KR20150050406A - Pharmaceutical composition comprising nicotinamide riboside as active ingredient for treatment or prevention of sepsis - Google Patents

Abstract

The present invention provides a pharmaceutical composition for treating or preventing sepsis, containing nicotinamide riboside as an active ingredient. The pharmaceutical composition of the present invention can be effectively used for sepsis treatment. In addition, the pharmaceutical composition of the present invention can improve conventional sepsis treatment effects by being used in combination with a drug such as a conventional antibiotic for sepsis.

Description

A pharmaceutical composition for the treatment or prevention of sepsis comprising nicotinamide ribose as an active ingredient.

The present invention relates to a pharmaceutical composition for treating or preventing sepsis comprising nicotinamide ribose as an active ingredient.

Sepsis is a systemic inflammatory reaction caused by excessive activation of the immune system of a living organism when a living organism is infected by various pathogenic bacteria. In case of severe symptoms, shock may be accompanied by sepsis. Severe sepsis is a major cause of death in hospitalized intensive care unit wards, with a mortality rate of 20-30%, which is very serious. Severe sepsis is a serious sepsis in the United States, with more than 200,000 people per year (Angus et al., Crit. Care Med. 29, 1303-1310, 2001).

In spite of the development of medical technology, there are many cases in which sepsis occurs due to the aftereffects of surgery worldwide. In addition, people with weak immunity in the body, such as newborns or elderly people, many. Typically, in the case of neonatal sepsis, it is known that about 3 out of 1,000 cases of term infants develop, and the prevalence rate of premature infants is known to increase 3 to 4 times.

In cases of septicemia, antibiotics are usually used. However, antibiotics alone can not provide effective treatment if a large number of microorganisms are proliferated due to delayed appropriate treatment, or if the infection is caused by a strain resistant to antibiotics. In this study, we investigated the effects of antibiotics on the pathogenicity of antibiotics, and found that the antibiotics were resistant to antibiotics (Aneja & Fink, Trends Microbiol 15, 31-37, 2007).

Nicotinamide riboside (NR) is a newly discovered vitamin, contained in several foods such as milk and beer, and is known to have no adverse effects due to water-soluble vitamins. However, studies on its pharmacological effects Is a trivial fact.

Nicotine amide riboside (NR) has been reported to reduce the incidence of obesity induced by high lipid diet when mixed with food at a dose of 400 mg / kg / day for 12 weeks in animal experiments with mice (Canto et al., The NAD (+) precursor nicotinamidiboside enhances oxidative metabolism and protects against high-fat diet-induced obesity, Cell Metab, 15, 838-47, 2012). In addition, nicotinamide rabbides reduced the incidence of cognitive dysfunction induced by Tg2576 mice, a mouse model of Alzheimer's disease, in mice administered at a dose of 250 mg / kg / day for 3 months (Gong et al., Nicotinamidiboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1 regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models, Neurobiol Aging, 34, 1581-8, 2013).

However, it is not known whether nicotinamide riboside has a therapeutic effect on sepsis.

As a result of continuing studies on sepsis treatment to meet the requirements of the prior art, the present inventors have found that when nicotinamide rabbide is administered to an animal model of sepsis (cecal ligation & puncture (CLP) surgery) The mortality rate was significantly reduced, and the present invention was completed.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for treating or preventing sepsis comprising nicotinamide ribose as an active ingredient.

It is also an object of the present invention to provide a pharmaceutical composition for treating or preventing sepsis comprising nicotinamide riboside as an active ingredient and at least one drug selected from the group consisting of antibiotics, antibacterial agents, antiinflammatory agents, antipyretic analgesics, blood coagulation inhibitors and antiallergic agents .

It is also an object of the present invention to provide a method for treating or preventing sepsis comprising administering the pharmaceutical composition to a subject.

In one aspect of the present invention, there is provided a pharmaceutical composition for treating or preventing sepsis comprising nicotinamide riboside as an active ingredient.

The active ingredient of the present invention, nicotinamide riboside, has the following structure and is synthesized or commercially available:

Also, nicotinamide ribose of the above formula may exist in different enantiomeric forms since it has an asymmetric center, and all optical isomers and R or S type stereoisomers and mixtures thereof are also intended to be included within the scope of the present invention. The present invention can include the active ingredient nicotinamide ribose as a racemate, in one or more enantiomeric forms, in one or more diastereomeric forms or as a mixture thereof, ≪ / RTI >

Nicotine amide riboside is a kind of water-soluble vitamin, so safety is guaranteed.

The pharmacological composition of the present invention is nicotine amide riboside, which is an active ingredient, dose-dependently reduces the mortality due to sepsis (Fig. 1).

The optimum dose of nicotinamide rabicide, an active ingredient of the present invention, is 30 to 172 μmol / kg (FIG. 2).

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent, and may be formulated for oral or parenteral administration.

Pharmaceutical compositions for oral administration may be presented as discrete units such as capsules or tablets; Powders or granules; May be formulated with a solvent, syrup or suspension.

Suitable excipients for tablets or hard gelatin capsules include lactose, corn starch or derivatives thereof, stearic acid or its salts. Suitable excipients for use in soft gelatin capsule formulations include, for example, vegetable oils, waxes, fats, semi-solids or liquid polyols. Excipients that can be used to prepare solvents and syrups include, for example, water, polyols and sugars. To prepare a suspension, oil (e.g., vegetable oil) may be used to provide an oil-in-water or water-in-oil suspending agent.

Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes (which are substantially contemporaneous with the blood of the recipient); And aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Excipients that may be used in the injectable solution include, for example, water, alcohols, polyols, glycerin and vegetable oils. Such compositions may be presented in unit-dose (one-time) or multi-dose (multi-dose) containers, such as sealed ampoules and vials, and may be presented in a sterile liquid carrier, Can be stored under freeze-drying conditions requiring only addition. Immediate injection solvents and suspensions may be prepared from sterile acid, granules and tablets.

The pharmaceutical composition of the present invention may further comprise at least one agent selected from the group consisting of an anti-inflammatory agent, a paracetamol, a blood coagulation inhibitor, an antibiotic, an antibacterial agent and an antiallergic agent. In this case in the pharmaceutical composition of the present invention, the additional drug may be formulated in a form mixed with nicotinamide riboside or packaged separately from nicotinamide riboside.

Antibiotics, antibacterial agents, antiinflammatory agents, antipyretic analgesics, blood coagulation inhibitors, and antiallergic agents which can be used in the present invention are antibiotics, antibacterial agents, antiinflammatory agents, antithrombotic agents, anticoagulants and antiallergic agents conventionally used for the treatment of sepsis.

The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount.

The term "pharmaceutically effective amount " as used herein means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined by the kind and severity of the patient's disease, age, sex, Activity, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The "pharmaceutically effective amount" of the pharmaceutical composition of the present invention is, for example, preferably 0.001 to 10 g / kg / day of the active ingredient of the pharmaceutical composition of the present invention. The administration may be carried out once a day or divided into several doses.

In yet another aspect, the present invention is also directed to a method for treating sepsis comprising the steps of: a) administering the pharmaceutical composition to a subject.

The method of treatment of the present invention may further comprise the step of administering b) at least one agent selected from the group consisting of anti-inflammatory agents, antipyretic analgesics, blood coagulation inhibitors, antibiotics, antibacterial agents and antiallergic agents. Preferably, steps (a) and (b) may be performed simultaneously, sequentially or in reverse order.

The term "individual" as used herein means, but is not limited to, a mammal such as a human, cattle, sheep, sheep, pig, goat, camel, .

The term "administering" in the present invention means introducing a predetermined substance into a subject by any appropriate method, and the administration route of the pharmaceutical composition of the present invention is administered through any ordinary route as long as it can reach the target tissue . But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. In addition, the pharmaceutical composition may be administered by any device capable of transferring the active agent to the target cell.

The pharmaceutical composition of the present invention can be effectively used for the treatment of sepsis. In addition, the pharmaceutical composition of the present invention can be used in combination with drugs such as existing antibiotics for sepsis to enhance the therapeutic effects of existing sepsis.

1 is a graph showing the therapeutic effect of the pharmaceutical composition of the present invention on sepsis in an animal model of sepsis. The pharmaceutical composition of the present invention significantly inhibited the mortality of an animal model of sepsis in a dose-dependent manner of the active ingredient.
Fig. 2 is a graph showing the optimal dose of nicotinamide rabicide, an active ingredient of the present invention, in sepsis model animals. Fig.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example

Reference Example  1: Preparation of experimental materials and animals

Nicotine amide riboside was purchased from 4Chem Laboratory (Suwon, Gyeonggi-do, Fitech New Technology Business Incubating Center, No. 201), a domestic venture company.

An experimental animal, ICR mouse (6 weeks old, M & J Ltd.), was used after an adaptation period of 7 days or 8 days. ICR mice were assigned to 5 or 4 polycarbonate urine per room (20 ° C to 25 ° C) and humidity (40% to 45%). Specification: The memorization cycle is 12 hours: 12 hours, and food (Samyang, Korea) and water are easily accessible.

All laboratory animals were handled in accordance with 'Guide for the Care' and 'Use of Laboratory Animals by Institute of Animal Resources, Commission on Life Science, National Research Council, USA on 1996, Washington DC'.

Reference Example  2: Preparation of an animal model of sepsis

ICR mice were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis through peritonitis and used as an animal model of sepsis.

Specifically, the ICR mouse was exposed under pentobarbital anesthesia to expose the cecum, and the exposed cecum was double-ligated just below the ileocecal valve, followed by a 2-gauge needle The peritoneal cavity was closed according to the general method.

The CLP model is the most closely mimicked human acute peritonitis and is the most clinically relevant animal model of sepsis and has been regarded as a valuable animal model for detecting anti-septic effects (Urbaschek and Urbaschek, 1987; Yan et al. 2004; Ghiselliet al., 2006; Wirtz et al., 2006). The CLP model more closely reflects the clinical course of human abdominal sepsis, with endogenous bacterial lesions leading to multifactorial infection with septic focus systemic inflammatory response syndrome (Dejager et al., Trends Microbiol., 198, 198- 208, 2011).

Test Example  1: In an animal model of sepsis Nicotinamide Riboside  Therapeutic effect

Nicotine amide riboside was subcutaneously injected into the sepsis animal model prepared in Reference Example 2 at an interval of 12 hours from 2 hours after the CLP operation at each dose. In the vehicle control, the same amount of physiological saline was administered in the same manner in place of nicotinamide ribose. Survival and death rates were measured once a day for 10 days after CLP surgery. Statistical analysis was performed using the log-rank test.

Specifically, ICR mice, an animal model of sepsis, were given a vehicle control group (9 mice), nicotinamide rabbide (NR) 16 mg / kg (62 μmol / kg) (125 μmol / kg) and NR 44 mg / kg (172 μmol / kg), respectively. The administration was administered subcutaneously every 12 hours and 6 times at a dose of 10 ml / kg using physiological saline as a medium.

The mortality rate of each group of mice was observed for 10 days, and the results are shown in Table 1 and FIG.

Days
sample 0 One 2 3 4 5 6 7 8 9 10 Vehicle control 9 7 2 2 One One One One One One One NR 16 mg / kg
(62 μmol / kg) group 5 5 4 3 3 One One One One One One NR 32 mg / kg
(125 μmol / kg) group 5 5 4 4 4 4 3 2 2 2 2 NR 44 mg / kg
(172 μmol / kg) group 5 5 5 5 5 5 5 5 5 5 5

 <Number of surviving mice per day>

As shown in Table 1 and FIG. 1, only one mouse of 9 mice survived until 10 days (survival rate: 11%), but mice administered with physiological saline alone were administered with nicotinamide ribose at a dose of 16 mg / kg Of the total 5 mice, 1 survived to 10 days (survival rate 20%) and 2 of the 5 mice survived to 10 days in the mouse group administered with nicotinamide ribose 32 mg / kg (survival rate 40 %, p = 0.07). In the group receiving nicotine amide ribose 44 mg / kg, all 5 mice survived until 10 days (survival rate 100%, p <0.01). Nicotinamide ribose has a significant protective effect on CLP-induced death in a dose-dependent manner.

These results indicate that the nicotinamide riboside - treated group shows a dose - dependent effect of reducing CLP mortality, that is, a therapeutic effect on sepsis.

Test Example  2: Nicotinamide Riboside  Optimal dose

Nicotinamide ribose was administered to more sepsis animal models at various concentrations to elicit an optimal dose of nicotinamide ribose for sepsis.

Basically, as in Test Example 1, nicotinamide riboside of each dose was subcutaneously injected into the sepsis animal model prepared in Reference Example 2 from 2 hours after CLP surgery to 6 times at intervals of 12 hours. In the vehicle control, the same amount of physiological saline was administered in the same manner in place of nicotinamide ribose. Survival and death rates were measured once a day for 10 days after CLP surgery. Statistical analysis was performed using the log-rank test.

Specifically, ICR mice (17 mice), 15 μmol / kg nicotinamide riboside (NR), 17 mice (NR) and 30 μmol / kg NR were administered to ICR mice in a vehicle control group , NR 60 μmol / kg group (17 rats), and NR 120 μmol / kg group (17 rats). The administration was administered subcutaneously every 12 hours and 6 times at a dose of 10 ml / kg using physiological saline as a medium.

The mortality rate of each group of mice was observed for 10 days, and the results are shown in Table 2 and FIG.

Days
sample 0 One 2 3 4 5 6 7 8 9 10 Vehicle control 17 15 12 7 6 6 6 5 5 4 4 NR 15 μmol / kg administration group 17 17 15 9 9 8 7 7 7 7 7 NR 30 μmol / kg administration group 17 17 16 15 13 13 13 11 11 11 11 NR 60 μmol / kg administered group 17 17 16 15 14 12 12 12 10 10 10 NR 120 μmol / kg administration group 17 17 17 17 16 16 16 14 14 14 14

   <Number of surviving mice per day>

As shown in Table 2 and FIG. 2, only 4 mice survived (mice survival rate: about 24%) in 17 mice until 10 days in the control mice to which only physiological saline was administered. In the experimental group, 7 out of 17 mice survived to 10 days in NR 15 μmol / kg group treated mice (survival rate approx. 41%). Of the 17 mice fed with NR 30 μmol / kg, 11 mice survived to 10 days (survival rate of about 65%), and 12 mice survived up to 7 days in the NR 60 μmol / kg group mice and 10 mice survived on the 10th day (Survival rate of about 59%). In the group administered with NR 120 μmol / kg, 16 mice survived until day 6, and the final 14 mice survived (survival rate of about 82%).

Based on the results of Test Example 1 and Test Example 2, it can be seen that the optimum dose of nicotinamide ribose for treatment or prevention of sepsis is 30 to 172 μmol / kg.

Claims (7)

A pharmaceutical composition for the treatment or prevention of sepsis comprising nicotinamide riboside as an active ingredient. The pharmaceutical composition for treating or preventing sepsis according to claim 1, wherein the pharmaceutical composition comprises at least one additional agent selected from the group consisting of an antibiotic, an antibacterial agent, an antiinflammatory agent, an antithrombotic agent, a blood coagulation inhibitor and an antiallergic agent Composition. The pharmaceutical composition for treating or preventing sepsis according to claim 2, wherein the additional drug is formulated separately from nicotinamide riboside. The pharmaceutical composition for treating or preventing sepsis according to claim 3, wherein the additional drug is administered first than nicotinamide ribose. The pharmaceutical composition according to claim 3, wherein the nicotinamide riboside is administered prior to the additional drug. The pharmaceutical composition for treating or preventing sepsis according to any one of claims 1 to 5, wherein the pharmaceutical composition further comprises at least one selected from the group consisting of a carrier, an excipient and a diluent. The pharmaceutical composition for treating or preventing sepsis according to claim 1, wherein the nicotinamide riboside is contained at 30 to 172 탆 ol / kg.

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