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Metadichol A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases

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An estimated 200 million individuals worldwide have a thyroid disorder. Thyroid diseases affect seven times more women than men. People not diagnosed make up the majority of thyroid patients. There is a need to find novel and safe ways to change the underlying disease processes, rather than merely stop excess thyroid hormone production as in hyperthyroidism. Metadichol® is a nano emulsion of an extract of long-chain alcohols from food that is an inverse agonist of VDR (Vitamin D receptor), AHR (Aryl Hydrocarbon Receptor), and RORC (RAR Related Orphan Receptor C). The work presented here shows that Metadichol® is an inverse agonist of THRA (Thyroid Receptor Alpha) and THRB (Thyroid Receptor Beta). Case studies are presented that show how it can safely treat a multitue of thyroid related diseases. Network and pathway enrichment studies are presented that show how Metadichol® may be involved in action on multiple receptors and exerting its effects through multiple pathways. Metadichol® is the first of a breed of molecules that moves the goal post from the concept of ‘one drug, one target’ toward simultaneously targeting multiple targets, that can potentially lead to successful treatment of many diseases. Given the safety profile of Metadichol®, it would not only mitigate thyroid disease but prevent it and reducing the burden on healthcare budgets worldwide.
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Research Article Open Access
Biology and Medicine
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ISSN: 0974-8369
Raghavan, Biol Med (Aligarh) 2019, 11:2
DOI: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Keywords
(Vitamin D receptor) VDR; Metadichol; Nano emulsion; Thyroid
Nuclear receptors; THRA (Thyroid Receptor Alpha); THRB (Thyroid
Receptor Beta); Inverse and Protean agonists; Hypothyroidism;
Hyperthyroidism; Thyroid antibodies; Hashimoto; Graves’ disease
Introduction
Thyroid disease affects about 12 percent of the US population.
While many people with thyroid disease don't even know they have
it, an overactive or underactive thyroid can cause a slew of problems,
including weight gain or loss, mood changes and infertility. In children,
an underactive thyroid can be fatal, which is why they are tested for a
deficiency at birth [1,2].
On a global scale, a staggering 200 million people have problems
with their thyroid glands, with over 50 percent remaining undiagnosed. It
affects women more disproportionately than men. Thyroid hormones are
essential for growth, neuronal development, reproduction and
regulation of energy metabolism. Hypothyroidism and
hyperthyroidism are common conditions with potentially devastating
health consequences that affect all populations worldwide.
The thyroid hormone receptors, THRA and THRB are members of
the nuclear receptor family [3]. The body relies heavily on the thyroid
hormone for digestion, the growth of hair and nails, sex drive, and
metabolism are dependent on the right levels of thyroid hormone for
proper functioning. The thyroid uptakes iodine from diet and converts
it into thyroid hormones.
decrease TSH secretion from the pituitary, and decrease thyroid
hormone synthesis [4].
yroid diseases and treatment
Today four drugs are currently being used for treating thyroid
diseases 3,5 diiodothyropropionic acid, amiodarone, L-triiodothyronine,
Levothyroxine.
Hypothyroidism is a disorder with multiple causes in which the
thyroid fails to secrete an adequate amount of thyroid hormone, this is
the most common thyroid disorder usually caused by primary thyroid
gland failure and may result from diminished stimulation of the thyroid
gland by TSH. Hypothyroidism can be treated with thyroid hormone
replacement drugs. Levothyroxine is a stereoisomer of thyroxine (T4)
which is degraded much slowly and can be administered once daily in
patients with hypothyroidism [5]. Hyperthyroidism results in excess
synthesis and secretion of thyroid hormones by the thyroid gland. e
synthetic form of the T3 hormone, known as liothyronine is sometimes
added to levothyroxine for T4/T3 combination treatment (Table 1).
Hashimoto's is an autoimmune disease, meaning that the immune
system inappropriately attacks your thyroid gland. yroid-attacking
antibodies produced are yroid Peroxidase antibodies (TPO)
and yroglobulin Antibodies (TgAb). Hashimoto disease leads to
conditions that cause inammation and gradual destruction of thyroid
gland over time leading to hypothyroidism.
Received: March 12, 2019; Accepted March 25, 2019; Published April 01, 2019
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid
Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh) 11: 458. doi:
10.4172/0974-8369.1000458
Copyright: © 2019 Raghavan PR. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Metadichol A Novel Inverse Agonist of Thyroid Receptor and its
Applications in Thyroid Diseases
Raghavan PR*
Nanorx Inc, Chappaqua, New York, USA
Abstract
An estimated 200 million individuals worldwide have a thyroid disorder. Thyroid diseases affect seven times more
women than men. People not diagnosed make up the majority of thyroid patients. There is a need to nd novel and safe
ways to change the underlying disease processes, rather than merely stop excess thyroid hormone production as in
hyperthyroidism.
Metadichol® is a nano emulsion of an extract of long-chain alcohols from food that is an inverse agonist of VDR
(Vitamin D receptor), AHR (Aryl Hydrocarbon Receptor), and RORC (RAR Related Orphan Receptor C). The work
presented here shows that Metadichol® is an inverse agonist of THRA (Thyroid Receptor Alpha) and THRB (Thyroid
Receptor Beta). Case studies are presented that show how it can safely treat a multitue of thyroid related diseases.
Network and pathway enrichment studies are presented that show how Metadichol® may be involved in action on
multiple receptors and exerting its effects through multiple pathways. Metadichol® is the rst of a breed of molecules
that moves the goal post from the concept of ‘one drug, one target’ toward simultaneously targeting multiple targets, that
can potentially lead to successful treatment of many diseases. Given the safety prole of Metadichol®, it would not only
mitigate thyroid disease but prevent it and reducing the burden on healthcare budgets worldwide.
        
       
          
         
       
The hypothalamus secretes Thyrotropin-Releasing Hormone
(TRH), that signals the pituitary that releases Thyroid-Stimulating
Hormone (TSH), signaling the thyroid gland to synthesize thyroid
hormones. High thyroid hormone levels will inhibit TRH production,
CEO,
Raghavan PR *Corresponding author
Chappaqua, New York, USA
E-mail raghavan@nanorxinc.com
,
Tel: +19146710224
Nanorx Inc
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 2 of 14
Graves' disease is an autoimmune disorder that causes
hyperthyroidism, or overactive thyroid. is is caused by
overstimulation of the thyroid. Graves’ disease leads to goiter and in
some cases thyroid nodules. is leads to cancer of the thyroids that
is most oen found in nodules in the thyroid gland. Hyperthyroidism
caused by Graves' disease may be treated with the thioamide drugs
propylthiouracil, carbimazole or methimazole, and rarely with Lugol's
solution. Additionally, hyperthyroidism and thyroid tumors may be
treated with radioactive iodine.
yroid cancer almost always involves removal of the thyroid
gland surgically or need Radioactive Iodine treatment (RAI). Patients
aer surgery are hypothyroid and require lifelong thyroid hormone
replacement treatment. In some cases, thyroid diseases and conditions
can have no symptoms at all, such as thyroid cancer or certain types of
thyroiditis.
yroid diagnosis
Diagnosis of a thyroid condition is usually by blood tests or
imaging tests. Blood testing: Levels of (TSH) test, free thyroxine (Free
T4) and free triiodothyronine (Free T3) and TPO, TgAB testing and for
reverse T3 levels. Imaging tests include CT, MRI and ultrasound scans
were carried out to further evaluate the size, shape, and function of the
thyroid gland.
ere is today a paucity of drugs for treating thyroid diseases and
a need for clinically safe molecule. yroid antagonists in general
have dual THRA and THRB activities. Development of selective
THRA and THRB small molecule antagonists has not been considered
clinically relevant. A specic small molecule thyroid antagonist is,
therefore, a desirable goal of the pharmaceutical industry to treat
hyperthyroidism. An increase in circulating thyroid agonists will lead
to hyperthyroidism. Whereas a loss in thyroid receptor gene signaling
leads to hypothyroidism. Compounds exhibiting thyroid antagonism
can cause serious side eects. Drugs amiodarone have thyroid
antagonist properties and can induce hypothyroidism in some people.
yroid and role of cytokines
A thyroid disease is an inammatory state characterized by elevated
cytokines. Modulating cytokine responses hold considerable promise
in the treatment of thyroid diseases [6]. Xinyang et al. showed that
constitutively activated NF-κB pathway also closely links Hashimoto's
thyroiditis with increased incidence of thyroid cancers and inhibition
of NF-κB, showed alone or with other signaling pathway inhibitors
may be of signicant therapeutic benets against aggressive thyroid
cancers [7]. Diez et al. reported that high plasma concentrations of
TNF-alpha and sTNFR-I are seen in patients with hypothyroidism or
hyperthyroidism [8]. Fukazawa et al. showed Intercellular Adhesion
Molecule 1 (ICAM1) in the sera of patients with Grave’s Disease [9].
is feature may be an important factor in the progression of cancer
of the thyroid gland. Similar work was reported by Zhang et al. that
ICAM1 expression is upregulated in PTC (Papillary yroid Cancer)
and in HT (Hashimoto’s disease) [10]. Buitrago et al. showed that
ICAM1 was upregulated in PTC at the levels of both gene and protein
expression. Moreover, this upregulated expression correlated with
aggressive tumor features [11].
Kemp et al. [12] conrmed expression of CCL2 (MCP-1), levels
were associated with serum levels of antithyroid peroxidase (anti-TPO
Ab) and antithyroglobulin antibodies (anti-TG Ab). is was conrmed
by Wahl et al. [13]. Kokkotou et al. [14] showed that serum CCL2 is
increased in women with chronic autoimmune thyroiditis, with family
history of hypothyroidism, suggesting a pathogenetic role for CCL2 in
this condition as conrmed by another study by Didushko et al. [15].
yroid and vitamin D
Research to date suggest the association of vitamin D deciency
with higher incidence of autoimmune thyroiditis [16,17]. More severe
deciency is oen accompanied by thyroid hypofunction [18]. e
levels of 25(OH)D3 seem to be an independent factor inuencing the
presence of TPOAb positivity [19,20].
It has been vitamin D below 12.5 ng/mL is a risk factor for
development of thyroid diseases. Whether supplemented with high
doses of vitamin D is preventive or could have therapeutic eect is
aa (delete aa) still being debate [21]. It has been shown by molecular
modelling studies that 1,25-D has a very high anity [22] for the alpha
yroid Nuclear Receptor (THRA). Since Metadichol® is an inverse
agonist of VDR (Vitamin D Receptor), a thyroid nuclear receptor assay
was carried out. It showed that Metadichol is an interestingly an inverse
agonist of THRA and THRB. Metadichol is also inhibitor of TNF alpha,
MCP1 (CCL2) and ICAM1 [23,24] have a role in thyroid diseases
and presented here are case studies that conrm Metadichol® and its
potential use in mitigating yroid diseases.
Methods
Experimental nuclear receptor assay
Nuclear receptor (NR) assays: e assays were performed by
Indigo Biosciences Inc, PA, USA using their proprietary assay methods.
Plasmids: is study utilized a hybrid receptor comprising the
N-terminal Gal4 DNA binding domain fused to the ligand binding
domain of the specic human nuclear receptor (THRA and THRB).
e reporter vectors used in these studies comprise the rey luciferase
gene functionally linked to either an upstream NR Response Element
(NRE) or the Gal4 activation sequence (UAS).
Compound Handling: Test compound was delivered as solution
dissolved in water. Stock of test compounds was stored at room
temperature.
Set up of NR Assays: e NR Assays were performed as depicted
in Figures 1 and 2.
Step 1: A suspension of Reporter Cells was prepared in Cell
Recovery Medium (CRM; containing 10% charcoal stripped FBS). For
antagonist assays, reporter cells were supplemented with a 2x-EC80
concentration of the appropriate reference agonist. For agonist and
antagonist assays, 100 mL of the reporter cell suspension was dispensed
into the wells of white, cell culture treated, 96-well assay plates. For
agonist and antagonist assays, 2x-concentration treatment media were
prepared.
Step 2: Immediately prior to assay setup, test compounds were
diluted using Compound Screening Medium (CSM; containing 10%
charcoal stripped FBS) to generate '2x-concentration' treatment media.
100 mL of each treatment medium was dispensed into triplicate assay
wells pre-dispensed with Reporter Cells. Assay plates were incubated at
37°C for 24 hours.
TSH T4T3
Hypothyroidism High low low
Hyperthyroidism low high high
Table 1: Typical Thyroid Hormone Levels in Thyroid Disease.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 3 of 14
Step 3: Following the 24 hour incubation period, treatment media
were discarded and 100 all/well of Luciferase Detection Reagent was
added. RLUs were quantied from each assay well to determine NR
activity.
Assay validation
Reference compounds were utilized to conrm the performance
of the specic lot of NR Reporter Cells treated with the Sponsor's test
compounds. Reference compound and test compound assays were
performed at the same time and, hence, were exposed to the same assay
reagents and environmental conditions. Refer to individual data sets
for the identities of specic reference agonist and antagonist and their
respective treatment concentration ranges. Reference groups always
include a 'Vehicle' control to determine background activity in the assay
and to calculate fold activation or percent-inhibition.
Data reduction
Microso Excel was used to manage and archive assay data, as well
as to calculate average RLU values +/- Standard Deviation (SD), Fold-
activation, Percent activation, Percent Coecients of Variation (%CV),
and Z' values. Graphical data methods (Table 2).
Dose Response Curve (DRC) analyses of the reference compounds
and test compounds were performed via non-linear curve-tting of
Fold-activation vs. compound for agonist assays. Percent inhibition vs.
compound for antagonist and inverse agonist assays. Graph Pad Prism
soware was used for calculations (Tables 3-6) (Figures 3-8).
Results of Experimental Assays
Results of case studies
Patient No 1: Male-38 (figures 9-14)
38 year old male with episodes ofsyncope associated withseizure
activity. It all began with a routine Hepatitis B injection and soon aer
he began getting seizures. Neurological tests were normal. Was initially
reated with anticonvulsants Dilantin and Keppra but the seizure
episodes have continued? In addition he suered from double vision,
auras and episodes of dizziness. Most episodes occurred during night
while sleeping. He usually collapses, and is completely unconscious for
a period of time (15-30 minutes) during which time he may or may not
have any movements. He returns to full rational consciousness aer the
end of these seizures. Needed to be hospitalized aer such episodes he
used to feel tired and rests for 1-2 days before he feels normal. He was
nally diagnosed with Hashimoto encephalopathy with elevated levels
of yroid antibodies. Treated with Metadichol @ dosage of 10 mg per
day in addition to other medications and began to show improvements.
ough s eizures c ontinued t he f requency l essened a nd w ith
Metadichol uses so far only mild seizure for 30 seconds and patient
returned to normal aer 10 minutes as opposed to 1-2 days before and
without need to be hospitalized. is improvement was reected in
his biomarkers levels. Patient reports normal blood pressure. Frequent
seizures have decreased and since starting with Metadichol. Patient has
stopped use of all medications. Patient reports he has very energetic
and feels less stressed mentally about his condition.
Patient No 2: Male-83(figure 15)
Male-83, lung cancer patient. Metadichol @ 10 mg per day. Patient
was on chemotherapy and not on any thyroid medications. TSH
levels returned to normal range.
Patient No 3: Female-74 (figure 16)
74 years old female with hypothyroid and co morbidities of
cardiovascular diseases, anemic and weak with low energy levels not on
any Thyroid medication. Patient reports improved energy levels
after use of Metadichol @ 5 mg per day.
Figure 1: Agonist Assays.
Figure 2: Antagonist Assays.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 4 of 14
Percent Coefcient of Variation (%CV) is: 100*(SD/Ave. RLU)
Fold-Activation in Agonist assays is: Ave RLU Test Cmpd/Ave RLU Vehicle
Percent-Activation of Ref Max is calculated by normalizing
test cmpd RLU values to the maximum RLU value of the
reference agonist (=100%), as follows:
100*(Ave. RLU Test Cmpd/Ave RLU Reference maximum)
Z' for Reference Agonists is: 1-[(3*[SD Vehicle + SD Ref Cmpd]) / (RLU Ref Cmpd - RLU Vehicle)]
Fold-Inhibition in Antagonist is: [Ave RLU EC80 agoinst / Ave RLU Test Cmpd]
Percent-Inhibition in Antagonist:
The theoretical minimum inhibition (0% inhibition) derives from EC80 agonist treatment only, no
treatment cmpd. % Inhibition is calculated as:
100*( 1-[Ave RLU Test Cmpd / Ave RLU EC80 agoinst)
Table 2: Graphical data methods.
Compound Conc. Human TRα Agonist Assays, Host cell line: HEK
Luc1 Luc2 Luc3 AVG SD Fold-
Activation %Activation of Refmax % CV
Water 0.20% 386 254 318 319 66 1 0.025 21
Metadichol (mg/mL) 0.0073 342 326 428 365 55 1.1 0.029 15
0.024 328 270 302 300 29 0.94 0.024 9.7
0.081 288 306 354 316 34 0.99 0.025 11
0.27 254 280 282 272 16 0.85 0.021 5.7
0.9 288 266 228 261 30 0.82 0.021 12
3 286 206 204 232 47 0.73 0.018 20
10 224 144 156 175 43 0.55 0.014 25
Reference Agonist:
Triidothyronine (nM) 0.029 526 454 394 458 66 1.4 0.036 14 Z'
0.12 3,335 2,734 2,186 2,752 574 8.6 0.22 21
0.47 72,967 64,891 61,845 66,568 5,748 208 5.3 8.6 0.74
1.9 6,00,780 3,91,861 3,67,490 4,53,377 1,28,235 1,420 36 28 0.15
7.5 10,58,970 8,51,942 8,07,433 9,06,115 1,34,234 2,837 71 15 0.56
30 14,56,630 12,32,700 11,13,220 12,67,517 1,74,332 3,969 100 14 0.59
120 16,47,590 12,56,070 11,46,010 12,01,040 77,824 3,761 95 6.5 0.81
Table 3: Results of TR alpha agonist assays of Metadichol and reference agonist Triiodothyronine.
Compound Conc. Human TRβ Antagonist Assays HEK
Luc1 Luc2 Luc3 AVG SD Fold-Inhibition %Inhibition % CV
Water 0.20% 10,00,450 10,17,700 10,43,760 10,20,637 21,804 1 0 2.1
Metadichol
(mg/mL) 0.0073 9,50,092 9,99,788 10,31,020 9,93,633 40,814 1 2.6 4.1
0.024 9,37,815 10,93,660 11,11,230 10,47,568 95,454 0.97 -2.6 9.1
0.081 9,08,237 9,82,324 10,56,140 9,82,234 73,952 1 3.8 7.5
0.27 9,37,650 9,81,457 10,01,420 9,73,509 32,619 1 4.6 3.4
0.9 7,85,643 7,45,300 7,81,945 7,70,963 22,301 1.3 24 2.9
3 5,14,370 4,67,836 4,85,441 4,89,216 23,496 2.1 52 4.8
10 1,98,260 1,89,334 2,01,774 1,96,456 6,413 5.2 81 3.3
Table 4: TR alpha antagonist assays of Metadichol and reference agonist Triiodothyronine.
Compound Conc. Human TRα Antagonist Assays, Host cell line: HEK
Luc1 Luc2 Luc3 AVG SD Fold-Inhibition %Inhibition % CV
Water 0.20% 8,03,254 8,07,166 8,29,297 8,13,239 14,044 1 0 1.7
Metadichol
(ug/mL) 0.0073 8,71,672 8,70,226 9,68,181 9,03,360 56,142 0.9 -11 6.2
0.024 8,61,060 7,68,219 8,42,466 8,23,915 49,122 0.99 -1.3 6
0.081 7,74,125 8,28,213 8,96,931 8,33,090 61,548 0.98 -2.4 7.4
0.27 7,35,981 8,31,026 7,86,600 7,84,536 47,556 1 3.5 6.1
0.9 6,04,043 6,26,890 6,56,405 6,29,113 26,252 1.3 23 4.2
3 3,53,284 3,32,801 4,17,058 3,67,714 43,943 2.2 55 12
10 89,689 1,14,198 1,08,014 1,03,967 12,746 7.8 87 12
Table 5: TR beta antagonist assays of Metadichol and reference agonist Triiodothyronine.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 5 of 14
Figure 3: Result of TR-alpha assay of standard Triiodothyronine.
Figure 4: Result of TR-alpha agonist assay of Metadichol .
Figure 5: Result of TR-alpha antagonist assay of Metadichol.
Figure 6: Result of TR-beta agonist assay of Metadichol.
Figure 7: Result of TR beta agonist assay of standard Triiodothyronine.
Figure 8: Result of TR-beta antagonist assay of Metadichol.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 6 of 14
Figure 9: TSH levels (mIU/mL).
Figure 10: Total T3 levels.
Figure 11: Free T4 levels.
Compound Conc. Human TRβ Agonist Assays, Host cell line: HEK
Luc1 Luc2 Luc3 AVG SD Fold-Activation % Activation of
Refmax % CV
Water 118 132 154 135 18 1 0.012 13
Metadichol 0.0073 124 120 156 133 20 0.99 0.012 15
(ug/mL)
0.024 144 108 142 131 20 0.98 0.012 15
0.081 110 134 122 122 12 0.91 0.011 9.8
0.27 142 136 120 133 11 0 Compound.99 0.012 8.6
0.9 104 120 148 124 22 0.92 0.011 18
3 106 80 182 123 53 0.91 0.011 43
10 60 68 74 67 7 0.5 0.006 10
Reference Agonist:
Triiodothyronine (nM) 3.3 176 172 174 174 2 1.3 0.015 1.1 Z'
9.9 2,140 1,942 1,652 1,912 245 14 0.17 13 0.55
30 97,190 95,283 81,040 91,171 8,826 677 8.1 9.7 0.71
89 7,92,651 8,52,420 7,91,517 8,12,196 34,840 6031 72 4.3 0.87
267 10,89,770 10,91,930 11,09,530 10,97,077 10,839 8,147 97 1 0.97
800 12,62,850 11,56,450 11,12,770 11,77,357 77,193 8,743 104 6.6 0.8
2400 10,71,220 10,86,870 12,26,570 11,28,220 85,532 8,378 100 7.6 0.77
Table 6: TR beta agonist assays of Metadichol and reference agonist Triiodothyronine.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 7 of 14
Figure 12: Thyroid antibody levels.
Figure 13: Thyroglobulin levels.
TPO (IU/mL)
Baseline
20.1
Week 4
24
Week 8
Less than 0.4
Week 12
Less than 0.4
week 16
Less than 0.4
week 20
20
week 24
6
week 32
less than 0.4
Figure 14: TPOab (Thyroid peroxidase antibodies) levels.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 8 of 14
Figure 15: TSH levels (mIU/mL).
Figure 16: TSH levels (mIU/mL).
Figure 17: TSH levels.
Figure 18: TSH levels.
Patient No 4: Female-51(figure 17)
Female 51 diagnosed with hypothyroidism was not on any yroid
medication. Metadichol® treatment at 5 mg per day. Patient
normalized over 20 weeks.
Patient 5: Female-27(figure 18-19)
Female 27 diagnosed with hypothyroidism. Was not on any thyroid
medication. Metadichol treatment @ 5 mg per day improved TSH
levels. Patient still on Metadichol. Patient reports improved energy
levels (Figures 18 and 19).
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 9 of 14
Patient No 6: Female-27 (figure 20-21)
Female 27 diagnosed with hyperthyroidism. Her doctor prescribed
Carimazol but she opted to use Metadichol. Aer 4 months all her
yroid biomarkers returned normal. She stopped Metadichol use at
10 month and a year later at month 22 her biomarkers are still in
the normal range .
Figure 19: Anti-thyroid peroxidase antibodies serum (IU/mL).
Figure 20: TSH levels (mIU/mL).
Figure 21: FreeT3 and Free T4 levels.
Discussion
e cases presented all showed improvement in all thyroid
biomarkers panel. Metadichol binds to thyroid nuclear receptors both
THRA and THRB but as an inverse agonist. ere are no known inverse
agonists of thyroid nuclear receptors known in literature today. For
inverse agonism to exist there must be constitutive activity present
i.e. receptors are actively signaling in the absence of an agonist [25].
Related to inverse agonism is what is referred to as protean agonism
[26] such ligands display both agonist and inverse agonist properties.
Ecacy of a ligand is depending on the level of receptor constitutive
activity of the receptor in the assay system used. erefore, a partial
agonist in one system can behave as an antagonist or an inverse agonist
in others. For protean agonism to exist there needs to be constitutive
receptor activity i.e. inverse agonism that is seen with Metadichol®.
e results show that it is eective against both hyperthyroidism and
hypothyroidism and normalizing T3, T4 and levels of antiobodies. It
is likely that Metadichol® is behaving as a protean agonist. Metadichol
is also an inverse agonist of other nuclear receptors VDR, AHR (Aryl
hydrocarbon receptor) and RORC (RAR related Orphan receptor C)
[24,27,28].
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 10 of 14
Figure 22: Pathway R-HSA-350864. Regulation of thyroid hormone activity generated by Evinet.
Gene set Number of links Enriched pathways FDR (False Discovery Rate) Reactome pathway
THRA, THRB 321 Regulation of Thyroid hormone 8.60E-292 R-HSA-350864
THRA, THRB 321 Transcriptional regulation of
white adipocyte differentiation 2.20E-112 R-HSA-381340
THRA, THRB 321 Thyroxine biosynthesis 1.40E-82 R-HSA-209968
THRA, THRB 321 Xenobiotics 1.60E-61 R-HSA-211981
THRA, THRB 321 CYP2E1-reactions 3.50E-48 R-HSA-211999
Table 7: Enriched pathways of THRA and THRB generated by EVINET.
With the experimental data of binding to the thyroid receptors use
a web-based program like EviNet [29] to see the network enrichment
analysis of the genes of interest. It allows applicability of genes found
in global network and to connect genes via one various molecular
mechanism. Using these just 2 genes THRA and THRB led to over
100 signicant pathways and the top 5 are shown in Table 7. From this
analysis the enriched Reactome pathways [30] from THRA and THRB
are linked to 321 genes in the network. Figure 22 shows the network of
genes involved with regulation of thyroid hormone pathway with a
FDR (False Discovery Rate) value of 8.6 E-292.
DIO 1: It catalyzes the activation, as well as the inactivation
of thyroid hormone. Responsible for the deiodination of T4
(3,5,3',5'-tetraiodothyronine) into T3 (3,5,3'-triiodothyronine) and of
T3 into T2 (3,3’-diiodothyronine) which is inactive.
DIO 2: Catalyzes the conversion T4 to bioactive T3. It has an
essential role in providing the brain with appropriate levels of T3 during
the critical period of development.
DIO 3: Responsible for the deiodination of T4 into RT3
(3,3',5'-triiodothyronine) and of T3 into T2 (3,3'-diiodothyronine).
RT3 and T2 are inactive metabolites.
e network clearly shows how genes DIO 1, 2 and 3 play a role in
maintaining appropriate levels of T3 and T4 in regulating the thyroid
hormone pathway. It is clear that binding to both THRA and THRB is
important in enhancing the thyroid pathway. Metadichol® binding to
thyroid nuclear receptors leads to control of TSH and also T3 and T4
levels.
e second pathway that is enriched is transcriptional regulation of
white adipocyte dierentiation. e adipose tissue is targeted by thyroid
hormones as this tissue is where energy stored and acts as a regulator
of energy balance, and modulating signals to maintain metabolic
control. yroid hormones regulate the gene markers of dierentiation
of adipocytes, lipogenesis, lipolysis, and thermogenesis in the adipose
tissue [31].
Research work on use of selective agonist of THRB in lipid
related disease though the results have been disappointing [32].
Metadichol also binds to VDR, AHR and ROR gamma as inverse
agonists. Given the cross talk that occurs between various nuclear
receptors a connected network of nuclear receptors [33] can be
generated using a soware like Innate DB [34-36] a database of genes,
proteins, experimentally-veried interactions and signaling pathways
involved in the innate immune response of humans. is is shown
in Figure 23. e numbers in the gure are known nu clear receptors.
What we see is binding to multiple receptors leads to activating other
nuclear receptors in this case 37 out of 48 known in humans. Binding
and or activation of these nuclear receptors leads to gene transcription
and leads to many pathways and thus many targets. Metadichol® has
already been shown to impact many diseases through a multidue of
pathways [37].
A macro level interaction network of TNF alpha, ICAM1 and the
nuclear receptors VDR THRA, THRB is shown in Figure 24. is was
generated using pathway commons [38]. VDR controls the expression
of THRA that interacts with THRB [39]. A more detailed interaction is
shown in Figure 25 generated by using InnateDB soware.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 11 of 14
Figure 23: Network of Nuclear receptors AHR, VDR, THRA, THRB and RORC.
Figure 24: Interaction network of thyroid related gene cluster.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 12 of 14
Figure 25: Interaction Network of TNF, ICAM1, CCL2, VDR, THRA, THRB.
Figure 26: Gene cluster; THRA, THRB, VDR, ICAM1, TNF, CCL2 and the resulting disease network.
Citation: Raghavan PR (2019) Metadichol® A Novel Inverse Agonist of Thyroid Receptor and its Applications in Thyroid Diseases. Biol Med (Aligarh)
11: 458. doi: 10.4172/0974-8369.1000458
Volume 11 • Issue 2 • 1000458
Biol Med (Aligarh), an open access journal
ISSN: 0974-8369
Page 13 of 14
Further analysis was carried out using a program like ToppCluster
[40] a multiple gene list feature enrichment analyzer for the dissection
of biological system. is cluster of six genes (TNF, ICAM1, CCL2,
VDR, THRA, THRB) target all the thyroid related diseases as shown
in Figure 26. Drugs are more eective if they are modulating multiple
genes [41]. All diseases need complex therapeutic approaches. In this
respect, as shown above Metadichol ® hits multiple genes belonging to
a network of interacting targets and thus has enhanced and ecacy
and an enormous advantage when compared to a single-target drug
or a combination of multiple drugs [42,43]. Compared to drugs uses
in treating diseases Metadichol is a safe and eective nutraceutical to
mitigate yroid related diseases.
Conclusion
Diseases generally are not the result of a single malfunctioning gene
or a single malfunctioning pathway. ere are m any genes that a ect
the same disease and need to tackle though multiple pathways. e
concept of one gene, one disease and one drug are no longer a viable
approach. us, there is a need to t arget nuclear receptors which is
the operating system of our body. Binding to vitamin D receptor for
example is known to aect over 2900 genes and the same is the case with
other nuclear receptors. e reason that we have failed to address many
diseases adequately in the past was the lack of information regarding
how genes are related to each other. Today a vast amount of information
is at our nger tips. e key to every biological problem must nally be
sought in the cells nucleus containing the 48 nuclear receptors which
leads to expression of thousands of genes and pathways all interlinked
and a road map to a better understanding of diseases and pathways and
clues to our understanding human biological process.
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