US20040259852A1 - Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome - Google Patents
Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome Download PDFInfo
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- US20040259852A1 US20040259852A1 US10/464,310 US46431003A US2004259852A1 US 20040259852 A1 US20040259852 A1 US 20040259852A1 US 46431003 A US46431003 A US 46431003A US 2004259852 A1 US2004259852 A1 US 2004259852A1
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Definitions
- Testosterone replacement therapy using transdermal delivery has also been of benefit to men with symptoms of testosterone deficiency, for example in men with Parkinson's disease (Okun, M. S. et al. 2002 . Arch. Neurol. 59:1750-1753).
- sex hormones in particular estrogens, progestins and now testosterone, are important for subjective feelings of well-being and quality of life, parameters that were not assessed in the Women's Health Initiative trial.
- U.S. Pat. No. 5,935,949 discloses a method of alleviating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome which involves oral administration of androgens, such as testosterone, to patients.
- the idea behind the use of testosterone therapy in the treatment of such conditions is that muscle pain and chronic fatigue, primary symptoms in women with fibromyalgia syndrome (FMS), relates, at least in part, to testosterone deficiency, since androgens are known to allow for increased musculature and improvement in fatigue.
- FMS fibromyalgia syndrome
- a small decrease in serum free testosterone concentrations has been documented for premenopausal fibromyalgia patients relative to healthy volunteers, but significance was not achieved for postmenopausal women (Dessein, P. H.
- testosterone can suppress pain is supported by the discovery of aromatase-positive cells in the spinal cord dorsal horn of higher vertebrates (quail), where initial processing of pain sensation occurs (Evard, H. Et al. 2000 . J. Compar. Neurol. 423:552-564).
- aromatase which converts testosterone to 17 ⁇ -estradiol.
- estrogen can induce the transcription of opiates in estrogen receptor-positive cells derived from the superficial layers of the spinal dorsal horn (Amandusson, A. et al. 1996 . Neurosci. Lett. 196:25-28; Amandusson, A. et al. 1996 . Eur. J. Neurosci.
- Testosterone may also act at the level of the brain. Testosterone concentrations were dramatically decreased in the brain and spinal cord of rats in response to pain-inducing subcutaneous injections of formalin into the paw. In these animals, the loss of testosterone in the central nervous system was demonstrated to be due to its metabolism by 5 ⁇ -reductase to dihydrotestosterone (Amini, H. Et al. 2002 . Pharmacol. Biochem. Behav. 74:199-204). These authors pointed out that dihydrotestosterone can be metabolized to 5 ⁇ -androstane-3 ⁇ ,17 ⁇ -diol, which is an effective modulator of GABA A receptor complexes in the brain.
- GABA A receptors are found throughout the brain, and actions of GABA A receptor modulators in the limbic system, specifically in the amygdala, are associated with feelings of fear.
- the GABA A receptor ion channel complex is one of the most important inhibitory ion channels in the brain.
- testosterone may be important not only for modulation of pain but also for feelings of emotional well-being via binding of its metabolites to the neurosteroid site of the GABA A receptor, although this remains to be demonstrated.
- fibromyalgia may also play a role in the pathogenesis and symptoms of fibromyalgia and chronic fatigue.
- studies have shown that fibromyalgia patients fail to exhibit a proper growth hormone response to acute exercise, a response that is likely related to increased levels of somatostatin a powerful inhibitor of growth hormone synthesis (Crofford, L. J. et al. 2002 . Arthr. Rheumat. 46:1136-1138; Paiva, E. S. et al. 2002 . Arthr. Rheumat. 46:1344-1350). It is well known that testosterone increases growth hormone secretion.
- Growth hormone secretion is reduced in senescence beyond the reduced levels of secretion seen in adult life after puberty. This reduction is thought to relate to the decreased lean body mass to adipose mass ratio known to occur in some individuals in senescence. Thus, increased somatostatin levels may reflect decreased anabolism and decreased muscle mass due to decreased testosterone and growth hormone concentrations in fibromyalgia patients. As a result, therapy with growth hormone may improve the condition of patients with fibromyalgia.
- transdermal hormone therapy in women can raise serum hormone concentrations to levels that approximate those normally found in premenopausal women, as well as relieve symptoms in patients with fibromyalgia.
- An object of the present invention is a composition for increasing androgen levels in blood which comprises an androgen at a concentration of about one percent and a pharmaceutically acceptable gel.
- the androgen compounds of the instant invention may comprise testosterone and its derivatives.
- Another object of the present invention is administration of the androgen gel formulation along with compounds that increase levels of growth hormone in blood, or growth hormone itself.
- Another object of the present invention is a method of alleviating the symptoms of fibromyalgia syndrome and chronic fatigue syndrome which comprises administering to a patient suffering from fibromyalgia syndrome or chronic fatigue syndrome an effective amount of the androgen gel formulation so that the symptoms are alleviated.
- the administered product can be a gel with a combination of androgen hormones as well as compounds that increase levels of growth hormone in blood.
- the method of the invention contemplates administration of the androgen gel formulation and separate injection of growth hormone in the patients.
- FIG. 1 depicts the levels of total testosterone in blood of the patients, an average of the group, over time on day 1 (shown with circles) and day 28 (shown with squares).
- FIG. 2 depicts the results of the tender point evaluations pre-treatment (day 0) and at the end of the study (day 28). The results reported are levels of pain on a scale of 0 (no pain) to 10 (highest level of pain).
- FIG. 3 depicts the results of the dolorimetry assessment of tender point pain pre-treatment (day 0) and at the end of the study (day 28).
- FIG. 4 depicts the severity of symptoms/conditions associated with fibromyalgia and chronic fatigue on a scale of 1 to 10 (10 being the highest increased level) on day 1 versus day 28 of the study.
- the syndrome of chronic fatigue has received much attention lately. No physical finding or laboratory test can be used to confirm diagnosis of chronic fatigue syndrome.
- this syndrome is generally characterized by fatigue persisting or relapsing for more than six months occurring concurrently with at least four or more of the following symptoms: impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, multi-joint pain, new headaches, unrefreshing sleep, and post exertion malaise.
- Early studies suggested an infectious or immune dysregulation mechanism for the pathophysiology of chronic fatigue syndrome. More recent studies have shown that neurologic, affective and cognitive symptoms also frequently occur.
- Fibromyalgia also referred to as fibrositis
- Fibromyalgia Syndrome FMS
- Most patients with Fibromyalgia Syndrome (FMS) are women, and of these patients, approximately 50-75% are women in their peri-postmenopausal years, aged 40-60.
- FMS Fibromyalgia Syndrome
- Approximately 2-5% of peri/post menopausal women are affected by FMS, with some estimates ranging from 0.5 to 20%. This disease is characterized by chronic widespread musculoskeletal pain syndrome with multiple tender points, fatigue, headaches, lack of restorative sleep and numbness.
- Fibromyalgia shares many features with chronic fatigue syndrome including an increased frequency in peri/post menopausal woman, absence of objective findings and absence of diagnostic laboratory tests. Further, these conditions have overlapping clinical features including chronic fatigue, headaches and lack of restorative sleep with musculoskeletal pain predominating in fibromyalgia and apparent increased susceptibility or hyperimmunologic responsiveness to infection predominating in chronic fatigue syndrome.
- transdermal administration of hormones, including androgens can alleviate symptoms in patients suffering from FMS or CFS.
- androgen therapy it is meant to include administration of a single androgen or a combination of androgens.
- alleviate it is meant to make less hard to bear, reduce or decrease, or lighten or relieve patients of the symptoms of FMS of CFS.
- symptoms of FMS or CFS it is meant to include muscle pain and atrophy, chronic fatigue, lack of restorative sleep, increased susceptibility to infection and headaches resulting from FMS or CFS.
- Women taking hormone replacement therapy were enrolled if they agreed to come off hormone therapy at least 2 weeks prior to, and for the duration of, the study, in addition to meeting other eligibility criteria.
- Pre- or peri-menopausal women were required to have adequate alternative contraception, a negative pregnancy test, and treatment was started within the follicular (proliferative) phase of the menstrual cycle. Patients were included if they were willing to exercise 20 minutes a day, 5 days per week during therapy, to promote the effects of testosterone; this was a requirement put in place by the Institutional Review Board.
- cardiac risk factors by lipid profile—total fasting cholesterol (>240 mg/dL), high density lipoprotein ( ⁇ 35 mg/dL), low density lipoprotein (>210 mg/dL), triglyceride (>300 mg/L); hepatic function by alanine aminotransferase (>1.5 ⁇ N, normal at 0-40 U/L), alkaline phosphatase (>2 ⁇ N, normal at 40-120 U/L), aspartate aminotransferase (>1.5 ⁇ N, normal at 10-30 U/L), serum albumin (>N, normal at 3.2-5.2 g/dL), total bilirubin (>N, normal at 0.2-1.3 mg/dL), and direct (conjugated, soluble) bilirubin (>N, normal at 0.0-0.3 mg/dL); kidney function by blood urea nitrogen (>2 ⁇ N, normal at 8-18 mg/dL
- the delivery vehicle for this study was a gel formulation. It was chosen for use as a goal of the study was to identify a transdermal delivery system for hormones that would result in effective levels of hormones in blood as a way to reduce side effects of androgen therapy.
- the gel used for this study was a 1% w/w testosterone gel, USP grade. The daily gel dose applied was 0.75 grams; an expected bioavailability of 10% would deliver 0.75 mg testosterone over 24 hr.
- the gel was formulated for women by Bentley Pharmaceuticals, Inc. (North Hampton, N.H.) using good manufacturing practice standards, and is colorless, comfortable on the skin, and non-staining.
- Testosterone concentrations were determined by enzyme linked immunoassay (EIA, Diagnostic Systems Laboratories or DSL, Inc, Webster, Tex.), where serum testosterone from study subjects competed with enzyme-linked testosterone bound to anti-testosterone mAb. This assay system was designed to detect the lower concentrations of testosterone found in women as well as concentrations in the upper ranges. Free testosterone concentrations were determined by EIA using an anti-testosterone antibody that recognizes the unbound testosterone in the test sample, and has low affinity for sex hormone binding globulin and albumin. For the purposes of determining mean testosterone concentrations, times were based on the nearest hour.
- EIA enzyme linked immunoassay
- time points taken for the pharmacokinetic data 10 time points per individual ⁇ 2 sets per individual ⁇ 12 individuals
- 1 time point was missed #012, 4 hr point
- 3 additional time points were in between the standard times for taking blood (#010, 8 hr point; #012, 4 hr and 10 hr points).
- Values for these time points were derived by interpolation for the purposes of deriving mean testosterone concentrations.
- WinNonlin Pro WinNonlin Pro (Pharsight, Mountain View, Calif.) used the exact time points recorded for all the patients
- Tender point exams were administered by a qualified rheumatologist experienced in treating women with fibromyalgia, and involved applying approximately 9 pounds of pressure at each tender point and asking whether the patient felt pain. This practice is in accordance with criteria specified by the American College of Rheumatology. Exams were administered just prior to Day 1 of therapy (and therefore designated as “pretreatment”), and at the end of therapy. The pretreatment tender point assessment was performed on all patients within 1 week before the start of therapy. Dolorimeter readings were taken from the bilateral second costochondral junction and trapezium tender points, for comparison, in 11 of the 12 study subjects.
- Pain parameters were also evaluated by patient questionnaire using a visual analog scale (VAS) from 0-10 (FIG. 4).
- VAS visual analog scale
- Libido serum testosterone concentrations relieves symptoms that most specifically relate to testosterone deficiency, e.g. loss of sexual desire, loss of muscle function and increased fatigue.
- Blood tests and physical exam at the end of the study verified testosterone therapy did not adversely affect the general health of the study patient, and no study patient reported any adverse events that were attributable to the treatment.
- a testosterone skin patch has been effective in HIV seropositive women with wasting syndrome (Miller, K. et al. 1998 . J. Clin. Endocrinol. Metab. 83:2717-2725; Javanbakht, M. et al. 2000 . J. Clin. Endocrinol. Metab. 85:2395-2401), but the skin patch causes topical skin irritation in many women, making its use problematic.
- the present invention involves use of a testosterone formulated as a gel in a concentration that is appropriate for women.
- This formulation to provide effective systemic delivery of testosterone in patients with fibromyalgia. 28 days of therapy with 0.75 g 1% (w/w) testosterone gel per day raised serum concentrations of total and free testosterone in fibromyalgia patients to concentrations approximating those in premenopausal women. At this dose, patients showed significantly decreased muscle pain, decreased stiffness, decreased fatigue and increased libido in response to testosterone therapy. Tender point pain was decreased, as well.
- the androgen therapy provides a useful means for alleviating symptoms associated with FMS or CFS in women preferably of peri/post menopausal age.
- peri/postmenopausal age it is most often meant to be approximately 40 to 60 years of age. Women outside of this range may also benefit since these syndromes have been known to be present in women 20 to 60 years of age.
- the androgen administered comprises testosterone, an active metabolite of testosterone such as dihydrotestosterone or androstenedione or a testosterone derivative such as methyltestosterone, testosterone enanthate or testosterone cypionate.
- Examples of available pharmacologic preparations of androgens believed to be useful in this invention include, but are not limited to danazol, fluoxymesterone, oxandrolone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenolone and dehydroepiandrosterone (DHEA).
- the androgens are administered transdermally in a gel formulation.
- This formulation has advantages over current oral methods as well as transdermal patch methods that include improved bioavailability and a low side effect profile.
- a combination of androgens such as testosterone or a testosterone derivative and DHEA can be administered to alleviate both the muscular and neurological symptoms of FMS or CFS.
- composition of the present invention comprises, in addition to the aforementioned androgen/anabolic agent, co-treatment with a pharmaceutically effective amount of growth hormone elicitor or effector, either growth hormone or an agent that is known to release growth hormone in effective amounts, i.e., a growth hormone releasing agent (“GRF”).
- GRF is an acronym based on the existence of an endogenous hormone known as GHRH.
- GHrelin or a growth hormone releasing peptide or analog include GHRP; GHRP-6, or hexarelin, His-DTrp-Ala-Trp-DPhe-Lys, and GHRP-2, or Dala-D-2-NaI-Ala-Trp-Dphe-Lys are examples), which have been shown to release effective amounts of growth hormone.
- GHRP growth hormone releasing peptide or analog
- IGF-1 insulin-like growth factor
- the hormonal effector is also prophetically considered to be any peptide or peptidomimetic agent that directly acts to release this secondary anabolic growth factor, (IGF-1), not necessarily through the intermediary route of secretion of growth hormone itself.
- IGF-1 secondary anabolic growth factor
- the indirect growth hormone route is preferred to elicit IGF-1, the latter route to directly release IGF-1 also is included by example.
- the composition comprises a pharmaceutically effective amount of a growth hormone or, more preferably, a growth hormone-releasing agent, or an elicitor of IGF-1 secretion, coupled with androgen treatment and such combined treatment being capable of counteracting the deleterious effects of aging, such as, for example, muscle weakness, body fat increases, and skin fragility in adults.
- a growth hormone-releasing agent may be employed in combination with any androgen, preferably one such as testosterone that possesses strong anabolic activity.
- Other anabolic agents that are not thought of as androgenic agents, or do not possess maximal androgenic activity may be used, as long as they have appreciable anabolic activity.
- this invention anticipates, and includes as a prophetic example, those anabolic agents that may be completely devoid of androgenic activity.
- growth hormone-releasing agents include: somatoliberins; growth hormone-releasing hormone active fragments, such as, for example, hGRF (1-29) amide and hexarelin (GHRP-6).
- Hexarelin is a growth hormone releasing peptide mimetic agent, i.e., it mimics the effects of growth hormone releasing peptide in the body and contains between 2 and 20 amino acids. In particularly preferred embodiments, more than one growth hormone-releasing agent may be used in combination.
- a preferred combination comprises growth hormone-releasing factor (GRF or GHRH) and a growth hormone releasing peptide or peptidomimetic (GHRP).
- GRF growth hormone-releasing factor
- GHRP growth hormone releasing peptide or peptidomimetic
- GH or IGF-1 secretagogue will reduce plasma androgen concentration in humans (Tapanainem J et. al, Fertility and Sterility 58: 726-732). This effect increases the need for exogenous androgen, such as testosterone, to be also administered as a co-treatment to restore and amplify existing levels.
- GH agents may be administered by a variety of means. These agents may be administered separately from the androgen administration, using the modalities of intranasal, transdermal, parenteral (subcutaneous or intravenous), or oral (with or without permeation enhancement and preferably with enteric protection, since proteins and peptides may be degraded by gastric exposure). GH itself is most preferably administered by parenteral means in practice, because it is a large protein that is of limited stability and limited absorption. However, intranasal administration is also an acceptable means for this and other large proteins or peptides.
- the androgen may be administered in a separate treatment with a different regimen.
- the desired method for androgen administration is preferably oral, transdermal, intravaginal, or intranasal delivery, although it is most preferred to be administered transdermally in the form of a gel or patch.
- the literature is replete with examples of compositions suitable in the context of this disclosure for the transdermal administration of these compounds in solution, gel, emulsion, or patch forms.
- the two may be combined in a single combination therapy.
- both could be incorporated together in an oral form, tablet, or suspension, with the caveat that any proteinaceous agent is suitably protected from gastric degradation.
- the combination of agents may be administered intranasally in one unit through separate delivery chambers, known to those of skill in intranasal delivery, or together in the same liquid, semi-solid, or solid delivery form.
- a microparticulate or nanoparticulate dry solid system could be administered intranasally.
- the combined agents could-be both administered transdermally.
- the two treatments could be incorporated together in a patch, or most preferably in a topical liquid or semi-solid (gel) delivery system.
- This latter method is most effectively realized in practice for GH agents of the secretagogue (GHSs) variety, such as GHRPs or GHRHs or suitable GHRH fragments that still retain the necessary GH releasing activity.
- GRSs secretagogue
- the reason for the suitability is based on the molecular size. It is known throughout the literature that smaller molecules have a higher potential for transdermal delivery than large molecules, such as oligopeptides including GH and IGF-1.
- the GHrelins and GHRH secretagogues are most preferably selected for the transdermal route based upon small molecular size, such as hexarelin, since transdermal delivery efficiency is good for a hexapeptide. In general, it is preferred that peptides below 30 amino acids are considered for the transdermal delivery format.
- Patients will be provided with a Patient Questionnaire Form to fill out to assess their symptoms and level of pain in a semi-quantitative manner at the baseline, 2 month and 5 month timepoints. Included in the questionnaire are parameters for patients to evaluate that are common to published and validated FMS patient questionnaires such as sleeplessness, fatigue, headache and stiffness (Wolfe et al., Arthritis and Rheumatism, 1990, 33(2):160-172; Goldenberg et al., Arthritis and Rheumatism, 1996, 39(11):1852-9; and Burckhardt et al., J. Rheumatology, 1991, 18:728-33).
- FMS patient questionnaires such as sleeplessness, fatigue, headache and stiffness (Wolfe et al., Arthritis and Rheumatism, 1990, 33(2):160-172; Goldenberg et al., Arthritis and Rheumatism, 1996, 39(11):1852-9; and Burckhardt et al
- the attending physician will also complete a Physician's Form at the baseline, 2 month and 5 month time points to verify that the patient fulfills the criteria for FMS by the American College of Rheumatology, and to document the intensity of the muscle pain for each of the 18 commonly recognized tender points that patients with FMS are known to have.
- Patients will be tested at the baseline, 2 month and 5 month time points for total serum hormone levels, serum estradiol levels, cardiac health and liver function. Patients will be tested at a common time of day, preferably a predetermined peak time for the androgen, after fasting since midnight, and on day 3 after the start of their menstrual period if they are still menstruating.
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US10/464,310 US20040259852A1 (en) | 2003-06-18 | 2003-06-18 | Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US10/677,673 US20040259784A1 (en) | 2003-06-18 | 2003-10-02 | Compositions and methods for treatment of muscle pain and muscle wasting |
AU2004251075A AU2004251075B2 (en) | 2003-06-18 | 2004-06-15 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
PCT/US2004/019201 WO2005000236A2 (en) | 2003-06-18 | 2004-06-15 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
JP2006517316A JP5717312B2 (ja) | 2003-06-18 | 2004-06-15 | 線維筋痛症候群または慢性疲労症候群の処置のための経皮的組成物および方法 |
EP04776655A EP1638575A4 (de) | 2003-06-18 | 2004-06-15 | Transdermale zusammensetzungen und verfahren zur behandlung von fibromyalgie und chronischem müdigkeitssyndrom |
EP08154166.6A EP2000143B1 (de) | 2003-06-18 | 2004-06-15 | Transdermale Gelzusammensetzungen enthaltend Testosteron und deren Verwendung zur Behandlung von Fibromyalgie |
CA2529575A CA2529575C (en) | 2003-06-18 | 2004-06-15 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US11/303,813 US7799769B2 (en) | 2003-06-18 | 2005-12-16 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US11/555,882 US20070066532A1 (en) | 2003-06-18 | 2006-11-02 | Compositions and methods for treatment of muscle pain and muscle wasting |
US12/837,310 US8999963B2 (en) | 2003-06-18 | 2010-07-15 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US12/949,644 US8883769B2 (en) | 2003-06-18 | 2010-11-18 | Methods for the treatment of fibromyalgia and chronic fatigue syndrome |
AU2011200914A AU2011200914B2 (en) | 2003-06-18 | 2011-03-02 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
JP2011126449A JP5651540B2 (ja) | 2003-06-18 | 2011-06-06 | 線維筋痛症候群または慢性疲労症候群の処置のための経皮的組成物および方法 |
US13/988,259 US9511079B2 (en) | 2003-06-18 | 2011-11-17 | Methods for the treatment of fibromyalgia and chronic fatigue syndrome |
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US11/303,813 Continuation US7799769B2 (en) | 2003-06-18 | 2005-12-16 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
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US12/837,310 Expired - Fee Related US8999963B2 (en) | 2003-06-18 | 2010-07-15 | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
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Cited By (8)
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US20060100186A1 (en) * | 2003-06-18 | 2006-05-11 | White Hillary D | Trandsdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US7799769B2 (en) | 2003-06-18 | 2010-09-21 | White Mountain Pharma, Inc. | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US20110009318A1 (en) * | 2003-06-18 | 2011-01-13 | White Mountain Pharma, Inc. | Transdermal Compositions and Methods for Treatment of Fibromyalgia and Chronic Fatigue Syndrome |
US20110118227A1 (en) * | 2003-06-18 | 2011-05-19 | White Mountain Pharma, Inc. | Methods for the Treatment of Fibromyalgia and Chronic Fatigue Syndrome |
US8883769B2 (en) | 2003-06-18 | 2014-11-11 | White Mountain Pharma, Inc. | Methods for the treatment of fibromyalgia and chronic fatigue syndrome |
US8999963B2 (en) | 2003-06-18 | 2015-04-07 | White Mountain Pharma, Inc. | Transdermal compositions and methods for treatment of fibromyalgia and chronic fatigue syndrome |
US9642862B2 (en) | 2010-11-18 | 2017-05-09 | White Mountain Pharma, Inc. | Methods for treating chronic or unresolvable pain and/or increasing the pain threshold in a subject and pharmaceutical compositions for use therein |
US9642863B2 (en) | 2010-11-18 | 2017-05-09 | White Mountain Pharma, Inc. | Methods for treating chronic or unresolvable pain and/or increasing the pain threshold in a subject and pharmaceutical compositions for use therein |
Also Published As
Publication number | Publication date |
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JP2012046483A (ja) | 2012-03-08 |
US20110009318A1 (en) | 2011-01-13 |
AU2011200914B2 (en) | 2014-07-03 |
JP5651540B2 (ja) | 2015-01-14 |
WO2005000236A2 (en) | 2005-01-06 |
CA2529575A1 (en) | 2005-01-06 |
WO2005000236A3 (en) | 2005-08-04 |
EP2000143B1 (de) | 2014-07-23 |
JP5717312B2 (ja) | 2015-05-13 |
JP2007523856A (ja) | 2007-08-23 |
EP2000143A3 (de) | 2009-09-30 |
AU2004251075A1 (en) | 2005-01-06 |
EP1638575A4 (de) | 2007-07-25 |
AU2011200914A1 (en) | 2011-03-24 |
US8999963B2 (en) | 2015-04-07 |
US7799769B2 (en) | 2010-09-21 |
US20060100186A1 (en) | 2006-05-11 |
EP1638575A2 (de) | 2006-03-29 |
EP2000143A2 (de) | 2008-12-10 |
AU2004251075B2 (en) | 2010-12-02 |
CA2529575C (en) | 2012-04-10 |
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