Pharmacokinetic and pharmacodynamic studies of subcutaneously administered recombinant human interleukin-3 following chemotherapy for non-Hodgkin's lymphoma

The pharmacokinetics and the pharmacodynamic profile of subcutaneously administered recombinant human non-glycosylated interleukin-3 (rhIL-3) was studied in lymphoma patients after standard CHOP chemotherapy. 30 patients received 0.5, 1.0, 5.0, 7.5 and 10 micrograms/kg (six patients at each dose level) of rhIL-3 for 14 d. Serum rhIL-3 samples were obtained regularly, during the treatment and serially over a 24 h period on the first (cycle day 2) and the last (cycle day 15) day of rhIL-3 treatment for pharmacokinetic evaluation. Following s.c. injection on cycle day 2. the maximum rhIL-3 serum concentration ranged from 289 pg/ml (0.5 micrograms/kg) to 4690 pg/ml (10 micrograms/kg). Both the maximum serum concentration (R = 0.90. P < 0.0001) and the area under the serum concentration-time curve (R = 0.95, P < 0.0001) were related to dose. The elimination half-life T1/2 beta was 160 min for 0.5 micrograms/kg and 134 min for 10 micrograms/kg, with no apparent dose relationship. The systemic clearance of 3.0-6.0 ml/min/kg was comparable at all dose levels. No significant difference was noted between pharmacokinetic parameters on the first day of rhIL-3 and the last day of treatment, and no accumulation of the drug was noted throughout the study. The pharmacokinetic parameters correlated poorly to the clinical response of the growth factor. where dose in micrograms/kg seemed to be the most important single factor.     

Distribution of tritiated dihydromicrocystin in swine

The distribution of tritiated dihydromicrocystin [3H]2H-MCLR was studied in anesthetized specific-pathogen-free pigs. Two doses were administered i.m. and one dose was given via an isolated ileal loop. At 4 hr after i.v. administration of the toxin at 25 micrograms/kg, 64.6% of the total dose (%TD) was located in the liver, with smaller amounts distributed to the kidneys (1.2% TD), lungs (1.75% TD), heart (0.22% TD), ileum (0.13% TD) and spleen (0.04% TD). A similar distribution was found at 4 hr postdosing in pigs given 75 micrograms/kg, although the liver contained a lower fraction of the total dose, at 46.99% TD, and the kidneys had somewhat more, at 2.19% TD, than the low dose. At the high dose, the fractions of the amount given accounted for by the lungs (0.55% TD), heart (0.23% TD), ileum (0.20% TD) and spleen (0.07% TD) were similar to those at the low dose. The livers of the pigs given 75 micrograms/kg via the ileal loop, at 5 hr postdosing, contained 49.5% TD and the ileum had 33.94% TD. Smaller amounts were distributed to kidneys (1.04% TD), lungs (0.65% TD), heart (0.81% TD) and spleen (0.16% TD). The livers of both groups dosed at 75 micrograms/kg contained higher concentrations of toxin, but lower percentages of the total dose, than the livers of pigs dosed at 25 micrograms/kg. Larger increases in serum arginase in the two 75 micrograms/kg groups were associated with histological evidence of more severe liver damage than at the 25 micrograms/kg dose. Analysis of radiolabeled compounds from hepatic tissue using fast atom bombardment mass spectrometry determined that the primary constituent was [3H]2H-MCLR, but two minor radioactive components were also isolated. These findings indicate that [3H]2H-MCLR is rapidly concentrated in the liver of swine, whether given i.v. or via an isolated ileal loop, that at extremely toxic doses uptake is slowed, and that it is as toxicologically active as the parent compound.     

新型TMT-硫酸铁固定剂对重金属污染土壤的修复研究

以新型TMT（三巯基均三嗪三钠盐）-硫酸铁复配混合物为化学固定剂,考察了其对湖南郴州某重金属污染土壤中铅、镉、砷的固定效果.结果表明,单一使用TMT（含15 %（质量分数）TMT的水溶液）为固定剂时,土壤中的有效态铅、镉去除率高于60 %,但对砷没有固定效果.使用TMT-硫酸铁复配固定剂时,控制硫酸铁投加量为35.7 g/kg,TMT投加量为0.1 L/kg时,有效态铅、镉去除率达到90 %以上.随着土壤含水量的增加,土壤中有效态铅、镉的含量显著降低.当控制硫酸铁投加量为35.7 g/kg,TMT投加量为0.04 L/kg,控制土壤含水量至田间持水量的70 %,固定60 d,有效态铅、镉的去除率在80 %以上,有效态砷的去除率可达到60 %.      

Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours

The pharmacokinetics of amphotericin B administered in a conventional 5% dextrose (glucose) (5% D) solution and in a 20% fat emulsion formulation (Intralipid; 20% IL) were compared in 16 patients (mean age, 42 years [range, 18 to 70 years]) who had been hospitalized for hematological malignancies and with proven or suspected fungal infections. All of the patients received 50 mg (approximately 1 mg/kg of body weight per day) of amphotericin B daily in random order, either as a 50-ml lipid emulsion (20% IL) (group I) or in 500 ml of 5% D (group II). Five serum samples were taken during the 24 h after drug administration, and the levels of amphotericin B were measured by high-pressure liquid chromatography. Serum amphotericin B concentrations declined rapidly during the first 6 h, and subsequent measurements revealed a slow terminal elimination phase in both groups. The maximum serum amphotericin B concentration was significantly lower when the drug was administered in 20% IL (1.46 +/- 0.61 versus 2.83 +/- 1.17 micrograms/ml; P = 0.02). The area under the concentration-time curve from 0 to 24 h was also much lower in group I (17.22 +/- 11.15 versus 28.98 +/- 15.46 micrograms.h/ml). The half-life of the distribution phase was approximately three times longer in group I (2.92 +/- 2.34 h versus 0.64 +/- 0.24 h; P = 0.011). Conversely, the half-lives of the elimination phase were approximately equal in the two groups (11.44 +/- 5.18 versus 15.23 +/- 5.25 h). The mean residence times were also similar in both groups (19.41 +/- 11.13 versus 19.65 +/- 7.86 h). The clearance and the steady-state volume of distribution of amphotericin B in group I were about twice as great as those in group II (62.97 +/- 35.51 versus 33.01 +/- 14.33 ml/kg/h and 1,043.92 +/- 512.10 versus 562.32 +/- 152.05 ml/kg [P = 0.034], respectively). Finally, the volume of distribution in the central compartment was greater in group I than in group II (618.17 +/- 231.80 versus 328.19 +/- 151.71 ml/kg; P = 0.013), but there were no differences in the volume of distribution in the peripheral compartment (425.75 +/- 352.87 versus 234.14 +/- 75.92 ml/kg). These results suggest that amphotericin B has a different pharmacokinetic profile when it is administered in 20% IL than when it is administered in the standard 5% D form and that the main difference is due to a clear-cut difference in the steady-state volume of distribution, especially that in the central compartment.     

No identifiable effect of ginseng (Gericomplex) as an adjuvant in the treatment of geriatric patients

The pharmacokinetics of cefixime, a third-generation broad-spectrum cephalosporin, were determined following administration of a 8 mg/kg single oral dose of cefixime suspension to six children with urinary tract infections, ages from 6 to 13 years and weights from 17 to 60 kg. Blood samples for determination of plasma cefixime concentrations were obtained for up to 12 hr and complete urine collections were obtained for urinary excretion of unchanged parent drug for up to 24 hr after administration. Plasma and urine concentrations of cefixime were determined using a reversed phase HPLC assay and pertinent pharmacokinetic parameters were estimated by model-independent standard methods. Mean peak plasma concentration was 4.04 micrograms/ml and was reached after 3.2 hr. The mean area under the plasma concentration-time curve was 33.07 micrograms.hr/ml and the mean elimination half-life was 3.91 hr. The mean apparent total clearance was 4.74 ml/min./kg and about 15% of the dose administered was recovered unchanged in urine. In conclusion, the estimated pharmacokinetic values of cefixime were comparable to those observed in healthy adult subjects based on equivalent mg/ kg doses. Plasma and urine concentrations of the drug were well above the reported minimal plasma and urinary concentrations for most common urinary tract pathogens for up to 12 and 24 hr after administration, respectively.     

湖南某冶炼区果园土壤Cd、Pb、Zn分布及生物可利用性评价

对湖南某废弃铅锌冶炼厂周边土壤的现场调查和取样分析,发现研究区土壤pH值范围为4.5~6.5。土壤中Cd、Pb、Zn平均含量分别为5.66 mg/kg、2 409.00 mg/kg、1 224.42 mg/kg,污染显著,且变异强度较大。风险评估编码方法(RAC)显示研究区土壤中Zn处于低风险及以下;Pb含量不均匀,污染最重者达到极高风险;Cd绝大部分处于中风险及以上。桔子样品中重金属含量的检测结果表明,Cd未超过《食品中污染物限量》标准;Pb富集程度最高,其含量最低的样品Pb含量为标准的4倍以上。     

Food poisoning and infections in 1992

The concentration of heavy metals and polycyclic aromatic hydrocarbons (PAH) were determined in the soils obtained from various traffic roads in Cracow including surroundings of steel works. The method of atom absorption spectrometry was using to determination of Ca, Mg, Pb, Fe, Zn, Cd, Cu. PAH (fluoranthene, pyrene, benz(a)anthracene + chryzene, benz(a)pyrene, benz(ghi)perylene, fenanthrene and perylene) were determined by gas chromatography. The highest concentration of heavy metals was found in zone of steel works. A steep fall concentration of Fe was observed in the soils with increasing distance from the works. It seems that the variety in concentration of metals don't depend only on vehicular traffic. The highest mean PAH concentration exceeding 800 micrograms/kg of dried soils was found in soil samples taken from roads where the traffic is the highest.     

Effects of lysozyme dimer on humoral response to sheep erythrocytes in non-treated and cyclophosphamide-immunosuppressed mice

The effects of lysozyme dimer on humoral response to sheep erythrocytes (SRBC) and restoration of the response impaired by a single cyclophosphamide dose (200 mg/kg) were tested on mice. The effect of lysozyme dimer on the humoral response to SRBC in non-treated with cyclophosphamide mice was determined in relation to doses (0.2, 2, 20 or 200 micrograms/kg) and the time of the drug administration with respect to the antigen before or after SRBC immunization. Moreover, the effect of lysozyme dimer on the humoral response in cyclophosphamide-treated mice was studied depending on the dose applied and time of exposure to the drug in relation to SRBC. It has been found that lysozyme dimer potentiates the humoral response to SRBC in mice, resulting in an increased number of splenocytes producing haemolytic antibodies (PFC) and the total and 2-mercaptoethanol resistant level of anti-SRBC antibodies. A single exposure to lysozyme dimer gave the strongest stimulating action on SRBC when the doses of 2 or 20 micrograms/kg were administered 2 h prior to the antigen. The potentiating effect of the drug was reduced when it was administered 24 h before the antigen and also when single doses were as high as 200 micrograms/kg and as low as 2 micrograms/kg. Exposure to four doses of lysozyme dimer at 24 h intervals was more activating than a single injection. A strong potentiating effect on the specific response to SRBC was noted after four injections of lysozyme dimer at doses from 0.2 to 20 micrograms/kg. The effect of the drug did not depend on the time of exposure to the antigen. It has also been found that lysozyme dimer significantly reduces the suppressive effect of a high cyclophosphamide dose (200 mg/kg) on the humoral response of SRBC-immunized mice. The protective action of lysozyme dimer was dose- and time-dependent. The strongest protection was observed after three doses of 20 micrograms/kg administered prior to pharmacological immunosuppression. Reduction in the dose to 2 micrograms/kg and shorter treatment resulted in reduced protective effects. We have also found that the protective action of three doses of lysozyme dimer (2 or 20 micrograms/kg each) administered between cyclophosphamide injection and the antigen, or after antigen administration is weaker than such a treatment prior to cyclophosphamide immunosuppression.     

Ex-Situ Remediation of a Metal-Contaminated Superfund Soil Using Selective Extractants

The Superfund Amendments and Reauthorization Act requires the use of remedial technologies that permanently and significantly reduce the volume, toxicity, or mobility of contaminated materials at affected sites. Extractive processes can accomplish the requirements of the Superfund Amendments and Reauthorization Act. Ethylenediaminetetraacetic acid (EDTA), N-2(acetamido)iminodiacetic acid (ADA), pyridine-2,6-dicarboxylic acid (PDA), and hydrochloric acid (HCl) were evaluated over a range of concentrations and reaction times in batch studies for their ability to remove lead (Pb) and cadmium (Cd) from a Superfund soil (Pbtotal= 65,200 mg∕kg, Cdtotal= 52 mg∕kg). Lead extraction was limited by a slow overall reaction. The order of Pb removal by extractant was EDTA > ADA > PDA > HCL. The soil was subjected to three repeated 1 h extractions in which a maximum of 86, 84, 70, and 54% of the total soil Pb was removed with EDTA, ADA, PDA, and HCl, respectively. The soil was not treated to below the Pb regulatory limit (1,000 mg∕kg), even after five extractions with 0.075 M EDTA; however, the remaining Pb occurred in a residual form. All extractants treated the soil below the proposed Cd regulatory limit (40 mg∕kg) within 1 h. With three repeated extractions EDTA, ADA, PDA, and HCl removed a maximum of 96, 100, 98, and 100% Cd, respectively. Lead recovery from spent solution was accomplished by hydroxide precipitation in the presence of excess calcium. Recovery at pH 11 was 70, 98, and 97% from the EDTA, ADA, and PDA complexes, respectively. The results indicate that the remediation of weathered, heavily Pb- and Cd-contaminated soils via extractive processes is possible under the appropriate conditions.     

Feasibility of Estimating Heavy Metal Contaminations in Floodplain Soils Using Laboratory-Based Hyperspectral Data—A Case Study Along Le'an River,China

It is necessary to estimate heavy metal concentrations within soils for understanding heavy metal contaminations and for keeping the sustainable developments of ecosystems. This study, with the floodplain along Le'an River and its two branches in Jiangxi Province of China as a case study, aimed to explore the feasibility of estimating concentrations of heavy metal lead (Pb), copper (Cu)and zinc (Zn) within soils using laboratory-based hyperspectral data. Thirty soil samples were collected, and their hyperspectral data,soil organic matters and Pb, Cu and Zn concentrations were measured in the laboratory. The potential relations among hyperspectral data, soil organic matter and Pb, Cu and Zn concentrations were explored and further used to estimate Pb, Cu and Zn concentrations from hyperspectral data with soil organic matter as a bridge. The results showed that the ratio of the first-order derivatives of spectral absorbance at wavelengths 624 and 564 nm could explain 52% of the variation of soil organic matter; the soil organic matter could explain 59%, 51% and 50% of the variation of Pb, Cu and Zn concentrations with estimated standard errors of 1.41, 48.27 and 45.15mg·kg-1;and the absolute estimation errors were 8%-56%,12%-118% and 2%-22%,and 50%,67% and 100% of them were less than 25% Pb, Cu and Zn concentration estimations. We concluded that the laboratory-based hyperspectral data hold potentials in estimating concentrations of heavy metal Pb, Cu and Zn in soils. More sampling points or other potential linear and non-linear regression methods should be used for improving the stabilities and accuracies of the estimation models.     

Survey of lead exposure around a closed lead smelter

OBJECTIVE: To test the hypothesis that elevated lead in soil is positively correlated with blood lead (BPb) levels in children in an urban population surrounding a closed lead smelter, a US Environmental Protection Agency Superfund clean-up site was surveyed. METHOD: A total of 827 volunteers including 490 children under 6 years of age participated. A questionnaire was administered. Blood lead was determined as was lead content of samples of house dust, soil, paint, and water of the participants' homes. RESULTS: The arithmetic mean venous BPb in 490 children between 6 and 72 months of age was 6.9 micrograms/dL (0.33 mumol/L) range 0.7 to 40.2 micrograms/dL (0.03 to 1.94 mumol/L). The BPb of 78 (16%) children in this group was > or = 10 micrograms/dL (0.48 mumol/L). Based on multiple regression modeling, lead in house dust accounted for 18% of the variance in BPb. Lead in paint together with the condition of the house were the main contributors to the dust lead variance (26%) with soil lead accounting for an additional 6%. Lead in paint alone accounted for 3% of the BPb variance. Lead in paint together with the condition of the house accounted for 12% of BPb variance, and lead in soil accounted for an additional 3%. Factors other than environmental lead such as education of parents, household income, and behavior were associated with BPb levels. CONCLUSIONS: The mean BPb in children was below the present level of concern of the Centers for Disease Control and Prevention. Children with BPb of > or = 10 micrograms/L (0.48 mumol/L) tended to live in poorly maintained older houses. Based on these findings lead in soil and paint in well-maintained homes contributed little to the lead exposure of children.     

Activity of a non-hallucinogenic ergoline derivative, lisuride, in an animal behavior model for hallucinogens

The behavioral effects of IP administration of lisuride, a non-hallucinogenic iso-lysergic acid amide analog structurally related to d-lysergic acid diethylamide (LSD), were examined in 15 cats. Ten animals were given saline or 6.25, 12.5, 25, 50, or 100 micrograms/kg of lisuride and observed for 1 h by a rater blind to dose. There was a statistically significant effect of lisuride dose on the frequency of occurrence of the behaviors limb flicking, grooming, and abortive grooming. A time-course study with five cats at the most effective lisuride dose, 50 micrograms/kg, revealed that the frequencies of occurrence of these behaviors reached a maximum during the first 2 h post dose, and were comparable to frequencies after saline by 6 h post dose. An acute tolerance study with four cats scored for 90 min post dose revealed no significant tolerance to a 50 micrograms/kg lisuride test dose administered 6, 24, or 72 h after an initial 50 micrograms/kg dose. Acute cross tolerance studies with four cats scored for 90 min after an initial dose of 50 micrograms/kg of LSD or of lisuride, followed 24 h later by 50 micrograms/kg of lisuride or LSD, revealed no significant cross tolerance. The potency of lisuride relative to LSD was evaluated in six cats that were scored for 60 min following 25 and 50 micrograms/kg of LSD and of lisuride. On a molar basis, scores after lisuride were 51% and 67% those after LSD for limb flicking and grooming. These results indicate that lisuride, a non-hallucinogenic iso-lysergic acid derivative, is a false positive in the animal behavior model for hallucinogens.     

Resistance to decamethonium neuromuscular block after prior administration of vecuronium

Prior administration of nondepolarizing neuromuscular blocking drugs reduces the potency of subsequently administered succinylcholine. To assess whether this interaction is also observed with the depolarizing drug, decamethonium, the potency of decamethonium alone and decamethonium after vecuronium (10 micrograms/kg) were assessed using a cumulative dose-response technique in two groups of six healthy patients each. Patients were premedicated with meperidine and promethazine and anesthetized with thiopental, isoflurane, and nitrous oxide in oxygen. Twitch tension was monitored using adductor pollicis mechanomyography in response to ulnar nerve stimulation at 0.1 Hz. The mean (SEM) dose of decamethonium producing 80% twitch tension depression (ED80) when administered alone was 37 (4.0) micrograms/kg. After recovery of twitch tension (but persistence of train-of-four fade) from vecuronium, the mean (SEM) ED80 for decamethonium was increased to 89 (4.4) micrograms/kg (P < 0.01). The shift to the right of the dose-response curve for decamethonium was nonparallel. Antagonism is observed when decamethonium is administered after a small dose of vercuronium; this interaction, which is also seen with succinylcholine, is likely to be a feature of depolarizing block. Nonparallel shift of the dose-response curve to decamethonium indicates that this is not likely to be a simple agonist-antagonist effect at a single site.     

Immobilization of Copper, Lead, and Tungsten in Mixed Munitions Firing Range–Contaminated Soils by Various Amendments

Batch and column leaching tests were conducted to assess the simultaneous stabilization of copper (Cu), lead (Pb), and tungsten (W) in eight representative contaminated firing range soils in the United States using various amendments. The amendments included granulated ferric oxide (GFO), granulated titanium dioxide (GTD), Pahokee peat soil (PPS), Gascoyne leonardite soil (GLS), Elliot silty loam soil (ESLS), calcium phosphate monobasic (CPM), and apatite II. The metal oxides and the organic soil amendments were applied at a dosage of 10%, and phosphates were applied at phosphorus to lead (P/Pb) molar ratio of 1.8. The experimental results indicated that GFO was superior to all materials tested for simultaneously stabilizing Cu, Pb, and W during the batch leaching tests. Flow-through column tests were conducted for one of the soil samples to test the effectiveness of GFO to immobilize Cu, Pb, and W. The concentrations of Cu, Pb, and W were significantly reduced in the effluent of the amended soil columns as compared with the control soil columns.     

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Benzydamine protection in a mouse model of endotoxemia

OBJECTIVE: Previous studies have shown that benzydamine (40 mg/kg s.c.) is able to inhibit tumor necrosis factor (TNF) production and to reduce mouse lethality when administered before or concomitantly with LPS. The present study was designed to further investigate benzydamine activity against LPS-induced toxicity in terms of potency and therapeutic effects. METHODS: Female Balb/c mice were used. A dose-response curve of animal lethality versus endotoxin dose was performed (LD50 = 45 micrograms/mouse). Therapeutic effects were studied selecting the dose of LPS to achieve an LD100 (160 micrograms/mouse). Mortality was assessed daily and mice were followed for 8 days. The potential mode of action of therapeutically administered benzydamine was also investigated. TNF alpha and IL-1 beta levels were measured, at 5 h after LPS injection, both in sera and in lungs. Moreover, the drug was assayed in a TNF-dependent cytoxicity test. RESULTS: Benzydamine, administered at 20 mg/kg s.c. simultaneously with the endotoxin, significantly increased LPS LD50 up to 230 micrograms/mouse (p < 0.05). Moreover, the drug significantly protected mice against LPS-induced lethality when administered either 30 min or 4 h after endotoxin injection (p < 0.001). Benzydamine, therapeutically administered at 20 mg/kg s.c., significantly reduced TNF alpha and IL-1 beta production induced by LPS both in serum and lungs and it was shown to inhibit TNF-dependent cytoxicity on L929 cells. CONCLUSIONS: These results clearly demonstrate the therapeutic activity of benzydamine in a simple model of endotoxic shock. Available data confirm the potential role of benzydamine as an anti-cytokine agent and provide suggestions for novel therapeutic applications of this anti-inflammatory drug.     

Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin. A morphologic study

Hepatocyte growth factor (HGF) is a humoral mediator of epithelial-mesenchymal interactions, acting on a variety of epithelial cells as mitogen, motogen, and morphogen. Exogenous HGF acts as a hepatotrophic factor and a renotrophic factor during experimental injury. To investigate whether HGF has a pulmotrophic function, human recombinant HGF was administered to C57BL/6 mice with severe lung injury by bleomycin (BLM). Low dose simultaneous and continuous administration of HGF (50 micrograms/mouse/7 d) with BLM (100 mg/mouse/7 d) repressed fibrotic morphological changes at 2 and 4 wk. Ashcroft score showed a significant difference in lung fibrosis with and without HGF at 4 wk (3.7 +/- 0.4 versus 4.9 +/- 0.3, p < 0.05). Furthermore, either simultaneous or delayed administration of high dose HGF (280 micrograms/mouse/14 d) equally repressed fibrotic changes by BLM when examined at 4 wk (Ashcroft score: 2.6 +/- 0.4 and 2.4 +/- 0.2 versus 4.1 +/- 0.2, p < 0.01). Hydroxyproline content in the lungs was significantly lower in mice with either simultaneous or delayed administration of high dose HGF as compared to those administered BLM alone (121.8 +/- 8.1% and 113.2 +/- 6.2% versus 162.7 +/- 4.6%, p < 0.001). These findings indicate that exogenous HGF acts as a pulmotrophic factor in vivo and prevents the progression of BLM-induced lung injury when administered in either a simultaneous or delayed fashion. HGF may be a potent candidate to prevent or treat lung fibrosis.     

Rapid determination of cholesterol in milk and milk products by direct saponification and capillary gas chromatography

The level and nature of the albendazole residues in milk of treated cows were determined as a function of the time of milking (12-h intervals), and the fate of those residues during cheesemaking, ripening, and storage was examined when the obtained milk was used for making Teleme cheese. Ion-pair liquid chromatographic analysis with fluorescence detection showed that the albendazole sulfoxide metabolite reached its maximum (523 +/- 199 micrograms/kg) at the 1st milking and declined below the detection limit by the 4th milking. The sulfone metabolite attained its highest level (812 +/- 99 micrograms/kg) more slowly (at the 2nd milking) and declined below detection limit by the 13th milking. The 2-aminosulfone metabolite, which was present in the milk obtained at the 1st milking, reached its maximum (128 +/- 36 micrograms/kg) at the 3rd milking, and slowly declined to a level below detection limit by the 15th milking. Whey and cheese analysis revealed that about 70% of each major metabolite initially present in milk could be distributed in the whey. The remaining 30% occurred in the cheese at residue levels higher than those initially present in the milk of the 1st or 2nd milking (688 versus 445 or 450 versus 230 micrograms/kg for albendazole sulfoxide; 890 versus 608 or 1502 versus 783 micrograms/kg for albendazole sulfone; 19 versus 15 or 161 versus 105 micrograms/kg for albendazole 2-aminosulfone). Ripening and storage of the cheeses made from milks from the 1st or 2nd milkings results in a decrease of the sulfoxide metabolite (to 225 or 206 micrograms/kg), an increase of the sulfone metabolite (to 1,181 or 1,893 micrograms/kg), and no effect on the 2-aminosulfone metabolite.     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Mononuclear cells contaminating acute lymphoblastic leukaemic samples tested for cellular drug resistance using the methyl-thiazol-tetrazolium assay

This study was performed to investigate the effects of clonidine on regional myocardial function in a canine model of regional myocardial ischemia. Myocardial systolic shortening (%SS) was used as an index of regional myocardial function. In eight dogs after thoracotomy, the left circumflex coronary artery (LCX) was occluded by screw clamp until regional myocardial function became impaired. After partial occlusion of the LCX, cumulative doses of clonidine (1.25, 2.5, and 5.0 micrograms/kg) were administered intravenously. After administration of clonidine, heart rate, mean arterial blood pressure (MAP), and norepinephrine concentration decreased in a dose-dependent manner. At a dose of 5.0 micrograms/kg of clonidine, the LCX flow and systolic shortening of the LCX area decreased to 76% and 81% of the poststenotic values (P < 0.05, respectively), whereas no significant changes were observed at a dose of 1.25 and 2.5 micrograms/kg. These results suggest that clonidine administration and an associated decrease in arterial blood pressure deteriorates regional myocardial function of the ischemic myocardium.