Phase I and pharmacokinetic study of LM985 (flavone acetic acid ester).

We have conducted a Phase I and initial clinical pharmacological evaluation of LM985, the first of a series of compounds based on the flavone ring structure to be considered for clinical trial in malignant disease. The drug was administered i.v. to 26 patients with advanced cancer on an every-21-day schedule. Patients were treated at 14 dosage levels ranging from 10 to 1500 mg/m2. Dose limiting toxicity was identified as acute reversible hypotension occurring during drug infusion; no leukopenia, alopecia, hepatic toxicity, or renal toxicity was observed, but at the higher dose range, mild sedation was apparent. Twenty patients had measurable disease and were evaluable for response. One patient with colorectal carcinoma had stable disease after three courses of LM985; however, no other responses were seen. Pharmacokinetic and in vitro drug degradation studies imply that the ester LM985 is hydrolyzed to LM975 (flavone acetic acid) rapidly in vivo. LM975 is active in a variety of animal tumor models, but it does not have the cardiovascular side effects seen with LM985 (hypotension and bradycardia) in pithed or anesthetized rats. We would recommend that LM975 be considered for clinical trial, because it seems likely that substantially higher doses of LM975 than of LM985 can be given without dose limiting cardiovascular toxicity.

Precise spectrophotometry of small quantities of drugs in the presence of irreproducible quantities of impurities.

A variety of methods of spectrophotometric assay of compounds in the presence of one or more irrelevant impurities have been recently described, employing, for example, the use of Legendre polynomials and trigonometric functions. The use of least-squares solutions of overdetermined systems (Scheid 1968) in spectrophotometry is outlined, with conditions under which simplified overdetermined systems have been used for precise spectrophotometric assay of small quantities of drug substances in the presence of largely irreproducible quantities of irrelevant impurities.

Adjustment of precompression force to reduce mixing-time dependence of tablet tensile strength.

The dependence of tablet tensile strength on lubricant mixing time, pre- and main compression pressure was measured with microcrystalline cellulose, dicalcium phosphate dihydrate and starch 1500 on a rotary tablet machine. Loss of tablet tensile strength arising from lubricant overmixing can be substantially reduced in the case of microcrystalline cellulose by adjustment of pre- and main compression. This facility may be used in addition to or instead of reducing mixing time, or displacing lubricant by adding extra formulation components.

In vitro heterogeneous degradation of poly(n-alkyl alpha-cyanoacrylates).

Methods by which in vitro heterogeneous phase degradation rates of the poly(n-alkyl alpha-cyanoacrylates) have been directly obtained are described. The data indicate that the rates of degradation in aqueous buffer solutions depend not only upon pH of the medium and length of the monomer alkyl side chain, but also critically upon polymer particle specific surface, particle size, polymer molecular weight, and molecular weight distribution. A modification of the currently held theory of degradation of these polymers is required, and postulated.