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Related Experiment Videos

LHRH antagonists

F Haviv1, E N Bush, J Knittle

  • 1Abbott Laboratories, North Chicago, Illinois 60064-3500, USA.

Pharmaceutical Biotechnology
|October 7, 1998
PubMed
Summary
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New LHRH antagonists show promise, with structural modifications reducing side effects and improving solubility. A-75998 formulation with Encapsin eliminated aggregation, demonstrating effective testosterone suppression in men.

Area of Science:

  • Endocrinology
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Research on LHRH antagonists has advanced significantly, yielding decapeptides in clinical trials.
  • Antagonist structures differ from LHRH, featuring unnatural D-amino acids and specific N- and C-terminal properties.
  • Early LHRH antagonists exhibited side effects (HR reactions) due to structural features, prompting further development.

Purpose of the Study:

  • To review the development of LHRH antagonists, focusing on structural modifications and formulation strategies.
  • To address challenges in solubility and aggregation encountered with LHRH antagonists.
  • To present findings on A-75998, including its improved solubility, aggregation elimination, and in vivo efficacy.

Main Methods:

  • Structural analysis and modification of LHRH antagonists.

Related Experiment Videos

  • Use of Dynamic Light Scattering (DLS) to assess aggregation in aqueous solutions.
  • Formulation development, including the use of Encapsin.
  • Pharmacokinetic and pharmacodynamic studies in men (single subcutaneous dose of A-75998).

    • Main Results:

    • Structural modifications at positions 5, 6, and 8 reduced side effects.
    • Substitution of NMeTyr at position 5 improved A-75998 water solubility 12- to 25-fold.
    • Formulation with Encapsin eliminated aggregation observed in A-75998 aqueous solutions.
    • A single 2 mg s.c. dose of A-75998 suppressed testosterone to castrate levels for over 30 hours in men.

    Conclusions:

    • LHRH antagonist research has progressed, with improved structures and formulations.
    • A-75998 demonstrates enhanced solubility and aggregation-free formulation, leading to sustained testosterone suppression.
    • Ganirelix and cetrorelix are also in clinical studies, with cetrorelix showing potential in prostate cancer and other conditions.