engleski

The development of PL 14736 for treatment of inflammatory bowel disease

PL 14 736, a 15 amino acide peptide, is a part of a larger protein, first isolated from human gastric juice. Pharmacological activity of PL 14736 has been tested in vitro and in vivo, revealing beneficial activity against experimental tissue damage. Pl 14736 has showen potent protective and healing properties in models of upper GI tract lesions and, in particular, in acute and subacute models of colitis. Hence the pre-clinical development of PL 14736 has been pursued for the treatment of inflammatory bowl disease. In order to fulfill regulatory requirements for the conduct of phase I and phase II clinical testing, adequate non-clinical safety studies were performen with Pl 14736. Acute oral and iv toxicity of Pl 14736 in mice revealed LD50>2000 mg/kg. repeated four-week iv as well as two-week intracolonic administration to rats and beagle dogs has no significant effect on clinical, gross pathology or histopathology parameters tested, with doses up to 10 and 25 mg/kg, recpectively. Safety pharmacology testing in Beagle dogs revealed no cardiovascular or respiratory symptoms. Pl 14736 is neither genotoxic or mutagenic: it did not cause chromosomal aberration in human lymphocyte culture in vitro nor micronuclei formation in polychromatic erithrocytes in mice bone marrow micronucleus test in vivo ; Ames test was negative. Following pre-clinical testing, a placebo-controlled phase I tolerability and pharmacokinetics study was conducted in 32 healthy volunteers. Phisical examination, observation of clinical signs as well as laboratory testing have revealed no significant adverse effects that could be attributed to single and repeated seven-dfay treatment with PL 14736 enemas. Base don these encourating efficacy and safety data, placebo-controlled phase II study with PL 14736 enemas has recently started in order to test the safety and efficacy of two-week treatment in patients suffering from acute to moderate ulcerative colitis.

IBD; mucosa protection; peptide; PL 14736

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