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。     

Gastric emptying and the pharmacokinetics of the cephalosporin antibiotic, cefpodoxime proxetil

The effects of gastric motility on the pharmacokinetics of cefpodoxime proxetil, an oral, broad spectrum, third-generation cephalosporin antibiotic were evaluated in 12 healthy subjects. In this open-label, crossover trial, each subject took a 200 mg dose (two 100 mg film-coated tablets) in each study period. There was an initial fasting period followed by a control period and then either a propantheline or metoclopramide period. Gastric motility was measured using [99mTc]-labeled sulfur colloid in oatmeal in the control, propantheline and metoclopramide periods. Treatment with propantheline or metoclopramide was given 30 min before dosing with the antibiotic and the radioisotope. Serial images with a gamma counter were made every 15 min for 2 h. Gastric emptying time was faster than control with metoclopramide, but generally slower with propantheline than control. The mean peak plasma concentration, mean area under plasma concentration time curve and mean half-life of cefpodoxime proxetil were similar in all groups as compared to control. The mean time to peak plasma concentration was delayed in the propantheline period and peak plasma concentrations were greater at all sampling times at six hours after dosing. This study utilized the gastric nuclear scan with modification of gastric motility by metoclopramide and propantheline and with simultaneous determination of the disposition of cefpodoxime proxetil to understand the absorption of the drug.     

头孢泊肟酯片人体药动学及生物等效性评价

目的:研究国产和进口头孢泊肟酯片在人体的药动学和生物等效性.方法:20名健康男性志愿者随机交叉口服单剂量国产和进口头孢泊肟酯片200 mg,采用高效液相色谱法测定其活性代谢产物头孢泊肟的经时血药浓度,计算其药动学参数和相对生物利用度,评价两种制剂的生物等效性.结果:国产和进口头孢泊肟酯片的主要药动学参数t1/2分别为(2.6±0.9)h和(2.7±1.1)h,tmax分别为(3.0±0.6)h和(3.0±0.5)h,Cmax分别为(4.3±0.7)mg·L-1和(4.2±0.8)mg·L-1,AUC0→12分别为(21.1±4.8)mg·h·L-1和(21.9±5.5)mg·h·L-1,AUC0→∞分别为(23.1±6.1)mg·h·L-1和(24.0±6.6)mg·h·L-1,国产头孢泊肟酯片的相对生物利用度为(97.8±13.5)%(F0→12)和(97.2±15.9)%(F0→∞).结论:经统计学分析,两种制剂具有生物等效性.     

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.     

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.     

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.     

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)     

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.     

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.     

头孢泊肟酯片人体相对生物利用度和生物等效性

目的:考察头孢泊肟酯片受试制剂和参比制剂的人体相对生物利用度,并评价两者的生物等效性。方法:22名健康男性志愿者随机交叉单剂量口服头孢泊肟酯片受试制剂200mg和参比制剂200mg,用HPLC法测定给药后血浆样本中头孢泊肟的浓度,用DAS软件计算其药动学参数,并评价两种制剂的相对生物利用度。结果:受试制剂和参比制剂的tmax分别为(2.6±0.6)和(2.9±0.7)h,Cmax分别为(2.9±0.8)和(3.4±0.6)mg.L-1,t1/2分别为(2.4±0.6)和(2.14±0.23)h,AUC0-t分别为(16.1±4.0)和(18.2±3.6)mg.h.L-1,AUC0-∞分别为(17.0±3.9)和(19.1±3.7)mg.h.L-1。受试制剂的相对生物利用度F0-tn和F0-∞分别为(88.6±15.6)%、(89.8±14.7)%。结论:两种制剂具有生物等效性。     

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。     

第3代口服头孢菌素——头孢泊肟酯

头孢泊肟酯口服后在肠壁水解成头孢泊肟经肠道吸收。头孢泊肟有广谱而强大的抗菌作用 ,组织分布广泛 ,T1/2 较长 ,对 β内酰胺酶稳定 ,耐受性良好 ,具有治疗剂量小 ,每日给药次数少的优点。本文主要对其抗菌活性、人体药动学、临床应用作一综述。     

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。     

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.     

Laboratory and clinical studies of cefpodoxime proxetil in pediatric field

We have carried out laboratory and clinical studies on cefpodoxime proxetil (CS-807, CPDX-PR). The results are summarized as follows. CPDX-PR was given via oral administration to each 2 children at a single dose of 3 mg/kg and to each of 3 children in a 100 mg tablet. After the oral administration, mean peak serum levels of CPDX obtained for the 2 dose levels were 1.86 +/- 0.35 micrograms/ml and 2.16 +/- 0.63 micrograms/ml at 2 hours, respectively, and mean half-lives were 1.31 +/- 0.02 hours and 1.47 +/- 0.18 hours, respectively. The mean urinary excretion rate of CPDX was 32.8 +/- 1.0% in the first 12 hours after the oral administration of 3 mg/kg. When a dose of 100 mg tablet was given to each of the 3 children, urinary excretion rates in the first 12 hours were 43.5%, 48.6% and 24.8%, respectively. Treatment with CPDX-PR was done in 38 cases of pediatric bacterial infections; 19 cases of tonsillitis, 3 cases of pharyngitis, 1 case of bronchitis, 3 cases of pneumonia, 3 cases of scarlet fever, 2 cases of impetigo, 4 cases of UTI and 1 case each of phlegmone, subcutaneous abscess and balanitis. Results obtained were excellent in 23 cases, good in 15 cases. No significant side effect due to the drug was observed in any cases.     

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)