AU2018267649B2

AU2018267649B2 - Method maintaining iron homeostasis with shogaols

Info

Publication number: AU2018267649B2
Application number: AU2018267649A
Authority: AU
Inventors: Vladimir Badmaev
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-04-27
Filing date: 2018-11-22
Publication date: 2021-03-04
Anticipated expiration: 2037-04-26
Also published as: AU2018267649A1

Abstract

METHOD MAINTAINING IRON HOMEOSTASIS WITH SHOGAOLS ABSTRACT Composition of shogaols and related compounds from Zingiberaceae family of plants for improved iron metabolism in health and prevention iron overload in patients in need of nutritional and/or therapeutic approach to ameliorate iron-overload.

Description

FIELD OF INVENTION

The present invention relates to method use polyphenolic compounds extracted from

Zingiber sp., especially shogaols in nutritional and/or pharmacologic prevention and

treatment of detrimental health consequences of high levels of circulating and tissue

iron. The invention is also directed to method of optimal utilization of iron for human

health and iron homeostasis.

BACKGROUND OF INVENTION

Diseases and health conditions associated with iron deficiency and iron overload are

prevalent across the world. Maintaining proper levels of body iron is critical for

hemoglobin synthesis. Diseases like myelodysplastic syndromes (MDS) requiring

regular blood transfusions typically lead to iron overload and without proper treatment

lead to significant morbidity and mortality.

MDS is a heterogeneous group of disorders characterized by ineffective hematopoiesis.

In current invention, MDS exemplifies a condition with risk of iron overload due to need

for frequent blood cell transfusions. Chelating excess iron from the overload prevents

reactive oxygen species (ROS) and may induce healthy hematopoietic cell

differentiation which is compromised in MDS. In clinical practice, it has been recognized

that chelation therapy in MDS patients ameliorates pathological effects of excess iron

and oxidative stress by decreasing iron-induced cytotoxicity, DNA damage, blocked

differentiation in hematopoietic cells, and possibly transformation to leukemia.

Effective management of iron overload results in excretion of unbound circulating iron

and or activates system(s) or mechanisms of removal excess iron from the body. The

examples of currently available chelating agents include deferoxamine, deferasirox and

deferiprone which bind with iron in the bloodstream and enhance its elimination in urine

and feces. However, current generation of chelating agents can result in nephrotoxicity

and liver toxicity.

One of the important mechanisms of iron homeostasis depends on the liver

manufactured hormone hepcidin which regulates proteins transporting iron in the body,

i.e. transferrin - a protein that carries iron to target tissues, ferritin - a cellular iron

storage protein, and ferroportin which exports iron from the body. Hepcidin synthesis

and secretion by the liver is controlled by iron stores, lingering inflammatory process,

hypoxia, erythropoiesis and nutritional factors, e.g. vitamin D.

In states in which the hepcidin level is abnormally high such as inflammation, serum iron

falls due to iron trapping within macrophages and liver cells and decreased gut iron

absorption. Hepcidin degrades iron transporting proteins and prevents iron

gastrointestinal absorption and systemic utilization. When the hepcidin level is

abnormally low such as in hemochromatosis, iron overload occurs due to decreased

iron efflux.

When transferrin's and ferritin iron-binding capacity is exceeded, non-transferrin-bound

iron (NTBI) is produced. The unbound circulating iron ion causes cellular damage via

production of reactive oxygen species (ROS) which oxidize lipids, proteins, and nucleic

acids, resulting in premature apoptosis, cell death, tissue and organ damage (e.g., iron- overload-associated liver cirrhosis, diabetes and other endocrinopathies, and cardiomyopathy) - contributing to increased morbidity and mortality in patients requiring regular blood transfusions.

The current invention is based on the study designed to test the efficacy of shogaols,

compounds derived from ginger roots (Zingiber officinale Roscoe, Zingiberaceae)

chemically related to gingerols, in improving the cytopenias of patients with low and

intermediate-1 risk myelodysplastic syndromes or MDS.

Shogaols, the dehydration products of corresponding gingerols during storage or thermal

processing, are different from gingerols chemically and in their biological properties. In the

in vitro study, shogaols had much stronger growth inhibitory effects than gingerols on H1299

human lung cancer cells and HCT-116 human colon cancer cells, especially prominent when

comparing [6]-shogaol with [6]-gingerol (IC5o: -8 pMvs. -150 pM). In addition, it was found that

[6]-shogaol had much stronger inhibitory effects on the arachidonic acid pathway and nitric oxide

(NO) synthesis than [6]-gingerol.

EXPERIMENTAL DESIGN

The low and Intermediate-1 risk MDS patients were selected to receive shogaols

standardized for 25% shogaols extracted from ginger roots with the C02 supercritical

extraction method. The rationale for using shogaols has been that it is a natural, non

toxic substance with anti-tumor, anti-proliferative and chemopreventive properties which

are likely to be well tolerated in MDS elderly population. The shogaols were intended as

chemopreventive and therapeutic modality and to look for improvement in cytopenias in

the treated patients.

Treatment protocol: Six patients, 2 women and 4 men, mean age 70 years old with a

confirmed diagnosis of low or Intermediate-1 risk myelodysplastic syndromes were

eligible for this trial. No other experimental agent aimed at treating MDS was allowed

during the period of protocol therapy. Therapy has been continued unless there were

signs of disease progression. Supportive care measures including the use of

transfusions have been permitted during the protocol duration. The dose of 20 mg/day

ginger root extract standardized for approximately 25 % shogaols in form of soft-gel

capsule was administered once a day for up to 12 months.

The diagram of the study protocol:

Low/Intermediate-1 Risk MDS patients

Start Shogaols at a dose of 20 mg/day ginger extract standardized for 25% shogaols

V Evaluate for response in bi-monthly intervals for 6 and 12 months. Continue therapy for

one year or unless disease progression. Responders may continue for as long as they

continue to experience benefit.

The six selected for the study patients were monitored at 2 month intervals for a period

of 6 and 12 months. The study product was disposed in white opaque bottles each 60

capsules. Each bottle with a label indicating: Shogaols 25% (Extract of Zingiber officinale roots) in soft-gel capsules - 20 mg per capsule. Use 1 capsule a day with a meal.

TABLE I. Hematologic results in 6 MDS patients (mean values) receiving daily 20 mg

shogaols 25% per day for 6 months.

TABLE II. Individual ferritin levels (normal=30-300ug/L) in six patients over 6 month

shogaols administration.

TABLE III. Individual ferritin levels (normal = 30-300ug/L) in patients over 6 and 12

month shogaols administration.

TABLE IV. Hematologic and liver function tests data in patient No. 1 during 6 and 12

month shogaols administration.

RESULTS

Administration of ginger root (Zingiber officinale Roscoe) extract standardized for 25%

shogaols for 6 and 12 months 20 mg/day to MDS patients showed no grounds to

discontinue the supplement, with no objective or subjective side effects, and in three out

of six patients a significant reduction in ferritin levels comparing to the baseline levels. In

addition, there was a significant reduction in mean values from 6 patients in the

reticulocyte count and the liver enzyme levels in a selected patient with a highest drop

in ferritin levels. These results with the shogaols therapy have not been previously

reported and provide grounds for the novel use of shogaols as a nutritional and

therapeutic support for patients in need of preventing iron overload and improving iron

homeostasis.

DESCRIPTION OF THE INVENTION

The natural components extracted from ginger (Zingiber officinale) roots, especially

shogaols, show an unexpected and previously unknown properties in regulating iron

homeostasis in hematologic patients and potentially healthy subjects in need of safe

and optimal iron utilization in the body. Shogaols were evaluated for their potential

clinical usefulness in patients with myelodysplastic syndromes (MDS), which may

exemplify iron overload condition and its impact on the overall health. The iron overload

is a common outcome and side effect of frequent blood transfusions, which are required

in hematologic patients to prevent anemia and enhance hematopoiesis. The excess iron

from red blood cells, may result in build-up of free circulating iron ion which generates

reactive oxygen species (ROS) related pathology. The ROS pathology leads to

increased morbidity in MDS patients, e.g. compromised liver and other organs

functions. Without being bound to any particular theory, it is hypothesized that shogaols

which are potent anti-inflammatory compounds may act as hypomethylating agents of

major proteins required to transport iron and may this way ameliorate iron overload. The

other plausible hypothesis is that shogaols may upregulate or downregulate levels of

hepcidin, a liver hormone, which is responsible for decreasing levels of proteins

responsible for iron transport and storage in the body. Shogaols may also prevent iron

caused mutation of genes responsible for expression of Human Hemochromatosis

protein (HFE) which controls transferrin, a major carrier of iron in the body, and prevents

mutation of genes responsible for progression of the hematologic pathology, potentially

acting as the chemopreventive and therapeutic agent. The invention provides shogaols

which in course of 12 months of daily administration to the MDS patients did not affect adversely patients' condition and health, while significantly lowering the following condition-elevated hematologic parameters: ferritin levels, reticulocyte count and liver function tests. In addition, it is proposed that shogaols may contribute to the optimal utilization of iron in healthy individuals.

FORMULATIONS

When used in a preparation for oral administration, and without being bound to a

specific recipe, the shogaols of invention maybe used at a daily dose of approximately

0.1-0.6 mg/kg of body weight, or, alternatively, at a dose of about 5 mg to 50 mg per

day for an average adult. For best therapeutic results the shogaols may be combined

with components from Terminalia chebula fam. Combretaceae, Terminalia bellerica

fam. Combretaceae, Emblica officinalis fam. Euphrobiaceae, Inula helenium fam.

Compositae, Rheum palmatum fam Polygonaceae, Gentiana lutea fam. Gentianaceae,

sodium sulfate, sodium chloride and sodium bicarbonate.

The compositions of the present invention may also include suitable excipients, fillers

and formulations e.g. microencapsulation, nanotechnology which facilitate

gastrointestinal absorption and target tissue and receptor site bioavailability. The

formulation may also include suitable technology for a parenteral delivery system.

The herbal compounds of invention are generally in form of a "Green technology"

solvent-free extraction prepared with the supercritical C02 extraction or adiabatic

extraction with methane or butane. The herbal compounds of invention, e.g. shogaols

can be obtained through a chemical synthesis.

TABLE I

variable Baseline(n=6) Month Month Month 2(n=6) 4(n=6) 6(n=5) Hb (128-175g/L) 115.2+28.7 118+24 117.3+23.5 114+28.2 RCC (4.2- 3.6+1.1 3.7+1 3.7+1 3.5+1.1 6.2x1012 /L) Hct (0.36-0.53) 0.35+0.09 0.36+0.07 0.36+0.08 0.35+0.09 MCV (80-100fL) 98.5+9.5 98.3+8.8 99.2+9.5 100+9.2 MCH (27-32pg) 32.7+3.3 32.6+3.6 32.6+3.6 32.9+3.6 MCHC (310-360g/L) 330.8+13.8 331.5+9.2 328.8+10 328.2+8.9 RDW (10-15) 17.6+5.2 17.9+5.4 17.8+5.3 18.7+5.5 WCC (4-11x109/L) 5.1+1.6 5+2 4.4+1.6 5+2.8 Neut (2-7.5x109/L) 2.1+0.8 2.1+1 1.8+0.9 2+0.8 ALC (1-4x109/L) 2+1 1.7+0.8 1.7+0.8 1.7+1 PItits (150- 191.7+149.8 165.2+163.4 154.3+149 185.4+168 450x109/1L) Retic (20-100) 71.7+53.4 55.6+32.2 56.3+39.6 52.4+27.3 % retic 2.1+1.8 1.5+0.7 1.5+0.9 1.5+0.5 Iron (5-30umol/L) 23.4+7 22+9.3 24.8+9.1 27.1+10.5 Transferrin(2-3.2 2.2+0.5 2.2+0.5 2.2+0.5 2.3+0.3 g/L) TIBC (46-70 umol/L) 47+7.1 47.8+8.4 47.8+7.7 50+7.2 Ferritin (30-300ug/L) 625.7+797.8 517.8+739.5 440+551.1 416.4+378 % saturation (10- 49.3+19.8 48.2+28.8 53.2+24.2 56.2+22.7 45%)

TABLE II

Patient no. Baseline Month 2 Month 4 Month 6 % change from baseline

1 2195 2017 1537 1071 -51

2 222 219 196 275

3 709 379 448 387 -45

4 94 148 114 122

336 139 117 -65

6 198 205 228 227

TABLE III

Pt bsl M2 M4 M6 % ch ps ps Bs12 M2 M4 M6 % ch no. f bsI fr bsl 1 2195 2017 1537 1071 -51 1057 1057 935 967 929 -58 2 222 219 196 275 24 3 709 379 448 387 -45 413 545 664 428 510 390 -45 4 94 148 114 122 30 336 139 117 -65 6 198 205 228 227 15

TABLE IV

BsIl M2 M4 M6 Bs12 M2 M4 M6 % ch fr bsl ferritin 2195 2017 1537 1071 1057 935 967 929 -58 GGT(5- 151 132 132 137 117 116 110 123 -19 50U/L) ALT(5- 80 81 59 43 54 49 39 38 -53 40U/L) AST(10- 70 73 51 48 48 47 37 42 -40 40U/L) Iron (5- 28 17.6 35.7 35.9 39.8 25.5 43.4 27.9 0 30umol/L) TIBC(46- 56 58 54 58 60 56 54 56 0

umol/L) %srn(10- 50 30 66 62 66 46 80 50 0 45%)

Claims

WE CLAIM:

1. A method treating an overload of hematologic iron, comprising administering daily an

effective amount of shogaols to an individual.

2. The method as described in claim 1, further comprising administering daily the

effective amount of shogaols extracted from ginger root.

3. The method as described in claim 2, wherein the amount of ginger root extract is

standardized for a minimum of twenty-five (25) percent shogaols.

4. The method as described in claim 1, wherein the daily amount of shogaols is

approximately 0.1-0.6 mg shogaols per kg body weight administered orally.

5. The method as described in claim 1, wherein the daily amount of shogaols is

administered parenterally.

6. A method as described in claim 1, wherein a preferred amount of shogaols

administered daily is 20 mg.

7. The method as described in claim 6, further comprising administering the effective

amount of shogaols daily to an individual in treatment for a myelodysplastic

condition.

8. The method as described in claim 6, further comprising administering an effective

amount of shogaols daily to the individual in treatment for a myelodysplastic

syndrome.

9. The method as described in claim 6, wherein administering the effective amount of

shogaols daily to the individual decreases serum ferritin.

10.The method as described in claim 6, wherein administering the effective amount of

shogaols daily to the individual decreases reticulocyte count.

11.The method as described in claim 6, wherein administering the effective amount of

shogaols daily to the individual decreases liver enzyme levels.

12.The method as described in claim 6, wherein administering the effective amount of

shogaols daily to the individual regulates serum hepcidin levels.

13.The method as described in claim 6, wherein administering the effective amount of

shogaols daily to the individual hypomethylates major proteins required for

transportation of iron.

14.A method of preventing an overload of hematologic iron, comprising administering

daily an effective amount of shogaols to an individual.

15.The method as described in claim 14, further comprising administering the effective

amount of shogaols daily to an individual in treatment for a myelodysplastic

syndrome.

16.The method as described in claim 13, wherein administering the effective amount of

shogaols daily to the individual decreases serum ferritin.

17.The method as described in claim 13, wherein administering the effective amount of

shogaols daily to the individual decreases reticulocyte count.

18.The method as described in claim 13, wherein administering the effective amount of

shogaols daily to the individual decreases liver enzyme levels.

19.The method as described in claim 13, wherein administering the effective amount of

shogaols daily to the individual regulates serum hepcidin levels.

20.A method treating the overload of hematologic iron, comprising orally administering

the effective amount of shogaols to an adult individual at a dose of about 5 mg to 50

mg per day.

21.The method of claim 19, wherein the effective amount of shogaols is combined with

one or more of components selected from the group consisting of Terminalia chebula

fam. Combretaceae, Terminalia bellerica fam. Combretaceae, Emblica officinalis

fam. Euphrobiaceae, Inula helenium fam. Compositae, Rheum palmatum fam

Polygonaceae, Gentianalutea fam. Gentianaceae, sodium sulfate, sodium chloride

and sodium bicarbonate.

22.A composition for treatment of myelodysplastic syndrome comprising:

polyphenolic compounds extracted from Zingiber officinale Roscoe

standardized for 25%w/w shogaols;

one or more of components selected from the group of Terminalia chebula

fam. Combretaceae, Terminalia bellerica fam. Combretaceae, Emblica officinalis

fam. Euphrobiaceae, Inula helenium fam. Compositae, Rheum palmatum fam

Polygonaceae, Gentiana lutea fam. Gentianaceae, sodium sulfate, sodium

chloride and sodium bicarbonate; and

a pharmaceutically acceptable carrier;

wherein administration of the composition in a daily dose of between

about 5 mg to 50 mg of the extracted polyphenolic compounds for a period of

between six-months to 12-months improves control of elevated hematologic

parameters by decreasing ferritin levels, reticulocyte count and liver function

tests.

23.A method of treating myelodysplastic syndrome comprising administering a

therapeutically effective amount of polyphenolic compounds extracted from Zingiber

officinale Roscoe standardized for 25%w/w shogaols, or a pharmaceutically

acceptable composition thereof, in combination with one or more of components

selected from the group of Terminalia chebula fam. Combretaceae, Terminalia

bellerica fam. Combretaceae, Emblica officinalis fam. Euphrobiaceae, Inula

helenium fam. Compositae, Rheum palmatum fam Polygonaceae, Gentiana lutea

fam. Gentianaceae, sodium sulfate, sodium chloride and sodium bicarbonate.

24.A method of treating myelodysplastic syndrome according to claim 23, wherein the

composition is administered in a daily dose of between about 5 mg to 50 mg of the

extracted polyphenolic compounds for a period of between six-months to 12-months

improves control of elevated hematologic parameters by decreasing ferritin levels,

reticulocyte count and liver function tests.

25.Use of polyphenolic compounds extracted from Zingiber officinale Roscoe

standardized for 25%w/w shogaols for the manufacture of a medicament

composition for the treatment of myelodysplastic syndrome, the composition

comprising polyphenolic compounds extracted from Zingiber officinale Roscoe

standardized for 25%w/w shogaols, in combination with one or more of components

selected from the group of Terminalia chebula fam. Combretaceae, Terminalia

bellerica fam. Combretaceae, Emblica officinalis fam. Euphrobiaceae, Inula helenium fam. Compositae, Rheum palmatum fam Polygonaceae, Gentiana lutea fam. Gentianaceae, sodium sulfate, sodium chloride and sodium bicarbonate; wherein the composition is administered in a daily dose of between about

5 mg to 50 mg of the extracted polyphenolic compounds for a period of between

six-months to 12-months improves control of elevated hematologic parameters

by decreasing ferritin levels, reticulocyte count and liver function tests.

26.An extract from Zingiber officinale Roscoe containing polyphenolic compounds

standardized for 25%w/w shogaols, or a pharmaceutically acceptable composition

thereof, when used in the treatment of myelodysplastic syndrome.

27.The extract of claim 26 or a pharmaceutically acceptable composition thereof, in

combination with one or more of components selected from the group of Terminalia

chebula fam. Combretaceae, Terminalia bellerica fam. Combretaceae, Emblica

officinalis fam. Euphrobiaceae, Inula helenium fam. Compositae, Rheum palmatum

fam Polygonaceae, Gentiana lutea fam. Gentianaceae, sodium sulfate, sodium

chloride and sodium bicarbonate, when used in the treatment of myelodysplastic

syndrome.