SHORT CHARACTERISTICS OF THE ACTIVE SUBSTANCE – dsRNA LARIFAN
Larifan (Lariphan) was developed at the Academy of Sciences of Latvia and at present is produced at “Larifan” Ltd.
Larifan is a double-stranded RNA (dsRNA) of natural origin obtained from bacteriophage-infected Escherichia coli cells. It is a heterogeneous population of dsRNA molecules with the mean molecular mass of about 500 kDa and the average length of RNA is 750 nt/p.
Larifan is a double-stranded ribonucleic acid (dsRNA) of natural origin, which is isolated from Escherichia coli cells, infected with bacteriophage. Larifan exhibits pleiotropic biological activity like ability to induce interferon, induce antiviral, immunostimulating, anti-cancer and anti-mutagenic effects. Biological activities are a result of the action of the induced endogenous interferon, but they also may be provoked directly by the dsRNA molecule. The latter is relevant in cases when for genetic reasons interferon formation is suppressed.
As to the pharmacodynamic properties, Larifan`s interferon inducing activity is observed both in humans and different kinds of animals, such as monkeys, calves, sheep, rabbits and small rodents. The level of induced interferon and formation dynamics depend on the medicament administration form. In human blood serum interferon can be found after 10 hours following Larifan administration in the form of rectal suppositories; after subcutaneous and intramuscular injection the maximal titres were detected after 6 to 10 hours, and already after 2 hours after aerosol administration. Human eye conjunctiva swab taken 4 hours after Larifan ointment application has demonstrated a substantial interferon titre increase. Larifan as well as interferon can be considered to be a universal antiviral medicament, as it interrupts virus replication in stages, which are common for all viruses. Larifan antiviral effects are demonstrated both in vitro and in vivo. During animal experiments and in tissue cultures, Larifan inhibits virus reproduction and infection process for herpes, flue, tick-borne encephalitis, encephalomyocarditis, Semiliki, Sindbis, Venezuelan encephalitis, Aujeski, rabies and other viral infection cases. Inhibitory Larifan effect on experimental clamydia infection in mice has also been demonstrated.
Antitumor effects have been observed in different experimental tumor models –Moloney sarcoma, Rauscher leukemia, lymphatic leucosis NK/Ly, sarcoma S-37, Lewis carcinoma 3LL, melanoma B-16 and others. Larifan suppresses the formation of primary tumor, prolongs survival time and in some models (Lewis carcinoma, melanoma B-16) markedly inhibits the formation and development of metastases.
Immunomodulating activities have been observed at local and parenteral application. When applied locally, it causes local lymphocytoses as well as an increase in NK cells. After parenteral administration Larifan stimulates macrophage phagocytic activity, acts as immunoadjuvant, activates NK cells, increases the amount of total and active T-cells and particularly some of their subpopulations, activates HLA expression, modifies structure of tumor cell surface antigens. Ex vivo studies show, that Larifan activates dendritic cells (DC) and promotes their differentiation, including formation of plazmacitodic cells.
Preclinical investigations have shown that Larifan does not exhibit carcinogenic, mutagenic, local irritating and allergic properties.
Within the body ribonucleic acids are subjected to ribonucleases (RN-ases) action. RN-ases commonly found in nature easily break up single-stranded RNA and to lower extent also dsRNA. However specifically dsRNA are broken only by RN-ase III. RN-ase III is specific for primates and is not found in lower animals. Therefore the fate of dsRNA in animals and humans is substantially different.
RN-ase III existing in the human body in few minutes time breaks up dsRNA into oligonucleotides which are not distinguishable from the usual body metabolites. It was found that unshielded free dsRNA molecule after contact with human serum in few minutes is broken into low molecular fragments and loses interferon-inducing activity. Low molecular weight compounds do not have biological activity typical for dsRNA molecule and they are not different from the usual body metabolites.
Mutagenic investigations have demonstrated that Larifan does not exhibit mutagenic properties. However, special investigations revealed that Larifan may decrease mutagenic activity of another antitumor medicament (Fotrin) and therefore has some antimutagenic activity.
Preclinical data of standard investigations about pharmacological safety, repeated dose toxicity and possible carcinogenicity did not reveal any special risks for humans.