A review of documentation requirements for preclinical sections, for marketing submissions in the European Community, Japan and the USA.

Standardization of the documentation requirements for preclinical sections, for marketing submissions in the European Community (EC), Japan and the USA is proposed. It is unnecessary to standardize the leading summaries of submissions as their format is predicated by the way in which the regulatory authorities review applications. Harmonization of the technical sections will reduce the duplication of effort expended by pharmaceutical companies to produce documentation specific for each regulatory authority. Elimination of requirements specific to individual authorities will further reduce the resource requirements. The proposals made in this paper are aimed to increase the 'user-friendliness' of the preclinical documentation and therefore expedite the review process.

Comparison of effect of peptide length and sulphation on acid secretory potency of gastrin in the cat in vivo and in vitro.

The gastric-acid secretory potency of gastrin peptides was investigated in vivo, in conscious cats prepared with gastric fistula, and in vitro, with kitten isolated gastric mucosae. The influence of peptide length on potency was investigated by comparing synthetic human gastrin heptadecapeptide, non-sulphate (shG17ns) with a synthetic gastrin butyloxycarbonyl hexapeptide (G6ns), and the influence of sulphation by comparison of G6ns with its sister sulphated peptide (G6s). When exogenous doses were compared, shG17ns was the most potent peptide (mean exogenous dose for half-maximal stimulation (EDe50) : 0.33 nmol kg-1 h-1), and was 15.8 times more potent than G6ns (EDe50:5.14 nmol kg-1 h-1). This potency ratio was reduced to 9.4 when circulating immunoreactive concentrations of the two peptides were compared (mean circulating concentration for half-maximal stimulation (EDc50) : shG17ns, 201 pM; G6ns, 1890 pM). The greater potency ratio when exogenous doses were compared was due to the greater metabolic clearance rate (m.c.r.) of the shorter gastrin (m.c.r.: shG17ns, 37 ml kg-1 min-1; G6ns, 121 ml kg-1 min-1). In vitro, shG17ns (mean concentration for half-maximal stimulation (EC50) : 1.99 nM) was 2.8 times more potent than G6ns (EC50: 5.57 nM). Sulphation of the hexapeptide increased its potency 3.6-fold when exogenous doses were compared (EDe50 G6s: 1.42 nmol kg-1 h-1). The greater potency of the sulphated peptide appeared to be due to its lower m.c.r. (20 ml kg-1 min-1), and was eliminated when circulating concentrations were compared; potency ratio G6ns: G6s, 1.1. We conclude that the increased potency of short gastrin peptides observed upon sulphation is likely to be due to increased resistance to metabolic clearance. Part of the increased potency observed with increasing peptide length can also be explained by increased resistance to clearance, but the small potency difference in vitro may reflect greater affinity for gastrin receptors.