaceutical preparations

Differential pulse polarographic (DPP) analytical procedure for the rifampicin antibiotic, which can be applied to monitor its synthetic process from the starting antibiotic of rifamycin B or rifamycin SV, has been developed based on the electrochemical reduction of an azomethine group. Rifampicin exhibited a cathodic peak due to the azomethine group in the side chain of 3-[(4-methyl-1-piperazinyl)imino]methyl moiety and another cathodic peak due to the carbonyl group in rifamycin SV by DPP The experimental peak potential shift of an azomethine reduction was -73 mV/pH in the pH range between 3.0 and 7.5, agreeing with involvement of 4 e- and 5 H+ in its reduction. By the cyclic voltammetric(CV) studies, the azomethine and the carbonyl reductions in rifampicin were processed irreversibly on the mercury electrode. The plot of peak currents vs. concentrations of rifampicin ranging 1.0 x 10(-7) M tp approximately 1.0 x 10(-5) M yielded a straight line with a correlation coefficient of 0.9996. The detection limit was 1.0 x 10(-8) M with a modulation amplitude of 50 mV. DPP has been successfully applied for the determination of rifampicin in the pharmaceutical preparations.     

Pharmacokinetics and tissue distribution of rifametane, a new 3-azinomethyl-rifamycin derivative, in several animal species

Single and repeated dose experiments in mice, rats, dogs and monkeys are reported in this study to assess the pharmacokinetics and tissue distribution of rifametane, a new semi-synthetic rifamycin with the chemical formula 3-[(1-diethylaminoethylidene)azinomethyl]rifamycin SV (CAS 94168-98-6, SPA-S-565). All the kinetic tests were carried out in comparison with known rifamycin derivatives, as rifampicin (CAS 13292-46-1) or rifamycin SV (CAS 6998-60-3). Mice received single i.v. and oral administration of 10 mg/kg of rifametane or of rifampicin and serum samples were obtained up to 96 h after dosing. The two antibiotics showed similar peak of serum concentrations, but rifametane showed a longer half-life and higher AUC values. In an additional experiment, the tissue/serum ratio after the 10 mg/kg oral dose was lower than unity for lungs and kidneys, while the liver/serum ratio exceeded the unity at all sampling times. After 4 weeks of once weekly administration measurable serum and tissue concentrations were observed, and after twice weekly administration for the same time period some blood and tissue accumulation was seen. Rats were treated with a single intravenous injection of 20 mg/kg of rifametane or rifampicin and with single oral or i.m. administration of 60 mg/kg of rifametane or reference standards (rifampicin and rifamycin SV resp.), in two separate trials. The serum half-life of the test antibiotic after i.v. dose was 6 times longer than that of rifampicin and the serum concentrations of rifametane after oral and i.m. doses were higher and longer-lasting than those of the reference compounds. Repeated daily administrations of rifametane at three dose levels (3, 10, 30 mg/kg p.o.) for 4 weeks induced very high serum and liver concentrations. Dogs received a single oral dose of 1.25 mg/kg of rifametane or 2.5 mg/kg of rifampicin. The serum half-life of rifametane resulted 3 times longer than that of rifampicin. Remarkable serum and tissue concentrations were observed after 3-4 weeks of daily oral administration of rifametane at 3, 10, 30 mg/kg dose. Monkeys were given single oral or i.m. administration of 30 mg/kg of rifametane or reference standards (oral rifampicin and i.m. rifamycin SV). The serum concentrations after rifametane were higher and more sustained than those of reference compounds and the half-lives of the test antibiotic were about 2.5 (p.o.) to 6 times (i.m.) longer. The urine excretion of rifametane after a single intravenous dose in rats and a single oral dose in dogs was very low, while rifampicin had a little higher urine concentrations.     

3-N-Substituted aminomethyl derivatives of rifamycin SV. A convenient method of synthesis, cyclization of certain derivatives, and anticellular and antiviral activities of several derivatives.

A new synthesis of Mannich bases of rifamycin SV using the Borch2 procedure with rifaldehyde is described. This new synthesis offers two advantages over the previously published method. It provides a route to monoalkyl-aminomethylrifamycins (le-h) and to unsubstituted aminomethylrifamycins that were not accessible by the old procedure. The new method also offers a preparative route to Mannich bases 1a and 1b were needed in multigram quantities for biological testing. In addition, the cyclization of certain of the monoalkylaminomethylrifamycins to the novel N,15-didehydro-15-epi[methano(alkylimino)]rifamycin SV derivatives (2) is described. The anticellular and antiviral effects of representatives of both series of compounds against cultured mouse cells and murine oncornavirus are are discussed.     

Effect of reduced glutathione (GSH) on pharmacokinetics and distribution of rifamycin SV in rats

Changes of the pharmacokinetic parameters of rifamycin SV in the blood and changes of the antibiotic concentration in rat organs after its coadministration with glutathione in reduced form (GSH). in oxidized form (GSSG) and with the individual amino acids entering the tripedtide were studied. The use of reduced glutathione together with rifamycin was found to accelerate the distribution phase in the kinetics of the antibiotic in the blood by acceleration of transport of the drug from central compartment (blood) to tissue compartment (tissues), this being reflected by increased K₁₂ and K₁₂/K₂₁ values. Studies of the distribution of rifamycin in individual rat organs have shown GSH to significantly elevate the concentration of the antibiotic in the lungs with concomitant reduction of its level in the liver. The blocking of free sulfhydryl groups of glutathione by its use in oxidized form completely abolished this effect. The administration of rifamycin together with l-cysteine resulted in increased concentration of the antibiotic in both lungs and liver. The two other amino acids entering GSH —glycine and l-glutamic acid — did not cause any changes of rifamycin concentration in the organs. From these results it may be concluded that the mechanism of the observed effect of glutathione on rifamycin concentration differs in the lungs and liver though both effects are mediated by the free sulfhydryl groups of glutathione.