Pharmaceutical development of a parenteral lyophilized formulation of the investigational antitumor neuropeptide antagonist [Arg6, D-Trp7,9, MePhe8]-Substance P {6-11}

Vries, Jantine D. Jonkman-de; Rosing, Hilde; Talsma, H.; Henrar, R.E.C.; Bosch, J. J. Kettenes‐van den; Bult, A.

doi:10.1023/a:1006041024109

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…7 Buffering is especially important for carzelesin because the ring closure step produces hydrochloric acid in addition to U-76,074. The overall rate constant (k obs ) for the degradation of carzelesin in buffer solutions is defined as where k 0 is the (pseudo-) first-order rate constant for the degradation in solvent only and k H and k OH are the secondorder rate constants for proton-and hydroxyl-catalyzed degradation, respectively.…”

Section: Ln[carzelesin] T ) Ln[carzelesin] 0 -K Obs T (1)mentioning

confidence: 99%

“…Accelerated stability studies (at 40°C) of carzelesin in the PET formulation showed that the variable stability characteristics were caused mainly by the pH differences between batches of PEG 400. 7 This stimulated us to investigate systematically the chemical stability of carzelesin in solutions, which can aid to further optimize the pharmaceutical formulation, and to get more insight into the degradation mechanism.…”

Section: Introductionmentioning

confidence: 99%

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Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Vries

Doppenberg

Henrar

et al. 1996

Journal of Pharmaceutical Sciences

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The chemical stability of the novel anticancer agent carzelesin in aqueous buffer/acetonitrile (1:1, v/v) mixtures has been investigated utilizing a stability-indicating reversed-phase high-performance liquid chromatographic assay. The degradation kinetics of carzelesin has been studied as a function of pH, buffer composition, ionic strength, and temperature. Degradation of carzelesin follows (pseudo-) first-order kinetics. A pH-rate profile, using rate constants extrapolated to zero buffer concentration, was constructed demonstrating that carzelesin is most stable in the pH region 1-4. The degradation rate of carzelesin was not significantly affected by buffer components and by the ionic strength. In addition to the formation of the degradation products U-76,073, U-76,074, and aniline in alkaline medium and in acetate buffer solution, another degradation product was formed in acetate buffer solution. In perchloric acid buffer solution (pH* < 3), U-76,073 and U-76,074 could not be detected as degradation products.

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Section: Ln[carzelesin] T ) Ln[carzelesin] 0 -K Obs T (1)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Vries

Doppenberg

Henrar

et al. 1996

Journal of Pharmaceutical Sciences

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Development of a gradient elution high-performance liquid chromatography assay with ultraviolet detection for the determination in plasma of the anticancer peptide [Arg6, d-Trp7,9, mePhe8]-substance P (6–11) (antagonist G), its major metabolites and a C-terminal pyrene-labelled conjugate

Cummings¹,

MacLellan²,

Mark³

et al. 1999

Journal of Chromatography B: Biomedical Sciences and Applicatio

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[Arg6, D-Trp7,9, NmePhe8]-substance P (6–11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy

et al. 2000

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[Arg6, D-Trp7,9, NmePhe8]-substance P (6–11) (antagonist G) inhibits small cell lung cancer (SCLC) growth and is entering Phase II clinical investigation for the treatment of SCLC. As well as acting as a neuropeptide receptor antagonist, antagonist G stimulates c-jun-N-terminal kinase (JNK) activity and apoptosis in SCLC cells. We extend these findings and show that the stimulation of JNK and apoptosis by antagonist G is dependent upon the generation of reactive oxygen species (ROS) being inhibited either by anoxia or the presence of N-acetyl cysteine (n-AC). Antagonist G is not intrinsically a free radical oxygen donor but stimulates free radical generation specifically within SCLC cells (6.2-fold) and increases the activity of the redox-sensitive transcription factor AP-1 by 61%. In keeping with this, antagonist G reduces cellular glutathione (GSH) levels (38% reduction) and stimulates ceramide production and lipid peroxidation (112% increase). At plasma concentrations achieved clinically in the phase I studies, antagonist G augments, more than additively, growth inhibition induced by etoposide. Our results suggest that antagonist G may be particularly effective as an additional treatment with standard chemotherapy in SCLC. These novel findings will be important for the clinical application of this new and exciting compound and for the future drug development of new agents to treat this aggressive cancer. © 2000 Cancer Research Campaign

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Pharmaceutical development of a parenteral lyophilized formulation of the investigational antitumor neuropeptide antagonist [Arg6, D-Trp7,9, MePhe8]-Substance P {6-11}

Cited by 3 publications

References 12 publications

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Systematic Study on the Chemical Stability of the Prodrug Antitumor Agent Carzelesin (U-80,244)

Development of a gradient elution high-performance liquid chromatography assay with ultraviolet detection for the determination in plasma of the anticancer peptide [Arg6, d-Trp7,9, mePhe8]-substance P (6–11) (antagonist G), its major metabolites and a C-terminal pyrene-labelled conjugate

[Arg6, D-Trp7,9, NmePhe8]-substance P (6–11) (antagonist G) induces AP-1 transcription and sensitizes cells to chemotherapy

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