Study of Safety and Tolerability of UNIFUZOL (Solution for Infusions) in Healthy Volunteers
Study of Safety and Tolerability of UNIFUZOL (Solution for Infusions) in Healthy Volunteers
Unifusol (R) is a solution of arginine sodium succinate for intravenous infusions. Its
 effects include vasodilation, protection of inner layer of blood vessels and improvement of
 blood viscosity. The present phase I study is aimed to evaluate the safety and tolerability
 of Unifusol infusions in healthy volunteers.
Unifuzol, solution for infusions,("NTFF POLYSAN" Ltd., Russia) contains succinic acid and
 arginine as active ingredients; it has demonstrated cardioprotective, anti-ischemic,
 endothelial protective and fibrinolytic activity in pre-clinical studies and is considered
 for clinical trials in peripheral vascular disease.

 The primary aim of the present Phase I study is to assess safety and tolerability of Unifusol
 (1.4% solution for infusions) at different infusion rates in healthy volunteers.

 Study objectives:

 1. Assess the safety parameters (vital signs, the incidence of AEs, SAEs, laboratory
 abnormalities) during infusion of Unifusol (1.4% solution for infusions) in healthy
 volunteers at different infusion rates.

 -  administration of a single infusion of 250 ml at a rate of 3 ml / min.

 -  administration of a single infusion of 250 ml at a rate of 4.5 ml / min

 -  administration of a single infusion of 500 ml at a rate of 4.5 ml / min

 2. Study the pharmacokinetics parameters of the active components of the Unifusol (succinic
 acid and arginine) in healthy volunteers after single infusion at a dose of 250 ml at a
 rate of 4.5 ml / min.

 Study methods:

 1. Determination of pharmacokinetic parameters of succinic acid administered at a single
 Unifusol infusion dose 250 ml at a rate of 4.5 ml / min (AUC, Cmax, Tmax, T1 / 2);

 2. Determination of pharmacokinetic parameters of arginine after a single Unifusol infusion
 at a dose 250 ml at a rate of 4.5 ml / min (AUC, Cmax, Tmax, T1 / 2);

 3. Determination of individual variations of the pharmacokinetic parameters of succinic
 acid and arginine in healthy volunteers;

 4. Identification of significant gender differences in the pharmacokinetics of the active
 ingredients of Unifusol (succinic acid and arginine) in healthy volunteers;

 5. Determination of the number of compartments in the pharmacokinetic model which will be
 most appropriate to the measured concentrations after a single infusion (single-chamber,
 two-chamber or three-chamber pharmacokinetic model).
Inclusion Criteria:

 1. Healthy condition, as verified by standard clinical, laboratory and instrumental
 methods of examination.

 2. The body mass index (BMI) of 18.5 to 30 and a body weight above 50 kg.

 3. Signed informed consent.

 4. For men - consent to use the double-barrier contraceptive method during the course of
 the study, and for 90 days after the study completion.

 5. For women - negative pregnancy test, absence of lactation, and consent to use the
 double-barrier method of contraception during the study and for 90 days after study
 completion. In the case of hormonal contraceptive use, the intake must be canceled no
 later than 2 months before the start of the study.

 Exclusion Criteria:

 1. Intolerance or hypersensitivity to the components of the study drug.

 2. Chronic diseases of the cardiovascular, bronchopulmonary (including bronchospastic
 disease), neuroendocrine system, chronic diseases of the gastrointestinal tract,
 liver, kidneys, blood, immune system, mental illness or substance abuse, or a history
 of alcoholism.

 3. Acute infectious diseases within 4 weeks before the start of the study.

 4. Any abnormalities of the laboratory findings before inclusion.

 5. The presence of mental disorders, or the history of mental illness.\

 6. Intake of medications and/or nutritional supplements for 14 days or 5 half-lives
 (whichever is longer) prior to the first dose of study drug, or using drugs that have
 a significant effect on hemodynamics, liver function, etc. (for instance,
 barbiturates, omeprazole, cimetidine) for 2 months prior to the first dose of study
 medication. Receiving herbal medicines and herbal supplements during the 28 days
 before the first dose of study medication.

 7. Hormonal methods of contraception with systemic effects (including oral and
 transdermal contraceptives, injectable progesterone, subcutaneous implants with a
 progestin intrauterine device with progesterone release) and hormone replacement
 therapy within 60 days prior to the first dose of study medication.

 8. The injection of any drug, depot (slow release) or the use of drug implant within 3
 months prior to the administration of the study drug.

 9. Abnormalities of vital signs: systolic blood pressure below 100 mm Hg or higher than
 130 mm Hg; diastolic blood pressure below 60 mmHg or above 90 mm Hg; heart rate below
 60 beats / min or above 90 beats / min.

 10. Data of 12-lead ECG demonstrating the QTc interval> 450 msec or the QRS> 120 ms on
 screening visit.

 11. Blood donation (450 ml of blood or more) in less than 3 months prior to inclusion.

 12. Participation in clinical trials of drugs in 3 months before inclusion.

 13. The regular consumption of more than 5 units of alcohol per week (each unit is equal
 to 30 ml of ethanol or 325 ml of beer) or the history of alcoholism, drug addiction,
 drug abuse.

 14. A positive test for alcohol in the exhaled air.

 15. Smoking more than 10 cigarettes per day.

 16. A positive urine test for drugs, such as amphetamine, marijuana, morphine, cocaine and
 methamphetamine, and tricyclic antidepressants, as revealed in urine by immunoassay
 analysis.

 17. The positive results of the analyzes for hepatitis B or C, HIV, and/or syphilis.

 18. Unwilling or unable to give up alcohol intake, smoking and excessive exercise 48 hours
 prior to study drug administration and up to 96 hours after administration of the
 drug, as well as food and beverages containing methylxanthines and grapefruit /
 grapefruit juice from the day prior to the screening visit and at follow-up.

 19. Compliance to a special diet (eg. vegetarian) or lifestyle (including night work and
 extreme exercise, such as sports or weight lifting) that may interfere with the study
 procedures.

 20. Planning inpatient treatment of the volunteer within one month after the first
 injection of the study drug.

 21. Lack of intention to comply with the study regimen.

 22. Obvious or probable inability of volunteer, according to the judgement of the
 researcher, to understand and evaluate information about the study and consciously
 sign the informed consent form, in particular with respect to the expected risks and
 possible discomfort.

 23. Expected problem with the placement of venous catheters or performing vein puncture.

 24. Pregnancy or breast-feeding; unwillingness or inability of a woman of childbearing age
 to use acceptable methods of barrier contraception, according to the protocol,
 starting at least 14 days prior to the first dose of study medication and for 90 days
 after study completion.