Linked Life Data

9052420

Source:http://linkedlifedata.com/resource/pubmed/id/9052420

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1997-3-20
pubmed:abstractText
The orally administered tubulin-binding agent 1069C85 was developed with the hope of overcoming the multidrug resistance associated with existing anti-tubulin agents, such as the vinca alkaloids. A phase I study was performed using a single oral dose every 3 weeks, administered as a suspension reconstituted in 0.1% Tween 80 and 0.9% saline. The starting dose was 2.8 mg m-2, and dose doubling was permitted until the area under curve (AUC) was > or = 40% of that at the mouse LD10; thereafter, a modified Fibonacci scheme was used. The formulation proved to be unsatisfactory, resulting in inconsistent absorption. The terminal elimination half-life was prolonged (range 18-73.5 h). Sporadic central neurotoxicity was observed, which was grade 3 in one patient treated at 200 mg m-2. A revised formulation with micronized drug was more easily suspended and appeared to increase the bioavailability by a factor of 2-4. Severe central neurotoxicity, up to grade 4, was then observed at doses of 50-100 mg m-2. Unfortunately, toxicity was not predictable and one patient, with a previous history of partial intestinal obstruction, treated at 50 mg m-2, cleared the drug very slowly, possibly because of prolonged, delayed absorption. This patient died from pancytopenia and severe gastrointestinal damage. It was concluded that such unpredictable behaviour would be incompatible with safe evaluation in phase II studies; the trial was closed and further clinical development abandoned.
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:issn
0007-0920
pubmed:author
pubmed:issnType
Print
pubmed:volume
75
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
608-13
pubmed:dateRevised
2009-11-18
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Phase I trial and pharmacokinetics of the tubulin inhibitor 1069C85--a synthetic agent binding at the colchicine site designed to overcome multidrug resistance.
pubmed:affiliation
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK.
pubmed:publicationType
Journal Article, Clinical Trial, Research Support, Non-U.S. Gov't, Clinical Trial, Phase I