[Overall clinical evaluation of panipenem/betamipron against infections in pediatric field].
R FujiiToshiaki AbeTakeshi TajimaI TerashimaH MeguroA MoriS NakazawaHaruka SatoK NiinouKeisuke Sunakawa
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To conduct a basic-clinical study on newly developed panipenem/betamipron (CS-533/CS-443, PAPM/BP) against various infections in pediatrics, a study group was organized and a joint research by 17 institutions and their related hospitals was undertaken. The obtained results are as follows. 1. Blood concentrations and urinary excretion Pharmacokinetics of PAPM/BP in children was studied using 30 minutes intravenous drip infusion of 10 mg/10 mg/kg, 20 mg/20 mg/kg and 30 mg/30 mg/kg, respectively. Maximum blood levels of PAPM/BP were observed at the completion of drip infusion and were 26.72 +/- 8.78 micrograms/ml/18.33 +/- 8.54 micrograms/ml (mean +/- S.D.) with administration of 10 mg/10 mg, 64.80 +/- 18.50 micrograms/ml/38.74 +/- 16.41 micrograms/ml with administration of 20 mg/20 mg and 91.70 +/- 29.42 micrograms/ml/50.08 +/- 22.41 micrograms/ml with administration of 30 mg/30 mg. Dose dependency was noted with these doses. The half-life was about 1 hour for PAPM and about 0.5 hour for BP. As for urinary excretion, PAPM was excreted about 30% and BP about 70% in the first 6 hours after the start of drip infusion. 2. Clinical results Twenty-five cases of exclusion and drop-out were deducted from a total of 391 cases and 8 cases having 2 diseases concurrently were added to the remaining 366 cases, hence 374 cases were evaluated in the study as the subjects of analysis of clinical effects. As for clinical effects in cases where pathogenic bacteria were detected, 215 out of 221 cases were rated as effective or above, hence the efficacy rate of 97.3% was obtained. In cases where pathogenic bacteria were not detected, 145 out of 153 cases were rated as effective or above, thus the efficacy rate was 94.8% which is similar to that in the cases where pathogenic bacteria were detected. The daily dose levels most commonly employed were 30 to 60 mg/kg (as PAPM) administered in 3 divided doses a day, and this regimen method accounted for 52.7% of the total cases, and the efficacy rate with this regimen was 97.0%. As for the bacteriological effect 87 (96.7%) out of 90 strains of Gram-positive bacteria (GPB) disappeared and 136 (91.3%) out of 149 strains of Gram-negative bacteria (GNB) disappeared upon the treatment. The overall bacterial eradication rate for the pathogenic bacteria was 93.4%.(ABSTRACT TRUNCATED AT 400 WORDS)Cite
The main objective of this investigation was to determine the absorption, distribution, excretion, and pharmacokinetics of the antimalarial drug pyronaridine tetraphosphate (PNDP) in Sprague-Dawley rats. Following oral administration of a single dose (10 mg/Kg) ofC C C C max T max
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Pharmacokinetics on the metabolism and excretion of tolbutamide (TB) following the rapid intravenous injection of TB was investigated in rabbits based on the kinetic model where TB is first oxidized to 1-butyl-3-p-hydroxymethylphenylsulfonylurea (HTB), which is secondly converted to 1-butyl-3-p-carboxyphenylsulfonylurea (CTB) and both the metabolites are excreted in urine. It was found that binding of TB to plasma proteins and/or blood cells could not be neglected and the excretion of HTB formed in body would be well interpreted by assuming an intervenient compartment between blood and urine. Furthermore, pharmacokinetics of HTB was investigated after the administration of HTB to rabbits. It became clear that the amount of CTB formed in body after the administration of HTB was far smaller than that formed in body after the administration of TB indicating that the assumption that a metabolite administered per se would behave in the same manner as the metabolite formed in body from its precursor is not always free from criticism, though it has been undoubtedly employed to many pharmacokinetic studies of drugs. On the contrary, it was suggested that CTB administered per se would behave samely in body as CTB formed through metabolic reaction from TB or HTB by the experiment in which rabbits were given CTB intravenously.
Tolbutamide
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Objective To study the urine pharmacokinetics of gentiopicroside(GPS) in healthy volunteers.Methods Twelve healthy volunteers were selected to intravenous drip 80,240,400 mg GPS in an open randomized crossover study.GPS concentration in urine were determined by LC/MS/MS,the urine pharmacokinetic parameter were calculated with the WinNonlin software.Results The result showed that the max urinary excretive rates of GPS were 20.5,60.8,105.5 mg·h-1,respectively(tmax were 0.75 h).The excretive rate-time curves were 51.1,144.7,269.8 mg and the cumulative excretion in 25.5 h were 61.3,172.7,319.1 mg,respectively,these dates were directly proportional to dose.The excretion t1/2 were 2.96,2.90,2.90 h and the excretion parameters k were 0.25,0.26,0.25 h-1,respectively.The mean urinary excretion percentage of GPS was 76.1 %,and the excretion in 0~7.5 h was 96.2 % percentage of total excretion.Conclusion The drug maily excreted through kidney quickly in human in form of GPS,the urine pharmacokinetics showed a linear pharmacokinetic feature in the range of 80~400 mg.
Crossover study
Urine collection device
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Sinoacutine is a natural isoquinoline alkaloid isolated from traditional Chinese medicine Stephanina yunnanensis H. S. Lo. Our aim was to study the pharmacokinetic characteristics of sinoacutine, which is essential during the development of new drugs.In this study, an accurate, sensitive, and efficient liquid chromatography (HPLC) method was developed and applied to evaluate the pharmacokinetics, tissue distribution, plasma protein binding rate, and excretion after intravenous injection of sinoacutine in rats.The pharmacokinetic parameters of sinoacutine were accorded with a two-compartment model in rats, and the AUC0-t in female was greater than that in male. Sinoacutine could be detected in heart, liver, spleen, lung, kidney, and brain, and the content in liver and kidney was relatively high. Meanwhile, it had a high plasma protein binding rate of 79.16%. Excretion of sinoacutine through faeces and urine was low, and the average excretion rate was 9.96%. There were gender differences in blood drug concentration, tissue distribution, and excretion significantly (p < 0.05).In summary, this study lays a foundation for elucidating the pharmacokinetic rule of sinoacutine and the data can provide a reliable scientific resource for further research.
Renal physiology
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rHuEPO plays a central role as chemicals for the treatment of many diseases. Due to its short half-life, the main aim for this pharmacokinetic study is to investigate a newly developed PEG-rHuEPO with large molecular weight in SD rats. After a single intramuscular administration of different doses of 125I-PEG-rHuEPO, pharmacokinetic parameters, tissue distribution, and excretion were analyzed. In in vivo half-life time measured after 125I-PEG-rHuEPO administration at the doses of 1, 2, and 3 μg/kg, t1/2α was 1.90, 1.19, and 2.50 hours, respectively, whereas t1/2β was 22.37, 26.21, and 20.92 hours, respectively; at 8, 24, and 48 hours after intramuscular administration, PEG-rHuEPO was distributed to all of the examined tissues, however, with high concentrations of radioactivity, only in plasma, blood, muscle at the administration site, and bone marrow. Following a 2 μg/kg single intramuscular administration, approximately 21% of the radiolabeled dose was recovered after almost seven days of study. Urine was the major route of excretion; 20% of the administered dose was recovered in the urine, while excretion in the feces was less than 1.4%. Therefore, this PEG-rHuEPO has potential to be clinically used and could reduce frequency of injection.
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AIM: To investigate the pharmacokinetics, distribution of tissue, and excretion of 3H-radiolabeled c-Myc antisense phosphorothioate oligodeoxynucleotide ( 3H-c-Myc AS-PS-ODN) after single intravenous administration in mice. METHODS: The plasma radioactivities of 3H-c-Myc AS-PS-ODN administered intravenously in mice at three dose of 5, 10, 20 mg·kg -1 respectively were assayed at several time points by liquid sciuntillation counting; in addition, the radioactivity in tissues and the radioactivity of excretion in urine, feces were detected at several time points after administration of 3H-Myc-AS-PS-ODN intravenously at the dose of 10 mg·kg -1, then the profile was analysed by pharmacokinetics system. RESULTS: A two-compartment model was selected as optional model. There was a linear relationship between the doses administered and the AUC. c-Myc AS-PS-ODN distributed extensively into tissues, but the relative affinity varied enormously, being higher for kidney, liver, spleen, and bone marrow and lower for other tissues. There was little c-Myc AS-PS-ODN distributing into brain, reproductive gland and fat. Within the first 24 h, the urinary excretion was reached 82 % of the administered dose, which was extraordinarily more than the excretion in feces. CONCLUSION: Distribution and elimination of c-Myc AS-PS-ODN is rapid except brain, reproduction gland and fat. C-Myc AS-PS-ODN is mainly excreted in urine.
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Studies were conducted to characterize the pharmacokinetics and excretion of hydroxysafflor yellow A (HSYA) in rats and dogs after administration by intravenous injection or infusion. Plasma, urine, feces and bile concentrations of HSYA were measured using five validated mild HPLC methods. Linear pharmacokinetics of HSYA after the intravenous administrations were found at doses ranging from 3 to 24 mg/kg in rats and from 6 to 24 mg/kg in dogs. At a dose of 3 mg/kg, HSYA in urine, feces and bile was determined. For 48 h after dosing, the amount of urinary excretion accounted for 52.6 ± 17.9 % (range: 31.1 - 78.7 %, n = 6) of the dose, and the amount of fecal amount accounted for 8.4 ± 5.3 % (range 1.7 - 16.4 %, n = 6) of the dose. Biliary excretion amount accounted for 1.4 ± 1.0 % (range 0.4 - 2.9 %; n = 6) of the dose for 24 h after dosing. Percent plasma protein binding of HSYA ranged from 48.0 to 54.6 % at 72 h. In summary, five mild HPLC methods for the determinations of HSYA in rat plasma, urine, feces, bile and dog plasma have been developed and successfully applied to preclinical pharmacokinetics and excretion of HSYA in rats and dogs. The results of excretion studies indicated that HSYA was rapidly excreted as unchanged drug in the urine. In view of previous pharmacological work, the concentration-dependent neuroprotective effect of HSYA in rats was defined.
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Objective: To study the pharmacokinetics,distribution and excretion of glufosfamide in animals.Methods: 6 Beagle dogs were given 60,30,15 mg·kg-1 glufosfamide individually by iv.Plasma concentration was analyzed by LC-MS/MS.Pharmacokinetic parameters were calculated by 3P97 software.18 mouse were divided into 3 groups and given 300 mg·kg-1 glufosfamide by iv,and thereafter decapitated to determine the tissues distribution.10 rats were divided into 2 groups and given 100 mg·kg-1 300 mg·kg-1 glufosfamide individually.Samples of urine and feces were collected and determined for the excretion study.Results:The pharmacokinetics of glufosfamide in Beagle dogs was consistent with the two-compartment model.T1/2β and AUC of 60,30,15 mg·kg-1 group were 614.8,544.0,596.3 min and 37173.1,21760.0,10741.7 μg·mL-1·min.The maximum concentration appeared in the kidney(2780.2 μg·g-1),ovary(2684.5 μg·g-1)and uterus 2369.4 μg·g-1 of mouse 4 h after injection.For 300 mg·kg-1 glufosfamide in rats,26.9% prototype was excreted through urine,with a maximum excretion rate of 1.36 mg·h-15-8 h after injection;0.12% was excreted through feces,with a maximum excretion rate of 4.3 μg·h-1 2-5 h after injection.For 100 mg·kg-1 glufosfamide in rats,46.8% was excreted through urine,with a maximum excretion rate of 1.29 mg·h-1 8-12 h after injection;0.21% was excreted through feces,with a maximum excretion rate of 6.1 μg·h-1 5-8 h after injection.Conclusions: After intravenous injection of glufosfamide,plasma concentration,AUC demonstrate linear relationship with the dose.The drug is widely distributed in mouse,mainly in kidney,ovary,uterus,lung,spleen.25%-50% prototype is excreted through the urine within 1-24 h.
Beagle
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