EXTENDED RELEASE L-TRI-IODOTHYRONINE SAFELY NORMALIZES KEY ELEMENTS OF MOLECULAR PATHOLOGY IN ALZHEIMERS DISEASE

Abstract

The precise trigger mechanisms for the initiation of Alzheimer's Disease (AD) remain unidentified. However, disturbances to the balance of thyroid hormone begin in the pre-clinical stage of Alzheimer's disease. Key elements of molecular pathology in AD can be correlated with a paucity of thyroid hormone activity in the brain. A method for reversing and/or slowing progression of AD and a method for formulation of a therapeutic agent for AD are presented herein wherein an active form of thyroid hormone, T3, is formulated into an extended release dose and administered to a patient safely normalizing key elements of molecular pathology of Alzheimer's Disease.

Claims

1) A method for preventing and reversing and halting progression of Alzheimer's Disease, the method comprising the steps of: a) providing T3 in a controlled release formulation; and b) administering said controlled release formulation to a human patient.

2) The method of claim 1 further comprising the step of providing T4 in the controlled release formulation.

3) The method of claim 2, wherein the ratio of T4 to T3 is not more than 40 to 1.

4) The method of claim 2, wherein the ratio of T4 to T3 is not more than 40 to 3.

5) The method of claim 2, wherein the ratio of T4 to T3 is not more than 40 to 6.

6) The method of claim 2, wherein the ratio of T4 to T3 is not more than 40 to 9.

7) The method of claim 2, wherein the ratio of T4 to T3 is not more than 40 to 12.

8) The method of claim 2, wherein the ratio of T4 to T3 is not more than 40 to 15.

9) The method of claim 2, wherein the ratio of T4 to T3 is not more than 60 to 15.

10) The method of claim 2, wherein the ratio of T4 to T3 is not more than 60 to 50.

11) The method of claim 1, wherein the formulation is free of gluten.

12) The method of claim 1, wherein administration causes concentration of L-tri-iodothyronine agonist at the thyroid hormone receptors in the brain of the patient are increased to normal levels.

13) The method of claim 1 further comprising maintaining a patient on a lowest therapeutic concentration, wherein the lowest therapeutic concentration is defined as the dose wherein after gradual increase of T3 concentration to the patient, symptoms of AD either lessen or disappear.

14) The method of claim 1, wherein administration results in blood levels of T3 more closely approaching steady state blood levels compared with the administration of an immediate release formulation of T3.

15) The method of claim 1, wherein the patient has TSH levels which are within the normal ranges.

16) The method of claim 1, wherein the patient has TSH levels which are outside the normal ranges.

17) A method for production of a therapeutic agent, the method comprising the steps of incorporating an active ingredient comprising T3 into a controlled release formulation.

18) The method of claim 14 further comprising the step of providing T4 in the therapeutic agent.

19) The method of claim 14, wherein the therapeutic agent is free of gluten.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Although the characteristic features of this invention will be particularly pointed out in the claims, the invention itself and manner in which it may be made and used may be better understood after a review of the following description, taken in connection with the accompanying drawings wherein like numeral annotations are provided throughout.

[0038] FIG. 1 depicts the brain balance of thyroid hormone in a healthy patient.

[0039] FIG. 2 depicts the brain balance of thyroid hormone in Alzheimer's disease.

[0040] FIG. 3A illustrates amyloid precursor protein gene regulation in the normal brain.

[0041] FIG. 3B illustrates amyloid precursor protein gene dysregulation in the Alzheimer brain.

[0042] FIG. 4A illustrates lipid regulation in the normal brain.

[0043] FIG. 4B illustrates lipid dysregulation in the Alzheimer brain.

[0044] FIG. 5A illustrates lipoprotein regulation in the normal brain.

[0045] FIG. 5B illustrates lipoprotein dysregulation in the Alzheimer brain.

[0046] FIG. 6A illustrates microtubular metabolism in the normal brain.

[0047] FIG. 6B illustrates microtubular consequences in the Alzheimer brain.

[0048] FIG. 7A depicts endoplasmic reticulum stress and oxidative stress in the Alzheimer brain without T3 supplementation.

[0049] FIG. 7B depicts endoplasmic reticulum stress and oxidative stress in the Alzheimer brain with T3 supplementation.

[0050] FIG. 8 presents a Venn Diagram showing Alzheimer's disease and hypothyroid dementia as overlap syndromes and shows a list of causes for each condition.

[0051] FIG. 9 is a graph showing transcriptional effects of ERT3 dosing every 48 hours.

[0052] Before explaining the disclosed embodiments of the present invention in detail, it is to be understood that the invention is not limited in its application to the details of the particular arrangement shown, since the invention is capable of other embodiments. Also, the terminology used herein is for the purpose of description and not of limitation.

DETAILED DESCRIPTION OF THE INVENTION

[0053] The therapeutic composition and method described herein is a treatment composition and method for preventing and/or reversing and/or halting progression of Alzheimer's Disease (AD) by introduction of T3 to a human patient via an extended release formulation. Alternately, a low-dose of T3 may be introduced over time. Further a combination of T3 and T4 may be administered. In addition, a method for creation of a therapeutic agent for treating AD is presented.

[0054] A scarcity of thyroid hormone (TH), being 3,5,3-triiodothyronine or T3, is proposed here as a cause of the Alzheimer Dementia Phenotype (ADP). This deficiency may be a primary or a secondary phenomenon. As a primary phenomenon it is, jointly or severally, the primary trigger for the pathogenesis of the phenotypical Alzheimer dementia. As a secondary phenomenon it may occur regardless of the primary cause.

[0055] FIG. 1 depicts the brain balance of steady state of TH in a healthy normal patient. In the healthy brain, the hypothalamus produces thyrotropin releasing hormone (TRH) stimulating the pituitary gland to release thyroid stimulating hormone (TSH). The thyroid gland produces T4 and T3, releasing the hormones into the central circulation via tributaries of the superior vena cava. The ratio of T4 to T3 produced by the thyroid gland ranges from 4:1 to 9:1. Eighty to 85% of the T3 in the peripheral circulation is derived, not from thyroid gland production but, from the peripheral conversion of T4 to T3 by D2. The healthy astrocyte 1 and the healthy neuron 2 are coordinated via control mechanisms to provide the precise and optimum BoTH for a given microanatomic locus and time frame. The astrocyte 1 contains iodothyronine deiodinase type-2 (D2) which converts L-thyroxine (T4) to 3,5,3-triiodothyronine (T3) by outer ring deiodination, thus achieving TH activation. The neuron 2 contains iodothyronine deiodinase type-3 (D-3) which converts T4 to reverse T3 (r-T3) by inner ring deiodination, thus achieving TH inactivation. Thus, in a healthy person, the coordination of activation and inactivation appropriately accommodates the required optimum balance 3 of thyroid hormone (BoTH). Under circumstances requiring maximum activation of thyroid hormone, the balance is then adjusted for maximum activation 4. Maximum activation in the healthy patient is arbitrarily defined here as that which provides sufficient T3 at the nuclear receptors such that 95% or more of the nuclear receptors 5 are occupied by T3.

[0056] FIG. 2 depicts the brain of an Alzheimer's Disease (AD) patient. In the brain, the hypothalamus produces thyrotropin releasing hormone (TRH) stimulating the pituitary gland to release thyroid stimulating hormone (TSH). The thyroid gland releases Thyroxine (T4) which is converted to 3,5,3-triiodothyronine (T3), the active form of thyroid hormone (TH) by iodothyronine deiodinase type-2 (D2). The healthy astrocyte and the healthy neuron are coordinated via control mechanisms to provide the precise and optimum BoTH for a given microanatomic locus and time frame. The astrocyte contains iodothyronine deiodinase type-2 (D2) which converts Thyroxine (T4) to 3,5,3-triiodothyronine (T3) by outer ring deiodination, thus achieving TH activation. The neuron contains iodothyronine deiodinase type-3 (D-3) which converts T4 to reverse T3 (r-T3) by inner ring deiodination, thus achieving TH inactivation. Once Alzheimer's disease progresses to a critical stage, a pathologic astrocyte 6 is no longer able to prosecute the activation reaction 8 utilizing D2 with the required sufficiency. Also, at or prior to this stage the gene for D3 is upregulated in the pathologic neuron 7 increasing the inactivation reaction 9. This upregulation is accomplished by TGF-beta whose effect is increased in AD. With this decrease in TH activation and this increase in TH inactivation, there is serious impairment 10 of the mechanisms for the maintenance of the balance of thyroid hormones (BoTH). As a consequence of the foregoing, the brain is unable to generate a sufficiency of thyroid hormone activation when conditions call for maximum activation 4. As a result, the occupancy of the nuclear thyroid hormone receptors falls below the required 95% 11. This paucity of T3 at the nuclear receptor for TH in AD is the milestone which defines the onset of clinically evident cognitive impairment. As the disease progresses further, the cognitive impairment increases in inverse proportion to the to the percentage occupancy of the nuclear receptors by the progressively decreasing concentrations of T3 in the nucleus. Cognitive impairment is likely profound at a level of receptor occupancy between 85-90%.

[0057] FIG. 3A depicts amyloid precursor protein gene regulation in the face of a normal brain balance of thyroid hormone, namely brain cellular euthyroidism 12. Under these normal conditions of brain cellular euthyroidism 12 thyroid hormone inhibits 13 transcription of the APP gene 14. The result is a restricted quantitative transcription of the APP gene 15. Transcripted APP gene m-RNA is also normal resulting in normal translation of the APP gene m-RNA 16. This results in normal levels of amyloid precursor protein 17.

[0058] FIG. 3B depicts APP gene dysregulation in the Alzheimer brain under conditions of the abnormal balance of thyroid hormone, as referenced in FIG. 2. The cellular hypothyroidism 18 that exists results in a sub-threshold concentration of T3 at the nuclear receptors 19. This results in a loss of inhibition by TH at the APP gene 20. The APP gene upregulates 21. The transcription of APP is increased 22. Translation of APP m-RNA to assemble amyloid precursor protein is increased 23. This results in increased amounts of amyloid precursor protein being produced 24. The cellular hypothyroidism 18 also results in downstream aberrations in APP processing 25 as described in FIG. 4B.

[0059] FIG. 4A depicts normal lipid regulation under conditions of cellular euthyroidism in the normal brain resulting in normal lipid raft structure and function. The prevailing cellular euthyroidism 12 results in normal Seladin-1 gene regulation 26. This leads to the assembly of lipid rafts which have normal composition and function 27. The regulation of the secretase enzymes (alpha, beta and gamma) is normal 28. The secretase enzymes function with normal activity 29. Amyloidogenic cleavage of APP is minimized 30 while non-amyloidogenic cleavage of APP is maximized 31. Consequently normal amounts of beta amyloid are produced 32.

[0060] FIG. 4B depicts the consequences of impaired TH activation in the Alzheimer brain leading to disordered lipid metabolism causing aberrations in the normal physiology outlined in FIG. 4A. TH is a critical modulator of lipid metabolism. Lipid rafts are sub-cellular domains found in the plasma membrane, golgi and lysosomes. The composition of lipid rafts consists of a specific ratio of its constituents including, but not limited to, cholesterol and sphingolipids. Normal lipid raft functions include cleavage of APP (amyloidogenic or non-amyloidogenic) minimizing amounts of beta amyloid produced. The selective Alzheimer disease indicator gene (Seladin-1) protein is believed to be responsible for normal lipid raft composition and assembly. The gene for this protein has been found to be downregulated in regions of the human brain most affected by AD pathology (Ishida (12)). Also considered critical for Seladin-1 gene expression are the TH-beta receptor (TR-B), liver X receptor (LXR-a), insulin-like growth factor-1 (IGF-1), estrogens and androgens. In AD lipid raft composition and function are both abnormal. This is believed to be due to lower Seladin-1 gene expression as a result of the cellular hypothyroidism in the AD brain resulting from the abnormal BoTH. In the presence of cellular hypothyroidism 18 resulting from sub-threshold levels of T3 at the nuclear receptors, the Seladin-1 gene is downregulated 33. This results in abnormal lipid raft composition and function 34. This leads to dysregulation of the activity of the secretase enzymes 35. Alpha secretase activity is reduced 36 resulting in a decrease in non-amyloidogenic cleavage of APP 37. Beta and gamma secretase activity is increased 38 resulting in increased amyloidogenic cleavage of APP 39. The net result is an increase in the production of beta amyloid 40.

[0061] Normal lipoprotein function is considered essential for the breakdown of beta amyloid in the brain and for export of beta amyloid out of the brain. In the case apolipoprotein-E (Apo-E), regardless of subtype, normal TH homeostasis is required for normal Apo-E executive functions to occur. Dyslipidemia causally related to TH is not only found in AD. There is precedent for this phenomenon in the disorder of intermediate density lipoprotein (IDL), known as Fredrickson type 3 hyperlipoproteinemia. In this condition patients who are homozygous for Apo-E2 develop this form of hyperlipoproteinemia when they become hypothyroid, producing excessive amounts of intermediate density lipoprotein (IDL). TH has a shepherding relationship with the lipoproteins, regulating their production and assisting with the discharge of their duties. Thus activated TH/T3 levels are critical. The primary producers of lipoproteins in the brain are the astrocytes and the microglia, both of which sustain progressive damage beginning early in the course of AD. Brain lipoprotein production in AD is compromised on at least two levels, The TH catalyst is compromised because of sub-threshold TH activation. In addition the cells responsible for lipoprotein production, astrocytes and microglia, are incapable of normal function because they are damaged due to the Alzheimer pathology. Certain proteins have been identified as critical for the export of A-B across the blood brain barrier and into the bloodstream. Examples of these transporters are lipoprotein receptor protein-1 (LRP-1) and the ABC transporter proteins such as ABCB-1. Research has shown that the genes for a number of these proteins are upregulated by TH. An additional and important function of the microglia is export of opsonized A-B from the brain. Microglial damage in AD impairs this process. A consequence of these deficiencies, involving the transporter proteins and the microglia, is the impaired transport of A-B across the blood-brain barrier and out of the brain. This produces a bottleneck for A-B exiting the brain.

[0062] FIG. 5A depicts normal lipoprotein regulation in the human brain under conditions of brain euthyroidism. Normal lipoprotein regulation 41 results in normal lipoprotein production and function 42. This is associated with normal function of Apolipoprotein E 43 which results in normal breakdown of beta amyloid 44. Normal lipoprotein production and function is also associated with the normal function of beta amyloid transporters 45 which results in normal transport of beta amyloid out of the brain 46. There is normal brain clearance of beta amyloid 47 and consequently there is no amyloid plaque formation in the brain 48.

[0063] FIG. 5B depicts the consequences of impaired brain TH activation on the lipoprotein physiology referenced in FIG. 5A. Under conditions of brain cellular hypothyroidism, lipoprotein dysregulation 49 occurs. This results in impaired lipoprotein production and function 50. Impaired function of Apo-E 51 occurs which leads to reduced breakdown of beta amyloid 52. Further, there is impaired function of the beta amyloid transporters 53 resulting in reduced transport of beta amyloid out of the brain 54. The net effect of the foregoing is the buildup of beta amyloid in the brain with the deposition of amyloid plaques 55.

[0064] FIG. 6A depicts normal microtubular metabolism under normal conditions of brain cellular euthyroidism 12. Normal genomic regulation by TH of MAP's controls production and regulation of MAP's 56. TH downstream effects 57 on assembly and of assembled microtubules maintains microtubular integrity. Consequently normal microtubular integrity, structure and function are maintained 58. No microtubular hyperphosphorylation or disassembly occurs 59. As there is no microtubular disassembly, there is no microtubular debris and no neurofibrillary tangles 60 form.

[0065] FIG. 6B depicts the physiologic steps shown in FIG. 6A under conditions of the brain cellular hypothyroidism 18 of AD. There is loss of the normal TH genomic control over MAP's 61. The subthreshold levels of TH result in the absence of the salutary downstream effects 62 of TH on microtubular integrity. MAP dysregulation and hyperphosphorylation 63 occur. This leads to a loss of microtubular integrity 64 which progresses to microtubular disassembly 65. This leads to debris which is deposited as neurofibrillary tangles 66.

[0066] FIG. 7A shows the endoplasmic reticulum stress and oxidative stress which are found in numerous disease processes including Alzheimers disease and type 2 diabetes. The endoplasmic reticulum 67 is shown in the schematic together with the mitochondrion 68 and the nucleus 69. Endoplasmic reticulum stress is caused by cellular hypothyroidism, the Thr92Ala polymorphism of D2, as well as conditions unrelated to TH dynamics. Regardless of the cause of endoplasmic reticulum stress, the molecular biologic derangements are complex. One of the most important of these derangements is disruption of the activity of D2 which is resident in the ER. The reason that this is important is that T3 is the most potent physiologic regulator of mitochondrial function, both qualitatively and quantitatively. The disruption of D2 activity eliminates the one remedy for the coexisting oxidative stress and, at the same time, worsens the oxidative stress further. The unfolded protein response (UPR) 70 is a natural cellular stress response related to and triggered by endoplasmic reticulum stress. It is conserved in all mammalian species. The UPR aims at restoring normal function to the cell by halting protein translation, degrading misfolded proteins and activating signaling pathways involved in normal protein folding. In the event that these objectives are not achieved within a certain time frame, the UPR shifts its goal to apoptosis by promoting cell death. Under circumstances of brain cellular hypothyroidism, the UPR lacks the resources to correct the situation. Correction 71 in the ER is minimal and apoptosis 72 is the main outcome.

[0067] FIG. 7B shows endoplasmic reticulum stress and oxidative stress when T3 73 is administered to compensate for the deficient D2 activity in the ER. The schematic shows the endoplasmic reticulum 67 the mitochondrion 68 and the nucleus 69. The supplemented T3 73 is now able to fulfill its' molecular biologic mandate. The UPR 70 triggered is now able to maximize the required correction 71 in the ER and to minimize apoptosis 72. Qualitative and quantitative mitochondrial activity is restored, ameliorating the oxidative stress.

[0068] The noradrenerigic neurotransmitter system is dependent on normal thyroid hormone activity for normal function. A deficient amount of thyroid hormone activity leads to downregulation of the noradrenergic system. This leads to attenuated postsynaptic effects and a failure to prosecute the noradrenergic mandate. In AD this phenomenon accounts for various signs and symptoms. There are aberrations of the diurnal rhythm including insomnia and daytime somnolence. Depression and/or anxiety may occur. Drooping of the upper eyelid (ptosis) is frequently seen in AD. The levator palpebrae superioris muscle, the elevator of the upper eyelid, is partially innervated by the sympathetic nervous system. As a testament to the veracity of the instant invention, administering T3 to patients with AD results in a rapid, within days, and dramatic wide-eyed countenance and an appearance of increased alertness. Rarely, as an additional manifestation of adrenergic dysregulation, skin picking may occur which may be minimized by T3 administration.

[0069] Due to the deleterious effects of low T3/activated TH in AD patients, the instant application is drawn to a method for treating AD, as well as a method of creating a therapeutic agent for treatment of AD, via administration of T3 or L-Triiodothyronine, also known as Liothyronine, or Liothyronine Sodium, known by the brand/trade name Cytomel. Liothyronine (L-Triiodothryonine) and 3,5,3-Triiodothyronine (T3/Activated TH) are nearly identical to one another, but Liothyronine is more potent and better absorbed orally. Liothyronine has been developed into a prescription medication and preparation known as Cytomel, Tiromel, Tertroxin, as well as others.

[0070] Because T3 is a stimulating hormone, excess can lead to cardiac complications which include cardiac hypertrophy, arrhythmias and high output heart failure. Even in the absence of sustained chronic T3 excess, immediate release T3, with its' supraphysiologic post-absorptive plasma levels, may produce cardiac arrhythmias, chiefly supraventricular. Therefore, immediate release T3 is not suitable, especially for older patients. Absorption of T3 (L-triidothryonine or liothyronine) is 90% with peak levels reached one to two hours following ingestion. Serum concentration, or amount of drug in circulation, may rise by 250% to 600%. T3 may have a short half-life being only nineteen hours. Single dose, immediate release T3 ingestion may place a patient at risk for cardiac arrhythmias, chiefly but not limited to supra-ventricular arrhythmias, and potentially other adverse effects. Consequently, the American Geriatric Society has designated desiccated thyroid (containing immediate release T3) as fitting the Beers Criteria, indicating a need for avoidance, or use with caution, in older adults.

[0071] A method for treating AD with T3 being L-triiodothyronine, liothyronine, liothyronine sodium, or similar formulations in an extended release system allows patients to be treated for AD in a safe manner. Extended release caplets or tablets or other suitable vehicle for administration, being via oral, injectable, or other suitable route of administration to a human patient, not limited to a tablet, capsule, gelcap, a powder dispensed in a beverage, orally disintegrating tablet, a vial, ampule, or other container of liquid such as a solution or suspension, a lozenge, lollipop, gum, inhalers, aerosols, injectables, creams, gels, lotions, ointments, balms, eye drops, suppostitories, and patches, with the minimum T3 dose, tailored to the individual patient for body weight and age for instance, being at least 2 g, or at least 5 g, or at least 10 g, or at least 12.5 g, or at least 15 g, or 20 g, or at least 25 g, or at least 30 g per day or higher, overcomes these concerns resulting in lower serum concentration levels. Alternately a drug dispensing device may be implanted either sub-dermally or otherwise and configured to release T3 in a slow manner. The post absorptive blood levels of this extended release T3 could more closely resemble a steady state or constant level of T3 in the blood rather than a high spike in post-absorptive blood levels of the immediate release formulation, thereby avoiding supra-physiologic or high serum concentration of T3 levels in the blood. This tailoring to the individual patient may be achieved by the treating physician making judgments based on the patients' symptoms and signs as well as results of thyroid function tests, as well as T3, T4, and TSH, and/or TH level monitoring.

[0072] A subset of patients taking T3 monotherapy (T3 without T4) will show thyroid function tests (TFT's) which demonstrate an apparently spurious rise in thyroid stimulating hormone (TSH). This occurs because the levels of plasma T3 generated in these patients are insufficient to result in central negative feedback inhibition/suppression of TSH. This central negative feedback inhibition/suppression of TSH is primarily a T4 mediated phenomenon, mediated by T3 only at higher blood levels in some patients. The origin of the apparently spurious rise in TSH is explained here. While the therapeutic T3 level in this subset of patients is too low for central negative feedback inhibition/suppression of TSH, it is not too low to produce negative feedback directly to the thyroid gland. This effect reduces production and secretion of T4 by the thyroid gland. As a consequence, the plasma level of T4 falls, reducing the central feedback inhibition/suppression of T4 on the central apparatus and thus the TSH rises. This phenomenon results in an elevated TSH, suggesting a hypothyroid state, when in fact the patient is euthyroid by virtue of the T3 treatment.

[0073] Therefore, in another embodiment, T3 may be formulated together with T4, or the two may be given in separate formulations at the same time, thereby maintaining T4 levels with a sufficiency such that central negative feedback inhibition is maintained and a normal TSH is preserved. Thus, it is appreciated that the optimum pharmaceutical in the instant case is an extended release formulation of a T4/T3 combination with variable T4/T3 ratios allowing for customized patient formulation. The T4/T3 ratio may be as much as 40:1, or 40:3, or 40:6, or 40:9, or 40:12, or 40:15, or 60:15, or other ratios.

[0074] Extended release formulations and/or delayed-release dosage forms have been used since the 1960s to enhance performance and increase patient compliance while also potentially minimizing unwanted side effects. The dosage forms may comprise those configured to release the active ingredient over a four-hour period, or over an eight-hour period, or a twelve, or twenty-four-hour period, or thirty-six hour period, or even forty-eight hour period. In other embodiments, the unit dosage form may comprise one or more extended-release dosage forms which are configured to release the active ingredient over a period of days. Matrix type extended release systems or diffusion-controlling membranes, or other extended release technologies may be employed. Non-active inert ingredients for drug delivery may be included in formulations.

[0075] Matrix type systems may be based on hydrophilic polymers wherein the drugs and excipients, being non-active inert ingredients, are mixed with polymer such as hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) and then formed as a tablet by conventional compression. Water diffuses into the tablet, swells the polymer and dissolves the drug or active ingredient, whereupon the drug may diffuse out being released into the body. This type of controlled or extended release technology is open to mechanical stress from food substances which may lead to increased release rate and a higher risk of dose-dumping. These systems also require a large amount of excipient and drug loading is comparatively low.

[0076] Diffusion-controlling membranes is another method of obtaining extended or controlled release of active ingredients. With this technology, a core that may be pure active ingredient, or mixture of active ingredient and excipient(s), is coated with a permeable polymeric membrane. Water diffuses through the membrane and dissolves the drug which then diffuses out through the membrane at a rate determined by the porosity and thickness of the membrane. Membrane polymers may be those such as ethylcellulose.

[0077] FIG. 8 is a Venn diagram presenting Alzheimer's disease 74 (AD) and hypothyroid dementia 75 (HD) as overlapping syndromes with a listing of purported etiologies in each category. Circle A 74 represents AD. This is a dementia with symptoms consistent with AD rather than other dementias. It is also a dementia in which elements of thyroid hormone kinetics and dynamics are clearly normal. Circle B 75 represents HD. This may be a dementia resembling AD but with least one key element of thyroid hormone kinetics or dynamics is clearly abnormal. The region of overlap 76 represents dementia consistent with AD but with elements of thyroid hormone kinetics and/or dynamics not clearly definitive one way or the other. Amyloid, or beta-amyloid, scans would be expected to be positive in both AD and HD. Proposed etiologic factors for AD 77 include deficiencies involving estrogen in the female, androgen in the male, liver X receptor (LXR-a) which is a nuclear receptor, insulin like growth factor-1 (IGF-1), which is a downstream growth hormone agonist, multifactorial (involving more than one of the foregoing) and potentially other factors as yet unknown. An important part of the instant invention relates to the chemical moieties mentioned here as proposed etiologic factors in AD. Estrogen is a critical factor in females with AD. The role of testosterone in the male is less clear. LXR-a IGF-1 are also believed to be important, as are other chemical moieties whose role has not yet been correlated with AD causation. These other proposed chemical moieties which are not TH act on the same elements of molecular pathology as have been described for TH in the instant invention. As such they may act as surrogates for TH actions. What this means is that a sufficiency of one or other in a patient susceptible to AD may compensate for an otherwise critical T3 brain deficit. The described method for treatment of AD, and therapeutic formulation presented herein, may also be applicable to HD, other hypothyroid conditions and other thyroid hormone dysregulation syndromes referenced above, including type 2 diabetes mellitus. Hypothyroid sub-categories 78 include primary hypothyroidism, due to thyroid gland insufficiency and including autoimmune thyroiditis, or Hashimotos disease, secondary hypothyroidism due to pituitary dysfunction, tertiary hypothyroidism due to hypothalamic dysfunction, single nucleotide polymorphisms of the iodothyronine deiodinase enzymes and TH receptor aberrations. Further, Celiac disease, with its attendant intolerance to gluten, is a comorbidity of autoimmune thyroiditis, wherein gluten consumption is believed to raise the levels of thyroid autoantibodies in these patients. Hence gluten may be excluded from the formulation of the optimum pharmaceutical for the instant invention.

[0078] With reference to FIG. 9. it has become known that certain compounding pharmacies (University Compounding Pharmacy, San Diego Calif. 92101; personal communication) are using technology which results in release of T3 which takes 2-8 hours to completion. This is not optimal for reasons stated elsewhere. The potency of T3 is such that a more prolonged release profile is preferred. In the event that the release profile suggested below is not technically feasible, then the objectives of the instant invention will still be met completely by a dose reduction and/or a shortening of the dosing interval. The optimum ERT3 release profile for the instant invention could be: [0079] 1. A profile beginning around 2-4 hours and lasting to about 20-24 hours. [0080] 2. A profile that results in physiologic blood levels of T3 which persist for 24-36 hours following dose administration. It has been referenced that the half-life of T3 in humans is 19 hours. [0081] 3. A release profile as in (1) & (2) which results in the lowest possible plasma levels of T3.

[0082] It is now appropriate to delve into the specifics of the art located at the opposite end of the release spectrum, said art constituting a portion of the art of the present invention. This is necessary to answer the following two questions: [0083] 1. What is the maximum dosing interval for ER T3 which accomplishes the goals, genomic and non-genomic, of the present invention? This involves the pharmacokinetics of the pharmaceutical of the instant invention and relates to its plasma half-life. [0084] 2. What is the time period, of the activity of the genomic and non-genomic effects triggered by the formulation of the instant invention, during which these beneficial effects of ER T3 are active? This involves the pharmacodynamics of the pharmaceutical of the instant invention and, for purposes of clarity of discussion here, this will be referred to as the transcriptional half-life.

[0085] It is proposed here that, subject to research confirmation, the maximum dosing interval for the formulation of the instant invention for use in AD is 48 hours. Notwithstanding the fact that confirmatory research may indicate that this maximum dosing interval is longer than 72 hours, the safety margin would not be expected to be further enhanced and the efficacy would be expected to be less. This 48 hour maximum dosing interval may be contrasted with other methods as described in U.S. Provisional Application Ser. No. 62/775,156, of which is claimed priority to and described herein, of the formulation of the instant invention. Thus the preferred dosing for ERT3 for AD may be either once every 24 or once every 48 hours, although this should not exclude other options. This 48 hour maximum dosing interval should be contrasted with that for a different application of the formulation of the instant invention, that for enhanced glycemic control in Type 2 diabetes, where the preferred dosing interval of the pharmaceutical is less, possibly every 12 hours.

[0086] It should be acknowledged that AD and DM often coexist, appearing to create a conflict as to ER T3 dosing. When this occurs, the dose chosen should be at the discretion of the treating physician. It will be appreciated that numerous different controlled release embodiments may be appropriate based on the concepts embodied by the instant invention. This matter is beyond the scope here. The omission of further detail on this tangential matter here does not affect the spirit or scope of the invention. The disadvantages of immediate release T3, which does not represent the art of the present invention, have been explained.

[0087] FIG. 9 is a schematic showing transcriptional effects of ERT3 dosing every 48 hours. The lowest graphic 79 represents plasma levels of the ERT3 pharmaceutical dosed every 48 hours, the X-axis extending out to 96 hours. The middle graphic 80 represents the genomic effect of TH generating the production of m-RNA for the hypothetical protein. The upper graphic 81 represents the translational protein synthesis levels from the m-RNA. It will be noted that according to this hypothetical, the half-life of T3 of 19 hours in combination with the not insignificant transcriptional half-life of T3 depicted here, a continuous and ongoing transcription with associated m-RNA production as well as continuous and ongoing m-RNA translation with the associated protein synthesis are provided. This occurs with dosing either once every 24 hours or once every 48 hours.

[0088] Although the present invention has been described with reference to the disclosed embodiments and example, numerous modifications and variations can be made and still the result will come within the scope of the invention. No limitation with respect to the specific embodiments disclosed herein is intended or should be inferred.

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