反相高效液相色谱法测定头孢泊肟酯干混悬剂中头孢泊肟酯的含量

目的　建立测定头孢泊肟酯干混悬剂中头孢泊肟酯含量的方法。方法　采用反相高效液相色谱法 ,色谱柱为Shim Pack苯基柱 ( 4 μm ,3.9mm× 15 0mm) ;流动相 :0 .0 0 5mol/L磷酸二氢钾 ( pH6 .5 ) 乙腈 甲醇 ( 6 0∶10∶30 ) ;检测波长为 2 6 0nm。结果　精密度及稳定性均良好 ;头孢泊肟酯 (按头孢泊肟计 )在 5 0～ 2 5 0 μg/mL内 ,峰面积与浓度呈良好的线性关系 ,相关系数为 0 .9999,平均回收率为 99.91% ,RSD =0 .4 2 %。结论　本方法简便、准确、灵敏可靠     

头孢泊肟酯中间体的合成

采用电离度大的甲基质子作为甲基化反应的底物，提高电离度有利于甲基化反应，选用DBU作缩合剂，红外光谱分析，得到预期产物，方法简便，易行。     

头孢泊肟酯的临床药理学

近年来,国产头孢泊肟酯的片剂、胶囊和干混悬剂相继上市,为了让广大医生和药师较全面了解头孢泊肟酯、合理应用,作者已在本刊今年第4期介绍了头孢泊肟酯的抗菌实验研究概况。而本文则从临床角度综述头孢泊肟酯的药动学和药效学。     

Investigation of factors responsible for low oral bioavailability of cefpodoxime proxetil

Learning about the behavior of a drug in biological environment enables application of better formulation strategies to improve bioavailability of the same. Cefpodoxime proxetil (CP) is a prodrug, which is orally administered cephalosporin with only 50% absolute bioavailability. Despite previous studies, reasons responsible for low bioavailability of CP remain poorly understood. The present study tries to ascertain reasons for the low oral bioavailability of CP. The in vitro, in situ and ex vivo studies showed interesting results, where metabolism of CP into cefpodoxime acid (CA) inside the intestinal epithelial cell and preferential efflux of CA into lumen was identified as primary reason for low oral bioavailability of CP. Presence of specific carriers or transportation mechanism on the apical side membrane of enterocyte, than basal side of the same was observed.     

Disposition of cefpodoxime proxetil in hemodialysis patients.

The disposition of cefpodoxime after single, oral 200-mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open-label study of six patients with end-stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half-life for the interdialytic period was 18.0 +/- 6.5 hours; apparent total body clearance was 28.6 +/- 13 mL/minute. The half-life during hemodialysis, 2.66 +/- 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 +/- 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 +/- 31 mL/minute, which was 57.1 +/- 13% and 71.7 +/- 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 +/- 0.25 hour hemodialysis session removed 22.4 +/- 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 +/- 0.33 mcg/mL was observed, at about one-half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted.(ABSTRACT TRUNCATED AT 250 WORDS)     

头孢泊肟酯的HPLC法含量测定

建立了头孢泊肟酯的含量测定HPLC方法.色谱条件采用ODS柱(4μm,250mm×4.6mm),0.02mol/L磷酸盐缓冲液(pH3.0)-乙腈-叔丁基甲醚(76186,V/V/V)为流动相,流速1.5ml/min,柱温50℃,检测波长240nm.头孢泊肟酯与有关物质分离良好.头孢泊肟酯在147～442μg/ml范围内呈良好的线性关系,日内RSD为0.5%,含量测定结果与日抗基方法所得结果相符.     

Pharmacokinetic and tolerance studies of cefpodoxime after single- and multiple-dose oral administration of cefpodoxime proxetil.

Cefpodoxime proxetil, a third generation, broad-spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of cefpodoxime proxetil were determined. Results from the single-dose study indicate that cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose-normalized AUC and Cmax, urinary recovery, and half-life between one or more of the higher-dose treatment groups and the 100-mg dosing group. After multiple-dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC- and microbiologic-determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single-dose study and antibiotic-associated diarrhea in one subject in the multiple-dose study.     

高效液相色谱法测定头孢泊肟酯及其制剂的含量

建立一种用高效液相色谱法测定头孢泊肟酯及其片剂，胶囊剂的含量及有关物质的方法。方法：以ODS为固定相。甲醇－水（41：59）为流动相；检测波长为240nm。结果：头孢泊肟酯的浓度在0.3-0.9mg/ml范围内线性关系良好，回归方程为：Y＝1460374，8X-4983．9，r=0.9999。头孢泊肟酯，头孢泊肟酯片和头孢泊肟酯胶囊重现性良好（n=9)，RSD分别为0．5％，1．0％和1．2％。头孢泊肟酯片和头孢泊肟酯胶囊平均回收率分别为100．6％（RSD＝1．0％，n=9)和99．8％（RSD＝0．8％，n=90。本方法简单，快速，结果准确。     

Clinical evaluation of cefpodoxime proxetil in the treatment of skin and soft tissue infections. A double blind comparison of cefpodoxime proxetil and cefaclor

In order to objectively evaluate the effectiveness, safety and usefulness of the new oral cephem cefpodoxime proxetil (CS-807, CPDX-PR) for the treatment of skin and soft tissue infections, a double-blind comparative study was undertaken using cefaclor (CCL) as the control drug. CPDX-PR and CCL were administered for 7 days at daily doses of 400 mg (divided into 2 portions) and 750 mg (divided into 3 portions), respectively. A total of 243 patients (118 in the CPDX-PR group and 125 in the CCL group) was treated in this study. The effectiveness, safety and usefulness were evaluated in 222 (106 in the CPDX-PR group and 116 in the CCL group), 234 (113 in the CPDX-PR group and 121 in the CCL group) and in 223 patients (107 in the CPDX-PR group and 116 in the CCL group), respectively. There were no differences in patients' backgrounds between the 2 groups, except for the presence or the absence of surgical treatments. The results we obtained are summarized below: 1. In the evaluation of clinical efficacy by the subcommittee, excellent, good, fair and poor efficacy were observed in 36, 43, 17 and 10 patients in the CPDX-PR group, respectively; the efficacy rate was, therefore, calculated to be 74.5%. As for the CCL group, respective results were observed in 50, 39, 17 and 10 patients, indicating an efficacy rate of 76.7%. There was no significant difference between the 2 groups. Improvement rates judged by physicians in charge were 80.2% in the CPDX-PR group and 88.8% in the CCL group. Moreover, no significant difference in diseases or severity were found between the 2 groups. 2. As for the bacteriological efficacy, the 2 groups showed high elimination rates, as 90.1% and 91.6% of the disease causing bacteria were eliminated in the CPDX-PR group and in the CCL group, respectively. Elimination rates in single infections with Staphylococcus aureus were determined to be 85.7% in the CPDX-PR group and 85.0% in the CCL group. 3. Although 6 patients in the CPDX-PR group and 2 patients in the CCL group developed side effects, which were mainly gastrointestinal symptoms, there was no significant difference in the incidence of side effects between the 2 groups. Abnormal laboratory values were found in 5 patients in the CPDX-PR group and 1 patient in the CCL group. 4. There was no significant difference in the usefulness between the 2 groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

A clinical evaluation of cefpodoxime proxetil in pediatrics

Children with acute infections were treated with cefpodoxime proxetil (CPDX-PR, CS-807), a new oral cephalosporin. 1. A girl of 4 years old, weighing 17 kg, and another girl of 12 years old, weighing 33 kg, were administered orally each 3 mg/kg of CPDX-PR. Blood levels of CPDX reached peaks of 1.39 and 2.26 micrograms/ml at 4 hours-post-dose, and T1/2's were 2.09 and 2.63 hours, respectively. Cumulative urinary recovery rates for 8 hours were 57.3 and 80.9%, respectively. 2. A total of 30 patients was treated with CPDX-PR. These patients included 10 with acute tonsillitis, 6 with acute bronchitis, 5 with bronchopneumonia, 2 with scarlet fever and 2 with urinary tract infections, and one each with acute pneumonia, acute otitis media, acute otitis media plus sweat gland abscess, staphylococcal scalded skin syndrome and acute lymphadenitis. The treatment was effective in 27 cases out of 29 (except one with an unknown response) with a clinical efficacy rate of 93.1%. 3. Bacteriological responses to CPDX-PR were as follows; eradication of pathogen in 7, and unknown in 2 out of 9 cases from whom pathogens had been isolated prior to the treatment. 4. As a side effect, diarrhea was observed in 1 patient, but it was possible to continue the treatment. With regard to laboratory tests, a slight elevation of GOT and slight elevations of GOT and GPT were found in 1 case each.     

头孢泊肟匹酯片溶出度测定方法

本文建立了头孢泊肟匹酯片溶出度测定方法。以盐酸溶液 (9→ 10 0 0 )为溶剂 ,转速 10 0 r/ min,采用紫外分光光度法测定头孢泊肟匹酯片溶出量 ,测定波长为 2 6 3nm。线性浓度范围 3～ 2 4μg/ ml,r=0 .9999。经 30 min取样 ,三批头孢泊肟匹酯片的溶出量均大于 90 %。方法简便、准确 ,重复性好     

Clinical and pharmacokinetic evaluation of cefpodoxime proxetil in children

Twenty nine children were treated with cefpodoxime proxetil (CPDX-PR, CS-807) and the clinical efficacy and side effects were evaluated. Ages of the patients ranged from 2 months to 10 years. Dose levels of CPDX-PR ranged from 7.5 to 12.0 mg/kg/day for 5 to 12.7 days. The 29 patients included 9 tonsillitis, 2 otitis media, 5 scarlet fever, 3 bronchopneumonia, 1 lymphadenitis, 8 urinary tract infections and 1 staphylococcal scalded skin syndrome, and they were evaluated for the clinical efficacy of CPDX-PR. Results were excellent in 21 and good in 8 patients. Out of the 29 patients, 3 cases showed diarrhea and 2 cases showed elevated GOT and GPT. The pharmacokinetics of CPDX-PR was studied in 9 patients whose ages ranged from 1 to 9 years. The serum peak concentrations of CPDX in 5 patients were between 1.37 and 4.10 micrograms/ml (mean: 2.53 micrograms/ml) at 1 to 6 hours after dosing 3 mg/kg before meals. Those of 4 patients ranged 3.29 to 4.88 micrograms/ml (mean: 4.36 micrograms/ml) at 2 hours after administering 6 mg/kg before meals. Portions of CPDX excreted into urine within 6 hours ranged from 20.3 to 34.3% (mean 27.1%) in 5 patients who were given 3 mg/kg, and ranged from 24.1 to 65.7% (mean 41.1%) in 4 patients given 6 mg/kg.     

头孢泊肟酯分散片的制备及溶出度测定

目的制备头孢泊肟酯分散片并建立其溶出度测定方法。方法以可压性、崩解时限、分散均匀性、溶出度为主要评价指标确定最终最佳处方;采用中国药典2005年版二部附录ΧC溶出度测定第一法,以0.05 mol.L^-1盐酸为溶出介质,转速为100 r.min-1,在第30 min取样,264 nm波长处测定其溶出度。结果最终处方为头孢泊肟酯43.3%,羧甲基淀粉钠21.7%,微晶纤维素10%,羟丙基纤维素10%,交联聚维酮4.33%,十二烷基硫酸钠0.67%,微粉硅胶5%,阿斯巴甜3.33%,桔子香精1.67%。头孢泊肟酯溶出度检测浓度的线性范围为6.25-31.25μg.mL-1（r2=0.999 6）;平均回收率为99.66%,RSD=0.5%（n=9）,6批样品30 min溶出度均＆gt;85%。与日本三共株式会社生产的头孢泊肟酯片相比,分散片前30 min的溶出速度快于普通片剂。结论头孢泊肟酯分散片制备工艺简单;溶出度测定方法操作简便、结果准确。     

Clinical studies of cefpodoxime proxetil in pediatric field

Clinical studies of cefpodoxime proxetil (CPDX-PR), a new cephem antibiotic, were carried out in 60 patients in the pediatric field. The overall efficacy rate on 54 patients with various infections was 98.1%, and few side effects, all of them very mild, were developed in 6 of 60 patients (10%). It was concluded that CPDX-PR was one of the most useful antibiotics in the pediatric field because of the high efficacy rate and the safety.     

国产头孢泊肟酯片-的生物等效性研究

目的研究国产头孢泊肟酯片的生物等效性.方法24例健康成年男性志愿者采用随机分组自身对照交叉试验设计法,单次口服国产和进口头孢泊肟酯片200mg,用反相高效液相色谱法测定血清中头孢泊肟浓度,并用3P97程序对试验数据进行处理.结果国产和进口头孢泊肟酯片的Tmax分别为(2.27±0.49)和(2.50±0.61)h,Cmax分别为(3.64±0.53)和(3.48±0.57)mg@L-1,AUC0-t分别为(18.12±2.79)和(17.95±3.07)mg@h@L;国产头孢泊肟酯片的相对生物利用度为(102.31±15.40)%.结论国产与进口头孢泊肟酯片具有生物等效性.     

The influence of cefpodoxime proxetil on the intestinal bacterial flora

The influence of cefpodoxime proxetil (CPDX-PR, CS-807), a new oral cephalosporin, on the intestinal bacterial flora was studied in tetra-contaminated mice and in pediatric patients. CPDX-PR dry syrup was administered at a dose of 10 mg/kg once a day for 5 consecutive days to mice contaminated with 4 different species of bacteria: Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve. No notable changes were observed in fecal viable cell counts except that slight decreases of E. coli counts were observed on the days 3 to 5 after starting administration. The subjects in the pediatric study were 5 children with infections, 3 boys and 2 girls at ages from 1 year 1 month to 6 years 10 months, with their body weights ranging from 9.3 to 23.8 kg. CPDX-PR dry syrup was administered at a dose between 3.0 to 3.7 mg/kg, 3 times a day for 4 to 7 days. Although some variations of the fecal bacterial flora were noticed between subjects during the administration of CPDX-PR, no notable changes were observed in major aerobic and anaerobic bacteria such as Enterobacteriaceae, Enterococcus, Bacteroides and Bifidobacterium in 4 of the 5 cases. Large decreases in Streptococcus, Enterobacteriaceae, Bifidobacterium, Eubacterium and anaerobic cocci and an increase in Enterococcus were observed in the other case. There was no case in which glucose non-fermenting Gram-negative rods and fungi became predominant. Regarding Enterobacteriaceae, transitory bacterial replacement was observed within the genus. Fecal concentration of CPDX during the administration of CPDX-PR was extremely low or below the detectable limit except one specimen from a case in which intestinal bacterial flora showed remarkable changes. From the above, CPDX-PR appears to be a drug with a relatively small influence on the intestinal bacterial flora.     

Evaluation of cefpodoxime proxetil in the pediatric field

Pharmacokinetic and clinical evaluation of cefpodoxime proxetil (CPDX-PR, CS-807) were performed in the field of pediatrics. The obtained results are summarized as follows. 1. Peak serum concentrations of CPDX upon single oral doses of 3.0 mg/kg and 4.4 mg/kg of CPDX-PR were 1.26-1.46 micrograms/ml and 1.45 micrograms/ml, respectively, achieved at 4 hours and 1 hour after administration. Urinary excretion rates for CPDX in the first 8 hours ranged between 28.1 and 30.2%. 2. Clinical efficacy rates for pediatric infections obtained at single dose levels ranging 3 to 6 mg/kg were 97.5%, and that at a single dose of 1 mg/kg were 90.9%. 3. Bacteriological effectiveness was determined in 45 strains identified in recent cases. Eradication rates for these bacteria at dose levels of 3 to 6 mg/kg and 1 mg/kg were 91.3% and 95.5%, respectively. 4. No side effect nor abnormal laboratory test data were found in any of the cases examined. From these results, CPDX-PR appeared to be a useful antibiotic agent in the field of pediatrics.     

Clinical studies of cefpodoxime proxetil in respiratory tract infections

Twelve patients with respiratory tract infections were treated with cefpodoxime proxetil (CS-807, CPDX-PR), a new cephem antibiotic. It was given orally at a dose of 200 mg 2 times a day for 4 approximately 15 days. Its clinical effects were evaluated as excellent in 1 case, good in 9 cases and poor in 2 cases. The efficacy rate was 83.3%. Its bacteriological effects were evaluated as eradication in 5 strains and decrement in 1 strain. The eradication rate was 83.3%. No adverse reactions and disorder of laboratory findings due to CPDX-PR were observed.     

An improved method for preparation of cefpodoxime proxetil

Cefpodoxime proxetil, a third-generation cephalosporin for oral administration, was synthesized by a method based on the following sequence of reactions: acylation of 7-aminocephalosporanic acid (7-ACA) with S-benzothiazol-2-yl(2-amino-4-thiazolyl)(methoxyimino)thioacetate (MAEM), chloroacetylation of the cefotaxime formed with chloroacetyl chloride, esterification of the acid function with 1-iodoethyl isopropyl carbonate and final cleavage of chloroacetamide protective group by treatment with thiourea in N,N-dimethylacetamide. The developed procedure allows us to obtain better yields of cefpodoxime proxetil and to eliminate the final purification step by column chromatography, necessary during the synthesis of this antibiotic by the previously reported methods.     

Cerebrospinal fluid pharmacokinetics of cefpodoxime proxetil in piglets

Cefpodoxime is an oral third-generation cephalosporin used for the treatment of acute upper-respiratory tract infections caused by susceptible bacteria in children. Although not indicated for the treatment of bacterial meningitis, it is used to treat other infections produced by organisms associated with meningitis and may obscure the result of cerebrospinal fluid (CSF) cultures in children who develop meningitis while receiving oral antibiotics if sufficient concentrations are achieved in the CSF. This study evaluated the disposition of cefpodoxime and penetration into CSF in piglets. Fifteen Landacre-Camborough cross piglets (10-20 days old) received cefpodoxime proxetil oral suspension (10 mg/kg). Repeated plasma and CSF samples were collected over 24 hours for quantitation of cefpodoxime by HPLC. Pharmacokinetic analysis was performed on both plasma and CSF data. The plasma concentration versus time data for cefpodoxime were best characterized using a one-compartment model with first-order absorption. The mean (+/- SD) pharmacokinetic parameters for Cmax, tmax, and AUC0-infinity were 23.3 +/- 12.9 mg/L, 3.9 +/- 1.4 h, and 237 +/- 129 mg/L.h, respectively. CSF/plasma ratios for AUC0-infinity demonstrated a mean cefpodoxime penetration of approximately 5%. CSF penetration of cefpodoxime was evident following a single oral dose of cefpodoxime proxetil suspension. Despite the small percentage of total cefpodoxime dose distributing into the CSF, the resultant concentrations approached or exceeded the MIC90 for many bacterial pathogens considered susceptible to cefpodoxime. Accordingly, clinicians should use caution in the interpretation of CSF cultures in patients who develop clinical signs and symptoms consistent with meningitis and who have been previously treated with cefpodoxime.