用重组噬菌体检测结核分枝杆菌耐药性

目的　建立一种特异性强 ,灵敏度高的结核分枝杆菌 (结核菌 )的检测及药敏试验方法。方法　采用生物发光技术检测可表达荧光素酶的分枝杆菌噬菌体phage 40 ,对不同细菌的发光反应和药敏试验进行测定 ,探讨噬菌体生物发光检测方法的灵敏度和特异性。结果　phage 40对各种分枝杆菌均有特异性发光 ,对非分枝杆菌发光值很低 ,两者差异有显著性意义 ;不同的分枝杆菌发光值有差异 :卡介苗的发光值最高 ,在 4 2× 10 6 ml时最大发光值为 2 84 7mV ,结核菌的发光值最低 ,H37Ra在 6 4× 10 6 ml时最大发光值为 72 4mV ,H37Rv在 7 6× 10 6 ml时的最大发光值是 74 3mV ;在含抗结核药物的培养基中 ,耐药结核菌的发光强度比非耐药结核菌强 ,其强度差异有显著性意义。phage40的药敏试验结果与常规罗氏培养基法符合率一致 ,可在 72h内得到结果。结论　生物发光技术可快速、敏感地检测结核菌 ,通过发光分析 ,建立了一种简便、快速的药敏试验方法     

结核分枝杆菌mRNA在利福平快速药敏试验中的初步应用

目的　建立一种Mycobacteriumtuberculosis(结核分枝杆菌 ,MTB)mRNA快速敏感的检测方法并初步探讨其在利福平快速药敏试验中的应用。方法　用超声粉碎和Tripure试剂提取MTB总RNA ,针对α抗原 85B的特定编码序列建立MTBmRNA的RT PCR检测方法 ;观察MTB在含 1、2、4 μg/ml利福平的液体培养基中生长时 ,85BmRNA的动态改变 ,确定快速检测利福平耐药菌株的最佳药物浓度和时间点 ,比较RT PCR和快速培养法对 2 0株临床分离菌株利福平耐药性检测的差异性。结果　 85BmRNA的RT PCR最低检测下限为 10 0 0个细菌。 85BmRNA的动态结果表明 ,在 4 μg/ml利福平中培养 2 4h为最佳药物浓度和时间点。RT PCR和快速培养法对 2 0株临床菌株利福平药敏试验检测结果无显著差异 (χ2 =0 .5 ,P >0 .0 5 ) ,但前者能显著缩短药敏检测周期。结论　检测结核分枝杆菌mRNA的RT PCR方法可望应用于利福平快速药敏试验     

结核分枝杆菌链霉素耐药性的噬菌体检测技术研究

目的 建立结核分枝杆菌（结核菌）链霉素耐药性的噬菌体快速检测技术，并探讨其临床应用价值。方法 应用分枝杆菌噬菌体感染结核菌建立链霉素耐药性的噬菌体检测技术，并对最佳测定条件进行探讨；将所建立的方法用于38株世界卫生组织药敏质控株和372株临床分离株链霉素耐药性测定，并与绝对浓度法和Bactec 960药敏结果比较，对不符合菌株进行最低抑菌浓度（MIC）和rpsL耐药基因检测。结果 链霉素终浓度5μg／ml作用24h、噬菌体10^8噬菌体形成单位／ml感染60min、杀毒剂5％室温作用5min为选择的检测条件。噬菌体法检测38株药敏质控株结果完全符合。372株临床分离株链霉素耐药性检测结果表明，如以绝对浓度法药敏结果为判断标准，则本法敏感性为97.4％、特异性为91．0％、阳性预测值为81.7％、阴性预测值为98.9％、准确性为92.9％；如以Bactec 960药敏结果为判断标准，则本法敏感性为97.2％、特异性为97.1％、阳性预测值为94.6％、阴性预测值为98.5％、准确性为97．1％。有22株噬菌体法药敏结果与常规药敏试验结果不符，其中的11株噬菌体法检测结果与MIC和rpsL耐药基因检测结果相同。结论 噬菌体法检测链霉素耐药性快速、简便，具有很高的敏感性和特异性，可作为结核菌链霉素耐药性的快速检测方法。     

结核分枝杆菌快速微量直视培养药敏试验方法的研究

目的建立一种经济、适用、快速的微量结核分枝杆菌（MTB）直视培养药敏方法。方法研制电脑控制无级连续超倍放大、微量培养和图像采集组成的MTB快速培养药敏及鉴定系统;用该系统进行MTB标准菌株H37Rv及临床分离菌株药敏试验;以改良罗氏法（L—J法）为对照,确定药敏试验药物最适浓度。结果本法药敏试验的药物：硫酸链霉素、异烟肼、利福平、乙胺丁醇、硫酸阿米卡星、硫酸卷曲霉素、盐酸左氧氟沙星及对氨基水杨酸异烟肼应用浓度分别为：1、0．1、1、5、5、10、4、1μg／ml;检出时间H37Rv为3d;临床分离菌165株平均5．6d。每实验孔仅需培养基100μl。结论快速法显著缩短了MTB药敏试验时间,节省试剂,操作简便,适合基层单位应用。     

分枝杆菌药物敏感试验快速荧光检测法的研究

目的 建立一种Mycobacterium(分枝杆菌)药敏试验的快速荧光检测法。方法 用自己研制的荧光检测管检测异烟肼(INH)、利福平(RFP)、乙胺丁醇(EB)、丁胺卡那霉素(AMK)、左旋氧氟沙星(LVFX)对分枝杆菌的体外抑菌活性,并用41例临床菌株与改良罗氏法进行了配对比较,确定各药物在药敏试验中的应用浓度：结果 5种药物的应用浓度分别确定为INH：0．1μg/ml、RFP;1μg/ml、EB：2μg/ml、AMK：2μg/ml、LVFX：2μg/ml;本法进行分枝杆菌的药敏试验仅需7—10d,较改良罗氏法的28d缩短了18—21d。2种方法的药敏试验结果无显著性差异。结论 本法经济实用并缩短了分枝杆菌药敏的报告时间。     

匡氏琼脂培养基用于痰结核菌直接药敏试验的效果研究

目的 调查匡氏琼脂培养基（简称匡氏培基）用于痰结核分枝杆菌（简称结核菌）直接药敏试验的效果。方法 匡氏培基痰结核菌直接药敏试验和间接药敏试验；罗氏培基间接药敏试验。结果 580例涂阳痰标本中的438例（占75．5％）获得全部8种药敏试验结果，72例（占12．4％）获得部分药敏试验结果，平均报告结果的时间少于3周。匡氏培养基直接药敏试验与间接药敏试验的符合率＞98．7％，与罗氏培养基间接药敏试验结果的符合率在94．4％－96．6％。结论 匡氏培养基用于涂阳痰标本直接药敏试验具有操作简便、快速、结果准确的优点，有推广应用价值。     

变色液体培养基系统快速鉴定结核分枝杆菌和耐药性测定

由于固体培养基鉴定结核分枝杆菌(结核菌)及药敏试验均需28 d,其制作过程需加热,且培养基中蛋白质对药物有吸附作用,故仅用于常规抗结核药敏试验,不适合用于分枝杆菌最低抑菌浓度(MIC)测定.多耐药结核菌和非结核菌对常用抗结核药物耐药,因此急需一种快速测定分枝杆菌药敏的方法,筛选新的药物.尽管Bactec系统可用于分枝杆菌药敏试验和MIC测定[1],但试剂和仪器昂贵.因此,我们采用快速变色液体培养基系统鉴定结核与非结核分枝杆菌,并测定了结核菌常规药物的敏感性和非结核分枝杆菌对9种药物的MIC,结果如下. 一、材料和方法 1.标本来源:128株结核菌,34株非结核分枝杆菌(其中15株龟分枝杆菌脓肿亚种、4株龟分枝杆菌龟亚种、14株偶发分枝杆菌和1株胞内分枝杆菌).上述菌株为深圳地区和广州地区分离株. 2.结核菌快速鉴定及药敏试剂、分枝杆菌MIC测定试剂和菌株鉴定试剂:对硝基苯甲酸(PNB)培养基、5%氯化钠耐受试验、芳香硫酸酯酶(3、14     

结核分枝杆菌对氟喹诺酮类药物敏感性的实验研究

目的 获得四种氟喹诺酮（FQ）对结核分枝杆菌的最小抑菌浓度（MIC）,评价PCR探针熔解曲线法（PMAA）检测结核分枝杆菌对氟喹诺酮药物耐药性的临床价值.方法 124例对氧氟沙星敏感的菌株和78例对氧氟沙星耐药的菌株,在96孔细菌培养板中,用Middlebrook 7H9液体培养基将药物进行连续倍比稀释后,加入5×10^-2 mg/ml菌液100 μl,用刃天青显色法测定MIC;并用PCR探针熔解曲线法（PMAA）检测结核分枝杆菌对氟喹诺酮（FQ）药物的耐药突变.结果 氧氟沙星折点浓度为2 μg/ml,加替沙星和莫西沙星对结核分枝杆菌的MIC90比氧氟沙星和左氧氟沙星要低4-8倍,具有比氧氟沙星和左氧氟沙星更好的抗结核分枝杆菌的活性.以罗氏比例法为金标准,PCR-PMAA检测敏感度、特异度、阳性预测值、阴性预测值和符合率分别为96.2％,97.6％,96.2％,97.6％和97.0％.结论 利用微量MIC方法较常规药敏方法可以获得更多的耐药信息.用PCR-PMAA法能高效快速的检出耐药突变菌株.两种方法结合应用,对临床肺结核疾病早期用药具有更好的指导价值.     

微量MIC检测判断结核分枝杆菌药敏的方法学研究

目的 建立用微量MIC值判断结核分枝杆菌药物敏感性的方法 ,并进行初步临床应用评价.方法 采用液体培养基MIC测定技术,在96孔U型板中进行检测,以60株已知药敏结果 的本院菌株库保存菌株作为试验菌株, 根据Bactec MGIT结果采用ROC曲线分析建立微量MIC药敏判断界值,最后用80株连续时间段内收集的结核分枝杆菌临床分离株对微量MIC药敏判断界值进行验证和修正.结果 微量MIC药敏法的最佳接种菌量为10~(-3)mg/ml数量级,7～10 d即可报告结果 ,链霉素、异烟肼、利福平、乙胺丁醇、氧氟沙星、阿米卡星和卷曲霉素的最佳判断界值分别为2、0.25、1、2、1、4和4 μg/ml,其敏感度分别为93.5%、97.7%、93.5%、84.4%、95.8%、91.7%和88.9%, 特异度分别为95.6%、94.6%、100.0%、93.8%、92.9%、95.6%和91.5%.其准确性分别达95.0%、96.3%、97.5%、90.0%、93.8%、95.0%和91.3%. 结论 微量MIC药敏检测方法 具有快速、准确、低成本和操作简单的优点,具有良好的推广应用前景,适合在我国各级结核病专业收治机构使用.     

变色液体培养基系统快速鉴定结核分枝杆菌和耐性测定

由于固体培养基鉴定结核分枝杆菌 (结核菌 )及药敏试验均需 2 8ｄ ,其制作过程需加热 ,且培养基中蛋白质对药物有吸附作用 ,故仅用于常规抗结核药敏试验 ,不适合用于分枝杆菌最低抑菌浓度 (ＭＩＣ)测定。多耐药结核菌和非结核菌对常用抗结核药物耐药 ,因此急需一种快速测定分枝杆菌药敏的方法 ,筛选新的药物。尽管Ｂａｃｔｅｃ系统可用于分枝杆菌药敏试验和ＭＩＣ测定[1] ,但试剂和仪器昂贵。因此 ,我们采用快速变色液体培养基系统鉴定结核与非结核分枝杆菌 ,并测定了结核菌常规药物的敏感性和非结核分枝杆菌对 9种药物的ＭＩＣ ,结果如下。…     

Rosaramicin Versus Penicillin G in Experimental Pneumococcal Meningitis

Rosaramicin, a new macrolide antibiotic, was compared with penicillin G in the treatment of pneumococcal meningitis in rabbits. Animals were infected intracisternally with 10(4) colony-forming units of Streptococcus pneumoniae type III (rosaramicin minimal inhibitory/bactericidal concentrations, 0.25/0.5 mug/ml; penicillin G minimal inhibitory/bactericidal concentrations, 0.03/0.06 mug/ml). Treatment was instituted 96 h later. Infusion of rosaramicin at 25 mg/kg per h intravenously for 8 h produced a peak cerebrospinal fluid (CSF) drug concentration of 1.54 mug/ml (range, 0.87-3.6 mug/ml). During this infusion the numbers of pneumococci in CSF decreased from 6.2 +/- 0.5 to 3.36 +/- 1.12 log(10) colony-forming units per ml. Penicillin G, infused at 30 mg/kg per h for 8 h, reached a similar concentration in CSF but caused a greater reduction (P < 0.01) in CSF bacteria, from 6.4 +/- 0.36 to 1.3 +/- 0.67 log(10) colony-forming units per ml. Penicillin G, at 100 mg/kg per day intramuscularly for 5 days, cured 7 of 10 rabbits with pneumococcal meningitis. A higher dose, 300 mg/kg per day for 5 days, was no more efficacious: 11 of 14 rabbits were cured. Rosaramicin at 100 mg/kg per day intramuscularly for 5 days cured only 5 of 15 rabbits with meningitis, but a higher dosage regimen of that drug (250 mg/kg per day intramuscularly) produced acute, fulminant enterocecitis and death within 48 h in seven of eight rabbits. No cytotoxin was detected in the feces of one rabbit with acute enterocecitis. Thus the efficacy of rosaramicin in experimental pneumococcal meningitis, measured by bacterial clearance from CSF and by treatment outcome, was less than that of penicillin G. In addition, high-dose parenteral rosaramicin caused acute, fulminant enterocecitis in a high proportion of treated rabbits.     

Cetirizine and loratadine: a comparison using the ED50 in skin reactions

To quantify objectively the comparative potencies of the antihistamines, loratadine and cetirizine, we determined the dose that inhibits histamine-induced skin reactions by 50% of the maximum response (ED50) for each drug. Cetirizine at 2.5, 5 or 10 mg, loratadine at 10, 20 or 40 mg or placebo were given to 14 healthy female subjects in a randomized double-blind crossover design. Inhibition of the wheal and flare response to the histamine prick test (10, 100 and 500 mg/ml) was evaluated. Depending on the histamine concentrations, the ED50s for wheals were in the ranges 4.3 - 4.7, 2.1 - 2.2 and 1.7 - 1.9 mg cetirizine, 2, 4 and 6 h after dosing, respectively. For loratadine, the ED50 for wheals were in the ranges 35.6 - > 40, 9.1 - 24.1 and 9.1 - 13.9 mg, 2, 4 and 6 h after dosing, respectively. Calculation of the ED50 demonstrated that, on average, cetirizine is seven to nine times more potent than loratadine at inhibiting wheal and flare reactions.     

Effects of AIDS and gender on steady-state plasma and intrapulmonary ethambutol concentrations

Our objective was to study the steady-state plasma and intrapulmonary orally administered ethambutol concentrations in healthy volunteers and subjects with AIDS. Ethambutol (15 mg/kg of body weight) was administered orally once daily to 10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women. The mean (+/-standard deviation [SD]) CD4 cell count for the 20 subjects with AIDS was (350 +/- 169) x 10(6) cells per liter. Blood was obtained for drug assay 2 h after the last dose and at the completion of bronchoalveolar lavage, performed 4 h after the last dose. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) was calculated by the urea dilution method. The total number of alveolar cells (AC) was counted in a hemocytometer, and differential cell counting was performed after cytocentrifugation. Ethambutol was measured by a new, sensitive and specific liquid chromotography-mass spectrometry method. The presence of AIDS, as defined in this study, or gender was without significant effect on the concentrations of ethambutol in plasma at 2 or 4 h or in ELF at 4 h following the last dose. Plasma drug concentrations (mean +/- SD) at 2 and 4 h were 2.1 +/- 1.2 and 2.1 +/- 0.8 microg/ml, respectively, and both values were not significantly different from the concentration of ethambutol in ELF at 4 h (2.2 +/- 1.1 microg/ml). The concentration of ethambutol was significantly greater in AC in all four groups (range, 44.5 +/- 15.6 to 82.0 +/- 39.4 microg/ml) than in ELF or plasma and was approximately 30 to 240 times the reported MIC for ethambutol-susceptible strains of Mycobacterium tuberculosis. The AC ethambutol concentration (mean +/- SD) in the smoking women (97.2 +/- 32.1 microg/ml) was more than twice the concentration in all other nonsmoking subjects (45.2 +/- 16.8 microg/ml) combined (P < 0.05). Two- and 4-h concentrations of ethambutol in plasma were not affected by AIDS status or gender. The high AC/plasma and AC/ELF concentration ratios suggest that substantial antimycobacterial activity resides in these cells. The data confirm earlier observations of active transport ex vivo of ethambutol into pulmonary macrophages.     

Failure of single doses of cefazolin and cefamandole to penetrate experimental chronic Escherichia coli abdominal abscesses.

Four perforated capsules were implanted into the abdominal cavity of each of three rabbits. After 4 to 5 weeks, single doses of cefazolin (30 mg/kg) or cefamandole (90 mg/kg) were administered intramuscularly. Peak levels of the respective drugs in serum were 104 +/- 10 and 127 +/- 5 micrograms/ml (mean +/- standard error); corresponding peak levels in capsule fluid were 6.3 +/- 2.3 micrograms/ml. Sixteen weeks after implantation, 2 X 10(6) colony-forming units of a strain of Escherichia coli susceptible to cefazolin (minimum inhibitory concentration, 1.0 microgram/ml) and cefamandole (minimum inhibitory concentration, less than 0.125 microgram/ml) was introduced into each of the 12 capsules. Chronic infection was established in seven of the capsules. At 4 to 6 weeks after infection, cefazolin and cefamandole were again administered. Peak serum concentrations were 102 +/- 3.3 micrograms/ml for cefazolin and 148 +/- 6.7 micrograms/ml for cefamandole. Peak concentrations in noninfected capsules were 7.5 +/- 3.4 and 12.1 +/- 2.1 micrograms/ml, respectively, not statistically different from the first study (P greater than 0.2). However, peak concentrations in infected capsules (less than 0.3 microgram/ml) were strikingly lower than in uninfected capsules (P less than 0.002). In keeping with the latter finding, quantitative cultures of E. coli in the infected capsules remained unchanged. Administration of [14C]cefamandole indicated that low drug levels were a result of poor drug penetration rather than drug inactivation or binding. Lack of vascularity and capsule wall necrosis may be responsible for poor drug penetration.     

Pharmacokinetics of E-5-(2-Bromovinyl)-2′-Deoxyuridine in Mice

The pharmacokinetics of the newly developed anti-herpes agent, E-5-(2-bromovinyl)-2'-deoxyuridine, was compared with that of the standard anti-herpes drug 5-iodo-2'-deoxyuridine. Both compounds were administered to mice at 100 mg/kg by either the intraperitoneal, subcutaneous, or oral route. The active blood drug levels achieved by E-5-(2-bromovinyl)-2'-deoxyuridine were considerably higher than those attained by 5-iodo-2'-deoxyuridine (serum peak concentrations: 40 to 100 and 4 to 10 mug/ml, respectively). Active blood drug levels could still be found 320 min after oral administration of E-5-(2-bromovinyl)-2'-deoxyuridine.     

In vivo microdialysis study of the penetration of daptomycin into soft tissues in diabetic versus healthy volunteers

Daptomycin is approved for the treatment of complicated skin and soft tissue infections, including diabetic wounds of the lower extremities, at a dose of 4 mg/kg of body weight once daily. For such localized tissue infections, drug concentrations in the interstitial space are an important determinant of successful therapy. In the diabetic population, peripheral arterial disease may limit antibiotic penetration into the target tissue. The objective of this study was to describe and compare the pharmacokinetic profiles of daptomycin in the interstitial fluid of soft tissues in diabetic and healthy volunteers by using in vivo microdialysis. Twelve subjects (six diabetic and six healthy) received a single 4-mg/kg dose of daptomycin intravenously. Samples of plasma and tissue were simultaneously collected over 24 h. Diabetic and healthy groups were matched in mean age (+/-10 years), gender ratio, mean weight (+/-10 kg), and creatinine clearance rate (+/-20 ml/min/1.73 m(2)). Pharmacokinetic parameters for plasma were similar between groups (P > 0.05). The mean peak drug concentrations +/- standard deviations in tissue were 4.3 +/- 3.3 microg/ml and 3.8 +/- 1.4 microg/ml for diabetic and healthy subjects, respectively. The degree of tissue penetration, defined as the ratio of the area under the free drug concentration-time curve for tissue to that for plasma, was 0.93 +/- 0.61 for diabetic subjects and 0.74 +/- 0.09 for healthy subjects (P = 0.46). Daptomycin at 4 mg/kg penetrated well into the soft tissue, reaching concentrations approximately 70 to 90% of those of the free drug in plasma. Moreover, these free, bioactive concentrations in tissue exceeded the MICs for staphylococci and streptococci over the 24-h dosing interval.     

Metabolic interactions of ciprofloxacin

The mechanism and clinical relevance of the inhibitory effect of ciprofloxacin on the metabolism of selected drugs were studied in patients with bacterial infections. In study A, antipyrine tests were carried out in two groups of patients taking 1000 mg (group 1) and 250 mg (group 2) of oral ciprofloxacin for 7-10 days. Antipyrine was given intravenously in a dose of 15 mg/kg body weight before and after ciprofloxacin treatment. Blood samples were taken at 0, 2, 4, 6, and 10 hr after dosing. In group 1, ciprofloxacin administration resulted in a significant decrease in antipyrine elimination (t1/2, 9.45 +/- 3.74 vs. 14.92 +/- 3.32 hr). The average decrease in antipyrine clearance was 35% (0.85 +/- 0.45 vs. 0.52 +/- 0.24 ml/min/kg). In group 2, the change in antipyrine kinetics was less pronounced (t1/2, 9.79 +/- 3.06 vs. 11.22 +/- 2.64 hr). Antipyrine clearance was decreased by only 10% (0.77 +/- 0.13 vs. 0.70 +/- 0.14 ml/min/kg). These results support the hypothesis that ciprofloxacin inhibits the oxidative metabolism in the liver. However, according to the analysis of variance data, the inhibitory effect is dose dependent. At a dose of 1000 mg daily, ciprofloxacin may induce drug interactions whereas, at a dose of 250 mg daily, the likelihood of drug interactions is improbable. In study B, cimetidine (1000 mg orally daily) and ciprofloxacin (500 mg twice daily) were administered simultaneously to eight patients. Blood samples for the determination of ciprofloxacin concentrations were taken at 0, 1, 2, 4, 6, and 12 hr after dosing on the first and seventh day of drug administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of AIDS and gender on steady-state plasma and intrapulmonary ethionamide concentrations

Ethionamide, 250 mg every 12 h for a total of nine doses, was administered to 40 adult volunteers (10 men with AIDS, 10 healthy men, 10 women with AIDS, and 10 healthy women). Blood was obtained for drug assay prior to administration of the first dose, 2 h after the last dose, and at the completion of standardized bronchoscopy and bronchoalveolar lavage, which were performed 4 h after the last dose. Ethionamide was measured in epithelial lining fluid (ELF) and alveolar cells (AC) using a new mass spectrometric method. The presence of AIDS or gender was without significant effect on the concentrations of ethionamide in plasma, AC, or ELF. Plasma concentrations (mean +/- standard deviation [SD]) were 0.97 +/- 0.65 and 0.65 +/- 0.35 microg/ml at 2 and 4 h after the last dose, respectively, and both values were significantly greater than the concentration of ethionamide in AC (0.38 +/- 0.47 microg/ml) (P < 0. 05). The concentration of ethionamide was significantly greater in ELF (5.63 +/- 3.8 microg/ml) than in AC or plasma at 2 and 4 h and was approximately 10 to 20 times the reported MIC for ethionamide-susceptible strains of Mycobacterium tuberculosis. For all 40 subjects, the ELF/plasma concentration ratios (mean +/- SD) at 2 and 4 h were 8.7 +/- 11.7 and 9.7 +/- 5.6, respectively. We conclude that the absorption of orally administered ethionamide, as measured in this study, was not affected by gender or the presence of AIDS. Ethionamide concentrations were significantly greater in ELF than in plasma or AC, suggesting that substantial antimycobacterial activity resides in this compartment.     

Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase

We gave alpha-difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six health men in single intravenous doses of 5 and 10 mg/kg body weight and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 hr after each dose. Urine was collected from 0 to 24 hr after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first-order kinetics with a mean half-life (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean total body clearance (ClT) for the four doses was 1.20 +/- 0.06 ml . min-1 . kg-1. Mean renal clearance was determined as 0.99 +/- 0.03 ml . min-1 . kg-1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 +/- 0.031 l/kg-1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24-hr urine samples was 47 +/- 7% and 40 +/- 11% after 10 and 20 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg intravenously. Bioavailability of the 10 mg/kg dose was estimated as 58% from the urinary recoveries and as 54% from the areas under the plasma concentration curves (AUC 0 leads to infinity). Since doubling of the dose resulted in a doubling of the mean AUC 0 leads to infinity and since other kinetic parameters, such as aVD, t 1/2, ClT, and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose-linear model.