Simultaneous pharmacokinetic assessment of cefadroxil and clavulanic acid in human plasma by LC-MS and its application to bioequivalence studies

A simple, rapid and selective liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry （LC-APCI-MS） assay method has been developed and fully validated for the simultaneous quantification of cefadroxil （CF） and clavulanic acid （CA） in human plasma. Analytes and internal standard （IS） were extracted from human plasma by solid- phase extraction （SPE） technique using Sam prep （3 mL, 100 mg） extraction cartridge. The extracted samples were chromatographed on a reverse phase Cls column using a mixture of methanol： acetonitrile： 2 mM ammonium acetate （pH 3.5） （25：25：50, v/v/v） as the mobile phase at a flow rate of 0.8 mL/min. Quantification of the analytes and IS were carried out using single quadrupole LC-APCI-MS through selected-ion monitoring （SIM） at m/z 362 and m/z 198, for CF and CA, respectively. Method validation was performed as per the FDA guidelines and the results met the acceptance criteria. Plasma concentration of CF and CA followed by the oral administration of CF/CA （500/125 mg） pill to healthy male volunteers （n= 12） was measured. Area under plasma concentration-time curve from 0 to 12 h （AUC0-12 h） and 0 h extrapolated to infinity （AUC0-∞） were calculated. The ratio of AUC0-12 h/AUC0-∞ was found to be 〉 85% for all the subjects, as recommended by the FDA guidelines.

Amoxicillin–clavulanic acid induced sperm abnormalities and histopathological changes in mice

Objective: To explore the genotoxic potential and histopathological changes induced in liver, kidney, testis, brain and heart after using the antibiotic drug amoxicillin/clavulanic acid(4:1).Methods: The study included chromosomal aberration analysis in bone-marrow and mouse spermatocytes, induction of sperm morphological abnormalities and histopathological changes in different body organs. The drug was administrated orally at a dose of81 mg/kg body weight twice daily(Total = 162 mg/kg/day) for various periods of time equivalent to 625 mg/men(twice daily).Results: The results revealed non-significant chromosomal aberrations induced after treatment with amoxicillin/clavulanic acid(AC) in both bone marrow and mouse spermatocytes after 7 and 10 days treatment. On the other hand, statistically significant percentages of sperm morphological abnormalities were recorded. Such percentage reached 8.10 ± 0.55, 9.86 ± 0.63 and 12.12 ± 0.58 at the three time intervals tested(7, 14 and 35 days after the 1 st treatment respectively)(treatment performed for 5 successive days) compared with 2.78 ± 0.48 for the control. The results also revealed histopathological changes in different body organs after AC treatment which increased with the prolongation of the period of therapy. Congestion of central vain, liver hemorrhage and hydropic changes in hepatocytes were noticed in the liver. Degenerative changes were found in kidney glomerulus and tubules while testis showed atrophy of seminiferous tubules, and reduction of spermatogenesis. AC also induced neurotoxicity and altered brain neurotransmitter levels. Hemorrhage in the myocardium, disruption of cardiac muscle fibers and pyknotic nuclei in cardiomyocytes were recorded as side effects of AC in heart tissue.Conclusions: The results concluded that AC treatment induced sperm morphological abnormalities and histopathological changes in different body organs. Clinicians must be aware of such results while describing the drug.

Development and Validation of Stability Indicating HPLC Method for Simultaneous Estimation of Amoxicillin and Clavulanic Acid in Injection

A simple, fast, precise, accurate and rugged stability indicating high performance liquid chromatography (HPLC) method has been developed for simultaneous estimation of Amoxicillin and Clavulanic acid from injectable dosage form. The stability indicating capability of the method was proven by subjecting the drugs to stress conditions as per ICH recommended test conditions such as alkaline and acid hydrolysis, oxidation, photolysis, thermal degradation and resolution of the degradation products formed therein. The separation was obtained using a mobile phase composition at a ratio of 95:5 (v/v) of pH 5.0 buffer and methanol on Inertsil C18 column (250 × 4.0 mm, 4 μm) with UV detection at 220 nm at a flow rate of 1 ml/minute. The photodiode array detector was used for stress studies. The order of elution of peaks was Clavulanic acid followed by Amoxicillin. The linear calibration range was found to be 79.51 to 315.32 μg/ml for Amoxicillin and 17.82 to 67.90 μg/ml for Clavulanic acid. The Amoxicillin and Clavulanic acid were found to be stable in solution up to 24 hours. The method validation data showed excellent results for precision, linearity, specificity, limit of detection, limit of quantification and robustness. The present method can be successfully used for routine quality control and stability studies.

The Quality and <i>in Vitro</i>Efficacy of Amoxicillin/Clavulanic Acid Formulations in the Central Region of Ghana

Aim: To assess the quality and in vitro efficacy of five brands of amoxicillin/clavulanic acid tablet, suspension and injectable preparations selected from pharmacies in the Central Region of Ghana. Method: Using a Stratified Representation Sampling method, forty preparations (tablets, suspensions and injectable powders) containing amoxicillin and clavulanic acid were sampled from nine different locations within the Central Region of Ghana. To determine drug quality, several procedures, namely, content assay, disintegration and dissolution testing were employed. In vitro drug efficacy was determined by comparing the Minimum Inhibitory Concentrations (MIC’s) obtained with published values. Results: All tablets passed the disintegration test, with disintegration time ranging between six (6) and fifteen (15) minutes. Analyses of all the tablets for drug content showed 100% failure (14 out of 14) for amoxicillin and 14% failure (2 out of 14) for clavulanic acid. Injectable formulations showed similar results. All four (4) samples analyzed for content failed the amoxicillin content assay (0 out of 4) but all passed clavulanic acid assay (4 out of 4). For tablet dissolution tests, there was a 93% (13 out of 14) pass rate for both amoxicillin and clavulanic acid. Content analysis of all suspension formulations involved twenty-two (22) samples from five (5) brands. Only 41% (9 out of 22) passed for both amoxicillin and clavulanic acid. All the other samples failed for either amoxicillin, clavulanic acid or both. Results obtained from drug quality tests were confirmed by in vitro efficacy tests against selected microorganisms. Conclusion: The samples were therefore not of good quality, since content assay is the most crucial test. It is hypothesized that this is due to poor storage conditions, and recommendations, such as air conditioning and more structured procedures along the supply chain, are put forward to counteract this.

Coordination of glycerol utilization and clavulanic acid biosynthesis to improve clavulanic acid production in Streptomyces clavuligerus

The glycerol utilization (gyl) operon is involved in clavulanic acid (CA) production by Streptomyces clavuligerus, and possibly supplies the glyceraldehyde-3-phosphate (G3P) precursor for CA biosynthesis. The gyl operon is regulated by GylR and is induced by glycerol. To enhance CA production in S. clavuligerus, an extra copy of ccaR expressed from Pgyl (the gyl promoter) was integrated into the chromosome of S. clavuligerus NRRL 3585. This construct coordinated the transcription of CA biosynthetic pathway genes with expression of the gyl operon. In the transformants carrying the Pgyl-controlled regulatory gene ccaR, CA production was enhanced 3.19-fold in glycerol-enriched batch cultures, relative to the control strain carrying an extra copy of ccaR controlled by its own promoter (PccaR). Consistent with enhanced CA production, the transcription levels of ccaR, ceas2 and claR were significantly up-regulated in the transformants containing Pgyl-controlled ccaR.

Development of a colorimetric assay for rapid quantitative measurement of clavulanic acid in microbial samples

We developed a colorimetric assay to quantify clavulanic acid （CA） in culture broth of Streptomyces clavuligerus, to facilitate screening of a large number of S. clavuligerus mutants. The assay is based on a β-1actamase-catalyzed reaction, in which the yellow substrate nitrocefin （λmax=390 nm） is converted to a red product （λmax=486 nm）. Since CA can irreversibly inhibit β-1actamase activity, the level of CA in a sample can be measured as a function of the A390]A486 ratio in the assay mixture. The sensitivity and detection window of the assay were determined to be 50 μg L -1 and 50 μg L to 10 mg L-1, respectively. The reliability of the assay was confirmed by comparing assay results with those obtained by HPLC. The assay was used to screen a pool of 65 S. clavuligerus mutants and was reliable for identifying CA over-producing mutants. Therefore, the assay saves time and labor in large-scale mutant screening and evaluation tasks. The detection window and the reliability of this assay are markedly better than those of previously reported CA assays. This assay method is suitable for high throughput screening of microbial samples and allows direct visual observation of CA levels on agar plates.

Proteome-wide alterations in an industrial clavulanic acid producing strain of Streptomyces clavuligerus

The usefulness of genetic/metabolic engineering for further improvement of industrial strains is subject of discussion because of the general lack of knowledge on genetic alterations introduced by iterative cycles of random mutagenesis in such strains.An industrial clavulanic acid(CA)-overproducer Streptomyces clavuligerus DEPA was assessed to understand proteome-wide changes that have occurred in a local industrial CA overproducer developed through succesive mutagenesis programs.The proteins that could be identified corresponded to 33 distinct ORFs for underrepresented ones and 60 ORFs for overrepresented ones.Three CA biosynthetic enzymes were overrepresented in S.clavuligerus DEPA;carboxyethylarginine synthase(Ceas2),clavaldehyde dehydrogenase(Car)and carboxyethyl-arginine betalactam-synthase(Bls2)whereas the enzymes of two other secondary metabolites were underrepresented along with two important global regulators[two-component system(TCS)response regulator(SCLAV_2102)and TetR-family transcriptional regulator(SCLAV_3146)]that might be related with CA production and/or differentiation.g-butyrolactone biosynthetic protein AvaA2 was 2.6 fold underrepresented in S.clavuligerus DEPA.The levels of two glycolytic enzymes,2,3-bisphosphoglycerate-dependent phosphoglycerate mutase and phosophoglycerate kinase were found decreased while those of dihydrolipoyl dehydrogenase(E3)and isocitrate dehydrogenase,with two isoforms were found as significantly increased.A decrease of amino acid metabolism,methionine biosynthesis in particular,as well as S-adenosylmethionine synthetase appeared as one of the prominent mechanisms of success of S.clavuligerus DEPA strain as a prolific producer of CA.The levels of two enzymes of shikimate pathway that leads to the production of aromatic amino acids and aromatic secondary metabolites were also underrepresented.Some of the overrepresented stress proteins in S.clavuligerus DEPA included polynucleotide phosphorylase/polyadenylase(PNPase),ATP-dependent DNA helicase,two isoforms of an anti-sigma factor and thioredoxin reductase.Downregulation of important proteins of cell wall synthesis and division was recorded and a protein with b-lactamase domain(SCLAV_p1007)appeared in 12 isoforms,5 of which were drastically overrepresented in DEPA strain.These results described herein provide useful information for rational engineering to improve CA production in Streptomyces clavuligerus.

Real World Evidence (RWE, Real World Data), of the Effectiveness of Amoxicillin-Clavulanate in the Treatment of Children with Upper Respiratory Tract Infections (Tonsillitis, Otitis, Sinusitis)

Real-world evidence (RWE) is clinical evidence on a medical product’s safety and efficacy that is generated using real-world data (RWD) resulting from routine healthcare delivery. This study evaluates the clinical efficacy of amoxicillin + clavulanic acid in children with pharyngitis, acute otitis, or acute rhinosinusitis with suspected bacterial origin under normal office and home conditions. Methods: This was a real-life, prospective, observational, pharmacovigilance study. It included children of both sexes between 2 and 12 years old, with a diagnosis of Rhinopharyngitis (tonsillitis), Acute Otitis Media and Rhinosinusitis. The main effectiveness variable evaluated was reduction and time to resolution of symptoms. All patients received Amoxicillin/Clavulanic Acid suspension 600 mg/42.9 mg/5 mL at a dose of 90 mg/Kg/day in two doses, every 12 hours for 7 days. The evaluations were carried out at the beginning, at 72 hours (3rd day) and at 7 days. All patients underwent culture and antibiogram. Results: The majority of cultures were negative for pathogenic germs, suspecting unidentifiable germs, or viral etiology despite the rigorous selection of subjects following validated scores. The most frequently isolated germ was Staphylococcus aureus;growth of gram-negative bacteria was reported in 33.33% of the cultures. There was a significant improvement in symptoms in children with tonsillitis and rhinosinusitis from the first 72 hours of treatment, persisting until the 7 days. In the otitis media group, returning to normal by the tenth day. During the conduction of this investigation, no adverse effects associated with the prescribed therapy were reported.

阿司匹林肠溶片在健康成年受试者中的生物等效性

目的评价阿司匹林肠溶片在中国健康成年受试者中的生物等效性及安全性。方法采用单中心、随机、开放、两制剂、两顺序、四周期、完全重复试验设计。受试者每周期空腹或餐后单次口服1片受试制剂(test preparation,T)或参比制剂(reference preparation,R)。采用LC-MS/MS法测定不同时间点血浆中乙酰水杨酸(acetylsalicylic acid,ASA)的血药浓度,并进行两制剂的生物等效性及安全性评价。结果餐后试验组口服T和R后ASA的主要药代动力学参数为:C max分别为(690.97±196.91)ng·ml^(-1)和(669.28±337.40)ng·ml^(-1),AUC 0-t分别为(867.37±228.64)ng·h·ml^(-1)和(821.16±349.85)ng·h·ml^(-1),AUC 0-∞分别为(883.48±233.72)ng·h·ml^(-1)和(923.59±287.95)ng·h·ml^(-1);T max分别为(8.98±2.47)h和(10.69±3.75)h。经对数转换后C max、AUC 0-t和AUC 0-∞的几何均值比均在80.00%~125.00%范围之内,两制剂生物等效。空腹试验组口服T和R后ASA的主要药代动力学参数:C max分别为(466.83±222.89)ng·ml^(-1)和(441.42±211.99)ng·ml^(-1),AUC 0-t分别为(753.24±269.49)ng·h·ml^(-1)和(678.50±278.85)ng·h·ml^(-1),AUC 0-∞分别为(809.11±309.27)ng·h·ml^(-1)和(726.51±267.00)ng·h·ml^(-1);T max分别为(5.81±2.53)h和(6.41±2.47)h。经对数转换后C max、AUC 0-t和AUC 0-∞的几何均值比不在80.00%~125.00%范围之内,两制剂生物不等效。试验过程中,空腹组无不良事件发生,餐后组共报告2例次不良事件,均无严重不良事件。结论两种阿司匹林肠溶片在餐后条件下人体内生物等效,空腹条件下人体内生物不等效,制剂安全。

阿莫西林克拉维酸钾联合水杨酸乙醇耳浴对化脓性中耳炎的疗效及免疫功能的影响

目的 探讨阿莫西林克拉维酸钾联合水杨酸乙醇耳浴对化脓性中耳炎的疗效及免疫功能的影响。方法 选取2019年5月-2022年6月贵州省人民医院收治的86例化脓性中耳炎患者。随机数表法分为对照组、研究组,每组43例。对照组给予水杨酸乙醇耳浴治疗,研究组在对照组基础上给予阿莫西林克拉维酸钾,两组均持续治疗2周后观察疗效。对比两组听力功能、致病菌清除率及临床疗效;比较两组的外周血炎症因子、免疫功能情况;记录治疗期间药物不良反应发生情况。结果 研究组治疗前后的气导阈值、骨导阈值的差值均高于对照组(P <0.05)。研究组致病菌率清除率、总有效率均高于对照组(P <0.05)。研究组治疗前后IL-4、TGF-β、IL-17和Th1/Th2、Th17/Treg、CD4^(+)/CD8^(+)的差值均高于对照组(P <0.05)。两组患者治疗期间未出现不良反应,心电图及肝肾功能亦无异常。结论 阿莫西林克拉维酸钾联合水杨酸乙醇耳浴治疗化脓性中耳炎可提高患者听力功能,清除致病菌,增强治疗疗效,进一步抑制炎症因子合成,改善患者免疫功能,安全可靠。

UPLC-MS/MS法测定犬血浆中阿莫西林和克拉维酸片剂的生物等效性研究

[目的]本文旨在建立检测犬血浆中阿莫西林和克拉维酸片的UPLC-MS/MS方法,并进行犬口服国产阿莫西林克拉维酸钾片与参比制剂的生物等效性评价。[方法]以乙腈和甲酸水溶液为流动相,经HSS T3色谱柱梯度洗脱,阿莫西林和克拉维酸分别用电喷雾正、负离子模式进行多反应监测(MRM),血浆样品用乙腈沉淀蛋白、二氯甲烷萃取,对于克拉维酸血浆样品的预处理增加正己烷除脂的步骤,经方法学验证后分别检测血浆样品中阿莫西林与克拉维酸浓度。生物等效性试验采用单剂量、双处理、双周期随机交叉试验设计,选用26只健康成年比格犬,按顺序分别空腹口服参比制剂或受试制剂250 mg,再用建立的UPLC-MS/MS法检测血浆中阿莫西林和克拉维酸的浓度;采用Phoenix Winnonlin 8.1药动学软件的非房室模型计算药物的药动学参数,对C_(max)、AUC_(0-t)和AUC_(0-∞)进行对数转换后分析药物生物等效性。[结果]该方法专属性良好;阿莫西林在20~10000 ng·mL^(-1)、克拉维酸在50~5000 ng·mL^(-1)浓度范围内的信号响应值与浓度线性关系良好(R^(2)>0.99);批内、批间准确度偏差均在±15%以内,批内、批间精密度均在15%以内;基质效应符合要求,阿莫西林和克拉维酸在试验条件下稳定。参比制剂和受试制剂中:阿莫西林的C_(max)分别为(10934.87±3118.79)ng·mL^(-1)和(11101.66±3185.09)ng·mL^(-1),AUC_(0-t)分别为(30983.24±9395.40)ng·h·mL^(-1)和(31646.91±9319.93)ng·h·mL^(-1),AUC_(0-∞)分别为(31093.42±9425.85)ng·h·mL^(-1)和(31843.77±9290.25)ng·h·mL^(-1);克拉维酸的C_(max)分别为(3494.90±1574.11)ng·mL^(-1)和(3694.26±1701.65)ng·mL^(-1),AUC_(0-t)分别为(5652.61±2409.17)ng·h·mL^(-1)和(6041.81±2458.42)ng·h·mL^(-1),AUC_(0-∞)分别为(5730.52±2392.78)ng·h·mL^(-1)和(6122.80±2469.20)ng·h·mL^(-1),C_(max)、AUC_(0-t)、AUC_(0-∞)经对数转换后几何均值比的90%置信区间均落在80.00%~125.00%,T_(max)经非参数检验无明显差异。[结论]所建UPLC-MS/MS方法符合生物样品分析要求,国产阿莫西林克拉维酸钾片与参比制剂在犬体内生物等效。

用HPLC-荧光检测同时测定阿莫西林和克拉维酸钾浓度

１２名男性健康受试者采用随机交叉给药方法。单剂量口服试验药阿莫西林－克拉维酸钾干混悬剂（４∶１）和对照药阿莫西林－克拉维酸钾（４∶１）干混悬剂，阿莫西林５００ｍｇ，克拉维酸钾１２５ｍｇ，进行人体生物利用度和药代动力学比较。用ＨＰＬＣ荧光检测同时测定阿莫西林和克拉维酸钾血浓度。结果试验药和对照药中阿莫西林的Ｔ_（ｍａｘ） １．５８ ± ０．３６和１．５６ ± ０．３４ｈ； Ｃ１３．９４± ２２０和１３．３８±２．６７ ｍｇ·Ｌ_（－１）； Ｔ_（１／２）； １．５７ ± ０．１９和１．５３ ± ０．２３ｈ； ＡＵＣ ５２．２８ ± ８．２２和５０．２４ ±９．４４ ｍｇ·ｈ·Ｌ^（－１），相对生物利用度１０４．８９％ ± ７．７３％。克拉维酸钾的Ｔ_（ｍａｘ） ０．９６±０．３７和１０６±０．５０ｈ；Ｃ_（ｍａｘ） ２．１３±０．４４和２６９±０．９９ｍｇ· Ｌ^（－１） Ｔ_（１／２） １．２７±０．１９和 １．２８ ± ０３２ｈ； ＡＵＣ ５．３８ ± ０．８３和 ５．６６ ±１．０４ｍｇ· ｈ· Ｌ^（－１），相对生物利用度９５．９１％±１１．２１％。两种制剂的ＡＵＣ和Ｃ_（ｍａｘ）经方差分析和双单侧ｔ检验，Ｔ_（ｍａｘ）用非参数法统计。

阿莫西林/克拉维酸国产分散片与进口糖浆人体生物等效性研究

20名健康受试者采用随机交叉给药方案 ,分别单剂量口服国产阿莫西林 /克拉维酸 (4∶ 1)分散片和进口制剂 (含阿莫西林 5 0 0 m g,克拉维酸 12 5 mg) ,进行人体药代动力学和生物等效性研究。采用高效液相色谱法测定血清中阿莫西林及克拉维酸的浓度 ,经 3P97程序拟合 ,阿莫西林采用梯形法计算的两者 AUC0 - t均值分别为 (2 2 .94± 5 .0 4)和 (2 3.0 6± 5 .87) mg· h/L ,实测 Cmax均值分别为 (10 .71± 3.2 7)和 (9.99± 2 .96 )mg/L ,实测 Tmax均值分别为 (1.0 3± 0 .2 7)和 (0 .95± 0 .2 6 ) h。克拉维酸采用梯形法计算的两者 AUC0 - t均值分别为 (5 .2 3± 1.5 0 )和 (5 .42± 1.49) mg·h/L,实测 Cmax均值分别为 (2 .5 0± 0 .6 1)和 (2 .44± 0 .6 9) mg/L,实测Tmax均值分别为 (1.0 0± 0 .32 )和 (1.0 5± 0 .33) h。经统计学分析 ,国产制剂和进口制剂具有生物等效性。阿莫西林的相对生物利用度为 (10 1.2± 15 .8) % ,克拉维酸的相对生物利用度为 (97.3± 13.7) %。

阿莫西林·克拉维酸钾片在健康志愿者体内的相对生物等效性

目的 比较两种不同工艺生产的阿莫西林·克拉维酸钾片在健康志愿者体内的药代动力学及相对生物等效性 ,确保临床用药质量 .方法 健康志愿受试者 18例 ,男性 ,采用标准二阶段交叉设计自身对照试验法 ,用 RP- HPL C法测定血浆中阿莫西林和克拉维酸的经时浓度 ,以双单侧 t检验统计法比较两种不同工艺生产的阿莫西林·克拉维酸钾片之间的差异 .结果 两种阿莫西林·克拉维酸钾片在健康志愿者体内的药时曲线均符合一级吸收的单室开放模型 ,主要的药代动力学参数阿莫西林 :tmax分别为 (71.7± 9.7)和 (6 9.2±9.1) min,ρmax,AUC( 0～ 3 6 0 min) 分别为 :(8.8± 1.5 )和 (8.0±1.3) mg· L- 1 ;(140 6± 30 8)和 (12 39± 2 5 0 ) (mg· m in- 1 ·L- 1 ) ,Cla:tmax分别为 (6 8.3± 7.7)和 (6 7.5± 7.7) m in,ρmax,AU C( 0～ 3 6 0 min) 分别为 :(6 .2± 0 .8)和 (5 .9± 0 .7) mg· L- 1 ;(10 33± 176 )和 (96 2± 136 ) (mg· min- 1· L- 1 ) ,药动学参数间均无统计学差异 (P>0 .0 5 ) ,相对生物利用度阿莫西林 F为 115 % ;克拉维酸 F为 10 8% .结论 两种阿莫西林·克拉维酸钾片在健康志愿者体内具有相同的生物效应 。

阿莫西林/克拉维酸钾(7∶1)分散片生物等效性研究

目的 :研究阿莫西林 克拉维酸钾 (7∶1)的国产分散片与进口干混悬剂的生物等效性。方法 :2 0例健康男性志愿者采用双周期随机交叉、单剂量口服国产阿莫西林 克拉维酸钾分散片 (7∶1)和进口干混悬剂 (7∶1) 2种制剂 ,服药剂量均为阿莫西林 80 0mg和克拉维酸 114mg。用HPLC法测定血清中阿莫西林和克拉维酸的浓度 ,并用 3P97程序对试验数据进行处理。结果 :国产分散片和进口干混悬剂中阿莫西林Cmax 分别为 (12 .39± 3.2 2 )和(12 .32± 3.2 7) μg·mL- 1 ;Tmax分别为 (1.2 8± 0 .4 0 )和 (1.2 4± 0 .36 )h ;AUC0～ 6 分别为 (31.91± 7.36 )和 (30 .84±6 .6 1) μg·h·mL- 1 ;国产药与进口药比较 ,阿莫西林相对生物利用度F0～ 6 为 (10 3.5 6± 8.33) %。国产分散片和进口干混悬剂中克拉维酸Cmax分别为 (2 .5 94± 1.0 4 4 )和 (2 .5 0 5± 0 .94 9) μg·mL- 1 ;Tmax分别为 (1.0 6± 0 .4 3)和 (1.0 5±0 .5 2 )h ;AUC0～ 6 分别为 (5 .6 6± 1.74 )和 (5 .5 7± 1.73) μg·h·mL- 1 ;国产药与进口药比较 ,克拉维酸相对生物利用度F0～ 6 为 (10 2 .4 9± 13.5 5 ) %。结论 :国产阿莫西林 克拉维酸钾分散片和进口干混悬剂具有生物等效性。

阿莫西林克拉维酸钾(7:1)分散片人体生物等效性

目的:研究阿莫西林克拉维酸钾(7:1)分散片试验制剂与对照制剂的人体生物等效性。方法:23名健康男性受试者随机双周期交叉单剂量口服阿莫西林克拉维酸钾(7:1)分散片(800:114,mg)试验制剂和对照制剂。用柱切换HPLC内标法测定阿莫西林和克拉维酸血药浓度,由3P97药动学程序计算有关药代动力学参数。结果:阿莫西林和克拉维酸药-时曲线均呈一室模型。阿莫西林试验制剂及对照制剂AUC_(0-8)分别为33.93±3.22及33.81±5.70 h·mg·L^(-1),C_(max)分别为13.22±0.91及12.09±2.88 mg·L^(-1),t_(max)分别为1.42±0.18 h及1.50±0.18。克拉维酸试验制剂及对照制剂AUC_(0-6)分别为5.01±0.77及5.51±0.18h·mg·L^(-1),C_(max)分别为2.39±0.31及2.72±0.29 mg·L^(-1),t_(max)分别为1.19±0.35及1.33±0.35 h。试验制剂对对照制剂相对生物利用度(F)阿莫西林为(103.4±30.5)％,克拉维酸为(91.0±27.0)％。阿莫西林及克拉维酸AUC和C_(max)经对数转换后双单侧t检验均P <0.05,阿莫西林试验制剂AUC_(0-8)90％可信限落在对照制剂97.0％～102.2％内,C_(max)90％可信限落在98.8％～118.1％内;克拉维酸试验制剂AUC_(0-6)90％可信限落在参比制剂84.1％～102.6％内,C_(max)90％可信限落在81.9％～101.0％内,t_(max)

阿莫西林与克拉维酸按7∶1配比的药代动力学和生物等效性研究

目的了解阿莫西林和克拉维酸在中国健康人体中的药代动力学并比较两种不同产地阿莫西林/克拉维酸低配比(7∶1)制剂的生物等效性。方法20名男性健康受试者采用随机交叉给药方案,分别口服1000mg阿莫西林/克拉维酸片(内含阿莫西林875mg,克拉维酸125mg),用HPLC法分别测定血清中阿莫西林和克拉维酸的浓度,按照最佳拟合的方法求算两种药物的药代动力学参数,并计算两种制剂的相对生物利用度。结果两种制剂的血药浓度—时间曲线符合一房室模型。两种制剂—对照药和试验药的阿莫西林、克拉维酸的达峰时间Tmax分别为(1.57±0.61)、(1.31±0.31)h和(1.75±0.53)、(1.33±0.33)h,Cmax分别为(11.05±2.16)、(2.10±0.54)mg/L和(11.56±7.71)、(2.00±0.51)mg/L。t1/2分别为(1.30±0.37)、(0.98±0.20)h和(1.29±0.25)、(0.91±0.17)h,AUC0-∞分别为(34.47±4.32)、(4.95±1.03)mg·h/L和(35.90±6.25)、(5.00±1.04)mg·h/L。试验药物的阿莫西林相对生物利用度为(104.4±16.5)%,克拉维酸为(96.7±11.7)%,AUC经统计学处理证实两种制剂生物等效。

阿莫西林和克拉维酸钾复合制剂的药物动力学

本文对阿莫西林－克拉维酸钾复合制剂在９名健康成人中进行药物代谢动力学和生物利用度研究。血浆中药物浓度分别用藤黄八叠球菌和克雷伯氏肺炎杆菌为检定菌（用井式琼脂平板法）测定阿莫西林和克拉维田钾。单剂量口服２５０ｍｇ阿莫西林和１２５ｍｇ克拉维酸钾后其阿莫西林的Ｔｍａｘ１．１７±０．３１ｈｆｏ０．９７±０．３３ｈ；Ｃｍａｘ３．５±０．６μｇ／ｍｌ和３．６±０．７μｇｍｌ；Ｔ１／２１．１±０．３ｈ和１．１５±０．２７ｈ。克拉维酸钾为：Ｔｍａｘ１．ｌｌ±０．２４ｈ和０．８９±０．２９ｈ；Ｃｍａｘ３．６±１．０μｇ／ｍｌ和４．０±１．４４μｇ／ｍｌ；Ｔ１／２０．７８±０．１９ｈ和０．８±０．４ｈ。颗粒剂的相对生物利用度阿莫西林为１０４±２０％，克拉维酸钾为１０８±１１％。

β-内酰胺酶抑制剂的研究进展

介绍了β -内酰胺酶抑制剂的用途和作用机理 ,并对目前临床上应用最广泛的三种β -内酰胺酶抑制剂 :克拉维酸、舒巴坦、他唑巴坦进行了重点介绍 ,包括它们的原料及合成方法等 。

单剂口服多潘立酮片在健康人体的生物等效性

目的评价2种多潘立酮片的生物等效性。方法选择健康成年男性20名,随机分为2组,每组10人,自身前后交叉分别口服2种多潘立酮片10mg;用高效液相色谱法测定血药浓度,用3P97软件计算药代动力学参数,考察其生物等效性。结果20名健康受试者口服2种多潘立酮片的主要药代动力学参数tmax分别为(0.73±0.23),(0.73±0.24)h;Cmax分别为(18.78±4.50),(19.69±6.97)μg·L-1;AUC0-t分别为(74.84±19.61),(78.74±22.14)μg·h·L-1;相对生物利用度为95.54%。结论2种多潘立酮片具有生物等效性。