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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of PEG-l-asparaginase and plasma and cerebrospinal fluidl-asparagine concentrations in the rhesus monkey (1993)
    Springer
    Cancer chemotherapy and pharmacology 32 (1993), S. 310-314 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of the polyethylene glycol-conjugated form of the enzymel-asparaginase and the depletion ofl-asparagine from the plasma and cerebrospinal fluid (CSF) following an i.m. dose of 2500 IU/m2 PEG-l-asparaginase was studied in rhesus monkeys. PEG-l-asparaginase activity in plasma was detectable by 1 h after injection and maintained a plateau of approximately 4 IU/ml for more than 5 days. Subsequent elimination from plasma was monoexponential with a half-life of 6±1 days. Plasmal-asparagine concentrations fell from pretreatment levels of 14–47 μM to 〈2 μM by 24 h after injection in all animals and remained undetectable for the duration of the 25-day observation period in four of six animals. In two animals, plasmal-asparagine became detectable when the PEG-l-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSFl-asparagine levels ranged from 4.7 to 13.6 μM and fell to 〈0.25 μM by 48 h in five of six animals. CSFl-asparagine concentrations remained below 0.25 μM for 10–14 days in four animals. One animal had detectable CSFl-asparagine concentrations within 24 h and another had detectable concentrations within 1 week of drug administration despite a plasma PEG-l-asparaginase activity profile that did not differ from that of the other animals. These observations may be useful in the design of clinical trials with PEG-l-asparaginase in which correlations among PEG-l-asparaginase pharmacokinetics, depletion ofl-asparagine, and clinical outcome should be sought.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686177
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  • 2
    Electronic Resource
    Electronic Resource
    Intrathecal administration of topotecan in nonhuman primates (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 121-124 
    Details
    ISSN: 1432-0843
    Keywords: Key words Topotecan ; Meningeal malignancies ; Intrathecal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg. Lactone and total drug concentrations were measured using a reverse-phase HPLC method with fluorescence detection. The mean peak concentrations of lactone and total drug in ventricular CSF were 83±18 μM and 88±25 μM, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3 h. The mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (AUC) to lactone was 450-fold greater following intraventricular administration of 0.1 mg topotecan than after systemic intravenous administration of a 40-fold higher dose (10 mg/m2). Peak lumbar concentrations ( n=1), which occurred 2 h after intrventricular drug administration, were 0.98 μM and 2.95 μM for the lactone and total drug, respectively. A transient CSF pleocytosis was observed in one animal following intraventricular topotecan administration and in one animal following intralumbar topotecan administration. No other acute or chronic neurologic or systemic toxicities were observed following a single intraventricular dose or weekly (×4) intralumbar topotecan. Compared with systemic topotecan, intrathecal administration provided a significant pharmacokinetic advantage in terms of CSF drug exposure and did not produce any significant neurotoxicity in a nonhuman primate model. Intrathecal topotecan should be evaluated clinically as a potential alternative therapy for refractory meningeal tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689195
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  • 3
    Electronic Resource
    Electronic Resource
    Plasma and cerebrospinal fluid pharmacokinetics of 9-aminocamptothecin (9-AC), irinotecan (CPT-11), and SN-38 in nonhuman primates (1998)
    Springer
    Cancer chemotherapy and pharmacology 41 (1998), S. 464-468 
    Details
    ISSN: 1432-0843
    Keywords: Key words Irinotecan ; 9-Aminocamptothecin ; CSF penetration ; Topotecan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The plasma and cerebrospinal fluid (CSF) pharmacokinetics of the camptothecin analogs, 9-aminocamptothecin (9-AC) and irinotecan, were studied in a nonhuman primate model to determine their CSF penetration. Methods: 9-AC, 0.2 mg/kg (4 mg/m2) or 0.5 mg/kg (10 mg/m2), was infused intravenously over 15 min and irinotecan, 4.8 mg/kg (96 mg/m2) or 11.6 mg/kg (225 mg/m2), was infused over 30 min. Plasma and CSF samples were obtained at frequent intervals over 24 h. Lactone and total drug forms of 9-AC, irinotecan, and the active metabolite of irinotecan, SN-38, were quantified by reverse-phase HPLC. Results: 9-AC lactone had a clearance (CL) of 2.1 ± 0.9 l/kg per h, a volume of distribution at steady state (Vdss) of 1.6 ± 0.7 l/kg and a half-life (t1/2) of 3.2 ± 0.8 h. The lactone form of 9-AC accounted for 26 ± 7% of the total drug in plasma. The CSF penetration of 9-AC lactone was limited. CSF 9-AC lactone concentration peaked 30 to 45 min after the dose at 11 to 21 nM (0.5 mg/kg dose), and the ratio of the areas under the CSF and plasma concentration-time curves (AUCCSF: AUCP) was only 3.5 ± 2.1%. For irinotecan, the CL was 3.4 ± 0.4 l/kg per h, the Vdss was 7.1 ± 1.3 l/kg, and the t1/2 was 4.9 ± 2.2 h. Plasma AUCs of the lactone form of SN-38 were only 2.0% to 2.4% of the AUCs of irinotecan lactone. The lactone form of irinotecan accounted for 26 ± 5% of the total drug in plasma, and the lactone form of SN-38 accounted for 55 ± 6% of the total SN-38 in plasma. The AUCCSF: AUCP ratio for irinotecan lactone was 14 ± 3%. SN-38 lactone and carboxylate could not be measured (〈1.0 nM ) in CSF. The AUCCSF: AUCP ratio for SN-38 lactone was estimated to be ≤ 8%. Conclusion: Despite their structural similarity, the CSF penetration of 9-AC and SN-38 is substantially less than that of topotecan which we previously found to have an AUCCSF: AUCP ratio of 32%.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050768
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  • 4
    Electronic Resource
    Electronic Resource
    Intrathecal administration of topotecan in nonhuman primates (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 121-124 
    Details
    ISSN: 1432-0843
    Keywords: Topotecan ; Meningeal malignancies ; Intrathecal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The cerebrospinal fluid (CSF) pharmacokinetics of topotecan were studied in a nonhuman primate model following intraventricular administration of 0.1 mg. Lactone and total drug concentrations were measured using a reverse-phase HPLC method with fluorescence detection. The mean peak concentrations of lactone and total drug in ventricular CSF were 83±18 μM and 88±25 μM, respectively. CSF drug elimination of the lactone was bi-exponential with a terminal half-life of 1.3 h. The mean clearance from ventricular CSF was 0.075 ml/min for the lactone and 0.043 ml/min for total drug. The ventricular CSF drug exposure (AUC) to lactone was 450-fold greater following intraventricular administration of 0.1 mg topotecan than after systemic intravenous administration of a 40-fold higher dose (10 mg/m2). Peak lumbar concentrations (n=1), which occurred 2 h after intraventricular drug administration, were 0.98 μM and 2.95 μM for the lactone and total drug, respectively. A transient CSF pleocytosis was observed in one animal following intraventricular topotecan administration and in one animal following intralumbar topotecan administration. No other acute or chronic neurologic or systemic toxicities were observed following a single intraventricular dose or weekly (×4) intralumbar topotecan. Compared with systemic topotecan, intrathecal administration provided a significant pharmacokinetic advantage in terms of CSF drug exposure and did not produce any significant neurotoxicity in a nonhuman primate model. Intrathecal topotecan should be evaluated clinically as a potential alternative therapy for refractory meningeal tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689195
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  • 5
    Electronic Resource
    Electronic Resource
    The plasma pharmacokinetics and cerebrospinal fluid penetration of the thymidylate synthase inhibitor raltitrexed (TomudexTM) in a nonhuman primate model (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 439-443 
    Details
    ISSN: 1432-0843
    Keywords: Key words Antifols ; Thymidylate synthase inhibitor ; Pharmacokinetic model ; Enzyme inhibition assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Raltitrexed (Tomudex™), ZD1694) is a novel quinazoline folate analog that selectively inhibits thymidylate synthase. Intracellularly, raltitrexed is polyglutamated to its active form which can be retained in cells for prolonged periods. The pharmacokinetics of raltitrexed in plasma and cerebrospinal fluid (CSF) were studied in a nonhuman primate model. Methods: Animals received 3 mg/m2 (n= 1), 6 mg/m2 (n= 3), or 10 mg/m2 (n= 3) i.v. over 15 min, and frequent plasma samples were obtained over 48 h. CSF samples were drawn from an indwelling 4th ventricular Ommaya reservoir over 48 h. Plasma and CSF raltitrexed concentrations were measured with a novel, sensitive enzyme inhibition assay with a lower limit of quantification of 0.005 μM. A three-compartment pharmacokinetic model was fitted to the raltitrexed plasma concentration-time data. Results: The plasma concentration-time profile of raltitrexed was triexponential with a rapid initial decline and a prolonged terminal elimination phase (t1/2 〉 24 h), which was related to retention of raltitrexed in a deep tissue compartment. At the peak approximately 30% of the administered dose was in the deep tissue compartment, and 24 h after the dosing 〉20% of the administered dose remained in the body with 〉99% in the deep tissue compartment. The mean peak (end of infusion) plasma concentrations after the 3, 6, and 10 mg/m2 doses were 1.5, 2.4 and 4.8 μM, respectively. The clearance of raltitrexed ranged from 110 to 165 ml/min per m2, and the steady-state volume of distribution exceeded 200 l/m2. The CSF penetration of raltitrexed was limited (0.6 to 2.0%) and drug could only be detected in the CSF following a 10 mg/m2 dose. Conclusions: The elimination of raltitrexed is triexponential with a prolonged terminal elimination phase. The pharmacokinetic profile is consistent with extensive polyglutamation and intracellular retention of ralitrexed. The three-compartment model presented here may be useful for the analysis of the pharmacokinetics of raltitrexed in humans.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051116
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  • 6
    Electronic Resource
    Electronic Resource
    A phase II trial of continuous-infusion 6-mercaptopurine for childhood leukemia (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 155-157 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A phase II pediatric trial of a continuous intravenous infusion of 6-mercaptopurine (6MP) in patients with refractory leukemia was performed. The dosing schedule, 50 mg m−2 h−1 for 48 h, was based on the results of a previous phase I trial of this approach. Among the 40 children treated for acute lymphoblastic leukemia (ALL), all of whom had received prior therapy with oral 6MP, 1 complete and 1 partial response were achieved. No response was observed in 17 patients with refractory acute nonlymphocytic leukemia (ANLL). Reversible hepatotoxicity, the primary dose-limiting toxicity, was observed in approximately 50% of cases. Mucositis was encountered infrequently and was usually not severe. 6MP given on the present continuous intravenous infusion schedule overcomes the limited and variable bioavailability of oral 6MP but shows limited activity as induction agent in children with recurrent ALL.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686410
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  • 7
    Electronic Resource
    Electronic Resource
    Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid penetration of doxorubicin in non-human primates (2000)
    Springer
    Cancer chemotherapy and pharmacology 45 (2000), S. 207-212 
    Details
    ISSN: 1432-0843
    Keywords: Key words Multidrug resistance ; P-glycoprotein ; Doxorubicin ; Cyclosporin A ; Blood-brain barrier
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: P-glycoprotein (Pgp) is a transmembrane drug efflux pump that is expressed in multidrug-resistant cancer cells and in a variety of normal tissues, including brain capillary endothelial cells which comprise the blood-brain barrier. We studied the effects of the Pgp inhibitor, cyclosporin A (CsA), on the cerebrospinal fluid (CSF) penetration of the Pgp substrate, doxorubicin, in non-human primates. Methods: The animals received doxorubicin alone (2.0 mg/kg i.v. over 60 min) or doxorubicin (1 mg/kg i.v. over 60 min) and CsA (loading dose 4.0 mg/kg i.v. over 2 h, followed by continuous infusion of 12 mg/kg per day over 48 h). Plasma and CSF were collected over 48 h and the doxorubicin concentration was measured by reverse-phase high-pressure liquid chromatography (HPLC) with fluorescence detection (detection limit 5 nM). A two-compartment model was fitted to the plasma concentration-time data. Results: Pgp was demonstrated to be present in the epithelium of the choroid plexus by immunohistochemical methods, indicating that CSF drug penetration could be used as a surrogate for blood-brain barrier penetration. Steady state whole blood CsA concentrations, which were measured with a fluorescence-polarization immunoassay (TDX) that detects both CsA and its metabolites, ranged from 551–1315 μg/l at 24 h. The clearance of doxorubicin in four animals was reduced by 34%, 38%, 45% and 49% when given with CsA. The doxorubicin concentration in the CSF was 〈5 nM in all animals, both after doxorubicin alone and doxorubicin with CsA. Conclusions: The Pgp inhibitor, CsA, at a concentration that alters systemic clearance of doxorubicin, does not appear to significantly increase the CSF penetration of doxorubicin.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050031
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  • 8
    Electronic Resource
    Electronic Resource
    Intrathecal 5-fluorouracil in the rhesus monkey (1992)
    Springer
    Cancer chemotherapy and pharmacology 31 (1992), S. 127-130 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Because meningeal spread of both leukemia and solid tumors remains a difficult therapeutic problem, there is a compelling need to develop new agents for intrathecal administration. 5-Fluorouracil (5FU), an active anticancer agent, penetrates into the central nervous system to some degree following intravenous dosing. Significant systemic toxicity, however, is associated with this route of administration. Therefore, the pharmacokinetic behavior of 5FU following its intrathecal administration was studied in a rhesus monkey model. After a 10-mg intraventricular dose, the disappearance of the drug from ventricular cerebrospinal fluid was monoexponential, the half-life being 51 min; the area under the concentration-time curve (AUC) being greater than 18mm h−1; and the peak ventricular 5FU concentrations ranging between 10 and 15mm. After a 1-mg intralumbar dose, the AUC was 1235 μm h−1. No toxicity was observed following intraventricular administration of 5FU. After intralumbar administration of either a 10-mg or a 1-mg dose, however, local toxicity was observed in the lumbar spinal cord. These findings suggest that intrathecal administration of 5FU is not presently a feasible means of achieving cytotoxic cerebrospinal fluid concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685099
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  • 9
    Electronic Resource
    Electronic Resource
    Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration (2000)
    Springer
    Cancer chemotherapy and pharmacology 45 (2000), S. 259-264 
    Details
    ISSN: 1432-0843
    Keywords: Key words Methotrexate ; Cerebrospinal fluid ; Intrathecal ; Pharmacokinetics ; AbbreviationsAUC area under the concentration-time curve ; CSF cerebrospinal fluid ; IT intrathecal ; i.v. intravenous ; MTX methotrexate ; Css steady-state concentration ; CVss steady-state ventricular CSF concentration ; CLss steady-state lumbar CSF concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: Intrathecal methotrexate achieves high concentrations in cerebrospinal fluid (CSF), but drug distribution throughout the subarachnoid space after an intralumbar dose is limited. The objective of this study was to quantify methotrexate distribution in CSF after intraventricular and intravenous administration and to identify factors that influence CSF distribution. Methods: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received methotrexate by bolus injection (0.5 mg) and infusion (0.05 to 0.5 mg/day over 24 to 168 h) into the lateral ventricle, as well as intravenous infusions. CSF was sampled from the lumbar space, fourth ventricle and the subarachnoid space at the vertex. Methotrexate in CSF and plasma was measured with the dihydrofolate reductase inhibition assay. Results: After bolus intraventricular injection, methotrexate exposure in lumbar CSF ranged from 11% to 69% of that achieved in the fourth ventricle. During continuous intraventricular infusions, methotrexate steady-state concentrations (Css) in lumbar CSF and CSF from the vertex were only 20% to 25% of the ventricular CSF Css. The dose, duration of infusion, and infusate volume did not influence drug distribution to the lumbar CSF, but probenicid increased the lumbar to ventricular Css ratio, suggesting the involvement of a probenicid-sensitive transport pump in the efflux of MTX from the CSF. During the intravenous infusions, the ventricular methotrexate Css was lower than the lumbar Css and the Css in CSF from the vertex. Conclusion: Methotrexate CSF distribution after intraventricular injection was uneven, and at steady-state CSF methotrexate concentrations were lower at sites that were more distant from the injection site.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050038
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  • 10
    Electronic Resource
    Electronic Resource
    Cerebrospinal fluid pharmacokinetics and toxicology of intraventricular and intrathecal arabinosyl-5-azacytosine (fazarabine, NSC 281272) in the nonhuman primate (1993)
    Springer
    Investigational new drugs 11 (1993), S. 135-140 
    Details
    ISSN: 1573-0646
    Keywords: arabinosyl-5-azacytidine ; cerebrospinal fluid ; pharmacokinetics ; toxicology ; nonhuman primate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Arabinosyl-5-azacytosine (AAC), a new nucleoside antimetabolite, is broadly active in preclinical tumor screening evaluations. To assess the potential for intrathecal use of this drug, we studied the toxicity and pharmacokinetics of intrathecal and intraventricular administration in nonhuman primates. Four adult male rhesus monkeys were given single 10 mg intrathecal (n=1) or intraventricular (n=3) doses of AAC to determine its acute toxicity and pharmacokinetic parameters. An additional 3 animals were given four weekly 10 mg intrathecal doses to assess the systemic and neurologic toxicity associated with chronic administration. Disappearance from the cerebrospinal fluid (CSF) was biexponential, and CSF clearance was 0.2 ml/min, which exceeds the rate of CSF bulk flow by 5-fold. The peak CSF concentration and area under the concentrationx time curve achieved with the intraventricular administration of 10 mg were one hundred, and fifty fold greater, respectively, than those achieved after an intravenous dose of 200 mg/kg (1500–2400 mg) in prior experiments. No clinically evident neurotoxicity was observed in either the single or the weekly × 4 dose groups. A slight, transient CSF pleocytosis and increased CSF protein was observed. Systemic toxicity was limited to one animal in the weekly × 4 dose group who demonstrated a mild and transient decrease in his peripheral leukocyte count unassociated with a change in his hematocrit or platelet count. These studies in nonhuman primates demonstrate a clear pharmacokinetic advantage for intrathecal vs systemic administration of AAC. This is demonstrated by a 50-fold greater CSF drug exposure with an intrathecal or intraventricular dose 1/200th of that which can be given systemically. Intrathecal AAC was found to be safe on a weekly dosing schedule. On the basis of these results, human trials evaluating intrathecal AAC are planned.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00874147
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