WO2001000196A2 - Mirtazapine for weight gain in wasting diseases - Google Patents

Mirtazapine for weight gain in wasting diseases Download PDF

Info

Publication number
WO2001000196A2
WO2001000196A2 PCT/US2000/017432 US0017432W WO0100196A2 WO 2001000196 A2 WO2001000196 A2 WO 2001000196A2 US 0017432 W US0017432 W US 0017432W WO 0100196 A2 WO0100196 A2 WO 0100196A2
Authority
WO
WIPO (PCT)
Prior art keywords
patient
enantiomer
pharmaceutically acceptable
cancer
dose
Prior art date
Application number
PCT/US2000/017432
Other languages
French (fr)
Other versions
WO2001000196A3 (en
Inventor
Michael A. Weitzner
David V. Sheehan
Original Assignee
University Of South Florida
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of South Florida filed Critical University Of South Florida
Priority to AU57649/00A priority Critical patent/AU5764900A/en
Publication of WO2001000196A2 publication Critical patent/WO2001000196A2/en
Publication of WO2001000196A3 publication Critical patent/WO2001000196A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • This invention relates to pharmacological treatment of weight-loss associated with the pathology of wasting diseases, including but not limited to cancer anorexia, cancer cachexia, AIDS, anorexia nervosa, and wasting arising from the medical treatment of other diseases.
  • Wasting diseases are those diseases that have in their pathology the loss of non- fluid body mass. Common wasting diseases include cancer, AIDS, anorexia nervosa, and wasting arising from medical treatment of other diseases, for example weight-loss associated with cancer chemotherapy. Wasting may be due to anorexia (a lack of appetite for food, often accompanied by nausea, vomiting and early satiety), and/or cachexia (a generally weakened, emaciated condition of the body that has a metabolic origin).
  • Cancer cachexia which illustrates many of the features present in other wasting diseases, is a complex metabolic syndrome clinically characterized by progressive, involuntary weight-loss, which can be fatal if left unchecked.
  • the major deficit in cachexia is a negative energy balance, in which food intake is inappropriately less than energy output, causing a loss of lean body mass.
  • Lean body mass is assessed by a number of anthropometric measurements such as weight, body mass index, triceps skinfold, mid-arm muscle circumference, and other measurements known to those of skill in the art.
  • Cancer cachexia comprises several nutritional abnormalities, at least some of which are found in most cancer patients at some stage of their illness.
  • the disease includes clinical features associated with progressive growth of a cancer, such as abnormalities of carbohydrate, fat, protein, and energy metabolism.
  • Ma, G., Alexander, H.R. (1998) Prevalence and pathophysiology of cancer cachexia.
  • Bruera, E., Portenoy, R.K. (eds.) Topics in Palliative Care, Vol. 2. New York, Oxford University Press, 91-129.
  • the mechanisms by which patients with cancer develop cachexia and/or anorexia and thereby suffer body compositional changes associated with severe malnourishment remain largely unknown.
  • Cancer cachexia including fatigue, weight loss, and anorexia, is present in approximately one-half of cancer patients during treatment.
  • the prevalence of the disease increases to nearly 100% as the disease progresses. See, e.g. Sloan, G.M., Maher, M. & Brennan, M.F. (198D Nutritional effects of surgery, radiation therapy, and adjuvant chemotherapy for soft tissue sarcomas.
  • Mveloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature, 336, 684-687; Preshaw, R.M., Attisha, R.P., Hollinworth, W.J. (1979) Randomized sequential trial of parenteral nutrition in healing of colonic anastomoses in man.
  • Progesterone analogues such as megestrol acetate or medroxyprogesterone acetate are among the most powerful and best studied appetite stimulants available for clinical treatment of wasting diseases. These drugs were reported to cause appetite stimulation and weight gain in patients with advanced breast or endometrial cancer. Gregory, E.J., et al (1985) Megestrol acetate therapy for advanced breast cancer. J Clin. Oncol., 3, 155-160. Initially, encouraging results were gained from pilot evaluations of megestrol acetate in patients with cancers other than those of the breast or endometrium, which suggested that these drugs stimulate appetite and lead to non-fluid weight gain. Tchekmedyian. et al.
  • corticosteroids can temporarily stimulate appetite in patients with advanced cancer.
  • Mirtazapine (Remeron), 1 ,2,3,4, 10, 14b-hexahydro-2-methyl-pyrazino[2, 1 -a]pyrido[2,3-c] [2] benzazepine (Org 3770), is a second generation antidepressant used primarily in the treatment of major depressive disorder. See, US Patent 4,062,848 to van der Berg, issued December 13, 1977. Mirtazapine has a pharmacological profile that is different from all other currently available antidepressants; it is termed a noradrenergic and specific serotonergic antidepressant (NaSSA). Stahl, S. M.
  • Mirtazapine exists in two enantiomeric forms ( Figure 1), depending upon the chirality of the two aliphatic carbon atoms in the seven-membered ring. These enantiomers are alternately designated either (R) and (S), or (+) and (-). Mirtazapine is currently administered clinically as a racemic mixture. However, the (-) enantiomer is reported to exhibit different adrenergic receptor specificities for compared to the racemic mixture. Haddjeri, N., Blier, P. & De Montigny, C. (1996) J. Pharm. Exp. Therapeutics 277:861-871. In addition to its use as an antidepressant, mirtazapine has been used in cosmetic applications
  • improved treatment methods and associated compounds that increase lean body weight, or decrease the rate of loss of lean body weight in such patients.
  • Such improved methods and medications would improve the quality of life of these patients, increase opportunities for therapeutic intervention to combat the underlying diseases, reduce patient fatigue, and enhance the ability of these patients to function independently.
  • improved medications would be efficacious, well-tolerated, and cause insignificant side-effects.
  • a method for ameliorating non- fluid weight loss in a patient afflicted with a wasting disease comprising administering to said patient an effective dose of a pharmaceutically acceptable salt of an enantiomer of l,2,3,4,10,14b-hexahydro- 2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof, whereby said non-fluid weight loss is ameliorated.
  • the present invention relates to the use of the selective serotonin reuptake antagonist mirtazapine or a pharmaceutially acceptable salt thereof, in an effective amount for the treatment of cancer cachexia and other wasting diseases.
  • the present invention confers numerous advantages compared with the prior art.
  • Administration of compounds according to the present invention does not produce serious side effects, and therefore treatment of patients who may be in a weakened condition is possible.
  • Treatment of wasting disease according to the present invention results in enhanced appetite and an increase in lean body mass, in contrast to the prior art, which only produces increased appetite.
  • the method of the present invention result in lessened fatigue and improved quality of life for patients thus treated, and the methods of the present invention lessen the likelihood that treatment of the underlying disease of a patient must be discontinued due to weakening of the patient through wasting associated with loss of lean body mass.
  • Figure 1 illustrates (A) the (R) enantiomer, and (B) the (S) enantiomer, of mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (Org 3770).
  • Non-fluid weight loss means loss of total body weight that cannot be attributed to dehydration or loss of bodily fluids.
  • Lean body mass is assessed by a number of anthropometric measurement, such as height, weight, triceps skinfold, and midarm circumference.
  • loss of weight is termed ameliorated when either (a) weight increases, or (b) the rate of weight loss that would otherwise occur is decreased.
  • a maximum effective dose is the highest dosage that is tolerated without the patient exhibiting symptoms of side-effects as described herein.
  • Examples of wasting diseases encompassed by the present invention include, but are not limited to, wasting disease, cancer anorexia, cancer cachexia, AIDS anorexia nervosa, and wasting diseases arising from medical treatment of another condition. Examples of the latter category are wasting caused by chemotherapy or radiotherapy in cancer patients.
  • mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l- a]pyrido[2,3-c][2] benzazepine can exist as two enantiomers, (R) and (S) that differ in their biochemical and optical rotatory properties as described herein.
  • R gastrointestinal disturbances
  • S SSRI antidepressants
  • mirtazapine produces, as a side effect, appetite stimulation and weight gain in 17% of patients. This activity may be due in part to the strong antihistamine properties of mirtazapine, but the mechanism does not appear to have been rigorously studied. It is this activity which is central to the present invention.
  • Mirtazapine is currently clinically administered as a racemic mixture.
  • the (-) enantiomer is reported to exhibit different adrenergic receptor specificities for compared to the racemic mixture.
  • mirtazapine overdose appears to produce few sequelae.
  • overdose appears to produce few sequelae.
  • the mirtazapine doses ranged from 10 to 30 times the maximum recommended dose, but there were no serious adverse effects of overdose.
  • compositions of Figure 1 are sufficiently basic or acidic to form stable nontoxic acid or base salts
  • administration of the compounds as salts may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • compositions may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of Figure 1 can be formulated as pharmaceutical compositions and administered to a patient, such as a human patient, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutical ly useful compositions is such that an effective dosage level will be
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its slats can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure-form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are disclosed in Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of Figure 1 can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949. Preferred and best modes for dosages in the instant invention are given in Examples 1-4.
  • concentration of the compound(s) of formula I in a liquid composition such as a lotion, will be from about 0.1-25 wt-%), preferably from about 0.5-10 wt-%.
  • the concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
  • Single dosages for injection, infusion or ingestion will generally vary between 5-1500 mg, and may be administered, i.e., 1-3 times daily, to yield levels of about 0.1-50 mg kg, for adults.
  • a preferred dosage of the present invention is between 7.5 to 45 mg per day, administered orally, with appropriate adjustment for the body weight of an individual.
  • the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Figure 1 as described above; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of one or more compounds of Figure 1 effective to treat wasting diseases in general and cancer cachexia in particular, are a preferred embodiment of the invention.
  • the present invention will be understood by reference to the following examples. Examples 1, 2 and 3 are case histories describing treatment of patients with cancer-induced anorexia/cachexia who have suffered significant weight loss as a result of the cancer and/or its treatment.
  • patients are selected that are without a diagnosis of major depressive disorder, and are treated with mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (Org 3770), with outcomes of significant weight gain and improved appetite.
  • mirtazapine treatment of wasting diseases is limited to those patients who have not been diagnosed with major depressive disorder: mirtazapine may effectively treat both depressive disorders and wasting diseases simultaneously.
  • Example 4 comprises the results of a controlled open-label pilot study of mirtazapine treatment for lung cancer anorexia and cachexia, and illustrates the efficacy, safety, and positive impact on quality of life of the present invention.
  • EXAMPLE 1 RP is seen initially on 10/17/97 for an evaluation of his mood. He is 68 years old and is diagnosed with melanoma in August, 1997 involving his left ear. He also has a left modified radical neck dissection, left posterior lymph node dissection, and left superficial parotidectomy. His pathology reveals Stage III metastatic melanoma to the parotid gland and regional lymph nodes. He begins IV interferon alpha treatment at the beginning of October, 1997, and experiences flu-like symptoms, fatigue, and depressed mood, which precipitates his psychiatric evaluation for depression. He is also receiving radiation therapy to his neck, which he completes at the end of November, 1997.
  • His psychiatric evaluation reveals several neurovegetative symptoms of depression. He admits to a depressed mood, anhedonia, and several somatic symptoms (ie. decreased appetite, weight loss, decreased concentration, and increased sleep). In addition, he admits to feelings of hopelessness, but not burden or guilt. He has no suicidal ideations, intent, or plan. He reports a prior history of depressive feelings nine months prior to his cancer surgery. He has never previously been evaluated by a mental health professional, but is prescribed fluoxetine by his primary care physician. He continues on that medication until his surgery, and notes improvement in his mood. He has no alcohol or illicit drug problem, and he denies any family psychiatric history for mental illness, or alcohol or substance abuse.
  • His mental status reveals a somewhat disheveled, older appearing, woman who is cooperative, engageable and psychologically minded. He is oriented in all spheres. He has some psychomotor retardation and his mood appears dysthymic, his affect being slightly blunted and constricted. Speech is slow and low in volume. Thought processes are goal-directed and thought content reveals no psychotic processes or suicidal or homicidal ideation. Cognitive examination reveals concentration and attention difficulties with verbal memory difficulties. He is diagnosed with a Mood Disorder Secondary to General Medical Condition (depressed with apathy)- 293.83 (related to the interferon). The somatic symptoms as well as the three cognitive symptoms are attributed to the interferon. He is started on bupropion (150 mg BID) and alprazolam (0.5 mg TID PRN) for his anxiety related to possible recurrence of his disease.
  • EXAMPLE 2 LH is initially seen for a psychiatric evaluation on 9/17/98, referred by his oncologist for evaluation of mood changes. He is diagnosed with gastric and esophageal cancer in September, 1996. He receives chemotherapy (5-FU and cisplatin) and radiotherapy, which he completes in November 1996. He undergoes a complete esophagogastrectomy in January, 1997. He has 9/9 peri- gastric nodes positive for metastatic disease. He does well until July, 1998, when he is diagnosed with pulmonary mass.
  • His mood is euthymic and his affect is pleasant with a wide range. Thought processes are goal-directed and thought content does not reveal any psychotic process, suicidal, or homicidal ideation.
  • Cognitive examination reveals no problems with memory or concentration. He is diagnosed with an Adjustment Disorder with physical symptoms and is started on mirtazapine for his loss of appetite. His starting weight is 220.6 lbs. He is quickly titrated to 30 mg QHS of mirtazapine. In October, 1998, he is informed that his pulmonary mass is metastatic disease. He is referred for neuropsychological testing for his fatigue. Testing reveals normal cognitive function. However, he is started on methylphenidate for the fatigue and is titrated to 20 mg BID over two weeks in December, 1998.
  • EXAMPLE 3 JH is seen for psychiatric assessment on October 19, 1998. He is 51 years old and has recently been diagnosed with nasopharyngeal carcinoma. He undergoes combined chemotherapy and radiotherapy and is into his third week of a total of seven weeks of treatment. He presents with anxiety symptoms. He reports anxiety prior to his diagnosis with cancer and has been taking lorazepam for this, with benefit. However, he denies any panic attacks. He adamantly denies any neurovegetative symptoms of depression. He remains very hopeful for the future. He mentions some limitations in his ability to engage in his usual activities, which he attributes to fatigue. He has no significant past psychiatric history.
  • Example four is a study using mirtazapine for cancer anorexia. Five patients complete the study. Two patients who had already completed chemotherapy gain weight during the three-month trial and have sustained improvement in their appetite. Of particular significance is the fact that the three other patients who complete the study are concurrently receiving chemotherapy for their cancers. They do not gain weight during chemotherapy, but they are able to maintain their weight, and their appetites either remain stable or improve. This is a significant illustration of the utility of the present invention, since weight and appetite are usually diminished during chemotherapy. No side effects of mirtazapine are observed other than those listed in the Physicians Desk Reference, and mirtazapine is well-tolerated.
  • This example illustrates the safety and clinical effectiveness of mirtazapine in doses ranging from about 7.5-45 mg daily for the treatment of cancer anorexia induced by lung cancer treatment, and the impact of mirtazapine on aspects of QOL other than weight gain, such as fatigue and role functioning.
  • This is accomplished by conducting standard anthropometric assessments (i.e., height, weight, skin- fold and circumference measurements of triceps and mid-arm, and body mass index), biochemical markers indicative of nutritional status (i.e., albumin, total protein, prealbumin), and QOL (depression, fatigue, and role functioning) before administration of mirtazapine and at weeks 4, 8, and 12.
  • Eligibility of participants of the present example is determined at the time of clinical follow- up through a chart review and a discussion with the patient's attending medical oncologist. Patients who meet all eligibility criteria are introduced to a research assistant by their medical oncologist at the conclusion of the medical visit. The investigators then explain the study to the patient.
  • Nonpsychopharmacological drugs with psychotropic effects are permitted if the participant has been receiving a stable dose of the drug for at least one month before baseline and is expected to continue taking the drug without dose changes throughout the study.
  • certain concomitant treatment nonpsychopharmacological drugs with psychotropic effects that are taken for less than one month before baseline on a scheduled basis are prohibited. This does not include antiemetic medications.
  • concomitant treatments are restricted for the purpose of this example, it should not be construed that the present invention is thus limited.
  • the dose is increased to one tablet once per day in the evening. Every 3 days thereafter, the dose is increased by one-half tablet in the evening. In this way, the dose is increased by one tablet every 6 days.
  • the dose is increased up to a maximum of 3 tablets per day unless: a) the onset of side effects precludes this; b) the increase is not deemed to be in the participant's best interest; or c) the participant has a sustained improvement of more than three weeks consisting of increased appetite and weight gain (a reduction in the frequency and severity of cancer cachexia to mild or none on the FACIT) and a score of +7 or higher on the Clinician Global Improvement Scale.
  • the dose range for the study medication is as follows: Mirtazapine: 7.5 mg to 45 mg/day. Medication is dispensed once per month according to the dosage schedule (TABLE I).
  • Dosage is adjusted to optimize the clinical response with minimum side effects.
  • the following demographic variables are assessed via self-report: age, race, gender, marital status, education, occupation, employment status, religion, and income.
  • the Nam-Powers Index of Occupational Status (Nam CB, Terrie EW (1988) 1980-based Nam-Powers Occupational Status scores (Working paper series 99-48). Tallahassee: Florida State University, Center for the Study of Population.), a measure of family SES, is used. Participants report their own, and their spouse's typical occupation, which is scored using standard criteria for quantifying occupational prestige on a scale of 0 (low) to 100 (high). The higher score of the married couple is used as the index of family SES, as assessed via a semi-structured interview.
  • stage of disease TPM based
  • PSR ECOG Performance Status Rating
  • Nutritional Characteristics Anthropometric measurements are obtained regarding height, weight, triceps skinfold, and midarm circumference. In addition, biochemical markers consisting of albumin and total protein are obtained. Through interview, a recall of a typical 24-hour period of food eaten will be documented. Changes in gastrointestinal symptoms such as appetite, early satiety, nausea, vomiting, stool frequency, or gastrointestinal discomfort are self-monitored.
  • SCID-I-RV (First MB, Gibbon M, Spitzer RL, et al (1996) Users Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders: Research Version. New York, NY., Biometrics Research.) is administered to assess mood.
  • the SCID-I-RV allows the clinician to determine if the interviewee meets criteria for selected Axis I disorders of the DSM-IV.
  • the SCID-I-RV consists of the following diagnostic modules: Mood Episodes, Psychotic Screening, Mood Disorders, Substance Use Disorders, Anxiety Disorders, Somatoform Disorders, Eating Disorders, and Adjustment Disorder.
  • the administration follows the standard SCID format in that all symptoms will be rated as present, subthreshold, or absent.
  • the subthreshold category represents the situation in which the threshold for criterion is almost, but not quite, met (e.g., the individual has been depressed for 10 days rather than the required two weeks).
  • the first 25 interviews are tape-recorded by both the primary rater and the criterion rater. Discrepancies are discussed following review of the tapes. Dual ratings are discontinued when the primary and criterion rater reach 100% agreement about the presence/absence of the disorders over 10 consecutive interviews. After this, ratings are performed by the primary rater. The ratings are periodically examined for reliability by having the criterion rater also rate every fifth interview. Discrepancies are discussed and corrections made for possible rater drift.
  • FACIT Functional Assessment of Anorexia/Cachexia Treatment
  • FACIT Functional Assessment of Chronic Illness Therapy
  • the FACIT system is a collection of QOL instruments targeted to the management of chronic illness and represents Version 4 of the FACT series of questionnaires.
  • the FACIT scale is a 27-item compilation of general questions divided into four primary QOL domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being.
  • the FAACT represents the FACIT subscales plus a subscale specific to Anorexia/Cachexia Treatment.
  • the FACIT system has undergone psychometric testing and possesses very good validity, test-retest reliability, and internal consistency.
  • CES-D Center for Epidemiological Study-Depression (CES-D): The CES-D (Radloff LS (1977) The CES-D scale. A self-report depression scale for research in the general population. Applied
  • Normative data is available for the general population as well as a psychiatric population.
  • the CES-D has very good internal consistency with alphas of 5 for the general population and .90 for the psychiatric population. Spearman-Brown reliability coefficients ranged from .11 -.92 and test-retest correlations range from .51-.67.
  • Fatigue Symptom Inventory (FSI): The FSI (Hann D, Jacobsen PB, Azzarello LM, et al (1998) Measurement of fatigue in cancer patients: Development and validation of the Fatigue Symptom Inventory. Qual Life Res, 7, 301-310.) assesses the frequency and severity of fatigue as well as its perceived interference with quality of life. Frequency is measured as the number of days in the past week (0 to 7) respondents felt fatigued as well as the percentage of each day on average they felt fatigued ( 0, none; 10, entire day). Severity is measured on four separate 11 -point scales ( 0, not at all fatigued; 10, as fatigued as I could be) that assess most, least, and average fatigue during the past week as well as current fatigue.
  • Perceived interference is measured on seven separate 11 -point scales (0, no interference; 10, extreme interference) that assesses the degree to which fatigue was judged to interfere with general level of activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood in the past week. Interference ratings are also summed to yield a total interference score. Previous research has shown the reliability and validity of the FSI with women who are diagnosed with breast cancer as well as women with no history of cancer.
  • GIS Global Improvement Scale
  • Detailed psychiatric and medical history with a DSM-IV multi-axial diagnostic evaluation including the Structured Clinical Interview for Diagnosis of DSM-IV Disorders (SCID).
  • SCID Structured Clinical Interview for Diagnosis of DSM-IV Disorders
  • a detailed appetite and weight loss history are obtained. If the potential participant have a prior psychiatric history, information on prior medication treatments, length of administration and therapeutic response, duration of any current episode of depression and the presence or absence of precipitating factors for the current episode is obtained.
  • Anthropometric measurements i.e., height, weight, triceps skin-fold, and mid-arm circumference.
  • Biochemical markers i.e., albumin, total protein, prealbumin.
  • Fatigue Symptom Inventory (FSI). 13. Screening Form (presence of inclusion criteria and the absence of exclusion criteria).
  • FSI Fatigue Symptom Inventory
  • the Week 12 measurements are obtained within 72 hours of the participant's last dose of study medication. Recognized side effects of mirtazapine include dry mouth, increased appetite, constipation, weight gain, and paradoxical somnolence (decreases with increasing dosage). Any single dose of mirtazapine greater than 1000 mg or any dose of mirtazapine taken in a suicide attempt or gesture considered to be an overdose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for ameliorating the loss of lean body mass that accompanies wasting diseases such as cancer cachexia and anorexia, AIDS, anorexia nervosa, and wasting conditions arising from other medical treatments such as cancer chemotherapy. Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2]benzazepine (Org 3770), is administered as a pharmaceutically acceptable salt in an efficacious dosage, preferably orally, and preferably at a dosage of 7.5 to 45 mg per day. Either (R), (S), or a racemic mixture of mirtazapine enantiomers may be used. The invention provides improved quality of life for patients suffering from wasting diseases, and improves the ability of cancer patients to tolerate chemotherapy.

Description

MIRTAZAPINE FOR WEIGHT GAIN IN WASTING DISEASES
RELATED APPLICATIONS
The present application is related to U.S. Provisional Application 60/140,753 filed 6/25/99, which is hereby incorporated in its entirety by reference.
FIELD OF THE INVENTION
This invention relates to pharmacological treatment of weight-loss associated with the pathology of wasting diseases, including but not limited to cancer anorexia, cancer cachexia, AIDS, anorexia nervosa, and wasting arising from the medical treatment of other diseases. Specifically, administration of mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (Org 3770), as the (R) enantiomer, as the (S) enantiomer, or as a racemic mixture thereof, is taught for the amelioration of non-fluid weight loss in patients suffering from such wasting diseases, whereby non-fluid weight-loss is minimized or reversed.
BACKGROUND OF THE INVENTION
Wasting diseases are those diseases that have in their pathology the loss of non- fluid body mass. Common wasting diseases include cancer, AIDS, anorexia nervosa, and wasting arising from medical treatment of other diseases, for example weight-loss associated with cancer chemotherapy. Wasting may be due to anorexia (a lack of appetite for food, often accompanied by nausea, vomiting and early satiety), and/or cachexia (a generally weakened, emaciated condition of the body that has a metabolic origin).
Cancer cachexia, which illustrates many of the features present in other wasting diseases, is a complex metabolic syndrome clinically characterized by progressive, involuntary weight-loss, which can be fatal if left unchecked. The major deficit in cachexia is a negative energy balance, in which food intake is inappropriately less than energy output, causing a loss of lean body mass. Norton, J.A., Peacock, J.L. & Morrison, S.D. (1987) Cancer cachexia. Crit Rev Oncol Hematol, 7, 289-327. Lean body mass is assessed by a number of anthropometric measurements such as weight, body mass index, triceps skinfold, mid-arm muscle circumference, and other measurements known to those of skill in the art. Cancer cachexia comprises several nutritional abnormalities, at least some of which are found in most cancer patients at some stage of their illness. The disease includes clinical features associated with progressive growth of a cancer, such as abnormalities of carbohydrate, fat, protein, and energy metabolism. Ma, G., Alexander, H.R. (1998) Prevalence and pathophysiology of cancer cachexia. In: Bruera, E., Portenoy, R.K. (eds.) Topics in Palliative Care, Vol. 2. New York, Oxford University Press, 91-129. The mechanisms by which patients with cancer develop cachexia and/or anorexia and thereby suffer body compositional changes associated with severe malnourishment remain largely unknown.
Cancer patients who are malnourished on the basis of cachexia cannot tolerate effective therapy and are more susceptible to the adverse effects of chemotherapy and radiotherapy. Cancer cachexia, including fatigue, weight loss, and anorexia, is present in approximately one-half of cancer patients during treatment. DeWys, W.D., Begg, D., Lavin, P.T. (1980) Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med, 69, 491-499. The prevalence of the disease increases to nearly 100% as the disease progresses. See, e.g. Sloan, G.M., Maher, M. & Brennan, M.F. (198D Nutritional effects of surgery, radiation therapy, and adjuvant chemotherapy for soft tissue sarcomas. Am J Clin Nutr, 34, 1094. Cancer cachexia develops in a majority of patients with advanced malignancy, which impairs their ability to undergo further cancer treatment, and is a major contributing cause of death in up to one-half of these patients. Kern, K.A. & Norton, J.A. (1988) Cancer cachexia. J. Parenter. Enteral. Nutr., 12, 286-298. Attempts at replenishment of the cachectic patient with enteral or parenteral nutrition have only been partially successful. In some reports, enteral or parenteral nutrition was effective in interrupting or reversing some of the metabolic sequelae of advancing malignancy. See, e.g. Daly, J.M., Copeland, E.M. & Dudrick, S J. (1978) Effects of intravenous nutrition on tumor growth and host immunocompetence in malnourished animals. Surgery, 84, 655-658; and Bozzetti, F., Migliavacca, S., Pupa, A., Ammatuna, M., Bonalumi, M.G., Terno, G. & Facchetti, G. (1987) Total parenteral nutrition prevents further nutritional deterioration in patients with cancer cachexia. Ann Surg, 205, 138-143.
However, only in certain groups of cancer patients does total parenteral nutrition appear to decrease operative morbidity and mortality. Muller, J.M., Brenner, U., Dienst, C. & Picklmaier, H. (1982) Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet, 1, 68-71. For example, one report suggests a benefit of parenteral nutrition to patients undergoing high-dose chemotherapy and bone marrow transplant. Ignoffo, RJ. (1992) Parenteral nutrition support in patients with cancer. Pharmaotherapy, 12, 353-357. In contrast, total parenteral nutrition has been shown not to improve survival in other groups of cancer patients. See, e.g. Williams, R.L., Hilton, D.J., Pease, S., Wilson, T.A., Stewart, C.L., Gearing, D.P., Wagner, E.F, Metcalf, D., Nicola, N.A. & Gough, N.M. (1988) Mveloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature, 336, 684-687; Preshaw, R.M., Attisha, R.P., Hollinworth, W.J. (1979) Randomized sequential trial of parenteral nutrition in healing of colonic anastomoses in man. Can J Cancer, 22, 437-439; and Lim, S.T.K., Choa, R.G., Lam, K.H., Wong, J. & Ong, G.B. (1981) Total parenteral nutrition versus gastrostomy in the preoperative preparation of patients with carcinoma of the oesophagus. Br. J. Surg., 68, 69-72.
Progesterone analogues such as megestrol acetate or medroxyprogesterone acetate are among the most powerful and best studied appetite stimulants available for clinical treatment of wasting diseases. These drugs were reported to cause appetite stimulation and weight gain in patients with advanced breast or endometrial cancer. Gregory, E.J., et al (1985) Megestrol acetate therapy for advanced breast cancer. J Clin. Oncol., 3, 155-160. Initially, encouraging results were gained from pilot evaluations of megestrol acetate in patients with cancers other than those of the breast or endometrium, which suggested that these drugs stimulate appetite and lead to non-fluid weight gain. Tchekmedyian. et al. (1987) High-dose megestrol acetate: A possible treatment for cachexia. JAMA. 257. However, a number of subsequent placebo-controlled, double-blinded, randomized clinical trials have been performed on patients with cancer anorexia/cachexia, but none of these studies have shown a positive effect on body weight. For example, a first trial demonstrated substantial increases in appetite and fluid intake in patients receiving 800 mg/day of megestrol acetate compared with placebo. Loprinzi, C.L., Ellison, N.M. & Schaid, D.J., et al (1990) Controlled trial of megesterol acetate for the treatment of cancer anorexia and cachexia. J. Natl. Cancer Inst., 82, 1127-1132. Similarly, four placebo-controlled clinical trials have all demonstrated that corticosteroids can temporarily stimulate appetite in patients with advanced cancer. Moertel, C.G., Schutt, A.J., Reitemeier, R.J. & Hahn, R.G. (1974) Corticosteroid therapy of pretenninal gastrointestinal cancer. Cancer, 33, 1607; Bruera, E., et al (1985) Action of oral methylprednisolone in terminal cancer patients: A prospective randomized double-blind study. Cancer Treat. Rep., 69, 751-754; Popiela, T., Lucchi, R. & Giongo, F. (1989) Methylprednisolone as an appetite stimulant in patients with cancer. Eur. J. Cancer Clin. Oncol., 25, 1823-1829; and Wilcox, J., et al (1984) Prednisolone as an appetite stimulant in patients with cancer, Br. Med. J., 288, 27. The main drawback to the use megestrol acetate in the treatment of cancer cachexia is therefore that, although appetite and fluid intake appear to be substantially increased, none of the studies to date have shown a positive effect on body weight. In addition, megestrol acetate has several untoward side effects.
Other agents have been tested for an ability to increase appetite, increase lean body weight, and thereby improve cancer anorexia or cachexia. However, none of the tested compounds have yet shown any efficacy in increasing lean body weight.
Mirtazapine (Remeron), 1 ,2,3,4, 10, 14b-hexahydro-2-methyl-pyrazino[2, 1 -a]pyrido[2,3-c] [2] benzazepine (Org 3770), is a second generation antidepressant used primarily in the treatment of major depressive disorder. See, US Patent 4,062,848 to van der Berg, issued December 13, 1977. Mirtazapine has a pharmacological profile that is different from all other currently available antidepressants; it is termed a noradrenergic and specific serotonergic antidepressant (NaSSA). Stahl, S. M. (1998) Basic Psychopharmacology of Antidepressants, Part 1 : Antidepressants Have Seven Distinct Mechanisms of Action J. Clin. Psychology 59:5-14. Mirtazapine has both pro-adrenergic and pro-serotogenic actions that are due to its 2 adrenoceptor antagonism, which disinhibits both serotonin and norepinephrine neurotransmission. Because of the serotonin receptor subtypes targeted by mirtazapine, this medication produces fewer side effects than other antidepressant serotonin selective reuptake inhibitors (SSRIs) such as nefadozone.
Mirtazapine exists in two enantiomeric forms (Figure 1), depending upon the chirality of the two aliphatic carbon atoms in the seven-membered ring. These enantiomers are alternately designated either (R) and (S), or (+) and (-). Mirtazapine is currently administered clinically as a racemic mixture. However, the (-) enantiomer is reported to exhibit different adrenergic receptor specificities for compared to the racemic mixture. Haddjeri, N., Blier, P. & De Montigny, C. (1996) J. Pharm. Exp. Therapeutics 277:861-871. In addition to its use as an antidepressant, mirtazapine has been used in cosmetic applications
(see, US patent 5,827,853 to Blanc Ferras et al., issued October 27, 1998), as a taxane conjugate (see, US patent 5,795,909 to Shashoua et al., issued August 18, 1998), and in a method of nicotine withdrawal (see, US patent 5,780,051 to Eswara et al, issued July 14, 1998).
Therefore, within the field of the treatment of wasting diseases in general, and cancer cachexia in particular, there is a clear need for improved treatment methods and associated compounds that increase lean body weight, or decrease the rate of loss of lean body weight in such patients. Such improved methods and medications would improve the quality of life of these patients, increase opportunities for therapeutic intervention to combat the underlying diseases, reduce patient fatigue, and enhance the ability of these patients to function independently. Preferably, improved medications would be efficacious, well-tolerated, and cause insignificant side-effects. The use of mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (Org 3770) in the novel invention disclosed herein fulfills this need and more.
SUMMARY OF THE INVENTION In accordance with the present invention, there is provided a method for ameliorating non- fluid weight loss in a patient afflicted with a wasting disease, comprising administering to said patient an effective dose of a pharmaceutically acceptable salt of an enantiomer of l,2,3,4,10,14b-hexahydro- 2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof, whereby said non-fluid weight loss is ameliorated.
It is therefore an objective of the present invention to provide a method for increasing the lean body weight of a patient suffering from a wasting disease. It is a further objective to provide a method for minimizing the loss of lean body weight that would otherwise occur in a patient as a result of a wasting disease.
It is therefore an objective of the present invention to provide a method of producing a reduction in nutritional symptoms related to anorexia such as nausea, vomiting, early satiety. It is a further objective to provide a method of preventing loss of lean body mass without producing undesired side effects such sexual dysfunction, gastrointestinal disturbances, or dangers associated with overdose. It is a further objective of the present invention to provide method for increasing appetite in a patient at risk of inappropriate loss of lean body mass related to a wasting disease.
It is a still further objective of the present invention to provide a method of increasing lean body mass as assessed by anthropometric measures such as weight, body mass index, triceps skinfold, and mid-arm muscle circumference.
It is a still further objective of the present invention to provide a method of improving a subjects quality of life by decreasing fatigue and improving the ability of a patient to function independently, where impairment of quality of life or independence is related to a wasting disease. The present invention relates to the use of the selective serotonin reuptake antagonist mirtazapine or a pharmaceutially acceptable salt thereof, in an effective amount for the treatment of cancer cachexia and other wasting diseases.
The present invention confers numerous advantages compared with the prior art. Administration of compounds according to the present invention does not produce serious side effects, and therefore treatment of patients who may be in a weakened condition is possible. Treatment of wasting disease according to the present invention results in enhanced appetite and an increase in lean body mass, in contrast to the prior art, which only produces increased appetite. The method of the present invention result in lessened fatigue and improved quality of life for patients thus treated, and the methods of the present invention lessen the likelihood that treatment of the underlying disease of a patient must be discontinued due to weakening of the patient through wasting associated with loss of lean body mass.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates (A) the (R) enantiomer, and (B) the (S) enantiomer, of mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (Org 3770). DETAILED DESCRIPTION OF THE INVENTION
In the following detailed disclosure of the invention, certain terms are used that are understood to have the following meanings, including all functional equivalents. Non-fluid weight loss means loss of total body weight that cannot be attributed to dehydration or loss of bodily fluids.
Lean body mass is assessed by a number of anthropometric measurement, such as height, weight, triceps skinfold, and midarm circumference.
Within the present invention, loss of weight is termed ameliorated when either (a) weight increases, or (b) the rate of weight loss that would otherwise occur is decreased.
A maximum effective dose is the highest dosage that is tolerated without the patient exhibiting symptoms of side-effects as described herein.
Examples of wasting diseases encompassed by the present invention include, but are not limited to, wasting disease, cancer anorexia, cancer cachexia, AIDS anorexia nervosa, and wasting diseases arising from medical treatment of another condition. Examples of the latter category are wasting caused by chemotherapy or radiotherapy in cancer patients.
As illustrated in Figure 1, mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l- a]pyrido[2,3-c][2] benzazepine (ORG 3770), can exist as two enantiomers, (R) and (S) that differ in their biochemical and optical rotatory properties as described herein. Of particular importance to the present invention are the lack of gastrointestinal disturbances compared to SSRIs, and lower incidence of sexual disfunction than occurs with SSRI antidepressants. When used as an antidepressant, mirtazapine produces, as a side effect, appetite stimulation and weight gain in 17% of patients. This activity may be due in part to the strong antihistamine properties of mirtazapine, but the mechanism does not appear to have been rigorously studied. It is this activity which is central to the present invention.
Mirtazapine is currently clinically administered as a racemic mixture. However, the (-) enantiomer is reported to exhibit different adrenergic receptor specificities for compared to the racemic mixture. Haddjeri, N., Blier, P. & De Montigny, C. (1996) J. Pharm. Exp. Therapeutics 277:861-871. as noted above. Therefore, the preferred embodiment of the present invention comprises administration of the most efficacious combination of enantiomers, whether a pure enantiomer or a racemic mixture.
A further benefit of the use of mirtazapine is that overdose appears to produce few sequelae. (Bremner J.D. et al. (1998) Safety of mirtazapine in overdose, J. Clin. Psychiatry 59:233-235). In 6 patients, the mirtazapine doses ranged from 10 to 30 times the maximum recommended dose, but there were no serious adverse effects of overdose. Two patients at special risk, a 90-year-old man and a 3 -year-old child, took higher-than-usual doses without serious sequelae.
Under conditions where compounds of Figure 1 are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made. The compounds of Figure 1 can be formulated as pharmaceutical compositions and administered to a patient, such as a human patient, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutical ly useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.
The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its slats can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions. For topical administration, the present compounds may be applied in pure-form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user. Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are disclosed in Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of Figure 1 can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949. Preferred and best modes for dosages in the instant invention are given in Examples 1-4. Generally, the concentration of the compound(s) of formula I in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%), preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%. Single dosages for injection, infusion or ingestion will generally vary between 5-1500 mg, and may be administered, i.e., 1-3 times daily, to yield levels of about 0.1-50 mg kg, for adults. A preferred dosage of the present invention is between 7.5 to 45 mg per day, administered orally, with appropriate adjustment for the body weight of an individual.
Accordingly, the invention includes a pharmaceutical composition comprising a compound of Figure 1 as described above; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. Pharmaceutical compositions adapted for oral, topical or parenteral administration, comprising an amount of one or more compounds of Figure 1 effective to treat wasting diseases in general and cancer cachexia in particular, are a preferred embodiment of the invention. The present invention will be understood by reference to the following examples. Examples 1, 2 and 3 are case histories describing treatment of patients with cancer-induced anorexia/cachexia who have suffered significant weight loss as a result of the cancer and/or its treatment. For illustrative purposes, patients are selected that are without a diagnosis of major depressive disorder, and are treated with mirtazapine, l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (Org 3770), with outcomes of significant weight gain and improved appetite. It should not be inferred from the foregoing that mirtazapine treatment of wasting diseases is limited to those patients who have not been diagnosed with major depressive disorder: mirtazapine may effectively treat both depressive disorders and wasting diseases simultaneously. Example 4 comprises the results of a controlled open-label pilot study of mirtazapine treatment for lung cancer anorexia and cachexia, and illustrates the efficacy, safety, and positive impact on quality of life of the present invention.
EXAMPLE 1 RP is seen initially on 10/17/97 for an evaluation of his mood. He is 68 years old and is diagnosed with melanoma in August, 1997 involving his left ear. He also has a left modified radical neck dissection, left posterior lymph node dissection, and left superficial parotidectomy. His pathology reveals Stage III metastatic melanoma to the parotid gland and regional lymph nodes. He begins IV interferon alpha treatment at the beginning of October, 1997, and experiences flu-like symptoms, fatigue, and depressed mood, which precipitates his psychiatric evaluation for depression. He is also receiving radiation therapy to his neck, which he completes at the end of November, 1997.
His psychiatric evaluation reveals several neurovegetative symptoms of depression. He admits to a depressed mood, anhedonia, and several somatic symptoms (ie. decreased appetite, weight loss, decreased concentration, and increased sleep). In addition, he admits to feelings of hopelessness, but not burden or guilt. He has no suicidal ideations, intent, or plan. He reports a prior history of depressive feelings nine months prior to his cancer surgery. He has never previously been evaluated by a mental health professional, but is prescribed fluoxetine by his primary care physician. He continues on that medication until his surgery, and notes improvement in his mood. He has no alcohol or illicit drug problem, and he denies any family psychiatric history for mental illness, or alcohol or substance abuse. His mental status reveals a somewhat disheveled, older appearing, gentleman who is cooperative, engageable and psychologically minded. He is oriented in all spheres. He has some psychomotor retardation and his mood appears dysthymic, his affect being slightly blunted and constricted. Speech is slow and low in volume. Thought processes are goal-directed and thought content reveals no psychotic processes or suicidal or homicidal ideation. Cognitive examination reveals concentration and attention difficulties with verbal memory difficulties. He is diagnosed with a Mood Disorder Secondary to General Medical Condition (depressed with apathy)- 293.83 (related to the interferon). The somatic symptoms as well as the three cognitive symptoms are attributed to the interferon. He is started on bupropion (150 mg BID) and alprazolam (0.5 mg TID PRN) for his anxiety related to possible recurrence of his disease.
Over the next six months, his mood improves gradually as well as his anxiety. In March 1998, methylphenidate is added to a total dose of 30 mg BID for his concentration difficulties and worsening fatigue. By the beginning of May, 1998, his secondary mood symptoms are resolved. Following neuropsychological testing in April, 1998, which reveals problems with psychomotor speed, memory, and executive function, his methylphenidate is increased to 40 mg BID. He experiences some worsening in fatigue related to interferon treatement, becomes concerned with the methylphenidate treatment, and requests its discontinuation. He is tapered off methylphenidate, which is completed by the middle of June, 1998. His mood continues to do well on bupropion treatement, and he is eventually tapered off bupropion in September, 1998, after completing the recommended treatment.
Throughout the disease course, his appetite and weight remain problematic. He starts his cancer treatment at a weight of 190 lbs. Over the course of one year, he loses almost 34 lbs. After coming off bupropion, no change is noted in his appetite or weight. His mood remains stable without evidence of depression. He is started on mirtazapine on October 1, 1998 at a starting weight of 156.6 lbs. He titrates quickly up to 30 mg QHS and on December 3, 1998, his weight was 168.2 lb. At that time, he is increased to 45 mg of mirtazapine. By February 28, 1999, his weight has increased to 182 lbs with full recovery of his appetite. He remains stable on this dose of medication.
EXAMPLE 2 LH is initially seen for a psychiatric evaluation on 9/17/98, referred by his oncologist for evaluation of mood changes. He is diagnosed with gastric and esophageal cancer in September, 1996. He receives chemotherapy (5-FU and cisplatin) and radiotherapy, which he completes in November 1996. He undergoes a complete esophagogastrectomy in January, 1997. He has 9/9 peri- gastric nodes positive for metastatic disease. He does well until July, 1998, when he is diagnosed with pulmonary mass.
During his psychiatric evaluations, he denies neurovegetative symptoms of depression. He endorses anxiety symptoms, mostly fears of recurrence and what that means for his life expectancy. He reports sleeping more than usual: 9-10 hours per night with an additional 4-6 hours during the day. He remains highly motivated to return to work. He denies any problems with memory or concentration. He is most concerned with the extreme fatigue he is experiencing, as well as the total loss of appetite. He denies any past psychiatric history or family psychiatric history. He does have a history of heavy alcohol use, but not currently. Upon mental status examination, he is well-groomed, cooperative, and engageable. He is oriented in all spheres. There is no psychomotor retardation or agitation. His mood is euthymic and his affect is pleasant with a wide range. Thought processes are goal-directed and thought content does not reveal any psychotic process, suicidal, or homicidal ideation. Cognitive examination reveals no problems with memory or concentration. He is diagnosed with an Adjustment Disorder with physical symptoms and is started on mirtazapine for his loss of appetite. His starting weight is 220.6 lbs. He is quickly titrated to 30 mg QHS of mirtazapine. In October, 1998, he is informed that his pulmonary mass is metastatic disease. He is referred for neuropsychological testing for his fatigue. Testing reveals normal cognitive function. However, he is started on methylphenidate for the fatigue and is titrated to 20 mg BID over two weeks in December, 1998. His weight has increased to 232.2 lbs over the two months of mirtazapine treatment with modest improvement in his appetite. Repeat neuropsychological testing shows no change in his cognitive functioning. However, subjectively, LH is no longer sleeping during the day and is more active. He continues to report fatigue. He loses 5 lbs after starting the methylphenidate, but reports no worsening of his appetite.
EXAMPLE 3 JH is seen for psychiatric assessment on October 19, 1998. He is 51 years old and has recently been diagnosed with nasopharyngeal carcinoma. He undergoes combined chemotherapy and radiotherapy and is into his third week of a total of seven weeks of treatment. He presents with anxiety symptoms. He reports anxiety prior to his diagnosis with cancer and has been taking lorazepam for this, with benefit. However, he denies any panic attacks. He adamantly denies any neurovegetative symptoms of depression. He remains very hopeful for the future. He mentions some limitations in his ability to engage in his usual activities, which he attributes to fatigue. He has no significant past psychiatric history. He has a son who has a diagnosis of Obsessive-Compulsive Disorder but is doing very well on fluvoxamine. JH is currently on leave from his teaching position at a university. He is diagnosed, at that time, with Generalized Anxiety Disorder and he is prescribed clonazepam. He is encouraged to engage in supportive counseling.
He returns to the clinic in March 1999 for a reassessment. He completes his radiation treatments, returns to work, and teaches two classes. Apart from continued fatigue, he is only concerned with his loss of appetite and significant weight loss. He states that he has lost approximately 45 pounds during his treatments. He states that he has no interest in eating and has lost a taste for food. He can force himself to eat only when he knows it is necessary. He continues to deny any neurovegetative symptoms of depression. He also continues to maintain a very positive attitude and is enjoying his usual activities. He is diagnosed with an Adjustment Disorder with anxious features and cancer treatment-induced anorexia. He is prescribed mirtazapine, titrating to a final dose of 30 mg per day. His weight is 166 lbs.
He returns to the clinic one month later weighing 171 lbs. He states that he has noticed significant changes in his appetite since starting mirtazapine. He further states that he is eating more and is more interested in his eating. He continues to have no neurovegetative symptoms of depression.
EXAMPLE 4
Example four is a study using mirtazapine for cancer anorexia. Five patients complete the study. Two patients who had already completed chemotherapy gain weight during the three-month trial and have sustained improvement in their appetite. Of particular significance is the fact that the three other patients who complete the study are concurrently receiving chemotherapy for their cancers. They do not gain weight during chemotherapy, but they are able to maintain their weight, and their appetites either remain stable or improve. This is a significant illustration of the utility of the present invention, since weight and appetite are usually diminished during chemotherapy. No side effects of mirtazapine are observed other than those listed in the Physicians Desk Reference, and mirtazapine is well-tolerated.
This example illustrates the safety and clinical effectiveness of mirtazapine in doses ranging from about 7.5-45 mg daily for the treatment of cancer anorexia induced by lung cancer treatment, and the impact of mirtazapine on aspects of QOL other than weight gain, such as fatigue and role functioning. This is accomplished by conducting standard anthropometric assessments (i.e., height, weight, skin- fold and circumference measurements of triceps and mid-arm, and body mass index), biochemical markers indicative of nutritional status (i.e., albumin, total protein, prealbumin), and QOL (depression, fatigue, and role functioning) before administration of mirtazapine and at weeks 4, 8, and 12. In addition, patients complete a standard 24-hour recall of foods eaten during a typical 24-hour period obtained by interview at baseline and at weeks 4, 8, and 12 on treatment. Patients with lung cancer who meet the criteria for anorexia are recruited and accrued to this study consecutively. After written informed consent is obtained, patients receive mirtazapine for 12 weeks. Patients who are taking other appetite stimulants at the time of recruitment to this study are excluded. (a) Selection of Participants
Eligibility of participants of the present example is determined at the time of clinical follow- up through a chart review and a discussion with the patient's attending medical oncologist. Patients who meet all eligibility criteria are introduced to a research assistant by their medical oncologist at the conclusion of the medical visit. The investigators then explain the study to the patient.
Prior to clinical follow-up, patients with lung cancer receiving treatment are seen every three to four weeks in a thoracic oncology clinic. Patients requiring chemotherapy receive Taxol and Carboplatin administered every three to four weeks. The neutropenia experienced by patients is minimal and blood counts are monitored on days 10-12. Navelbine and Gemcitabine chemotherapy regimens are administered weekly, and blood counts are monitored weekly. After completion of treatment, patients are monitored every three months for one year, and then every six months for another two years. All concomitant medications taken during the study are recorded, along with dosage information, start and stop dates. Certain concomitant treatments are permitted within this study: Temazepam, or Restoril, (up to 60 mg at bedtime; maximum 4 times/week) is permitted through day 21 if needed for sleep. Antiemetic medications are permitted.
Nonpsychopharmacological drugs with psychotropic effects are permitted if the participant has been receiving a stable dose of the drug for at least one month before baseline and is expected to continue taking the drug without dose changes throughout the study. However, certain concomitant treatment: nonpsychopharmacological drugs with psychotropic effects that are taken for less than one month before baseline on a scheduled basis are prohibited. This does not include antiemetic medications. Although concomitant treatments are restricted for the purpose of this example, it should not be construed that the present invention is thus limited.
(b) Treatment Protocols Medication is taken orally once per day in the evening with food. Participants are treated with mirtazapine for up to 12 weeks. Participants are seen monthly and are contacted weekly by the investigator and research assistant to monitor progress and to decide possible dosage increases.
Participants complete the outcome assessments at baseline before beginning medication and then at weeks 4, 8, and 12 after starting the medications. Patients complete standardized self-report questionnaires assessing cancer anorexia, fatigue, depression, role functioning, and global improvement. Patients also complete an interview-guided 24-hour recall of food eaten, have a small amount of blood taken for evaluation of the biochemical markers of nutrition, and complete symptom diaries for gastrointestinal symptoms. Mirtazapine doses are in keeping with its labeling for major depression. Mirtazapine is supplied in 15 mg tablets divided in half. The dosing schedule (TABLE I) follows a flexible dosing format, which is standard practice in the dosing of antidepressant medications. Therefore, each participant begins medication by taking one-half tablet once a day in the evening. After one (1) day, the dose is increased to one tablet once per day in the evening. Every 3 days thereafter, the dose is increased by one-half tablet in the evening. In this way, the dose is increased by one tablet every 6 days. The dose is increased up to a maximum of 3 tablets per day unless: a) the onset of side effects precludes this; b) the increase is not deemed to be in the participant's best interest; or c) the participant has a sustained improvement of more than three weeks consisting of increased appetite and weight gain (a reduction in the frequency and severity of cancer cachexia to mild or none on the FACIT) and a score of +7 or higher on the Clinician Global Improvement Scale. Throughout the remainder of the study there is flexible dosing to permit the clinician to get the best optimal balance between side effects and benefit for the participant. The dose range for the study medication is as follows: Mirtazapine: 7.5 mg to 45 mg/day. Medication is dispensed once per month according to the dosage schedule (TABLE I).
Dosage is adjusted to optimize the clinical response with minimum side effects.
TABLE I Dosage Levels and Schedule of Administration
Week Day Bedtime Total # Capsules Mirtazapine
1 1 2 2 7.5 mg
2-4 1 1 15 mg
5-7 1 2 1 2 22.5 mg
2 8-10 2 2 30 mg
1 1-13 2 2 2 2 37.5 mg
14 3 3 45 mg
3-12 15-84 3 3 45 mg
( _c Assessment Methods
The following demographic variables are assessed via self-report: age, race, gender, marital status, education, occupation, employment status, religion, and income. The Nam-Powers Index of Occupational Status (Nam CB, Terrie EW (1988) 1980-based Nam-Powers Occupational Status scores (Working paper series 99-48). Tallahassee: Florida State University, Center for the Study of Population.), a measure of family SES, is used. Participants report their own, and their spouse's typical occupation, which is scored using standard criteria for quantifying occupational prestige on a scale of 0 (low) to 100 (high). The higher score of the married couple is used as the index of family SES, as assessed via a semi-structured interview.
The following medical variables of the participant are assessed via chart review and discussion with the physician co- investigators: stage of disease (TNM based), ECOG Performance Status Rating (PSR). (Zubrod CG, Schneiderman M, Frei E, et al (1960) Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and trimethylene thiophosphoramide. Journal of Chronic Diseases, 11, 7-33.), time since cancer diagnosis, time since surgery, number of chemotherapy cycles and names of chemotherapy agents, total cGy of radiation treatments, other current medications, and other medical conditions.
Nutritional Characteristics: Anthropometric measurements are obtained regarding height, weight, triceps skinfold, and midarm circumference. In addition, biochemical markers consisting of albumin and total protein are obtained. Through interview, a recall of a typical 24-hour period of food eaten will be documented. Changes in gastrointestinal symptoms such as appetite, early satiety, nausea, vomiting, stool frequency, or gastrointestinal discomfort are self-monitored.
Structured Clinical Interview for the DSM-IV, Research Version (SCID-I-RV): The
SCID-I-RV (First MB, Gibbon M, Spitzer RL, et al (1996) Users Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders: Research Version. New York, NY., Biometrics Research.) is administered to assess mood. The SCID-I-RV allows the clinician to determine if the interviewee meets criteria for selected Axis I disorders of the DSM-IV. The SCID-I-RV consists of the following diagnostic modules: Mood Episodes, Psychotic Screening, Mood Disorders, Substance Use Disorders, Anxiety Disorders, Somatoform Disorders, Eating Disorders, and Adjustment Disorder. The administration follows the standard SCID format in that all symptoms will be rated as present, subthreshold, or absent. The subthreshold category represents the situation in which the threshold for criterion is almost, but not quite, met (e.g., the individual has been depressed for 10 days rather than the required two weeks). The first 25 interviews are tape-recorded by both the primary rater and the criterion rater. Discrepancies are discussed following review of the tapes. Dual ratings are discontinued when the primary and criterion rater reach 100% agreement about the presence/absence of the disorders over 10 consecutive interviews. After this, ratings are performed by the primary rater. The ratings are periodically examined for reliability by having the criterion rater also rate every fifth interview. Discrepancies are discussed and corrections made for possible rater drift. Functional Assessment of Anorexia/Cachexia Treatment (FAACT): This instrument is a symptom-specific subscale of the Functional Assessment of Chronic Illness Therapy (FACIT). The FACIT system is a collection of QOL instruments targeted to the management of chronic illness and represents Version 4 of the FACT series of questionnaires. The FACIT scale is a 27-item compilation of general questions divided into four primary QOL domains: Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, and Functional Well-Being. The FAACT represents the FACIT subscales plus a subscale specific to Anorexia/Cachexia Treatment. The FACIT system has undergone psychometric testing and possesses very good validity, test-retest reliability, and internal consistency. Cella, D. (1997) Manual of the Functional Assessment of Chronic Illness Therapy (FACIT) Scales. Evanston, IL: Center on Outcomes, Research, and Education; Cella, D.F., Tulsky, D.S., Gray, G., Sarafian, B, Lloyd, S, et al (1993) The Functional Assessment of Cancer Therapy (FACT) Scale: Development and validation of the general measure. J Clin. Oncol., 11, 570-579.
Center for Epidemiological Study-Depression (CES-D): The CES-D (Radloff LS (1977) The CES-D scale. A self-report depression scale for research in the general population. Applied
Psychological Measurement, 1, 385-401. Devins, G.M., Orme, CM., Costello, C.G., Binik, Y.M., Frizzell, B, Stam H.J., Pullin, W.M. (1988) Measuring depressive symptoms in illness populations: Psychometric properties of the Center for Epidemiologic Studies Depression (CES-D) Scale. Psychology and Health, 2, 139-156.) is a 20-item scale that measures current level of depressive symptomatology, with emphasis on the affective component—depressed mood. The items are selected from a pool of items from previously validated depression scales, from the literature, and from factor analytic studies. Normative data is available for the general population as well as a psychiatric population. The CES-D has very good internal consistency with alphas of 5 for the general population and .90 for the psychiatric population. Spearman-Brown reliability coefficients ranged from .11 -.92 and test-retest correlations range from .51-.67.
Fatigue Symptom Inventory (FSI): The FSI (Hann D, Jacobsen PB, Azzarello LM, et al (1998) Measurement of fatigue in cancer patients: Development and validation of the Fatigue Symptom Inventory. Qual Life Res, 7, 301-310.) assesses the frequency and severity of fatigue as well as its perceived interference with quality of life. Frequency is measured as the number of days in the past week (0 to 7) respondents felt fatigued as well as the percentage of each day on average they felt fatigued ( 0, none; 10, entire day). Severity is measured on four separate 11 -point scales ( 0, not at all fatigued; 10, as fatigued as I could be) that assess most, least, and average fatigue during the past week as well as current fatigue. Perceived interference is measured on seven separate 11 -point scales (0, no interference; 10, extreme interference) that assesses the degree to which fatigue was judged to interfere with general level of activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood in the past week. Interference ratings are also summed to yield a total interference score. Previous research has shown the reliability and validity of the FSI with women who are diagnosed with breast cancer as well as women with no history of cancer.
Global Improvement Scale (GIS), Participant-Rated and Clinician-Ratedi The GIS
(Sheehan DFV, Harnett- Sheehan K (1990) Psychometric assessment of anxiety disorders. In: Sartorius N, Andreoli V, Cassano G, Eisenberg L, Kielholz P, Pancheri P, Racagni G (eds.) Anxiety: Psychobiological and clinical perspectives. Washington, DC: Hemisphere Publishing Corporation, 85- 100.) is a one- item scale that combines a likert-type response with a linear analogue scale. The clinician and participant are asked to rate the participant's improvement since starting treatment with a score ranging from -10 (very bad, could not be worse) to 10 (major improvement. Back to normal self). This scale has been used in numerous psychopharmacological trials and has been shown to have good face validity. Sheehan, D.V., Raj, AB., Harnett-Sheehan K, Soto, S, Knapp, E (1993) The relative efficacy of high dose buspirone and alprazolam in the treatment of panic disorder: A double- blind placebo-controlled study. Acta Psychiatrica Scandinavica, 88(1), 1-1 1; Sheehan, D.V., Dunbar, G.C., Fuell, D.L. (1992) The effect of paroxetine on anxiety and agitation associated with depression. Psychopharmacology Bulletin, 28(2), 139-143. Roth, D., Mattes, J, Sheehan KH, Sheehan DV (1990) A double-blind comparison of fluvoxamine, desipramine and placebo in outpatients with depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 14, 929-939).
(d) Baseline Evaluation
The following data is collected from participants at the Baseline Evaluation:
1. Detailed psychiatric and medical history with a DSM-IV multi-axial diagnostic evaluation, including the Structured Clinical Interview for Diagnosis of DSM-IV Disorders (SCID). A detailed appetite and weight loss history are obtained. If the potential participant have a prior psychiatric history, information on prior medication treatments, length of administration and therapeutic response, duration of any current episode of depression and the presence or absence of precipitating factors for the current episode is obtained.
2. Physical Examination. 3. Vital Signs — oral temperature (degrees Fahrenheit), systolic and diastolic blood pressure and heart rate.
4. ECOG Performance Status Rating (PSR).
5. Anthropometric measurements (i.e., height, weight, triceps skin-fold, and mid-arm circumference).
6. Body Mass Index.
7. Biochemical markers (i.e., albumin, total protein, prealbumin).
8. Frequency and severity of cancer cachexia and anorexia using the Functional Assessment of Chronic Illness Therapy (FACIT)- Anorexia/Cachexia Scale. 9. Standard 24-hour recall of foods eaten during a typical 24-hour period obtained through interview.
10. Personal Data Inventory.
11. Center for Epidemiological Study-Depression (CES-D).
12. Fatigue Symptom Inventory (FSI). 13. Screening Form (presence of inclusion criteria and the absence of exclusion criteria).
14. Concomitant medication record.
15. Study medication record.
(e) Repeat Evaluations
The following self-report instruments and measurements are administered at weeks 4, 8, and 12:
1. Anthropometric measurement.
2. Body Mass Index. 3. Biochemical markers
4. Frequency and severity of cancer cachexia and anorexia using the Functional Assessment of Chronic Illness Therapy (FACIT)- Anorexia/Cachexia Scale.
5. Standard 24-hour recall of foods eaten during a typical 24-hour period obtained through interview. 6. Center for Epidemiological Study-Depression evaluation (CES-D).
7. Fatigue Symptom Inventory (FSI).
8. Clinician Global Improvement Scale (10-point).
9. Participant Global Improvement Scale (10-point).
10. ECOG Performance Status Rating (PSR). 11. Concomitant medication record.
12. Study medication record.
Efficacy is assessed with the following rating scales as outlined above on weeks 4, 8, and 12:
1. Anthropometric measurements.
2. Body Mass Index.
3. Biochemical markers.
4. Frequency and severity of cancer cachexia and anorexia using the Functional Assessment of Chronic Illness Therapy (FACIT)- Anorexia/Cachexia Scale.
5. Clinician Global Improvement Scale (10-point)
6. Participant Global Improvement Scale (10-point)
7. Center for Epidemiological Study-Depression (CES-D).
8. Fatigue Symptom Inventory (FSI). 9. Standard 24-hour recall of foods eaten during a typical 24-hour period obtained through interview.
The Week 12 measurements are obtained within 72 hours of the participant's last dose of study medication. Recognized side effects of mirtazapine include dry mouth, increased appetite, constipation, weight gain, and paradoxical somnolence (decreases with increasing dosage). Any single dose of mirtazapine greater than 1000 mg or any dose of mirtazapine taken in a suicide attempt or gesture considered to be an overdose.
(f) Results TABLE II illustrates weight gain or decreased weight loss in lung cancer patients treated with mirtazapine. Patients numbered 5, 8 and 13 undergo chemotherapy concurrently with this study. Patients numbered 1 and 16 have completed chemotherapy prior to this study.
Figure imgf000021_0001
All of the above-cited patents, publications, and references are hereby expressly incorporated by reference in their respective entireties.
It will be apparent to one of ordinary skill in the art that other embodiments can be readily contemplated in view of the teachings of the present specification. Such other embodiments, while not specifically disclosed nonetheless fall within the scope and spirit of the present invention. Thus, the present invention should not be construed as being limited to the specific embodiments described above, and is solely defined by the following claims.

Claims

What is claimed is:
1. A method for ameliorating loss of lean body mass in a patient having a wasting disease, the method comprising: administering to said patient at least one effective dose of an enantiomer of l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof.
2. The method as in claim 1, wherein said enantiomer is (R).
3. The method as in claim 1, wherein said enantiomer is (S).
4. The method as in claim 1, wherein said enantiomer is a racemic mixture of (R) and (S).
5. The method as in claim 1, wherein said wasting disease comprises one or more diseases selected from the group consisting of cancer anorexia, cancer cachexia, acquired immune deficiency syndrome, and anorexia nervosa.
6. The method as in claim 1, wherein said wasting disease results from medical treatment of another condition.
7. The method as in claim 1, wherein said dose is less than 1000 mg per day.
8. The method as in claim 7, wherein said dose is about 7.5 to about 45 mg per day.
9. The method as in claim 1, wherein said dose is administered orally or is injected.
10. The method as in claim 1, wherein said method is continued for at least 12 weeks.
11. The method as in claim 1 , wherein each said dose is administered once each day.
12. The method as in claim 1, wherein each said dose is administered in two parts each day.
13. The method as in claim 1, wherein a first dose of said enantiomer is about 7.5 mg per day.
14. The method as in claim 13, wherein subsequent doses of said enantiomer are between about 7.5 and about 45 mg per day.
15. The method as in claim 14, wherein said subsequent doses are titrated to provide a maximum effective dose.
16. The method as in claim 1, wherein said effective dose is sufficient to increase the lean body mass of said patient.
17. The method as in claim 1, wherein said effective dose decreases the loss of lean body mass of said patient.
18. The method as in claim 1, wherein said effective dose increases the appetite of said patient.
19. The method as in claim 1, wherein said patient has depressive a condition.
20. A method for increasing the tolerance of a cancer patient to chemotherapy or radiotherapy, the method comprising: administering to said patient an effective dose of an enantiomer of 1,2,3, 4, 10, 14b- hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof.
21. The method as claim 20, wherein said method increases said tolerance by maintaining or improving the appetite of said patient.
23. The method as claim 21 , wherein said method increases said tolerance by maintaining the weight of said patient.
24. A method for improving the quality of life of a patient having a wasting disease, the method comprising: administering to said patient an effective dose of an enantiomer of 1,2,3,4,10,14b- hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof.
25. The method of claim 24, wherein said improvement is loss of fatigue or improved role functioning.
26. The method of claim 24, wherein said improvement is improvement in at least one of physical well-being, social well-being, family well-being, emotional well-being, or functional well-being.
27. A method for increasing biochemical markers of nutrition in a patient having a wasting disease, the method comprising: administering to said patient an effective dose of an enantiomer of 1,2,3,4,10,14b- hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof.
28. The method of claim 27, wherein said markers are serum albumin, serum prealbumin, or total serum protein.
29. A method for increasing lean body mass in a patient having a wasting disease, the method comprising: administering to said patient an effective dose of an enantiomer of 1,2,3,4,10,14b- hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof.
30. The method as in claim 29, wherein said increase in lean body mass is measured by at least one anthropometric measurement of height, weight, triceps skin- fold, or mid-arm circumference.
31. A method for decreasing the loss of lean body mass in a patient having a wasting disease, the method comprising: administering to said patient an effective dose of an enantiomer of 1,2,3,4,10,14b- hexahydro-2-methyl-pyrazino[2,l-a]pyrido[2,3-c][2] benzazepine (ORG 3770), or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier, wherein said enantiomer is selected from the group consisting of (R), (S), and a mixture thereof.
PCT/US2000/017432 1999-06-25 2000-06-26 Mirtazapine for weight gain in wasting diseases WO2001000196A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57649/00A AU5764900A (en) 1999-06-25 2000-06-26 Mirtazapine for weight gain in wasting diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14075399P 1999-06-25 1999-06-25
US60/140,753 1999-06-25

Publications (2)

Publication Number Publication Date
WO2001000196A2 true WO2001000196A2 (en) 2001-01-04
WO2001000196A3 WO2001000196A3 (en) 2002-01-10

Family

ID=22492658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/017432 WO2001000196A2 (en) 1999-06-25 2000-06-26 Mirtazapine for weight gain in wasting diseases

Country Status (2)

Country Link
AU (1) AU5764900A (en)
WO (1) WO2001000196A2 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102352A1 (en) * 2004-04-21 2005-11-03 N.V. Organon Pharmaceutical composition comprising a salt of mirtazapine
US20140271727A1 (en) * 2013-03-18 2014-09-18 National Yang-Ming University Method of using an antidepressant for increasing immunity of a subject and treating cancer
WO2015092738A1 (en) * 2013-12-20 2015-06-25 Virbac Injectable mirtazapine for treating appetite loss and nutritional disorders in cats
WO2018160510A1 (en) * 2017-02-28 2018-09-07 India Globalization Capital, Inc. Method and composition for treating eating disorders
US10117891B2 (en) 2014-09-16 2018-11-06 India Globalization Capital, Inc. Cannabinoid composition for treating pain
US10596159B2 (en) 2015-08-12 2020-03-24 India Globalization Capital, Inc. Method and composition for treating cachexia and eating disorders
US10751300B2 (en) 2015-01-25 2020-08-25 India Globalization Capital, Inc. Composition and method for treating seizure disorders
CN113602530A (en) * 2021-07-11 2021-11-05 西北工业大学 Novel single-degree-of-freedom foldable columnar structure
US11351152B2 (en) 2016-06-15 2022-06-07 India Globalization Capital, Inc. Method and composition for treating seizure disorders

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0813873B1 (en) * 1996-06-19 2002-02-13 Akzo Nobel N.V. Pharmaceutical composition comprising mirtazapine and one or more selective serotonin reuptake inhibitors

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102352A1 (en) * 2004-04-21 2005-11-03 N.V. Organon Pharmaceutical composition comprising a salt of mirtazapine
JP2007533705A (en) * 2004-04-21 2007-11-22 ナームローゼ・フエンノートチヤツプ・オルガノン Pharmaceutical composition comprising a salt of mirtazapine
AU2005235383B2 (en) * 2004-04-21 2010-05-27 N.V. Organon Pharmaceutical composition comprising a salt of mirtazapine
JP2013136626A (en) * 2004-04-21 2013-07-11 Msd Oss Bv Pharmaceutical composition comprising salt of mirtazapine
US20140271727A1 (en) * 2013-03-18 2014-09-18 National Yang-Ming University Method of using an antidepressant for increasing immunity of a subject and treating cancer
FR3015289A1 (en) * 2013-12-20 2015-06-26 Virbac MIRTAZAPINE INJECTABLE
WO2015092738A1 (en) * 2013-12-20 2015-06-25 Virbac Injectable mirtazapine for treating appetite loss and nutritional disorders in cats
US10071102B2 (en) 2013-12-20 2018-09-11 Virbac Injectable mirtazapine for treating appetite loss and nutritional disorders in cats
US10117891B2 (en) 2014-09-16 2018-11-06 India Globalization Capital, Inc. Cannabinoid composition for treating pain
US10933082B2 (en) 2014-09-16 2021-03-02 India Globalization Capital, Inc. Cannabinoid composition and method for treating pain
US10751300B2 (en) 2015-01-25 2020-08-25 India Globalization Capital, Inc. Composition and method for treating seizure disorders
US10596159B2 (en) 2015-08-12 2020-03-24 India Globalization Capital, Inc. Method and composition for treating cachexia and eating disorders
US11351152B2 (en) 2016-06-15 2022-06-07 India Globalization Capital, Inc. Method and composition for treating seizure disorders
WO2018160510A1 (en) * 2017-02-28 2018-09-07 India Globalization Capital, Inc. Method and composition for treating eating disorders
CN113602530A (en) * 2021-07-11 2021-11-05 西北工业大学 Novel single-degree-of-freedom foldable columnar structure

Also Published As

Publication number Publication date
WO2001000196A3 (en) 2002-01-10
AU5764900A (en) 2001-01-31

Similar Documents

Publication Publication Date Title
Josephs et al. Neurophysiologic studies in Morvan syndrome
TWI314053B (en) Use of compounds that are effective as selective opiate receptor modulators
ES2433080T3 (en) Selective norepinephrine-serotonin reuptake inhibitors for the treatment of fibromyalgia syndrome, chronic fatigue syndrome and pain
US8309535B2 (en) Compositions and methods to treat recurrent medical conditions
EA002554B1 (en) Use of cabergoline in the treatment of restless legs syndrome
AU2002232470A1 (en) New drug combinations of norepinehrine reuptake inhibitors and neuroleptic agents
WO2002053140A2 (en) New drug combinations of norepinehrine reuptake inhibitors and neuroleptic agents
PT2701693T (en) Tapentadol for preventing and treating depression and anxiety
KR100567154B1 (en) Pharmaceutical Formulations Containing Tramadol
US12239623B2 (en) Sleep-improving compositions and methods of use
EP4048263A1 (en) Methods for treating neurological disorders with alpha 1a-ar partial agonists
JP2025508069A (en) Compositions containing Atica plant
RU2268725C2 (en) Combination of medicinal agents comprising mirtazapine for treatment of depression and associated disorders
AU2024204716A1 (en) Treatment of alopecia areata
US20030059374A1 (en) Nasal administration of agents for the treatment of gastroparesis
WO2001000196A2 (en) Mirtazapine for weight gain in wasting diseases
JPS63243028A (en) Antidepressant for alleviating basic depression
JP2022133449A (en) Levodopa division dose composition and use
WO2022115576A2 (en) Treatment of raynaud's disease
KR102693607B1 (en) Treatment for restless legs syndrome
CN114786660A (en) Methods of treatment using modulators of MTORC1
Kiersch et al. The onset of action and the analgesic efficacy of Saridon®*(a propyphenazone/paracetamol/caffeine combination) in comparison with paracetamol, ibuprofen, aspirin and placebo (pooled statistical analysis)
WO2006080524A1 (en) Medicinal composition for ameliorating or treating glucose intolerance, borderline diabetes, insulin resistance and hyperinsulinemia containing hypoglycemic agent
RU2672555C2 (en) Combination of pi3 kinase inhibitor with paclitaxel for use in treatment or prevention of head and neck cancer
US20110245212A1 (en) Methods of alleviating the symptoms of premenstrual syndrome/late luteal phase dysphoric disorder

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP