Seizure and migraine treatments using denosumab   

Abstract: Therefore, denosumab reduces seizure and migraine risk. 4) Denosumab reduces Ca++ released from bone. 3) Conversely, reducing Ca++ released from bone reduces seizure and migraine risk. 2) Increased Ca++ released from bone increases seizure and migraine risk by a) depolarization of nerve membranes, b) enhanced calcium channel mediated neurotransmitter release and increases muscle contractility by c) enhanced neurotransmitter release at the neuromuscular junction and d) enhanced removal of the tropomyosin block between actin and myosin. 1) Known seizure and migraine triggers increase osteoclast mediated release of Ca++ from bone. A novel pathogenesis underlying certain types of seizures and migraines is disclosed and the validated set of premises presented enable the deductive conclusion to be made that drugs that reduce the amount of calcium ions (Ca++) released from bone reduce seizure and migraine risk. The premises validated as true in the specifications include:

This application is a divisional of application Ser. No. 12/322,764 filed on Feb. 6, 2009, which in turn was a continuation of application Ser. No. 11/975,465 filed on Oct. 19, 2007. Application Ser. No. 12/322,764 disclosed the etiology underlying certain types of seizures and migraines, which had not previously been known. The disclosures in turn provided enablement to make a broad set of valid claims using deductive reasoning. In deductive reasoning, the conclusion follows necessarily from the premises and the conclusion is true, provided the premises are true. The premises validated as true in the specifications of the parent application were: 1) known seizure and migraine triggers increase osteoclast mediated release of Ca++ from bone 2) increased Ca++ released from bone increases seizure and migraine risk 3) Conversely, reducing Ca++ released from bone reduces seizure and migraine risk.

Under deductive reasoning, the conclusion that necessarily follows is that: 4) Therefore, drugs that reduce Ca++ released from bone reduce seizure and migraine risk.

Under patent office practice, each application is limited to a single drug for examination. The claims of the parent application were restricted to raloxifene. This divisional application restricts the claims to denosumab.

Not Applicable.

Not Applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to compositions and methods for the treatment of seizures and migraines.

2. Description OF RELATED ART

The etiology of headaches, migraines, and most seizures has eluded prior art researchers. The novel etiology/pathogenesis provided in instant application ties all three together to a common underlying etiology. Novel etiology/pathogenesis based treatment methods for seizures and migraines are disclosed, versus prior art\'s symptom/observation based treatment methods.

Many prior art theories have been proposed, related to both migraines and seizures, however none have been able to account for all of the observed symptoms and diagnostic test results. Instant application provides a novel etiology and underlying pathogenesis which accounts for the disparate observations.

In summary, present invention discloses that oscillations in endocrine levels (e.g. estrogen, testosterone, prostaglandins, the active form of vitamin D, and others) alter the bone micro environment (i.e. osteoclast and/or osteoblast activity) in a manner the results in release of calcium (Ca2+) from the bone into the extracellular fluid, which in turn alters the nerve micro environment (via nerve membrane depolarization, enhanced neurotransmitter release at the synapse, and post tetanic potentiation) and alters the muscular micro environment (via enhanced neurotransmitter release at the neuromuscular junction and via enhanced muscular contractility). Any of the underlying endocrine oscillations mentioned above will result in the same pathogenesis and often multiple endocrine oscillations can occur simultaneously, contributing to the severity of the resulting migraine or seizure.

In contrast, prior art theories are based on localized observations, and as such cannot adequately explain the full spectrum of observed effects. Many different prior art theories exist.

Because it is estimated that two thirds of the world\'s 300 million migraine sufferers are women aged 15 to 55, suggesting estrogen plays a role, (Dodick and Gargus, “Why Migraines Strike”, Scientific American, August 2008, p. 58) a large part of the migraine discussion in this application is focused on comparing the novel pathogenesis presented under present invention to the large body or prior art work done on menstrual cycle related migraines. However, the same pathogenesis applies to seizures in people with low seizure thresholds as well as the same pathogenesis occurs in other endocrine—bone microenvironment mediated seizures and migraines.

Premenstrual Headaches: For purposes of present invention, premenstrual headaches are meant to loosely refer to the following set of symptoms, as described by one sufferer. The headache starts the day before the start of menstrual bleeding and lasts until the start of menstrual bleeding. The headache first manifests as a low level headache and ramps up over several hours into persistent, intense pain that in not at the very back or very front of the head and is accompanied by a hypersensitivity to sound. The headache may be accompanied by nausea and irritability. The sufferer prefers a dark, quiet room and going to sleep, as the headache is gone by the next morning at the start of menstruation.

Premenstrual Migraines: Premenstrual migraines are pulsating in nature, are often one sided, and may be more focused toward the front of the head. Migraines commonly occur before and during menstruation and may last from several hours to three days. Migraines have been associated with irritation of the trigeminal nerve (in the face), a spreading depolarization in brain, low serotonin levels in the brain, and vasoconstriction in the brain.

Prior art attention to premenstrual headaches is minimal, and prior art treatment methods are minimal. The entire Medscape article on managing premenstrual syndrome (Moline and Zendell, “Evaluating and Managing Premenstrual Syndrome”, 2000, Medscape) has only a single sentence relating to treatment of premenstrual headaches which reads: “Women with premenstrual headaches should try any of the common nonprescription analgesics (aspirin, acetaminophen, ibuprofen) at the onset of the headache.”

Prior art has given considerably more attention to premenstrual migraine headaches and numerous observations and theories about both migraines and premenstrual migraines exist.

One of the first theories to explain migraines was the classic theory of vasoconstriction/vasodilation—more specifically that migraines were caused by constriction of blood vessels in the brain, followed by dilation. Brain studies during migraine have shown that blood flow to the brain is abnormal.

The theory of hyper excitability built on the idea of vasoconstriction/vasodilation by adding that migraine sufferers were extra susceptible to normal triggers, such as stress. During periods of excitability, more calcium flows from extracellular fluid to intracellular space, resulting in vasoconstriction. This theory was bolstered by studies that calcium channel blockers could prevent migraine.

Irritation of the trigeminal nerve has also been implicated in migraines. Activation of the trigeminal nerve by compounds such as nitroglycerine or capsaicin triggers migraines, lending credence to the involvement of the trigeminal nerve in migraine headaches.

A spreading area of depolarization in the cortex has also been associated with migraines, which may begin 24 hours before an attack, with the onset of the headache occurring around the time of the largest area of the brain is depolarized.

Serotonin has also been implicated in migraines, as serotonin levels in the brain are low during migraines. This theory is bolstered by the fact that serotonin agonists, such as triptans, can provide pain relief.

Although no single theory exists under prior art to explain migraines, numerous treatments exist, that provide varying degrees of relief. Migraine medications include serotonin agonists, nonsteroidal anti-inflammatory drugs, combinations of over the counter pain killers, ergot alkaloids, corticosteroids, botox injections, opiate analgesics, lidocaine applied in the nasal cavities, magnesium, butterbur root, feverfew, riboflavin (vitamin B 2), coenzyme Q10, and S-adenosyl-L-methionine.

Menstrual migraines are more specifically tied to the ovulation cycle, and are triggered during declining estrogen levels, although some women are thought to suffer migraine from the progesterone decline.

A comprehensive synopsis of prior art work related to ovarian hormones and the pathogenesis of menstrual migraine is contained in the Martin and Behbehani article enclosed under IDS (Martin V T MD and Michael Behbehani, PhD, “Ovarian Hormones and Migraine Headache: Understanding Mechanisms and Pathogenesis—Part I”, ©2006 Blackwell Publishing, Medscape Jan. 26, 2006). Migraines are 3 times as common in women than in men and migraine attacks are commonly triggered by declines in serum estrogen levels. Accordingly, prior art menstrual migraine research is focused on ovarian hormone effects on A) serotonergic, B) noradrenergic, C) glutamatergic, D) GABAergic, and E) opiatergic systems, as disclosed in the article. The article then considers other possibilities, focusing on ovarian hormone effects on specific structures relevant to migraine headache such as meningeal arteries and the trigeminal nerve. A synopsis of the prior art synopsis is provided for reference:

A) Serotonergic. Serotonin (5-hydroxytryptamine; 5-FIT) is a neurotransmitter that acts on seven distinct families of 5-HT receptors (5-HT1 to 5-HT7) and each receptor has multiple subtypes. Under prior art “Substantial evidence exists to suggest that the serotonergic system is important in the pathogenesis of migraine headache. A positron emission tomography (PET) study demonstrated increased serotonin synthesis capacity throughout all regions of the brain in migraine patients as compared to controls. Medications which are agonists of the 5-HT1B, 5-HT1D, and 5-HT1F receptors are efficacious abortive treatments for migraine headaches” (Martin and Behbehani).

Prior art has also demonstrated that estrogen effects serotonin by three pathways. First, estrogen treated monkey showed a nine-fold increase in tryptophan hydroxylase (TPH), the rate-limiting enzyme in synthesis of serotonin. Second, the serotonin reuptake transporter (SERT) removes serotonin from the synaptic cleft to terminate serotonergic transmission. Short term estrogen treatment of monkeys decreased amounts of SERT mRNA and longer treatments led to increased amounts of SERT mRNA. Third, monoamine oxidases, the primary enzymes that degrade serotonin, were reduced in monkeys receiving estrogen. Less compelling evidence suggests estrogen/progesterone combinations may modulate gene expression and binding potentials of serotonin receptors.

B) Noradrenergic System. The Martin and Behbehani article discloses that estrogen has been shown to up-regulate production of noradrenaline by up-regulating gene expression of tyrosine hydroxylase, a rate-limiting step in the production of noradrenaline. Studies also exist to show that estrogen may effect various subtypes of adrenoreceptors. The article also discloses that noradrenaline levels are decreased in migraineurs during headache free periods, suggestive of a state of chronic sympathetic hypofunction. Other studies imply that estrogen alone reduces central sympathetic activity, but the addition of progesterone may actually increase sympathetic tone. C) Glutamatergic System. Glutamic acid is the major excitatory neurotransmitter in the central nervous system (CNS). The studies reviewed by Martin and Behbehani indicate that estrogen is a significant facilitator of the glutamatergic system and that certain effects can be attenuated by addition of progesterone. D) GABAergic System: GABA is the major inhibitory neurotransmitter in the CNS. In vitro studies indicate that both estrogen and progesterone modulate GABAergic neurons. In vivo, women with premenstrual dysphoric disorder (PMDD) demonstrated increased cortical GABA during luteal phase (when both estrogen and progesterone levels are high) when compared to follicular phases (when estrogen is high but progesterone is low). The control group showed the opposite results with higher GABA levels in the follicular phases than the luteal phases. E) Opiatergic System: The opiatergic system is important for pain control and regulation of reproductive behavior. Estrogen has been shown to increase levels of spinal cord enkephalin and enhance neuronal responsiveness of certain opioid receptors.

The article also covers other prior art theories by reviewing effects of ovarian hormones on specific structures relevant to migraine headaches.

Trigeminal Nerve: The trigeminal nerve is know to be involved in migraine headaches. The effects of ovarian hormones on the trigeminal nucleus caudalis (TNC) have been well studied. Animal model data show greater response magnitude and response duration of TNC neurons (i.e. enhanced sensitivity) is observed when estradiol and progesterone levels are high. It should be noted this is inconsistent with a premenstrual migraine, as falling levels of both hormones would predict reduced sensitivity of the TNC. However, TNC hypersensitization is consistent with falling estrogen levels under the novel etiology provided in present invention.

Brainstem Nuclei: The Martin and Behbehani article also postulate that ovarian steroids could potentially modulate neurotransmission within the brainstem nuclei to account for the increased blood flow to the dorsal pons observed on PET scans during spontaneous migraines.

Autonomic Nervous System: Estrogen alone reduces central sympathetic activity, reducing heart rate and sympathetic tone, while increasing parasympathetic tone. Addition of progesterone increases sympathetic tone. Chronic sympathetic hypofunction during headache-free period has been suggested in 10% to 15% of migraineurs.

Vascular Endothelium: Estrogen produces vasodilation through endothelium-dependent and non endothelial dependent mechanisms. The article suggests TNC sensitization by vasodilation of meningeal arteries.

Cortex: The anterior cingulate and insular cortices are activated on PET studies during a migraine attack. The article suggests ovarian steroids may modulate migraine on a cortical level.

Prostaglandin levels have also been associated with premenstrual/menstrual conditions, however, under prior art, the focus has been on the relation of prostaglandins and primary dysmenorrhea (menstrual cramping). Women with primary dysmenorrhea have increased activity of the uterine muscle with increased contractility and increased frequency of contractions. Cramping associated with dysmenorrhea usually begins a few hours before the start of bleeding and may continue for a few days. Prior art dysmenorrhea treatment methods center around prostaglandin inhibition. Prostaglandin levels have been found to be higher in women with severe menstrual pain than in women who experience mild or no menstrual pain. Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthesis can provide relief and include drugs such as Naproxen, Ibuprofen, and Mefenamic Acid. However, many NSAIDs can cause gastrointestinal upset as a side effect and COX2 inhibitors are sometimes prescribed instead. Oral contraceptives are effective in preventing dysmenorrhea as they suppress ovulation and menstruation.

According to the Epilepsy Foundation, recurring seizures are generally a symptom of epilepsy and in about 70% of people with epilepsy, no cause can be found. In the remainder, causes include head injuries, brain damage from hypoxia at birth, brain tumors, lead poisoning, genetic conditions such as tuberous sclerosis, and infections such as meningitis or encephalitis. The intermittent burst of electrical activity are much more intense than usual and may occur in just one area of the brain (partial seizures) or may affect nerve cells throughout the brain (generalized seizures). Seizures are often associated with sudden and involuntary contraction of a group of muscles.

The “Seizure Threshold” concept holds that “everyone has a certain balance (probably genetically determined) between excitatory and inhibitory forces in the brain. The relative proportions of each determine whether a person has a low threshold for seizures (because of the higher excitatory balance) or a high threshold (because of the greater inhibition). According to this view, a low seizure threshold makes it easier for epilepsy to develop, and easier for someone to experience a single seizure.” (Epilepsy Foundation, http://www.epilepsyfoundation.org/about/science/index.cfm, provided under IDS). Prior art anti-seizure medications work by modulating the balance between these excitatory and inhibitory forces in the brain.

Seizures, and the prior art drugs used to treat them, will be reviewed in light of the novel etiology/pathogenesis of present invention for consistency.

SUMMARY

The present invention discloses a novel underlying etiology/pathogenesis that results in headaches, migraines, and seizures. The present invention will explain the prior art observations in context of the new pathogenesis and will explain why prior art drugs used to treat migraines and seizures are consistent with the pathogenesis of present invention. Based on the novel disclosures, novel, more potent etiology based treatment methods are provided.

More specifically, present invention discloses that changes in certain endocrine levels result in alterations in the bone micro environment which in turn results in elevated extracellular calcium concentrations which in turn result in hypersensitization of nerves and hypercontractility of muscles that result in headaches, migraines, and increased seizure risk in people with low seizure thresholds. The present invention will cover several common endocrine oscillations (estrogen, testosterone, prostaglandins, 1.25 Vitamin D) and disclose the resulting pathogenesis that leads to alterations in the nerve and muscle micro environments that result in headaches, migraines, and seizures. Based on the disclosures provided, novel treatment methods that focus on modulating the bone microenvironment as a treatment for seizures and migraines will be provided.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows estrogen levels during the ovulation cycle.

FIG. 2 shows estrogen\'s effect of “reservoiring” and “release” of calcium and growth factors (via osteoclast population density modulation) during the ovulation cycle

FIG. 3a shows the region of the brain where the somatosensory and auditory cortex are located and

FIG. 3b shows the mapping of peripheral sensory nerves to the somatosensory cortex.

DETAILED DESCRIPTION

Prior art has focused on numerous possible pathophysiologies for migraines, yet no single prior art theory can explain all of the symptoms and observations. Prior art does not know what causes 70% of seizures.

In contrast, present application presents a single underlying event that occurs, which in turn effects several physiological systems, which in turn accounts for all of the symptoms and observations.

The present invention discloses how common endocrine oscillations (e.g. estrogen, testosterone, prostaglandins, 1.25 vitamin D) can alter the bone microenvironment, which in turn results in a transient elevation in Ca2+ levels, which in turn results in hypersensitization of nerves and muscles that result in headaches, migraines, and seizures.

Novel treatment methods are then provided that target the underlying etiology/pathogenesis.

Because the underlying pathogenesis of present invention starts with the oscillation in the endocrine levels affecting the bone micro environment, a brief background of the bone micro environment is provided for reference.

Normal bone undergoes a continual remodeling process that essentially replaces the entire skeleton every 10 years. Remodeling is mediated by two cell types, osteoclasts which dissolve bone (resorption), and osteoblasts which are the bone builders. Both cell types come together in three to four million remodeling sites scattered throughout the skeleton. During childhood and adolescence, bone formation proceeds at a faster rate than resorption. By around age 40 bone resorption begins to outpace bone formation and bone thinning begins to manifest. On average, women attain a peak bone mass that is about 5% below that of a man, so they have less “in the bank” to start with at the onset of age related bone loss. For this and other reasons, risk of osteoporosis (literally “porous bone”) is greater in women, who account for 80% of cases.

Osteoblasts (the bone building cells) secrete collagen and other bone proteins creating a matrix onto which calcium, phosphorous, and other minerals crystallize (˜90% of bone mass), which removes calcium from extracellular fluid and blood circulation. Osteoclasts (the bone dissolving cells) secrete both proteolytic and hydrolytic enzymes and hydrochloric acid that result in destruction of the bone\'s protein matrix, which results in mobilization of calcium, phosphorous, and bone resident growth factors, into the extracellular fluid. The cyclicality of bone destruction followed by bone building appears to be an important aspect required for maintenance of bone density. Intermittent administration of parathyroid hormone (PTH), which increase osteoclast activity, results in an eventual increase in bone mass (whereas continued administration results in bone loss).

In addition to providing structural support and organ protection, bone serves as a repository of calcium and is used to maintain serum calcium concentrations. The average adult human body contains 13 kg of calcium of which 99% is contained in bones and teeth, 1% in cells of soft tissue, and 0.15% in the extracellular fluid. Normal serum plasma levels of calcium range from 8.0 to 10.8 mg/dl (2.2 to 2.7 mmol/L) with 40%-43% bound to plasma proteins, 5%-10% combined with anions such as phosphate and citrate to form non ionized complexes, and the remaining 40%-50% being free ionized calcium. Because of the large reservoir of bone calcium (i.e. 99%), versus the extremely small extracellular amount (i.e. 0.15%), perturbations resulting in the release of reservoired bone calcium have the potential for profound transient effects on extracellular calcium concentrations.

The primary hormone responsible for increasing serum concentrations of calcium is parathyroid hormone(PTH) and the primary hormone responsible for reducing serum concentrations of calcium is calcitonin, which is produced by the parafollicular cells of the thyroid. When calcium sensors in the parathyroid gland detect low serum calcium concentrations, production of PTH is upregulated, resulting in upregulated osteoclastic activity and increased renal reabsorption of calcium. High serum calcium concentrations result in upregulated production of calcitonin, resulting in decreased osteoclastic activity and up to a 5 fold increase in renal excretion of calcium.

In addition to calcium, phosphorus and various growth factors are also stored in the bone, and are mobilized into the extracellular fluid by osteoclast activity. The calcium to phosphorous ratio in bone is 2.5 to 1 and phosphorus is involved in numerous physiological processes including transport of cellular energy via adenosine trisphosphate (ATP), phosphorous is important for key regulatory events such as phosphorylation, and phospholipids are the main structural components of cellular membranes. Phosphorous is also used in maintenance of extracellular/intracellular ion concentration gradients via transmembrane ATPase pumps. Growth factors that are stored in bone and liberated by osteoclast activity include platelet-derived growth factors (PDGF), fibroblast growth factors (FGF), insulin like growth factors (IGFs) I and II, transforming growth factor-beta (TGF-beta), endothelin 1 (ET-1), urokinase type plasminogen activators, and others. The growth factors released from bone are potent mitogens. PDGF and FGF are mitogens that stimulate progression of many cell types through the early part of the G-1 Phase and IGF-1 and IGF-2 are potent mitogens that promote cell progression through the later part of the G-1 Phase. It is believed the release of these growth factors plays a crucial role in stimulating osteoblast development, required for bone rebuilding.

Osteoblasts arise from osteoprogenitor cells located in the bone marrow and periosteum. Osteoprogenitors are induced to differentiate under the influence of growth factors, including the bone morphogenic proteins (BMPs), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β).

Osteoclasts arise through the differentiation of macrophages. Osteoclasts are regulated by several hormones including PTH from the parathyroid gland, calcitonin from the thyroid gland, estrogen, vitamin D, and growth factor interleukin 6 (IL-6). Osteoclast population density is modulated by three molecules produced by osteoblasts—two that promote osteoclast development and one that suppresses osteoclast development. The two osteoclast promoter molecules are 1) macrophage colony-stimulating factor that binds to a receptor on macrophages inducing them to multiply and RANKL (receptor activator of NF-kB ligand) that binds to a different receptor (RANK receptor) inducing the macrophage to differentiate into an osteoclast. The molecule that inhibits osteoclast formation is osteoprotegerin (OPG), which blocks osteoclast formation by latching on to RANKL and blocking its function.

Osteoclast activity is modulated by various compounds through the following pathways.

PTH interacts with its receptor on osteoblasts to upregulate production of RANKL, which upregulates macrophage differentiation into osteoclasts. Additionally, PTH increases calcium reabsorption by the renal tubules and stimulates conversion of vitamin D to its active form (calcitriol).

Calcitonin receptors have been found in osteoclasts and osteoblasts and single injections of calcitonin result in the loss of the ruffled osteoclast border responsible for resorption of bone and a marked transient inhibition of the ongoing bone resorptive process. Calcitonin also increases renal excretion of calcium by decreasing reabsorption by the kidneys and evidence exists that it reduces absorption of calcium in the gastrointestinal tract.

Estrogen has a “triple whammy” (Rosen C J, “Restoring Aging Bones”, Scientific American, March 2003) effect in inhibiting osteoclast activity by binding to osteoblasts and 1) increasing their output of OPG and 2) suppressing their RANKL production. In addition, estrogen appears to prolong lives of osteoblasts while simultaneously 3) promoting osteoclast apoptosis. As estrogen levels drop after menopause, these “brakes” on osteoclast inhibition are removed, tipping the balance in favor of osteoclast dominated bone destruction which results in osteoporosis.

Androgens also have an inhibitory effect on bone resorption, and studies suggest that this occurs through local aromatization of androgens into estrogen, however direct androgen interactions with androgen receptors(AR) related to bone remodeling have been observed in animal models.

Vitamin D is a steroid-like chemical that promotes osteoclast activity by binding to vitamin D receptors (VDR) in osteoblasts and upregulating expression of RANKL. Vitamin D also enhances intestinal absorption of calcium and enhances renal retention of calcium.

Serum estrogen levels vary throughout the ovulation cycle as shown in FIG. 1, which is excerpted from a reference text graph of ovulation hormone levels (Biochemical Pathways, edited by Gerhard Michal, Wiley & Sons, 1999, page 205, FIG. 17.1-6). Beginning about 20 days prior to the start of menstrual bleeding, estrogen levels rise to double to triple the levels observed during menstruation. A few days prior to start of menstrual bleeding, estrogen levels begin to decline, with the most precipitous decline occurring the day before the start of menstrual bleeding.

From osteoporosis research, it is known that estrogen inhibits osteoclast activity by at least 3 pathways (i.e. the “triple whammy” previously disclosed). Accordingly, elevated estrogen levels tip the balance in favor of osteoblast activity, which result in net bone building activity, which in turn includes storage of calcium and growth factors in bone. This is referred to as “reservoiring” in this application and occurs during the time estrogen levels are elevated as shown in FIG. 2. The subsequent drop in estrogen levels removes the inhibitory effects on osteoclasts, which tips the balance in favor of bone resorption activity, which in turn includes release of calcium and growth factors along the approximate timeline shown in FIG. 2.

The most precipitous decline in estrogen levels occurs a day or so prior to the start of menstrual bleeding, and accordingly the highest release of bone resident calcium would also occur around this time, hereinafter referred to as the “calcium spike”. As extracellular concentrations of calcium begin to rise, the concentrations work their way through into blood circulation, where the escalating serum concentrations activate the body\'s serum calcium control mechanisms (via calcitonin). Blood calcium concentrations are tightly controlled (unlike extracellular concentrations the have a greater range of variability) and renal excretion of serum calcium can increase 5 fold (provided it does not get overwhelmed) to maintain serum calcium homeostasis and osteoclasts activity is inhibited (osteoclasts lose their ruffled border that dissolves bone) to reduce the amount of calcium being mobilized from the bone into the extracellular fluid.

Although calcitonin has significant calcium lowering effects in some species, in humans, calcitonin\'s influence on blood calcium levels is much smaller. Human calcitonin is not used for management of hypercalcemia, instead salmon calcitonin is used, as it is around 40-50 times more potent than human calcitonin and has a longer duration of action. Despite the higher potency of salmon calcitonin, its effects on reducing serum calcium levels are often inadequate to manage conditions such as hypercalcemia of malignancy, requiring the use of even more potent drugs such as bisphosphonates that induce osteoclast apoptosis.

Accordingly, the naturally weak human calcitonin based serum Ca2+ downregulation system would likely be playing catch-up with the progressively elevating Ca2+ release caused by the premenstrual estrogen decline. Furthermore, the rising extracellular calcium concentrations would not have the direct benefit of renal clearance that blood circulation does, and there would be much sharper escalations in extracellular calcium concentrations than in blood. This is important to note, as extracellular calcium concentrations (and more specifically concentrations surrounding nerve and muscle membranes) are of primary importance to present invention, and not blood concentrations.

The worst peak in calcium concentrations would occur the day prior to start of menses (i.e. as a result of the sharp premenstrual estrogen drop), after which point calcium levels would start normalizing as estrogen levels normalized and calcitonin would have finally caught up and eventually managed to work its way back to reducing extracellular calcium concentrations.

Transiently increased extracellular Ca2+ levels effectively “hypersensitize” nerves by three pathways described below.

The fundamental task of a neuron is to receive, conduct, and transmit signals. Neurons can be classified by function into sensory neurons, motor neurons, or interneurons, however they all have the same overall structure. Neurons have a spherical central cell body (soma) that contains the typical organelles found in all cells, branching dendrites on one side to receive signals, and a long axon on the other side for transmitting information. The axon commonly divides into many branches at its far end so it may pass the message to many target cells simultaneously. A signal travels along the neuronal membrane as an electrical pulse until it reaches the end of the axon, where typically the electrical pulse results in neurotransmitter release across the synapse, which in turn results in an electrical pulse being induced in the next neuron.

Neurons contain ion channels that maintain a balance between potassium, sodium, and chloride so that the resting membrane potential inside of the neuron is around −85 mV relative the outside of the cell (ranges from −30 mV to −100 mV depending on cell type). The cell membrane acts as a capacitor, storing charge separated by the thickness of the membrane, and has a typical capacitance of about 1μ Farad per square centimeter. Changes to the membrane potential are called “depolarizing” if they make the inside of the cell less negative or “hyperpolarizing” if they make the inside of the cell more negative. Electrical impulses that travel along the neuron are called action potentials and are transient perturbations in the membrane potential. Action potentials are conducted in a all-or-none manner and for an action potential to be generated the input signal must depolarize the neuron by more than its “threshold” membrane potential. As an example, for the −85 mV resting membrane potential neuron above, the threshold voltage is around −70 mV, meaning that the input signal must depolarize the membrane by at least 15 mV to generate a nerve impulse (i.e. action potential).

Changing the extracellular or intracellular concentrations of ions changes the resting membrane potential. Depolarizing concentrations (i.e. that make the inside of the cell less negative) bring the resting membrane potential closer to the threshold potential, and consequently the neuron requires a smaller input voltage to trigger an action potential. Polarizing concentrations (those that make the inside more negative) move the resting membrane potential farther away from the threshold potential and result in a larger input signal being required to trigger an action potential.

A traveling nerve impulse opens voltage gated Na+ channels and K+ channels, which allow Na+ to flow into the cell and K+ to flow out of the cell, passively along their respective electrochemical gradients. Both the Na+ channels and K+ channels are rapidly inactivated by a “ball and chain” amino acid complex that rapidly plugs the respective channels. Potassium (K) is the most significant ion in impulse transmission because of the large disparity between the extracellular and intracellular concentrations. Typical extracellular concentrations potassium and sodium are about 3 mM of K+ and 117 mM of Na+ and the typical intracellular concentrations are about 90 mM of K+ and 30 mM of Na+. The 30 fold concentration gradient disparity of K+ (i.e. 90/3) overwhelms the 4 fold gradient disparity of Na+ (i.e. 117/30).

The resting (equilibrium or E) membrane potential for a given ion (e.g. potassium) can calculated using the Nernst equation:

Ek=RT/zF(ln([K]o/[K]i))

where: Ek is the equilibrium (or resting) membrane potential for potassium R is the gas constant (831 joules/mole/° K) T is the absolute temperature (Kelvin=273+° C.) z is the valence of the ion (+1 for potassium) F is the Faraday constant (amount of charge on a mole of ions, 96,500 coulombs/mole) Ko is the outside (extracellular) concentration of potassium (in mM) and Ki is the inside (intracellular) concentration of potassium At room temperature (20° C.=293° K) and for potassium:

RT/zF=(8.31)(293)/(+1)(96,500)=0.02523 V=25 mV

and for concentrations of 3 mM outside the cell and 90 mM inside the cell:

Ek=(25 mV)(ln([K]o/[K]i))=(25 mV)(ln 3/90)=(25 mV)(−3.4)=−85 mV

The effect of elevating extracellular concentrations of positive ions can be seen from the Nernst equation. Increasing extracellular concentration of the positive ion K+ results in a more positive resting membrane potential, which is by definition depolarizing, and brings the resting membrane potential closer to the threshold potential. This means a smaller input signal voltage is required to trigger the “all-or-none” action potential.

As an example, as extracellular concentrations of K+ are raised to 4 mM, the resting membrane potential becomes more positive:

Ek=(25 mV)(ln( 4/90))=(25 mV)(−3.11)=−78 mV

Using the −70 mV threshold voltage, the input voltage required to initiate an action potential is now only 8 mV versus 15 mV. Applicant refers to this as “neuronal membrane hypersensitization” in present application.

The actual resting membrane potential is a summation of all ions that are permeable and can be more precisely calculated using the Goldman Hodgkin Katz equation (GHK) for computing the resting membrane potential:

Vm = 58   log   ( pk  [ K ]  o + p  Na  [ Na ]  o + p  Cl [ Cl }  i ) ( pk  [ K ]  i

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