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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
• • A—HUMAN NECESSITIES
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  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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• • A—HUMAN NECESSITIES
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Definitions

• the present invention relates generally to treatment or prevention of symptoms of hormonal variation, such as hot flashes, night sweats, and insomnia.
• Hot flashes are the most common symptoms experienced by women who are perimenopausal or postmenopausal.
• a hot flash is a sudden sensation of warmth, which is usually accompanied by skin reddening, perspiration, palpitation, anxiety, irritability, and even panic, and night sweats.
• a chill may follow a hot flash because of a subsequent drop in core temperature.
• Hot flashes vary: they can be several times a week or once per hour, they can be characterized by mild warmth to profuse sweating, and they can last from several seconds to 60 minutes. Such symptoms can disrupt sleep and work and interfere with quality of life.
• Hot flashes occur with sudden onsets of sensation of warmth in the chest, which then spreads upward to involve the neck and face. Hot flashes can last from a few seconds to several minutes. However, the severity of the sensations vary greatly both from time to time in the same woman and from woman to woman. Hot flashes may be accompanied by dizziness, nausea, headaches, palpitations, profuse sweating and night sweats. How often a woman experiences hot flashes also varies, ranging from many times a day to once a week or less. Such symptoms can disrupt sleep and work and interfere with quality of life. In some women, hot flashes are provoked by several factors such as hot weather, stress, eating, or drinking alcohol.
• hot flashes result from a transient lowering of the hypothalamic temperature regulatory set point (Steams et al., "Hot flushes,” Lancet, 360:1851-1861 (2002)). Because of the temporal relation between changes in sexual hormone concentrations and the onset of hot flashes, it is believed that such symptoms result from declining estrogen levels or increased gonadotropin concentrations. Thus, hot flashes occur commonly in menopausal women, but also in women taking anti- estrogen drugs, such as tamoxifen. Men on androgen deprivation treatment may also experience such symptoms.
• estrogen replacement therapy can effectively minimize or prevent hot flashes in women
• many women are concerned about potential risks of hormone replacement therapy. This is especially true for women who suffer from breast cancer or have a family history of breast cancer, and/or a history of clotting disorder (Col et al., "Patient-specific decisions about hormone replacement therapy in postmenopausal women," JAMA, 277;1140-1 147(1997); Gail et al., "The menopause,” Lancet, 353:571-580 (1999)).
• Clonidine is a centrally-acting Ct 2 adrenergic receptor agonist. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (e.g., epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla.
• catecholamines e.g., epinephrine, also known as adrenaline, and norepinephrine
• clonidine causes the brain...to reduce its signals to the adrenal medulla, leading to lower catecholamine production. The result is a lowered heart rate and blood pressure.
• clonidine was shown to be moderately more efficacious than placebo (Goldberg et al., "Transdermal clonidine for ameliorating tamoxi fen-induced hot flashes," J CHn. Oncol, 12:155-158 (1994); Pandya et al., "Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study," Ann Intern Med. 132:788-793 (2000)), but adverse effects are common, including dry mouth, dizziness, and blurred vision.
• embodiments of the invention relate to methods for treating or preventing symptoms of hormonal variation.
• a method in accordance with one embodiment of the invention includes administering an effective amount of a receptor antagonist to a subject having one or more symptoms of hormonal variations, wherein the receptor antagonist binds to at least one selected from the group consisting of a serotonin type 2 A (5-HT 2A ) receptor and a dopamine type 2 (D 2 ) receptor.
• the receptor antagonist is one selected from risperidone, quetiapine, clozapine, olanzapine, aripiprazole, ziprasidone, zotepine, and 9-hydroxyrisperidone.
• Embodiments of the invention relate to methods for treating or preventing symptoms associated with hormonal variations, particularly those associated with hormonal changes accompanying menopause.
• numerous details are set forth to provide an understanding of the present invention. However, it would be understood by those skilled in the art that the present invention may be practiced without these details and that numerous variations or modifications from the described embodiments are possible without departing from the scope of the invention.
• the methods of the invention may involve administering an effective amount of a therapeutic agents by oral administration, injection, inhalation, transdermal patch, or any other routes commonly used in the art.
• a range of from 1 to 10 is to be read as indicating each and every possible number along the continuum between about 1 and about 10.
• a certain range is expressed, even if only a few specific data points are explicitly identified or referred to within the range, or even when no data points are referred to within the range, it is to be understood that the inventors appreciate and understand that any and all data points within the range are to be considered to have been specified, and that the inventor have possession of the entire range and all points within the range.
• Hot flashes are generally systemic and likely result from an alteration in the thermoregulatory set- point centre, which is located in the pre-optic anterior hypothalamus, with involvement of dopamine, serotonin, nor- epinephrine, and alpha- adrenergic receptors.
• a method for treating or preventing symptoms of hormonal variations may comprise the use of an effective amount of an antagonist of 5-HT 2A serotonin receptor and/or D 2 dopamine receptor.
• An effective amount of an antagonist that binds 5-HT 2 A and/or D 2 receptors will depend on the mode of administration, frequency of administration, and the type of pharmaceutical composition used to deliver the compound into a patient, as well as weight, gender, age, and physical conditions of the patient. Generally, effective amounts of such compounds will be about 0.002 mg to about 0.5 mg/kg body weight per day, preferably about 0.005 mg to 0.1 mg/kg body weight per day, and more preferably about 0.005 to about 0.034 mg/kg body weight per day.
• daily doses may range from about 0.1 to about 25 mg per day for an adult patient weighing about 50 Kg (110 Ib), or from about 0.2 to about 50 mg per day for an adult patient weighing about 100 Kg (220 Ib). While individual needs vary, determination of optimal range of effective amounts of each compound is within the skills of one skilled in the art.
• embodiments of the invention either reduce the number (occurrence or frequency), duration, and/or severity of symptomatic events.
• Administering a compound of the invention to a patient may be via any suitable route used for administering similar pharmaceuticals to a patient, including oral administration, injection, and transdermal patch, to name a few.
• the compound may be administered with any pharmaceutically acceptable carrier or excipient.
• Serotonin (5-HT) receptors comprise about 15 different receptors.
• Type 2 (5-HT)
• HT 2 serotonin receptors are G q /G ⁇ coupled receptors that mediate cellular effects by increasing cellular levels of inositol triphosphate (IP 3 ) and diacylglycerol (DAG).
• IP 3 inositol triphosphate
• DAG diacylglycerol
• serotonin type 2A receptor is the target for treating or preventing symptoms associated with hormonal variation. Rreduction in 5-HT levels increases the sensitivity of 5-HT 2A receptor in the hypothalamus, which is involved in thermoregulation. Therefore, modulators of 5- HT 2A receptors may be useful in the management of symptoms associated with hormone variations.
• risperidone may be used to treat symptoms of hormonal variations.
• Risperidone (Belivon ® , Rispen ® , Risperdal ® in the United States) is an antipsychotic medication that functions by interfering with the communication among nerves in the brain. Risperidone acts as a 5-HT 2A antagonist and can be used to quickly and effectively block the effects of 5- HT 2A agonists at a low dose. Risperidone is also a potent dopamine type 2 (D 2 ), and ⁇ . 2 adrenergic receptor antagonist.
• D 2 potent dopamine type 2
• risperidone has been used in the treatment of psychotic disorders, for example, schizophrenia.
• risperidone has been unexpectedly found to be effective in reducing or eliminating symptoms associated with hormonal variations.
• 9- hydroxyrisperidone may be used as a treatment for the symptoms of hormonal variations.
• 9-Hydroxyrisperidone is the principal active metabolite of risperidone, and they had similar binding profiles and affinity for 5-HT 2A receptors and D 2 receptors.(Leysen et ah, "Risperidone: a novel antipsychotic with balanced serotonin- dopamine antagonism, receptor occupancy profile, and pharmacologic activity," J Clin Psychiatry: 55 Suppl: 5-12 (1994)).
• 9-hydroxyrisperidone can effectively treat or prevent the symptoms associated with hormonal variations its antagonist activity for 5-HT 2A and/or dopamine receptors.
• receptor antagonists that can bind to 5-HT 2A and/or D 2 dopamine receptors may also be used to control symptoms associated with hormonal variations.
• these other antagonists may include quetiapine, clozapine, olanzapine, aripiprazole, ziprasidone, and zotepine.
• quetiapine may be used as a treatment for the symptoms of hormonal variations.
• the antipsychotic effect of quetiapine is thought to be mediated by its antagonist activity against dopamine and 5-HT receptors.
• a and 5 -HT 2 subtypes are antagonized.
• Serial PET scans evaluating the D 2 dopamine receptor occupancy of quetiapine have revealed that quetiapine rapidly disassociates from the D 2 receptor.
• Quetiapine also has an antagonistic effect on the H 1 histamine receptor. This may be responsible for the sedative effect of the drug.
• clozapine may be used as a treatment for the symptoms of hormonal variations.
• Clozapine is classified as an 'atypical' antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by more typical anti-psychotics.
• clozapine has a high affinity for the D4 receptor and it also interferes to a lower extent with the binding of dopamine with D], D 2 , D 3 and D 5 dopamine receptors.
• clozapine does not induce catalepsy, nor does it inhibit apomorphine-induced phenotype in animal models seen with 'conventional' neuroleptics.
• Clozapine is preferentially more active at limbic than at striatal dopamine receptors and may explain its relatively mild extra-pyramidal side effects and its strong anti-cholinergic activity. Clozapine is also a strong antagonist of different subtypes of adrenergic, cholinergic, histaminergic and serotonergic receptors.
• olanzapine may be used as a treatment for symptoms of hormonal variations.
• Olanzapine is structurally similar to clozapine, and has a high affinity for dopamine and serotonin receptors.
• Olanzapine has a low affinity for histamine, cholinergic muscarinic and ⁇ -adrenergic receptors.
• the mechanism of action of olanzapine is unknown.
• olanzapine's antipsychotic activity is mediated primarily by antagonism of dopamine receptors, specifically D 2 dopamine receptor.
• 5-HT antagonism may also play a role in the effectiveness of olanzapine.
• the significance of 5- HT 2 A antagonism is debated among researchers.
• aripiprazole may be used as a treatment of symptoms of hormonal variations.
• Aripiprazole (Abilify from Bristol-Myers Squibb) is a new atypical antipsychotic medication awaiting approval by the FDA for the treatment of schizophrenia.
• Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes associated with bipolar disorder.
• Aripiprazole appears to mediate its antipsychotic effects primarily by acting as a partial agonist of the D 2 receptor.
• Partial agonism at D 2 receptors has been shown to modulate dopaminergic activity in areas where dopamine activity may be high or low, such as the mesolimbic and mesocortical areas of the schizophrenic brain, respectively.
• aripiprazole is also a partial agonist of the 5-HTi A receptor.
• aripiprazole exhibits antagonist activities against the 5-HT 2A receptor.
• Aripiprazole has moderate affinities for histamine and ⁇ -adrenergic receptors, but no appreciable affinity for cholinergic muscarinic receptors.
• ziprasidone may be used as a treatment of symptoms of hormonal variations.
• Ziprasidone has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a moderate affinity for histaminic receptors.
• Ziprasidone is somewhat unique among the "atypicals” in that it can also inhibit synaptic reuptake of serotonin and norepinephrine, although the clinical significance of this is unknown.
• the mechanism of action of ziprasidone is unknown. However, it is thought that its antipsychotic activity is mediated primarily by its antagonism against dopamine receptors, specifically D 2 dopamine receptor.
• Serotonin antagonism may also play a role in the effectiveness of ziprasidone, but the significance of 5-HT 2A antagonism of ziprasidone is debated among researchers. Antagonism at histaminic and alpha adrenergic receptors likely explains some of the side effects of ziprasidone, such as sedation and ortho stasis.
• zotepine may be used as a treatment of symptoms of hormonal variations.
• Zotepine has a high affinity for the Di and D 2 dopamine receptors. It also affects the 5HT2 A , 5HT2 C , 5HT 6 , and 5HT 7 receptors. In addition, it can also inhibit the reuptake of noradrenaline.
• Embodiments of the invention involve administering a therapeutically effective amount of an antagonist (such as risperidone or 9-hydroxyrisperidone) of 5- HT 2A and/or D 2 dopamine receptor to alleviate symptoms associated with hormone variations.
• an antagonist such as risperidone or 9-hydroxyrisperidone
• 5- HT 2A and/or D 2 dopamine receptor for example, 5- HT 2A and/or D 2 dopamine receptor to alleviate symptoms associated with hormone variations.
• an antagonist such as risperidone or 9-hydroxyrisperidone
• Her biochemical and hematological results such as sodium and potassium levels, 140 mmol/L and 4.0 mmol/L, respectively, were all within normal ranges.
• Plasma Cortisol levels were within the normal range and showed diurnal rhythm.
• EEG showed no focal epileptiform discharges nor abnormal background activities.
• Brain MRI showed aging brain changes, but no lesion in hypothalamus or brain stem. 24-hour Holter's scan showed normal sinus rhythm. Echocardiography demonstrated normal cardiac chamber size, normal LV systolic performance, and wall motion.
• a regimen of a 5-HT 2A antagonist may provide an effective therapy for symptoms of hormonal variations, such as hot flashes.
• the patient was treated with risperidone (2 mg/day). After three days of treatment, her hot flashes reduced markedly to a frequency of once per 1-2 weeks. Associated symptoms, such as palpitation and anxiety, also improved significantly. Thereafter, the dosage of anti- hypertension drugs was reduced. With the patient's permission, risperidone therapy was discontinued and hot flashes reoccurred within 2-3 days after discontinuing the treatment. The symptoms were again alleviated 3-4 days after resuming risperidone treatment.
• Patient 2 was a 57-year-old woman who began developing intolerable hot flashes and night sweats after natural menopause that occurred seven years ago. Although she responded well to hormone replacement therapy (Premarin ® 0.625 mg per day), she discontinued the therapy one year prior to this study because she was concerned about the potential risk of breast cancer. One month after discontinuing hormone replacement therapy, she developed hot flashes up to ten times per day, night sweats up to three times per night that disrupted her sleep, and headaches. The patient then sought neurological consultation. The patient also suffered from headaches twice per day and fluctuating blood pressure.
• hormone replacement therapy Premarin ® 0.625 mg per day
• Risperidone was started at a dose of 2 mg per day and the patient reported that the occurrence of hot flashes reduced markedly two days after starting risperidone treatment and was completely eliminated by day 7. In addition, she slept well and her blood pressure stabilized. To assess the relationship between risperidone therapy and the resolution of hot flashes, risperidone was tapered off over 2 days. The patient experienced hot flashes and night sweats again two days after risperidone treatment was completely discontinued. Risperidone 2 mg daily was resumed and the patient has not suffered another hot flash since.
• Patient 3 was a 46-year-old woman who was diagnosed with perimenopause, based on increased levels of follicle-stimulating hormone, increased variability in menstrual cycle length, development of hot flashes, and insomnia. The patient had had these symptoms for two years. She responded well to estrogen therapy. Because of health risks, the patient discontinued estrogen treatment and sought supplementary therapy, such as soy isoflavones, but without success. Risperidone treatment (1 mg per night) was started. At that time, the patient was experiencing seven hot flashes per day. The patient reported that the frequency and intensity of her hot flashes were markedly reduced three days after starting risperidone therapy.
• risperidone was tapered off over two days, and the hot flashes developed again three days later. After risperidone treatment (1 mg daily) was resumed, the patient no longer experienced hot flashes, and the quality of her sleep and her life improved. Three months later, the dosage of risperidone was decreased to 0.25 mg or less per day, and the patient's hot flashes were still markedly eliminated.
• Patient 4 was a 56-year-old woman who had developed hot flashes, with a frequency of once per hour, palpitation, insomnia, headache, restlessness, and unstable blood pressure for over seven years. Initially, the patient visited a psychiatrist for her sleep disorder and a cardiovascular specialist for her high blood pressure. A year later, because of intolerable hot flashes and other menopausal symptoms, she received hormone replacement therapy (Divina ). Although her hot flashes were reduced to twice per day, headaches persisted and her blood pressure fluctuated from 180 to 210/1 10 to 90 mm Hg despite treatment with anti-hypertension drugs.
• the patient was started on risperidone treatment, 1 mg at bedtime for the first two days, followed by 2 mg per night, for residual hot flashes.
• the patient's hot flashes were completely eliminated three days after starting the risperidone therapy. Additionally, the patient was able to take hormone four times a day and discontinue the use of all anti-hypertension drags because her blood pressure stabilized within the normal range.
• risperidone or similar receptor antagonists are effective in alleviating the symptoms associated with hormonal variations, such as hot flashes and blood pressure fluctuations. It is also contemplated that administration of a compound of the invention for alleviating symptoms associated with hormonal variations may be carried out in combination with other suitable therapeutic treatments which are useful for treating symptoms of hormonal variations, including hot flashes.
• Hot flashes are generally systemic and likely result from an alteration in the thermoregulatory set-point centre, which is located in the pre-optic anterior hypothalamus, with involvement of dopamine, serotonin, nor- epinephrine, and alpha- adrenergic receptors (Steams et al., "Hot flashes,” Lancet 360;1851-1861 (2002)).
• Risperidone a benzisoxazole derivative
• Risperidone is an atypical antipsychotic drag, which binds with high affinity to the serotonin type 2 A 5-HT 2 A, dopamine type 2 (D 2 ), and a ⁇ -adrenergic receptors.
• Risperidone binds with lower affinities to the a 2 - adrenergic and H, histamine receptors. Risperidone does not bind to D, dopamine receptors and has no affinity (when tested at concentrations >10 M) for muscarinic cholinergic receptors. (Grant and Fitton, "Risperidone.
• Pulsatile luteinizing hormone (LH) secretion theory is another common explanation for the development of hot flashes because administration of LH-RH agonist can result in hot flashes.
• the dopaminergic system seems to be involved in both pulsatile LH secretion and hot flashes in post-menopausal women.
• Anti- dopaminergic drugs could act on the thermoregulatory nucleus to reduce hot flashes by directly decreasing adrenergic effects on the thermoregulatory nucleus, or indirectly through mechanisms such as the short-loop feedback exerted by hyperprolactinaemia on the tuberoinfundibular dopamine neurons with a secondary dopamine-like activity, or by stimulating the opioid system (Melis GB et al., "Effects of the dopamine antagonist veralipride on hot flashes and luteinizing hormone secretion in postmenopausal somen," Obstet. Gynecol.
• Risperidone has high affinities for 5-HT 2 A and D 2 receptors. Risperidone can counteract enhancement of 5-HT activity as well as decrease nor-epinephrine activity in the anterior hypothalamus in the serotonin syndrome (Nisijima et al., "Risperidone counteracts lethality in an animal model of the serotonin syndrome," Psychopharmacology 150:9-14 (2000)).
• risperidone may elevate circulating prolactin levels in healthy subjects and schizophrenic patients (Markianos et al., "Neuroendocrine serotonergic and dopaminergic responsivity in male schizophrenic patients during treatment with neuroleptics and after switch to risperidone," Psychopharmacology, 157:55-59 (2001)). Risperidone can also reduce or prevent hot flashes through anti-dopaminergic effects on the loop of tuberoinfundibular dopamine neurons and on nor-epinephrine activity in the anterior hypothalamus.
• Embodiments of the invention can provide compositions and methods for the treatment of the symptoms of hormonal variations including hot flashes and night sweats. Additionally, these methods and compositions can also achieve normalization of blood pressure and elimination/reduction of palpitations.
• Compositions of the invention may comprise a serotonin type 2A (5-HT 2A ) receptor, dopamine type 2 (D 2 ) receptor, and/or a ⁇ -adrenergic receptor antagonist and can provide a plethora of treatment options for improving the quality of life of women experiencing the symptoms of hormonal variations.

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• Obesity (AREA)
• Anesthesiology (AREA)
• Pain & Pain Management (AREA)
• Hematology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Hospice & Palliative Care (AREA)
• Otolaryngology (AREA)
• Reproductive Health (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Steroid Compounds (AREA)

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ID=39528142

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• 2006
  • 2006-12-13 US US11/638,282 patent/US7645750B2/en active Active
• 2007
  • 2007-10-26 TW TW096140356A patent/TWI330083B/zh not_active IP Right Cessation
  • 2007-11-27 EP EP07872103A patent/EP2101781B1/en not_active Not-in-force
  • 2007-11-27 CA CA2671954A patent/CA2671954C/en active Active
  • 2007-11-27 WO PCT/IB2007/004514 patent/WO2008087491A2/en not_active Ceased
  • 2007-11-27 CN CN201210178935.XA patent/CN102697785B/zh not_active Expired - Fee Related
  • 2007-11-27 JP JP2009540891A patent/JP4643742B2/ja not_active Expired - Fee Related
  • 2007-11-27 AT AT07872103T patent/ATE506065T1/de not_active IP Right Cessation
  • 2007-11-27 MY MYPI20092347A patent/MY162095A/en unknown
  • 2007-11-27 DE DE602007014102T patent/DE602007014102D1/de active Active
  • 2007-11-27 CN CN2007800463514A patent/CN101588804B/zh not_active Expired - Fee Related
  • 2007-11-27 KR KR1020097012120A patent/KR101435695B1/ko not_active Expired - Fee Related
• 2009
  • 2009-12-11 US US12/636,552 patent/US20100093762A1/en not_active Abandoned
• 2015
  • 2015-03-03 US US14/637,200 patent/US20150246056A1/en not_active Abandoned

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