Experimental studies on absorption, distribution and excretion of fosfomycin. I. Absorption distribution and excretion of fosfomycin calcium salt (author's transl)]

In order to develop some oral drug preparations containing calcium salt of fosfomycin ((minus)-cis-1,2-epoxypropylphosphonic acid) which is a new antibiotic, the absorption, distribution and excretion were studied when it was administered orally to fasted test animals such as rats, rabbits and dogs. The results are as follows: 1) In the case of rats, the more dose size was increased, the more ratio of excretion in urine as index of gastrointestinal absorption was reduced and ratio of excretion in stools was adversely increased, which suggested a decrease in absorption efficiency. But, as absolute amount of excretion in urine became larger with dose size, it was considered that increase in dose size would serve for elevation of serum levels. 2) When the calcium salt was given to rats and rabbits in form of solution and suspension, the former was more eminent than the latter regarding to absorption efficiency, as generally known. The solution, however, needed relatively large quantity of water to solubilize the calcium salt, and it was not considered that the absorption efficiency depends on only dissolution step or dissolution rate. 3) Difference of the particle size varying from 1.50 mu(bulk particle size) and 0.64 mu(mechanical limit size) measured by Kozeny-Carman method did not affect on the absorption in rats and dogs. So it was considered that the bulk could be use directly without micronizing in manufacturing process for the oral preparations. 4) There were some differences of absorption among the animal species. Good absorption was shown in turn in rats, dogs and rabbits. These differences might depend not only on physiological factors but also anatomical differences such as length of gastrointestinal tract. 5) In rabbits high concentration was observed successively in kidney, lung, heart and so on. In any organ its level decreased similarly to the serum level, not sustaining its initial high concentration. The calcium salt did not possess any affinity to certain organs. 6) In conclusion, though some differences of gastrointestinal absorption were observed among the animal species, fosfomycin calcium salt was well absorbed without problem of micronizing the bulk particles. Moreover, it was perceived that fosfomycin calcium salt, once distributed, would not remain in particular organs, being excreted out of body.     

磷霉素钠在甲硝唑注射液中的稳定性考察

目的研究磷霉素钠在甲硝唑注射液中的稳定性。方法在5℃、25℃、35℃条件下,0、1、2、6、8小时内考察其pH、外观、含量变化情况。结果二者混合液在5℃30分钟后出现少量浑浊;25℃和35℃条件下,8小时内基本稳定。结论磷霉素钠与甲硝唑注射液可以配伍使用。     

注射用磷霉素钠中磷霉素钠二醇物含量测定方法的研究

目的:建立液相色谱串联质谱法和高效液相色谱-示差折光法测定注射用磷霉素钠中的磷霉素钠二醇物含量,并与现行中国药典方法比较,提高对药品的质量控制。方法:液相色谱串联质谱法采用Promosil CN(250 mm×4.6 mm,5μm)色谱柱,流动相为5 mmol.L-1醋酸铵-甲醇(82∶18),采用(-)ESI电离源,多反应监测(MRM)扫描方式,用于定量分析的离子分别为m/z 154.9→80.9(磷霉素二醇物)和m/z 120.9→77.1(内标苯甲酸)。高效液相色谱-示差折光法采用Agilent Zorb-ax NH2(250 mm×4.6 mm,5μm)色谱柱,流动相为10.89 g.L-1磷酸二氢钾溶液,流速为1.0 mL.min-1;柱温36℃;检测器温度为35℃。结果:采用液相色谱串联质谱法,二醇物在22.46～359.4 ng.mL-1范围内线性关系良好,定量限为4.492 ng.mL-1,每一样品的分析时间为5 min。采用高效液相色谱-示差折光法,二醇物在0.104～5.205 mg.mL-1浓度范围内线性关系良好,精密度为0.7%,重复性良好。结论:本研究2种方法专属性高、简便、可靠,可用于注射用磷霉素钠的质量研究和质量控制。     

应用离子对HPLC-ELSD法测定磷霉素钠中磷霉素及有关物质的含量

建立了HPLC-ELSD法测定磷霉素钠中磷霉素及有关物质的含量。采用ODS柱，柱温35℃，以0．015mol／L正辛胺溶液（用冰乙酸调节pH至5．2）：乙腈（90：10）为流动相，蒸发光散射检测器温度为45℃，雾化气体压力为0．35MPa。磷霉素及其二醇物分别在26．0-207．7和7．6～60．6μg/ml 范围内呈良好的线性关系，两者的定量限分别为8．7和7.7μg/ml 。     

磷霉素钠172例临床应用分析

目的 了解我院注射用磷霉素钠的临床使用情况,为合理使用该药提供依据.方法 回顾分析我院2007年1～11月172份住院患者使用磷霉素钠的临床资料,根据磷霉素钠的用法、用量、适应性、联合用药等分析该药使用是否正确.结果 172份病历中,磷霉素钠单一用药占50.00%,二联用药占45.34%,三联用药占4.65%:与注射用磷霉素钠联合用药的抗菌药物构成比为,青霉素类占25.28%.喹诺酮类占23.26%,头孢类占20.93%,β-酶抑制剂类占16.28%,氨基糖苷类占13.95%;用药时间构成比为,1～3天占40.70%,4～6天占32.60%,7～9天占12.79%,9天以上占13.95%;临床应用构成比为,治疗用药110例,占64%,预防用药62例,占36%.结论 各科室对磷霉素钠的使用基本正确,但存在用药起点过高.使用时间过长,不必要的联合用药,不作病原学检查等问题.     

A study of the influence of pH on the buccal absorption and renal excretion of procainamide

Summary The buccal absorption of procainamide was studied in 4 normal, male volunteers over a pH range of 5–11. In another investigation the same 4 volunteers collected their urine for 24 h after taking 250 mg of procainamide hydrochloride orally on 3 separate occasions, during which urine pH was uncontrolled, acidified by ammonium chloride ingestion or alkalinised by sodium bicarbonate ingestion. The procainamide remaining after buccal absorption and present in the urine samples was determined spectrophotometrically. It was found that neither the buccal absorption nor the renal excretion of procainamide was substantially altered by changes in pH.     

Acid-catalyzed hydrolysis of fosfomycin and its implication in oral absorption of the drug

The kinetics of hydrolytic opening of the epoxide ring in fosfomycin were studied in aqueous solutions at 37°C over the pH range 0.25–4.0. The rate of hydrolysis showed a first-order dependency on the parent drug concentration and its variation with pH could be accounted for in terms of specific acid-analyzed reactions of fosfomycin-free acid and the monoanionic species. Half-lives for the hydrolysis were 27, 37 and 133 min at pH 1.0, 1.2 and 2.0, respectively. Data are presented suggesting that the poor and variable bioavailability reported for fosfomycin upon oral administratten can be attributed, at least in part, to hydrolytic degradation of the antibiotic in the stomach.     

Experimental studies on absorption, distribution and excretion of a new antibiotic, fosfomycin. II. Absorption of oral preparations of fosfomycin calcium salt in dogs (author's transl)]

To establish the best usage and dosage of fosfomycin granule and capsules which had been prepared based on our fundamental experiences as described in the first report, absorption of calcium salt contained in both preparations was evaluated using dogs as test animals. (1) Granule containing the calcium salt equivalent to 200 mg of fosfomycin free acid per g showed almost the same absorption as the bulk (fosfomycin calcium), having no disadvantage due to processing. (2) Capsules containing the calcium salt equivalent to 250 mg and 500 mg of the free acid per capsule showed slightly more retarded absorption than the bulk, probably due to some inevitable factors such as disintegration rate of capsules and dispersion rate of the calcium salt. But, once dispersed, the calcium salt in capsules was well absorbed as well as the bulk material. (3) Gastrointestinal absorption of granule and the capsule contents was almost the same. (4) Simultaneous administration of capsules and water improved the absorption efficiency. Though administration after feeding caused somewhat retarded absorption of the drug, the serum levels were rather well sustained with a slight drop but sufficiency of absorption, suggesting better clinical advantages than in the fasted animals. (5) Fosfomycin calcium salt in both preparations was well absorbed in the test animals through gastrointestinal tract as well as the bulk calcium salt, without any possible disadvantage caused by processing. In addition, the absorption efficiency was improved by giving with water or meal to the animals.     

夫西地酸钠联合磷霉素钠治疗MRS感染的临床疗效观察

目的 评价夫西地酸钠联合磷霉素钠治疗耐甲氧西林葡萄球菌(MRS)院内感染的疗效性和安全性.方法 回顾性分析我院3年来临床夫西地酸钠联合磷霉素钠治疗耐甲氧西林葡萄球菌院内感染的265例患者的临床资料.数据资料采用SPSS13.0分析软件进行统计分析,计量资料采用t检验,组间比较采用x2检验,以P＜0.05为差异有统计学意义.结果 2009年1月至2011年12月265例耐甲氧西林葡萄球菌院内感染患者中,耐甲氧西林金黄色葡萄球菌(MRSA)和耐甲氧西林表皮葡萄球菌(MRSE)分别为139例(52.5％)和126例(47.5％).夫西地酸钠联合磷霉素钠治疗的有效率为90.2％,细菌清除率为81.5％,药物的主要不良反应为静脉炎,发生率为7.5％.结论 夫西地酸钠联合磷霉素钠治疗耐甲氧西林葡萄球菌感染安全、有效,临床可根据患者感染的具体状况选择夫西地酸钠联合磷霉素钠优化治疗.     

Enhancement of jejunal and colonic absorption of fosfomycin by promoters in the rat

A means of enhancing absorption of the antibiotic, fosfomycin, has been investigated using promoters in rat jejunum and colon. Polyoxyethylene lauryl ether (BL-9EX), saponin, the sodium salts of fatty acids and mixed micelles were effective at 1% in increasing fosfomycin absorption. Of the sodium salts of saturated medium-chain fatty acids examined, the strength of this effect was in the order caprate greater than laurate greater than caprylate. Mixed micelles, consisting of fusogenic lipids and sodium taurocholate, enhanced fosfomycin absorption independently of the degree of unsaturation of the lipids; their effectiveness far exceeded that of sodium taurocholate alone. The action of these promoters was more evident in the colon than in the jejunum, except for the sodium salts of bile acids and disodium ethylenediaminetetraacetate (EDTA-2Na). The effects of glycocholate and taurocholate were essentially the same at both absorption sites, but that of EDTA-2Na was much greater in the jejunum than the colon. Improved fosfomycin absorption was observed at more than 0.5% sodium caprate concentrations in both the jejunum and colon. BL-9EX was effective at 0.1% in the jejunum or at 0.05% in the colon. The effectiveness at these low concentrations demonstrates the practicality of promoters for improving fosfomycin absorption with only minor membrane damage, especially in the colon.     

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets

The aim of this case study was to develop a drug‐specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus? software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentration–time profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate‐release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitro–in vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyright © 2012 John Wiley & Sons, Ltd.     

Fundamental and clinical studies on fosfomycin sodium in the field of obstetrics and gynecology

Fosfomycin sodium (FOM-Na) was studied both fundamentally and clinically in the field of obstetrics and gynecology with following results. It showed good transference into the uterine tissues when given intravenously. The peak concentrations achieved in the uterine tissues following intravenous administration of 2 g of FOM-Na were 26.56 to 53.48 micrograms/g when given as one shot injection and 20.16 to 39.47 micrograms/g as drip infusion. In the serum of vein and uterine artery, peak concentrations of 163.6 to 143.40 micrograms/ml and 120 to 113.12 micrograms/ml were reached following one shot injection and drip infusion, respectively. In general, FOM-Na concentrations in the uterine tissues showed similar changes as those observed for serum concentrations. Clinically, FOM-Na was used in the treatment of 17 cases of obstetrical and gynecological infections at 2 g per dose twice daily as intravenous drip infusions. In all of these cases, good clinical efficacy was obtained. No side effects were observed.     

A reappraisal of current dosing strategies for intravenous fosfomycin in children and neonates

The rising incidence of multi-drug resistant bacterial pathogens has renewed interest in the long-known antibacterial fosfomycin. Not least because of its low toxicological potential, there is good clinical experience with intravenous fosfomycin for various Gram-positive and Gram-negative infections in the treatment of children and neonates. However, the current dosing recommendations for intravenous fosfomycin vary widely in paediatric patients. In the present review, we summarized available plasma pharmacokinetic data derived from neonates or children following intravenous administration of fosfomycin. Subsequently, we used this information for recalculation of different dosing strategies and simulated a variety of clinically applied dosing regimens. The percentage of time above the minimal inhibitory concentration (T>MIC) was calculated for each dosing strategy, as this pharmacokinetic-pharmacodynamic parameter was shown to be most predictive of antimicrobial and clinical success of fosfomycin treatment. Our data corroborate the current practice of selecting the dosage of intravenous fosfomycin primarily on the basis of bodyweight and age in paediatric patients. As with other 'time-dependent' antibacterials, a dosing interval of 6-8 hours should be preferred over 12 hours except for immature neonates. Given a T>MIC target of 40-70%, currently recommended dosing strategies appear to be insufficient in children aged 1-12 years, if pathogens with MICs of ≥32 mg/L are suspected and subjects are presenting with normal renal function. Likewise, the lowest recommended daily dose for neonates and infants (aged up to 12 months) of 100 mg/kg bodyweight of fosfomycin should be considered only for pre-term neonates with a postmenstrual age below 40 weeks.     

Experimental study of the ototoxicity of fosfomycin

Two tenths ml of 5% fosfomycin sodium solution (10 mg) was injected into the tympanic cavity of guinea pigs once a day for 7 days. Auditory brain stem response (ABR) was performed to examine the effect of the drug on the experimental animals. Additionally, a scanning electron microscopic study was also performed to observe the effect of the drug on outer hair cells of the organ of Corti and on vestibular sensory epithelia. No degenerative changes were observed in outer hair cell cilia of the organ of Corti and the vestibular sensory cilia at 1 day, 7 days, 14 days and 1 month after injection. No changes of the threshold of ABR were also noticed.     

磷霉素钠注射液临床不良反应分析及与中药联合用药现状

目的 探讨某医院临床上磷霉素钠注射液所致不良反应的规律和特点,分析磷霉素钠与中药联合用药现状,为临床上合理使用磷霉素钠提供参考。方法 采用回顾性分析方法,对浙江某医院101例患者发生不良反应的资料进行了分类整理分析。采用文献检索的方式,分析目前磷霉素钠与中药联合用药相关研究。结果 在101例患者中,磷霉素钠所致不良反应发生率在性别和年龄方面并无特异性;不良反应的发生与给药剂量的高低具有一定相关性;不良反应发生时间多集中在10～30min以内(43.56%),且过敏性休克等严重不良反应发生在10min以内;磷霉素钠所致不良反应以过敏样反应表现形式居多;原患疾病以呼吸系统疾病为主(58.42%);绝大部分患者经过减慢滴速、停药或者相关药物治疗得以缓解恢复正常,治愈率为99%;磷霉素钠可与云南白药、栀子金花汤以及自拟肺心Ⅰ号方等中药联合用药用于临床治疗。结论 磷霉素钠注射液所致不良反应的临床表现类型呈现多样化,严重可引起过敏性休克,临床应加强对此药的监测,同时,可考虑磷霉素钠与中药联合应用,确保临床用药安全。     

磷霉素钠不良反应分析

目的对磷霉素钠不良反应发生的情况进行分析,为临床合理用药提供参考.方法对国内近10年使用磷霉素钠出现的115例不良反应报道进行分类统计与分析.结果 115例涉及的不良反应有皮肤、黏膜过敏反应30例(26.09%),严重过敏反应27例(23.48%),过敏性休克25例(21.74%),神经系统损害9例(7.83%),低钙血症6例(5.22%),肺水肿4例(3.48%),死亡3例(2.61%),药物热3例(2.61%),心脏损害2例(1.74%)等.结论临床医师、药师与护士应重视磷霉素钠的不良反应.     

磷霉素钠静滴致儿童过敏性休克

患者女,15岁。因恶心、呕吐20d,加重1d,于2002年5月20日15:00左右来我院就诊。患者于1d前出现恶心、喷射性呕吐,呕吐胃内容物3-4次。曾多次到医院就诊不见好转。近1d来呕吐加重。以呕吐原因待查收住院。住院后给予10%葡萄糖注射液150mL 0.9%氯化钠注射液100mL 磷霉素钠4.0g静滴治疗。于下午16:00静滴上组药物约5min时,患者出现恶心、多汗、周身皮疹,继而昏厥,四肢湿冷,心音低钝,HR120次/min,脉搏微弱,BP80/60mmHg(1mmHg=0.133kPa)。考虑为过敏性休克,立即停用磷霉素钠注射剂治疗,给予地塞米松8mg肌注、山莨菪碱注射液10mg静注、5%碳酸氢…     

微生物比浊法与管碟法测定磷霉素钠效价的评价

目的验证比浊法测定磷霉素钠效价方法的可行性。方法应用比浊法测定磷霉素钠含量,并对微生物比浊法、管碟法测定磷霉素钠效价的结果进行评价。结果比浊法、管碟法效价测定结果一致。结论比浊法测定磷霉素钠效价快速、可行,对中间产品的检验更具有重要意义。