Semax International Inc.

SEMAX®
Clinical and Technical Aspects

TESTING PROCEDURES

Test procedures were carried out in the following way:

Preclinical testing ( 1982 – 1990 ) on laboratory animals to prove safe
use of preparation, indicated that the SEMAX® is free from hormonal or doping effects, is not toxic, does not evoke the habituation syndrome and meets the standards and requirements for use in public health.

Clinical Trials ( 1990-1994 ).
303 patients were tested in Military
hospitals. 200 patients were treated with SEMAX® and 103 patients were treated with conventional treatment (without SEMAX®).
A double–blind placebo controlled- type test was applied on 59 patients, among whom one group of patients was administered SEMAX® and the other group a placebo.
This trial, which lasted for 4 years, proved that SEMAX® could be used in hospitals and polyclinics for treatment and rehabilitation of patients with intellectual and memory disturbances, and to improve the mental working capacities of normal, healthy persons working under great mental and physical stress conditions

Clinical Trials ( 1994-1996 ).
These Trials lasted 2 years and involved several thousand patients in medical centers around the Russian Federation.
It was shown that SEMAX® met all standards and requirements for use in public health, and its mode of action as a neuroactive regulatory peptide was achieved without evoking any side effects.

Research and Development
The neuroactive properties of short fragments of ACTH (Adenocorticotropic Hormone) are well documented. The Dutch scientists D de Wied and J.Jolles, Van Reizen et al, observed non-specific activation of the brain, in which non-specific processes of memory (motivation, attention, sensitivity/irritability) are strengthened, or to the inclusion of fragments of ACTH into specific memorizing processes (consolidation, strengthening of memory).

Using the fragment ACTH(4-10) (Met-Glu-His-Phe-Arg-Trp-Gly) scientists discovered through the process of dissociation of the amino acids and utilizing substitution and special linkages, a peptide which was free from any hormonal effects but possessed neuroactive endogenous modulatory and regulatory properties, the sum of which manifested in a significant neuroprotective effect against ischemic insults.

The compound which was named SEMAX® consisted of the bioactive portion of
ACTH4-10, : Met-Glu-His-Phe, and the substitution of Arg-Trp-Gly with: Pro-Gly-Pro.
The P-G-P binding resulted in much improved stability due to increased resistance towards blood peptidases.
In essence the molecule became :
Pro8-Gly9-Pro10 ACTH(4-10) or ACTH(4-7) Pro-Gly-Pro.
Another novel approach was the method of administration, although a much improved resistance towards peptidases had been achieved through the PGP binding, the relatively small size of the molecule allowed utilization of the route by retrograde axonal transport through the N.Olfactorius or N.Trigeminus, by administering

SEMAX® as a solution/drops onto the nasal mucosa or sublingual mucosa.
Adan A.R et al, and Gozes I observed excellent results administering peptides through the intranasal route and concentrations two to threefold those achieved by the I.V route have been reported. The combination of avenues of access to the brain via the retrograde axonal transport and microcirculation routes contribute towards the achievement of significant concentrations of the substance in the brain in a relatively short period (1-3 minutes) and a significant duration of therapeutic effect (20 hours).