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Ironwood Pharmaceuticals, Inc. Message Board

  • old_dogg_with_new_trix old_dogg_with_new_trix Jun 22, 2012 10:56 PM Flag

    SGYP vs IRWD

    I am watching both, but I thought this article was very interesting.

    Linaclotide is a GCCR agonist and synthetic analog of E. coli STa toxin that stimulates
    intracellular c-GMP activity and active Cl secretion. Linaclotide is released and degraded
    rapidly in the duodenum (Kessler et al., 2008). This being the case, the stool hydrating effect
    of linaclotide must rely on a rapid burst of secretion in the upper intestine. Colonic motor
    dysfunction could potentially blunt or eliminate the subsequent therapeutic responses to
    linaclotide, reflecting the prodigious organ specific capacity for water reabsorption by the
    colon, coupled with prolonged transit (Debongnie & Phillips, 1978). Titration of distal stool
    volume might be difficult to control by a proximally active mechanism, resulting in wider
    swings in fecal output and higher rates of diarrhea-associated adverse events. Consistent
    targeting of specific sites along the length of the GI tract could be difficult with a luminally
    active agent. A 10-fold to 100-fold inter-individual variability in GCC mRNA expression has
    been observed in the human intestine (Bharucha et al., 2010), adding to the challenge of
    proper dosing in individual patients.
    Plecanatide is a synthetic analogue of naturally occurring uroguanylin that mediates basal
    secretion and cell volume in humans (Shailubhai et al., 2010). In contrast to linaclotide,
    which is stabilized by three disulfide bonds that maintain the peptide in a tight
    configuration (Harris & Cromwell, 2007), the molecular structure of plecanatide contains
    only two disulfide bonds (Shailubhai et al., 2010), potentially rendering it less stable at its 150 Constipation – Causes, Diagnosis and Treatment
    intestinal site of action. Furthermore, its binding to GCC receptors is pH-dependent.
    Perhaps as a result of these properties, plecanatide manifests three-fold to five-fold lower
    potency compared with linaclotide in human studies on a concentration basis (Lembo et al.,
    2010a; Shailubhai et al., 2010). Plecanatide was associated with a lower incidence of diarrhea
    in a preliminary trial of constipated patients, but this could potentially be representative of
    lower rates of intestinal secretion induced by the compound (Shailubhai et al., 2010).

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