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  • 1
    Electronic Resource
    Electronic Resource
    Synthesis and pharmacokinetics of a dihydropyridine chemical delivery system for the antiimmunodeficiency virus agent, dideoxycytidine (1993)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 36 (1993), S. 529-537 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00057a002
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  • 2
    Electronic Resource
    Electronic Resource
    A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid β-peptide (2001)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 77 (2001), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of p53 in preclinical studies in the cancer therapy field, we synthesized the compound pifithrin-α and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodegenerative disorders. Pifithrin-α protected neurons against apoptosis induced by DNA-damaging agents, amyloid β-peptide and glutamate. Protection by pifithrin-α was correlated with decreased p53 DNA-binding activity, decreased expression of the p53 target gene Bax and suppression of mitochondrial dysfunction and caspase activation. Mice given pifithrin-α exhibited increased resistance of cortical and striatal neurons to focal ischemic injury and of hippocampal neurons to excitotoxic damage. These preclinical studies demonstrate the efficacy of a p53 inhibitor in models of stroke and neurodegenerative disorders, and suggest that drugs that inhibit p53 may reduce the extent of brain damage in related human neurodegenerative conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2001.00220.x
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  • 3
    Electronic Resource
    Electronic Resource
    New Pharmacological Strategies for Cognitive Enhancement Using a Rat Model of Age-Related Memory Impairment (1994)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 717 (1994), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1994.tb12070.x
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  • 4
    Electronic Resource
    Electronic Resource
    Learning from the gut (2003)
    [s.l.] : Nature Publishing Group
    Nature medicine 9 (2003), S. 1113-1115 
    Details
    ISSN: 1546-170X
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Medicine
    Notes: [Auszug] When it comes to signal transduction pathways, neuroscientists have reaped the harvest of seeds planted by scientists in other disciplines. For example, we now know that signals originally identified in the immune system (cytokines and chemokines) and the skin (growth factors) have fundamental ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/nm0903-1113
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  • 5
    Electronic Resource
    Electronic Resource
    Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier (1992)
    Springer
    Cancer chemotherapy and pharmacology 30 (1992), S. 164-164 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686413
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  • 6
    Electronic Resource
    Electronic Resource
    Brain and plasma pharmacokinetics and anticancer activities of cyclophosphamide and phosphoramide mustard in the rat (1990)
    Springer
    Cancer chemotherapy and pharmacology 27 (1990), S. 1-7 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary By a sensitive and quantitative fluorometric assay, brain and plasma time-dependent concentration profiles were generated for phosphoramide mustard (PM) and active alkylating metabolites derived from cyclophosphamide (CPA) administration to rats. Whereas PM rapidly disappeared from plasma, with a monophasic half-life of 15.1 min, equimolar administration of CPA generated active metabolites in plasma that disappeared monoexponentially, with a composite half-life of 63 min. As a consequence, the time-dependent concentration integral of active alkylating metabolites derived from CPA administration, calculated between 5 min and infinity, was 3-fold that of PM. Pharmacokinetic parameters were calculated for each compound. The brain/plasma concentration-integral ratios of PM and active alkylating metabolites derived from CPA were 0.18 and 0.20, respectively. The cerebrovascular permeability-surface area product of PM was 7.5×10−5s−1, which is similar to that of other watersoluble anticancer agents that are restricted from entering the brain. The activities of a range of daily doses of PM and CPA were assessed against subcutaneous and intracerebral implants of Walker 256 carcinosarcoma tumor in rats. Inhibition of subcutaneous tumor growth by 50% was caused by CPA and PM doses of 6.6 and 12.0 mg/kg (daily for 5 consecutive days, starting 36 h after tumor implantation), respectively. However, administration of daily doses of up to 40 mg/kg did not significantly increase the survival of animals with intracerebral tumor implants. These studies indicate that active metabolites of CPA are restricted from entering the brain and that only subtherapeutic concentrations are achieved in brain tissue after systemic administration of CPA or PM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689268
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  • 7
    Electronic Resource
    Electronic Resource
    Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier (1991)
    Springer
    Cancer chemotherapy and pharmacology 29 (1991), S. 89-94 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The relative affinity of six anticancer amino acid drugs for the neutral amino acid carrier of the blood-brain barrier was examined in rats using an in situ brain perfusion technique. Affinity was evaluated from the concentration-dependent inhibition ofl-[14C]-leucine uptake into rat brain during perfusion at tracer leucine concentrations and in the absence of competing amino acids. Of the six drugs tested, five, including melphalan, azaserine, acivicin, 6-diazo-5-oxo-l-norleucine, and buthionine sulfoximine, exhibited only low affinity for the carrier, displaying transport inhibition constants (K i, concentrations producing 50% inhibition) ranging from 0.09 to 4.7 mM. However, one agent −d,l-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid (d,l-NAM) — demonstrated remarkably high affinity for the carrier, showing aK i value of ∼0.2 μM. The relative affintty (1/K i) ofd,l-NAM was 〉100-fold that of the other drugs and 〉10-fold that of any compound previously tested. As the blood-brain barrier penetrability of most endogenous neutral amino acids is related to their carrier affinity, the results suggest thatd,l-NAM may be a promising agent which may show enhanced uptake and distribution to brain tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00687316
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of chlorambucil-tertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain (1990)
    Springer
    Cancer chemotherapy and pharmacology 25 (1990), S. 320-325 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Equimolar doses of chlorambucil (10 mg/kg) and the lipophilic chlorambucil derivative, chlorambuciltertiary butyl ester (13 mg/kg), were given i. v. to rats. Plasma and brain concentrations of chlorambucil and its active metabolites, 3,4-dehydrochlorambucil and phenylacetic mustard, as well as of chlorambucil-tertiary butyl ester were then determined by HPLC between 2 and 240 min after drug administration. Chlorambucil demonstrated a monophasic disappearance from plasma following its administration, with a half-life of 28 min. Significant amounts of phenylacetic mustard were detected after 15 min, and this agent maintained high levels of active compounds in plasma throughout the study. Only low concentrations of chlorambucil and phenylacetic mustard were detected in brain between 2 and 120 min. Following equimolar chlorambucil-tertiary butyl ester administration, it rapidly disappeared from plasma, with a half-life of approximately 2 min, and maintained low plateau concentrations between 15 and 120 min after treatment. It was not detected thereafter, although significant amounts of chlorambucil and phenylacetic mustard were detected throughout the study. Significant amounts of chlorambucil-tertiary butyl ester entered and remained within the brain, achieving a peak concentration at 15 min and disappearing thereafter with a half-life of 37 min. Low levels of chlorambucil and phenylacetic mustard were also detected. Calculated from the areas under the concentration vs time curves of total active compounds derived from chlorambucil and chlorambucil-tertiary butyl ester in brain and plasma, the brain: plasma concentration integral ratios were 0.018 and 0.68, respectively. Following equimolar doses of chlorambucil and chlorambucil-tertiary butyl ester, a 7-fold greater concentration integral was achieved by chlorambucil-tertiary butyl ester in brain at a 5-fold lower plasma concentration integral. Chlorambucil-tertiary butyl ester may be of value in the treatment of brain-sequestered tumors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686230
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  • 9
    Electronic Resource
    Electronic Resource
    Physicochemical and pharmacokinetic parameters of seven lipophilic chlorambucil esters designed for brain penetration (1990)
    Springer
    Cancer chemotherapy and pharmacology 25 (1990), S. 311-319 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This report describes the physicochemical and pharmacokinetic parameters of seven chlorambucil esters, which were compared with those of chlorambucil. These esters were designed as chlorambucil prodrugs to increase the brain penetration and concentration vs time profile of chlorambucil within the CNS for potential treatment of brain tumors. They include four aliphatic esters from one to eight carbon chains in length (chlorambucil-methyl,-propyl,-hexyl, and-octyl esters) and three aromatic esters, including the phenylmethyl, phenylethyl and prednisolone ester of chlorambucil, prednimustine. The esters were lipophilic and possessed log octanol: water partition coefficients (log P values) that ranged from 4.05 to 〉8.0. All retained alkylating activity, which was reduced compared with that of chlorambucil. In addition, all were metabolized in vivo in the rat to yield chlorambucil alone. Measurement of the in vitro rate of ester hydrolysis of the compounds to yield chlorambucil in rat plasma demonstrated that short-chain aliphatic and aromatic chlorambucil esters were rapidly broken down to their parent compound. The plasma half-lives of the compounds increased with the increasing length and complexity of their ester chain. This may have been related to an increase in the binding of the long-chain esters to plasma proteins, protecting the ester from nonspecific plasma esterases, and to a reduced affinity of plasma esterases to these esters. Pharmacokinetic analysis of chlorambucilhexyl,-octyl, and-prednisolone esters by HPLC demonstrated that following their intravenous administration in the rat (in doses equivalent to equimolar chlorambucil, 10 mg/kg), they yielded only low concentrations of active compounds in plasma and brain. The brain: plasma ratio of these was low and similar to that of chlorambucil, and no ester demonstrated anticancer activity superior to that obtained after the administration of equimolar chlorambucil (5 mg/kg i. v., days 1–5) against brain-sequestered Walker 256 carcinosarcoma in the rat.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00686229
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  • 10
    Electronic Resource
    Electronic Resource
    Comparative brain and plasma pharmacokinetics and anticancer activities of chlorambucil and melphalan in the rat (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 1-8 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Equimolar doses of chlorambucil and melphalan (both 10 mg/kg) were administered i.v. to anesthetized rats, and the plasma and brain concentrations of chlorambucil, its metabolites 3,4-dehydrochlorambucil and phenylacetic mustard, and melphalan were determined by high-performance liquid chromatography from 5 to 240 min therafter. Chlorambucil demonstrated a monophasic disappearance from plasma, with a half-life of 26 min. The compound was 99.6% plasma-protein-bound. Chlorambucil underwent β-oxidation to yield detectable concentrations of 3,4-dehydrochlorambucil and substantial amounts of phenylacetic mustard in the plasma. Low concentrations of chlorambucil and phenylacetic mustard were detected in the brain. Calculated from the areas under the concentration-time curves, the brain: plasma concentration integral ratios of chlorambucil and phenylacetic mustard were 0.021 and 0.013, respectively. Melphalan demonstrated a biphasic disappearance from plasma, with half-lives of 1.9 and 78 min. The compound was approximately 86% plasma protein-bound. Low concentrations of melphalan were detected in the brain, and its brain: plasma ratio was 0.13. These data demonstrate that following the administration of chlorambucil and melphalan, only low concentrations of active drug are able to enter the brain. As a consequence, concentrations of both drugs that cause the complete inhibition of extracerebrally located tumor have no effect on those located within the brain. Further, the brain uptake of melphalan, although low, is greater than that of chlorambucil and its active metabolites, which coincides with its slightly greater intracerebral activity following the systemic administration of very high doses.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00262729
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