头孢菌素的分类、药效及临床应用

头孢菌素类（cephalosporins）是冠头孢菌（cephaloseporium acremonium）培养得到的天然头孢菌素C（cephaloseporin C），分离到活性母核7-氨基头孢烯酸（7-ACA），经半合成改造其侧链而得到的一类抗生素。[第一段]     

海洋天然产物Polycarpaurines C的合成及其对新型冠状病毒SARS-CoV-2的抑制作用

摘 要：目的：合成海洋天然产物，含硫海洋生物碱Polycarpaurines C，并测试其对SARS-CoV-2的抑制作用。方法：将4-乙酰基苯硼酸为原料经过过氧化氢氧化、甲基化、溴化、引入甲胺基、与2-乙基异硫脲氢溴酸盐缩合、与S2Cl2氧化偶联等反应，经过7步合成Polycarpaurines C，并对其测试对于SARS-CoV-2的抑制作用，利用分子对接技术测试Polycarpaurines C与Mpro的结合。结果：合成了目标天然产物Polycarpaurines C，并对其测试了对SARS-CoV-2的抑制作用，结果显示Polycarpaurine C对SARS-CoV-2具有不错的抑制作用，测得IC50为13.76 μM，但是与阳性药还有一定的差距，可作为药物进一步开发的模板骨架。     

夜香树叶正丁醇提取物中流份C6和C7对人胃癌细胞SGC7901增殖和凋亡作用的影响

目的:研究夜香树(CN)叶正丁醇提取物中流份C6、C7对人胃癌细胞SGC7901增殖和凋亡的影响。方法:采用不同比例的氯仿-甲醇(1∶9、1∶7)对CN叶正丁醇部位梯度洗脱,得到流份C6和C7。将SGC7901细胞分为空白对照组和C6、C7组。分别用0(空白对照)、5、10、20、40、80μg/ml的C6、C7培养SGC7901细胞72 h后采用MTT法检测其对细胞的增殖抑制作用,计算增殖抑制率、半数抑制浓度(IC50);用10μg/ml C6、C7培养SGC7901细胞72 h后,采用集落形成法检测其对细胞的集落形成能力的影响,计算集落形成率;瑞氏-姬姆萨混染法、Hoechst 33258/碘化丙啶(PI)染色法观察细胞形态学变化。结果:MTT结果显示,流份C6、C7对SGC7901细胞增殖有不同程度的抑制作用,抑制率分别为22.1%~80.0%、19.6%~79.7%,IC50分别16.4、18.05μg/ml。与空白对照组比较,C6和C7组细胞的集落形成率降低,差异有统计学意义(P<0.05);给药组细胞凋亡细胞、死细胞更多。结论:CN叶正丁醇提取物中流份C6、C7可显著抑制SGC7901细胞增殖并诱导其凋亡。     

氨噻肟头孢菌素

序言氨噻肟头孢菌素(CTX)是由西德Hoec-hst公司和法国Rousell Uclaf公司共同研究成功的半合成头孢菌素(CEPs),在第10次I.C.C.及第18次I.C.A.A.C.会议上介绍它超越了以往CEPs的概念,完全作为新范畴的抗生素而登上舞台。7-氨基头孢烷酸(7ACA)的母核7位上导入a-(顺式-甲氧基亚胺基-氨基噻唑)-乙酰基,从其抗菌活性、抗菌谱,对β-内酰胺酶的稳定性,以及青霉素结合蛋白(PBP)的结合等方面来看,CTX已经达到近乎理想的物质。     

喜泊分

[通用名称]hematoporphyrin，血卟啉 [商品名]喜泊分 [化学名称]1，3，5，8，-四甲基-2，4-二（α-羟乙基）-卟吩-6，7-二丙酸，相对分子质量598．7，分子式C34H38N4O6。     

氟罗沙星的不良反应

氟罗沙星是第三代氟喹诺酮类抗生素。其化学名为6，8-二氟-1-（2-氟乙基）1，4-二氢-7-（4-甲基-1-哌嗪基）-4-氧-3-喹啉羧酸，分子式：C17H18F3N3O3，该药抗菌机制主要是通过抑制DNA旋转酶活性，而达到细胞内杀菌作用，其杀菌作用不受细菌生长期的影响，并且由于其抗菌谱广。杀菌作用强，被广泛应用于临床。近年来国内有文献报道其不良反应，现介绍如下：     

头孢菌素的分类、药效及临床应用

头孢菌素类(cephalosporins)是冠头孢菌(cephaloseporium acremonium)培养得到的天然头孢菌素C(cephaloseporin C),分离到活性母核7-氨基头孢烯酸(7-ACA),经半合成改造其侧链而得到的一类抗生素.     

4种呼吸道感染治疗方案的成本-效果分析

目的评价呼吸道感染的4种治疗方案的药物经济学效果。方法采用回顾性研究方法，选择114例呼吸道感染患者，按治疗方案分为4组（A，B，C，D组），分别观察其疗效并运用成本-效果分析法（CEA）进行分析。结果4组治疗方案成本分别为190．40，403．20，1380．96，174．72元，临床有效率分别为86．7％，86．7％，90．0％，62．5％，成本-效果比（C／E）分别为2．19，4．65，15．34，2．79，A，B，C组相对于D组的增量成本一效果比（△C／△E）分别为0．65，9．44，43．86。结论A组（头孢曲松组方案）为最佳的治疗方案。     

7-氨基-3-乙烯基头孢烷酸的酶解制备

头孢克肟是第三代口服头孢菌素 ,具有高效 ,长效 ,耐酶 ,剂量小等优点。其母核的合成 ,文献 [1]报道一般采用 7-氨基头孢烷酸 (7- ACA)或去乙酰头孢菌素 C钠盐 (DCCNa)为原料。我们初步探索了 C3位引入乙烯基的反应 ,发现难度较大。本文采用 7-苯乙酰胺基 - 3-氯甲基头孢烷酸对甲氧基苄酯(GCLE,2 )为原料 [2 ] ,经 3位 Wittig反应 ,4位脱甲氧苄基及 7位水解等 3步反应制得 7-氨基 - 3-乙烯基头孢烷酸 (7- AVC,1 )。收稿日期 :1999-0 8-16基金项目 :1999年度广州市重点科技攻关计划 (99-Z-119-0 1)作者简介 :许淑文 (196 8) ,女 ,工…     

用酶法从头孢菌素C生产7-氨基头孢霉烷酸

本文简介两种从头孢菌素以酶法生产7-氨基头孢霉烷酸(7-ACA)的方法,介绍如下:1.应用脱酰基化的酰基转移酶从 GL7-ACA 制取7-ACA 的方法:把头孢菌素 C进行氨基氧化,经过酮型7-ACA 制取7-(4-羧丁酰胺)-3乙酰氧甲基-3-头孢烯-4-羧酸(GL7-ACA)的方法已经完成。从头孢菌素 C 制取 GL7-ACA 的方法,有酶法和化学法二种。利用酶法使头孢菌素 C 的     

Enhancement of phosphatidylcholine biosynthesis by angiotensin-(1-7) in the rat renal cortex

In the present paper, we investigated the effect of angiotensin-(1-7) (Ang-(1-7)) on phospholipid biosynthesis in the rat renal cortex. A significant increase in phosphatidylcholine (PC) labeling was observed when cortical slices, prelabeled with [32P]orthophosphate, were incubated for 30 min in the presence of Ang-(1-7) (1 pM to 100 nM). Neither the phospholipase C inhibitors, neomycin or db-cAMP nor the protein kinase C inhibitors, chelerythrine or H7, modified the stimulatory effect induced by 0.1 nM Ang-(1-7). The enhancement of PC biosynthesis caused by 0.1 nM Ang-(1-7) was unmodified by either losartan, an AT(1) receptor antagonist, or (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate) (PD 123319), an AT(2) receptor antagonist, but was partially blocked by [D-Ala(7)]Ang-(1-7), an Ang-(1-7) specific antagonist. However, losartan potentiated the effect of 100 nM Ang-(1-7) on PC biosynthesis. Losartan by itself increased the de novo synthesis of PC. These results suggest that the Ang-(1-7)-mediated increase in PC biosynthesis is independent of AT(1) and AT(2) receptor activation but mediated by a specific Ang-(1-7) receptor. This mechanism is independent of phospholipase C and PKC activation.     

Temperature modulation of α- and β-adrenoceptors in the isolated frog heart

1. The effects of adrenaline on the isolated frog's heart at 27 degrees C are not antagonized by phentolamine (1.5 x 10(-6)M) but are abolished at 7 degrees C.2. At 27 degrees C isoprenaline was more potent than noradrenaline, but at 7 degrees C noradrenaline was more potent than isoprenaline.3. Phenoxybenzamine (1.5 x 10(-5)M) or dibenamine (1.5 x 10(-5)M) at 7 degrees C abolished the work output induced by adrenaline. When the temperature was raised to 24 degrees C, adrenaline caused an increase in work output.4. It is concluded that in the isolated frog heart there are at least two pools of adrenoceptors, the availability of which can be governed by temperature.     

In vitro inhibition of the classical pathway of human complement by a natural microbial product, colistin sulphate

Colistin sulphate was found to be an inhibitor of the classical pathway of the complement system. The main sites of inhibition were the interaction of EAC14 with C2 and EAC142 with C3. It also inhibited EAC14 formation from EA and C2-deficient serum, EAC1-7 formation from EAC1-3, C5, C6 and C7 and the interaction of EAC1-7 with C8 and C9, though less efficiently. It did not inhibit formation of C3/C5 convertase of the alternative pathway. The inhibition of the classical pathway was reversible since hemolytic activity was completely restored after dialysis.     

Evolution of the bioavailability and other pharmacokinetic parameters of levodopa (with carbidopa) in rabbits

Levodopa pharmacokinetics show important inter- and intraindividual differences when it is administered by the oral route. As a result of fluctuating drug plasma concentrations, patients may develop motor fluctuations and dyskinesias. Therefore, it is important to perform studies on levodopa pharmacokinetics in the same individual. The aim of this study was to contribute to a better knowledge of the evolution of the pharmacokinetics of levodopa administered with carbidopa. The study involved the oral administration of 20/5 mg/kg levodopa/carbidopa to rabbits for two different time periods (7 or 14 days), due to the fact that inhibition of aromatic L-amino-acid decarboxylase by carbidopa is not immediate. After 7 days of treatment, the levodopa AUC increased by 12.6% from day 1 (range: 114.2-150.7 microg.min/ml) to day 7 (range: 131.1-166.0 microg.min/ml) and C(max) increased by 9.6% (range: 1.90-2.86 microg/ml on day 1 and 2.12-3.13 microg/ml on day 7). After 14 days of treatment, the increase in AUC was 17.0% (range: 119.6-160.1 microg.min/ml on day 1 and 142.9-172.7 microg.min/ml on day 14) and C(max) increased by 6.5% (range: 2.29-2.96 microg/ml on day 1 and 2.41-3.07 microg/ml on day 14). The values obtained for C(min) (sample obtained immediately before levodopa/carbidopa administration) in both groups increased progressively with the duration of the treatment. C(max) and AUC values were very similar after 7 or 14 days of treatment. The time needed for C(min) stabilization was slightly higher, because we found significant differences until day 11 of treatment.     

Characterization of the antimuscarinic effect of heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl ammonium bromide)

The effect of heptane-1,7-bis-(dimethyl-3'-phthalimidopropyl ammonium bromide) (C7/3'-phthalimidopropyl), an alkane bisquaternary compound with muscarinic receptor blocking activity was studied in guinea-pig atria and ileal longitudinal muscle. C7/3'-phthalimidopropyl was a more potent inhibitor of atrial muscarinic receptors, the cardioselectivity being ca. 32-fold. Previous studies in guinea-pig atria have shown that its antimuscarinic effect was of an allosteric nature. In ileal longitudinal muscle C7/3'-phthalimidopropyl (3 to 100 microM) appeared to behave in a competitive manner towards carbachol but the combination of atropine or homatropine with C7/3'-phthalimidopropyl produced a supra-additive inhibitory effect on the responses to carbachol. In both atria and ileal longitudinal muscle homogenates, C7/3'-phthalimidopropyl also slowed the dissociation rate of [3H]QNB suggesting an allosteric mechanism. In binding studies using either [3H]QNB or [3H]oxo-M, C7/3'-phthalimidopropyl recognized two binding sites in atria and ileum. In both tissues, C7/3'-phthalimidopropyl bound with high affinity (ca. 30-70 nM) to 60-85% of the sites and with low affinity (ca. 1-9 microM) to the remaining sites. Correlation of these affinity constants with the dissociation constants obtained in functional studies in the two tissues is discussed.     

Trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant recipients

AIMS: The influence of the trimethoprim-sulphamethoxazole combination on the steady-state pharmacokinetics of sirolimus, a potent macrocyclic immunosuppressant, was studied in renal transplant recipients. METHODS: Fifteen kidney transplant recipients were treated with sirolimus 8-23 mg m(-2) in combination with azathioprine and prednisolone from the day of transplantation. Whole blood sirolimus AUC and C(max) were determined on days 6 and 7 after transplantation. On day 7, sirolimus was coadministered with the first dose of trimethoprim (80 mg) and sulphamethoxazole (400 mg). RESULTS: On day 6, the mean (95% confidence interval) whole blood sirolimus AUC((0-24 h)) was 1040 (846, 1234) ng ml(-1) and mean C(max) was 109 (88, 129) ng ml(-1). Corresponding values on day 7 were AUC((0-24 h)) 1060 (826, 1293) ng ml(-1) and C(max) mean 107 (87, 127) ng ml(-1). The mean difference in the dose-corrected AUC((0-24 h)) was 0.40% (-9.4, +10). CONCLUSIONS: A single dose of trimethoprim-sulphamethoxazole does not affect the pharmacokinetics of sirolimus in renal transplant patients.     

Identification of the human cytochromes P450 catalysing the rate-limiting pathways of gliclazide elimination

AIMS: To identify the human cytochrome P450 (CYP) enzymes responsible for the formation of the 6beta-hydroxy (6beta-OHGz), 7beta-hydroxy (7beta-OHGz) and hydroxymethyl (MeOH-Gz) metabolites of gliclizide (Gz). METHODS: 6beta-OHGz, 7beta-OHGz and MeOH-Gz formation by human liver microsomes and a panel of recombinant human P450s was measured using a high-performance liquid chromatography procedure, and the kinetics of metabolite formation was determined for each pathway. Effects of prototypic CYP enzyme selective inhibitors were characterized for each of the microsomal metabolic pathways. RESULTS: Microsomes from six human livers converted Gz to its 6beta-OHGz, 7beta-OHGz, and MeOH-Gz metabolites, with respective mean (+/- SD) K(m) values of 461 +/- 139, 404 +/- 143 and 334 +/- 75 microm and mean V(max) values of 130 +/- 55, 82 +/- 31 and 268 +/- 115 pmol min(-1) mg(-1), respectively. V(max)/K(m) ratios for the microsomal reactions parallelled relative metabolite formation in vivo. Sulfaphenazole inhibited microsomal 6beta-OHGz, 7beta-OHGz and MeOH-Gz formation by 87, 83 and 64%, respectively, whereas S-mephenytoin caused significant inhibition (48%) of only MeOH-Gz formation. Recombinant CYP2C9, CYP2C18 and CYP2C19 catalysed all hydroxylation pathways, whereas CYP2C8 formed only 6beta-OHGz and 7beta-OHGz. CONCLUSION: Taken together, the results indicate that CYP2C9 is the major contributor to Gz metabolic clearance, although CYP2C19 may also be involved in MeOH-Gz formation (the major metabolic pathway). Factors known to influence CYP2C9 activity will provide the main source of variability in Gz pharmacokinetics.     

Effect of high-dose vitamin C on the steady-state pharmacokinetics of the protease inhibitor indinavir in healthy volunteers

STUDY OBJECTIVE: To determine whether daily high-dose vitamin C alters the steady-state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1. DESIGN: Prospective, open-label, longitudinal, two-period time series. SETTING: University medical center. SUBJECTS: Seven healthy volunteers. INTERVENTION: Indinavir 800 mg every 8 hours was given to subjects for four doses on days 1 and 2. Plasma samples were then collected for indinavir pharmacokinetic determination. After a 7-day washout period, subjects were given vitamin C 1000 mg/day for 7 days. Beginning on day 6 of vitamin C administration, indinavir 800 mg every 8 hours was restarted for four doses. Plasma was then collected from subjects to determine indinavir pharmacokinetics. All subjects were given a vitamin C content-controlled diet for 1 week before the study began and throughout the study period. MEASUREMENTS AND MAIN RESULTS: Steady-state plasma samples were collected before dosing (0 hr) and 0.5, 1, 2, 3, 4, and 5 hours after dosing to determine indinavir pharmacokinetics. Parameters of interest were maximum plasma concentration (C max ), time to C max , area under the plasma concentration-time curve from 0-5 hours after the dose (AUC 0-5 ), an extrapolated 8-hour AUC (AUC 0-8 ), trough (minimum) plasma concentration (C min ), and oral clearance. Mean steady-state indinavir C max was significantly reduced (20%) after 7 days of vitamin C administration (10.3 +/- 1.5 vs 8.2 +/- 2.9 microg/ml, p=0.04). The corresponding mean AUC 0-8 was also significantly decreased (14%; 26.4 +/- 7.2 vs 22.7 +/- 8.1 microg*hr/ml, p=0.05). Although not statistically significant, the mean indinavir C min was 32% lower in the presence of vitamin C (0.27 +/- 0.17 C vs 0.18 +/- 0.08 microg/ml, p=0.09). Indinavir oral clearance and half-life were not significantly different. CONCLUSION: Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations. Subtherapeutic concentrations of antiretroviral agents have been associated with viral resistance and regimen failure, but the clinical significance of our findings remains to be established.     

A 2-iminohydantoin from the oxidation of guanine

The nucleobase guanine was oxidized with dimethyldioxirane (DMDO) to explore the role of epoxidizing agents in oxidative DNA damage. Treatment of guanine with 10% molar excess DMDO in aqueous solution at 0 degrees C and pH 7.5 followed by workup under mild conditions gave 5-carboxamido-5-formamido-2-iminohydantoin (1) as the sole isolable product in 71% yield. The structure of 1 was established on the basis of mass spectrometry and NMR studies on 1 and its isotopomers generated by the oxidation of [4-(13)C] and [7-(15)N]guanine, which yield [5-(13)C]1 and [7-(15)N]1. The distribution of 13C and 15N labels in the isotopomeric products supports initial epoxidation of the C4-C5 bond of guanine followed by a 1,2-acyl migration of guanine C6. Compound 1 is suggested as a possible primary DNA lesion from putative epoxidizing agents, including hydroperoxides present during biological processes such as lipid peroxidation.