EP1511500A2 - Combination of anti-muscarinic agents and non-glucocorticoid steroids - Google Patents
Combination of anti-muscarinic agents and non-glucocorticoid steroidsInfo
- Publication number
- EP1511500A2 EP1511500A2 EP03784741A EP03784741A EP1511500A2 EP 1511500 A2 EP1511500 A2 EP 1511500A2 EP 03784741 A EP03784741 A EP 03784741A EP 03784741 A EP03784741 A EP 03784741A EP 1511500 A2 EP1511500 A2 EP 1511500A2
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- clo
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- This invention relates to a composition and formulations comprising a dehydroepiandrosterone(s) of chemical formula (I), (II), (III), (IV) and (V), and or salts thereof, and an anti-muscarinic receptor agent(s), and/or salts thereof, and optionally other bioactive agents and formulation components.
- a dehydroepiandrosterone(s) of chemical formula (I), (II), (III), (IV) and (V), and or salts thereof, and an anti-muscarinic receptor agent(s), and/or salts thereof, and optionally other bioactive agents and formulation components are useful in the treatment of respiratory and lung diseases in general and in the treatment of conditions such as COPD, asthma, allergic rhinitis, and the like.
- Respiratory ailments are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. In some cases they are accompanied by inflammation, which aggravates the condition of the lungs.
- Diseases such as Chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, and Acute Respiratory Distress Syndrome (ARDS), including RDS in pregnant mothers and in premature born infants, among others, are common diseases in industrialized countries, and in the United States alone, they account for extremely high health care costs. These diseases have recently been increasing at an alarming rate, both in terms of prevalence, morbidity and mortality. In spite of this, their underlying causes still remain poorly understood.
- COPD chronic obstructive pulmonary disease
- ARDS Acute Respiratory Distress Syndrome
- COPD is characterized by airflow obstruction that is generally caused by chronic bronchitis, emphysema, or both.
- Emphysema is characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis.
- Chronic bronchitis is characterized by chronic cough, mucus production, or both, for at least three months for at least two successive years where other causes of chronic cough have been excluded.
- COPD characteristically affects middle aged and elderly people, and is one of the leading causes of morbidity and mortality worldwide.
- COPD cardiovascular diseases
- Stopping smoking reverts the decline in lung function to values for non-smokers.
- Many COPD patients will use medication chronically for the rest of their lives, and will need increased doses and additional drugs during exacerbations.
- short-term benefits, but not long term effects were found on its progression, from administration of anti-cholinergic drugs, j32 adrenergic agonists, and oral steroids.
- anti-cholinergic drugs nor j32 adrenergic agonists have an effect on all people with COPD; nor do the two agents combined.
- the adverse effects of theophyllines and the need for frequent monitoring limit their usefulness.
- Asthma is a condition characterized by variable, in many instances reversible obstruction of the airways. This process is associated with lung inflammation and in some cases lung allergies. Many patients have acute episodes referred to as “asthma attacks,” while others are afflicted with a chronic condition.
- the asthmatic process may be triggered in some cases by inhalation of antigens by hypersensitive subjects. This condition is generally referred to as “extrinsic asthma”.
- Other asthmatics have an intrinsic predisposition to the condition, which is thus referred to as “instrinsic asthma", and it encompasses conditions of different origin, including those mediated by the adenosine receptor(s), allergic conditions mediated by an immune IgE-mediated response, and others.
- ARDS Acute Respiratory Distress Syndrome
- stiff lung, shock lung, pump lung and congestive atelectasis is believed to be caused by fluid accumulation within the lung which, in turn, causes the lung to stiffen.
- the condition is triggered within 48 hours by a variety of processes that injure the lungs such as trauma, head injury, shock, sepsis, multiple blood transfusions, medications, pulmonary embolism, severe pneumonia, smoke inhalation, radiation, high altitude, near drowning, and others.
- ARDS occurs as a medical emergency and may be caused by other conditions that directly or indirectly cause the blood vessels to "leak" fluid into the lungs.
- ARDS the ability of the lungs to expand is severely decreased and produces extensive damage to the air sacs and lining or endothelium of the lung.
- ARDS' most common symptoms are labored, rapid breathing, nasal flaring, cyanosis blue skin, lips and nails caused by lack of oxygen to the tissues, breathing difficulty, anxiety, stress, tension, joint stiffness, pain and temporarily absent breathing.
- ARDS appears to be associated with other diseases, such as acute myelogenous leukemia, with acute tumor lysis syndrome (ATLS) developed after treatment with, e.g. cytosine arabinoside.
- ATLS acute tumor lysis syndrome
- ARDS is associated with traumatic injury, severe blood infections such as sepsis or other systemic illness, high dose radiation therapy, chemotherapy, and inflammatory responses that lead to multiple organ failure, and in many cases death.
- premature babies premature babies
- lung surfactant a material critical for normal respiration
- premies often hyper- express the adenosine A ⁇ receptor and/or underexpress the adenosine A 2a , receptor, and are, therefore, susceptible to respiratory problems including bronchoconstriction, lung inflammation and ARDS, among others.
- RDS Respiratory Distress Syndrome
- allergic rhinitis afflicts one in five Americans and occurs at all ages, thus accounting for an estimated $4 to 10 billion in health care costs each year. Symptoms include nasal congestion, discharge, sneezing, and itching, as well as itchy, watery, swollen eyes. Over time, allergic rhinitis sufferers often develop sinusitis, otitis media with effusion, and nasal polyposis, and may exacerbate asthma. It is associated also with mood and cognitive disturbances, fatigue and irritability. In allergic rhinitis, typically, IgE combines with allergens in the nose to produce chemical mediators, induction of cellular processes, and neurogenic stimulation, causing an underlying inflammation.
- Non-allergic rhinitis may be induced by infections, such as viruses, or associated with nasal polyps, as occurs in patients with aspirin idiosyncrasy, as well as by pregnancy, hypothyroidism, and exposure to occupational factors or medications.
- NARES syndrome a non-allergic type of rhinitis associated with eosinophils in the nasal secretions, typically occurs in middle- aged individuals and is accompanied by loss of smell.
- Saline is often recommended to improve nasal stuffiness, sneezing, congestion, and mucosal irritation or dryness, minimize mucosal atrophy, and dislodge encrusted or thickened mucus, while causing no side effects, and may be tried first in pregnant patients. If used immediately before intranasal corticosteroid dosing, saline helps prevent local irritation. Anti-histamines often serve as a primary therapy.
- Anti-histamines are typically combined with a decongestant to help relieve nasal congestion.
- Sympathomimetic medications are used as vasoconstrictors and decongestants, the three most common decongestants being pseudoephedrine, phenylpropanolamine and phenylephrine. These agents, however, cause hypertension, palpitations, tachycardia, restlessness, insomnia and headache.
- Anti-cholinergic agents, such as Cromolyn have a role in patients with significant rhinorrhea or for specific entities such as "gustatory rhinitis", which is usually associated with ingestion of spicy foods, and have been used on the common cold.
- Topical and nasal spray corticosteroids such as Vancenase are somewhat effective in the treatment of rhinitis, especially for symptoms of congestion, sneezing, and runny nose.
- Topical steroids are generally more effective than Cromolyn, particularly in the treatment of NARES, but side effects limit their usefulness except for temporary therapy in patients with severe symptoms.
- Immunotherapy while expensive and inconvenient, often can provide substantial benefits, especially the use of drugs that produce blocking antibodies, alter cellular histamine release, and result in decreased IgE.
- Presently available treatments such as propranolol, verapamil, and adenosine, may help to minimize symptoms.
- Verapamil is most commonly used but it has several shortcomings, since it causes or exacerbates systemic hypotension, congestive heart failure, bradyarrhythmias, and ventricular fibrillation. In addition, verapamil readily crosses the placenta and has been shown to cause fetal bradycardia, heart block, depression of contractility, and hypotension. Adenosine has several advantages over verapamil, including rapid onset, brevity of side effects, theoretical safety, and probable lack of placental transfer, but may not be administered to a variety of patients.
- Pulmonary fibrosis, interstitial lung disease (ILD), or interstitial pulmonary fibrosis include more than 130 chronic lung disorders that affect the lung by damaging lung tissue, and producing inflammation in the walls of the air sacs in the lung, scarring or fibrosis in the interstitium (or tissue between the air sacs), and stiffening of the lung, thus the name of the disease. Breathlessness during exercise may be one of the first symptoms of these diseases, and a dry cough may be present. Neither the symptoms nor X-rays are often sufficient to tell apart different types of pulmonary fibrosis. Some pulmonary fibrosis patients have known causes and some have unknown or idiopathic causes. The course of this disease is generally unpredictable. Its progression includes thickening and stiffening of the lung tissue, inflammation and difficult breathing. Some people may need oxygen therapy as part of their treatment.
- Cancer is one of the most prevalent and feared diseases of our times. It generally results from the carcinogenic transformation of normal cells of different epithelia. Two of the most damaging characteristics of carcinomas and other types of malignancies are their uncontrolled growth and their ability to create metastases in distant sites of the host, particularly a human host. It is usually these distant metastases that may cause serious consequences to the host since, frequently, the primary carcinoma is removed by surgery.
- the treatment of cancer presently relies on surgery, irradiation therapy and systemic therapies such as chemotherapy, different immunity-boosting medicines and procedures, hyperthermia and systemic, radioactively labeled monoclonal antibody treatment, immunotoxins and chemotherapeutic drugs.
- Steroid hormones are potent chemical messengers that exert dramatic effects on cell differentiation, homeostasis, and morphogenesis. These molecules diverse in structure share a mechanistically similar mode of action. The effector molecules diffuse across cellular membranes and bind to specific high affinity receptors in the target cell nuclei. This interaction results in the conversion of an inactive receptor to one that can interact with the regulatory regions of target genes and modulate the rate of transcription of specific gene sets. Upon ligand binding, these receptors generate both rapid and long lasting responses. Steroids can act through two basic mechanisms: genomic and non- genomic. The classical genomic action is mediated by specific intracellular receptors, whereas the primary target for the non-genomic one is the cell membrane. Many clinical symptoms seem to be mediated through the non-genomic route.
- Steroid receptors are members of a large family of nuclear transcription factors that regulate gene expression by binding to their cognate steroid ligands, to the specific enhancer sequences of DNA (steroid response elements) and to the basic transcription machinery.
- Steroid receptors are basically localized in the nucleus, regardless of hormonal status, and considerable-amounts of unliganded steroid receptors may be present in the cytoplasm of target cells in exceptional cases Most steroid receptors are phosphoproteins, which are further phosphorylated after ligand binding. The role of phosphorylation in receptor transaction is complex and may not be uniform to all steroid receptors. However, phosphorylation and/or dephosphorylation is believed to be a key event regulating the transcriptional activity of steroid receptors. Steroid receptor activities can be affected by the amount of steroid receptor in the cell nuclei, which is modified by the rate of transcription and translation of the steroid receptor gene as well as by proteolysis of the steroid receptor protein.
- Some of the steroid receptors appear to bind specific protease inhibitors and exhibit protease activity. Some steroid receptors are expressed as two or more isoforms, which may have different effects on transcription. Receptor isoforms are different translation or transcription products of a single gene. Isoform A of the progesterone receptor is a truncated form of PR isoform B originating from the same gene, but it is able to suppress not only the gene enhancing activity of PR-B but also that of other steroid receptors. Before hormone binding, the receptors are part of a complex with multiple chaperones which maintain the receptor in its steroid binding conformation.
- the complex dissociates and the receptors bind to steroid response elements in chromatin.
- Regulation of gene expression by hormones involves an interaction of the DNA-bound receptors with other sequence-specific transcription factors and with the general transcription factors, which is partly mediated by co- activators and co-repressors.
- the specific array of cis regulatory elements in a particular promoter/enhancer region, as well as the organization of the DNA sequences in nucleosomes, specifies the network of receptor interactions. Depending on the nature of these interactions, the final outcome can be induction or repression of transcription.
- DHEA Dehydroepiandrosterone
- G6PDH glucose 6-phosphate dehydrogenase
- DHEA or 3f3-hydroxyandrost-5-en-17-one or dehydroiso-androsterone, is a 17-ketosteroid which is quantitatively one of the major adrenocortical steroid hormones found in mammals.
- DHEA has been used systemically and topically for treating psoriasis, gout, hyperlipemia, and it has been administered to post-coronary patients.
- DHEA has been shown also to have weight optimizing and anti-carcinogenic effects, and it has been used clinically in Europe in conjunction with estrogen as an agent to reverse menopausal symptoms and in the treatment of manic depression, schizophrenia, and Alzheimer's disease.
- DHEA has been used clinically at 40 mg/kg/day in the treatment of advanced cancer and multiple sclerosis. Side effects such as mild androgenic effects, hirsutism, and increased libido were observed and may be overcome by monitoring the dose and/or by using analogues. DHEA is used subcutaneously, orally, and as a patch to treat infections. DHEA is also a metabolic precursor of more powerful agents that increase immune response in mammals.
- DHEA is biphasic: it acts as an immuno-modulator when converted to androstenediol, androst-5-ene-3)8,17
- DHEA-S Dehydroepiandrosterone sulfate
- eosinophilia and neutrophilia have been shown to effectively attenuate eosinophilia and neutrophilia, as well as improving compliance and resistance, in three animal models of respiratory disease (mouse, rabbit, non-human primate").
- Chronic persistent asthma has been shown to be predominantly a neutrophil-driven disease (Gibson et al. (20- -?)
- COPD has long been known to be neutrophil driven
- neutrophilia is observed in allergic rhinitis as well.
- G6PDH is the rate limiting enzyme of the hexose monophosphate pathway, a major source of intracellular ribose-5-phosphate and NADPH.
- Ribose-5 phosphate is a necessary substrate for the synthesis of both ribo- and deoxyribonucleotides required for the synthesis of RNA and DNA.
- NADPH is a cofactor also involved in nucleic acid biosynthesis and the synthesis of hydroxmethylglutaryl Coenzyme A reductase (HMG CoA reductase).
- HMG CoA reductase is an unusual enzyme that requires two moles of NADPH for each mole of product, mevalonate, produced.
- HMG CoA reductase would be ultrasensitive to DHEA-mediated NADPH depletion, and that DHEA-treated cells would rapidly show the depletion of intracellular pools of mevalonate.
- Mevalonate is required for DNA synthesis, and DHEA arrests human cells in the Gl phase of the cell cycle in a manner closely resembling that of the direct HMG CoA.
- G6PDH produces mevalonic acid used in cellular processes such as protein isoprenylation and the synthesis of dolichol, a precursor for glycoprotein biosynthesis, DHEA inhibits carcinogenesis by depleting mevalonic acid and thereby inhibiting protein isoprenylation and glycoprotein synthesis.
- Mevalonate is the central precursor for the synthesis of cholesterol, as well as for the synthesis of a variety of non-sterol compounds involved in post-translational modification of proteins such as farnesyl pyrophosphate and geranyl pyrophosphate; for dolichol, which is required for the synthesis of glycoproteins involved in cell-to-cell communication and cell structure.
- Inhaled anti-muscarinic agents are the treatment of choice, recommended by guidelines, in chronic obstructive pulmonary disease (COPD).
- COPD chronic obstructive pulmonary disease
- ipratropium showed important effects beyond relaxation of airway smooth muscle, e.g. reduction of exacerbations of COPD.
- phase III clinical trials the new generation anti- muscarinic tiotropium, inhaled once daily, has provided more than 24 hours of stable bronchodilation, that was sustained over the one-year treatment period.
- tiotropium in comparison to placebo and even ipratropium has been shown to provide improvement in dyspnea, reduction of exacerbations of COPD, reduced hospital admissions for exacerbations, reduced duration of hospitalizations as well as improved health-related quality of life.
- Chronic effects such as reduction of hospitalizations, are conventionally attributed to an anti-inflammatory action and not to symptomatic bronchodilation.
- the 24 hour stabilisation of airway patency avoiding fluctuations of the diameter with occasional closure and consequent need for reopening, may explain the extended therapeutic profile of tiotropium.
- Inhibition by anti-muscarinics of pro-inflammatory cholinergic effects may also occur, e.g.
- Anti-muscarinics agents have shown substantial value as a therapeutic approach in COPD.
- a handful of medicaments have been used for the treatment of respiratory diseases, although they all have limitations.
- glucocorticoid steroids leukotriene inhibitors, anti-cholinergic agents, anti-histamines, oxygen therapy, theophyllines, and mucolytics.
- Glucocorticoid steroids are the ones with the most widespread use in spite of their well documented side effects. Most of the available drugs are nevertheless effective in a small number of cases, and not at all when it comes to the treatment of asthma.
- Theophylline an important drug in the treatment of asthma, is a known adenosine receptor antagonist.
- Selective adenosine Al receptor antagonists, 8-cyclopentyl-l, 3-dipropylxanthine (DPCPX) and an anti- sense oligonucleotide were also reported to inhibit adenosine-mediated bronchoconstriction, inflammation and bronchial hyperresponsiveness in allergic rabbits.
- glucocorticosteroids two classes of compounds have dominated the treatment of asthma: glucocorticosteroids and bronchodilators. Examples of glucocorticosteroids are beclomethasone and corticoid 21-sulfopropionates.
- bronchodilator examples include an older ⁇ l adrenergic agonist such as albuterol, and a newer one such as salmeterol.
- ⁇ l adrenergic agonists such as albuterol
- salmeterol a newer one
- glucocorticosteroids are taken daily either by inhalation or orally, they attenuate inflammation.
- the ⁇ l adrenergic agonists on the other hand, primarily alleviate bronchoconstriction.
- glucocorticosteroids are not useful in general for acute settings, bronchodilators are used in acute care, such as in the case of asthma attacks.
- glucocorticosteriods particularly when taken for prolonged periods of time, have extremely deleterious side effects that, although somewhat effective, make their chronic use undesirable, particularly in children.
- the present invention relates to a composition, formulations and treatments employing a first active agent comprising a dehydroepiandrosterone(s) of chemical formula (I), (II), (III), (IV), and (V) and/or its salts in combination with a second active agent comprising an anti-muscarinic agent(s) and/or its salts, and optionally other bioactive agents including other types of anti-inflammatories and bronchodilating agents, and formulation ingredients.
- This composition and formulations are useful for treating lung and respiratory diseases and conditions such as Chronic Obstructive Pulmonary Disease (COPD), asthma, allergic rhinitis and many others that are associated with brochoconstriction, lung inflammation and/or allergies as well as with changes in pulmonary surfaces.
- COPD Chronic Obstructive Pulmonary Disease
- Figure 1 illustrates the inhibition of HT-29 SF cells by DHEA.
- Figure 2a and 2b illustrates the effects of DHEA on cell cycle distribution in HT-29 SF cells.
- Figures 3a and 3b illustrate the reversal of DHEA-induced growth inhibition in HT-29 cells.
- Figures 4a, 4b, 4c, and 4d illustrates the reversal of DHEA-induced Gi arrest in HT-29 SF cells.
- the present invention arose from a desire by the inventors to improve on prior treatments of respiratory and lung diseases, and other pathologies secondarily afflicting the lung.
- the present treatment is effective for treating a plurality of respiratory and lung diseases, whatever their cause, whether due to inhalation of tobacco components, other paniculate matter or allergens, to steroid administration, abnormalities in adenosine or adenosine receptor metabolism or synthesis, or any other cause.
- the present invention provides a composition, formulations and a method for treating respiratory and lung diseases and conditions regardless of their mechanism.
- the present products are particularly suitable for treating diseases and conditions such as chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis, cystic fibrosis (CF), dispnea, emphysema, wheezing, pulmonary hypertension, pulmonary fibrosis, hyper- responsive airways, increased adenosine or adenosine receptor levels, particularly those associated with infectious diseases, lung inflammation and/or allergy(ies), surfactant depletion, chronic bronchitis, bronchoconstriction, difficult breathing, impeded or obstructed lung airways, adenosine test for cardiac function, pulmonary vasoconstriction, impeded respiration, Acute Respiratory Distress Syndrome (ARDS), infantile Respiratory Distress Syndrome (infantile RDS), pain, decreased lung surfactant, or chronic bronchitis, among others.
- COPD chronic obstructive pulmonary disease
- COPD chronic obstructive pulmonary disease
- asthma asthma
- ipratropium bromide had no significant effect on the decline in the functional effective volume of the patient's lungs whereas smoking cessation produced a slowing of the decline in the functional effective volume of the lungs.
- Large amounts of ipratropium bromide are required when this drug is administered by itself, and at these doses it produces serious adverse effects, such as cardiac symptoms, hypertension, skin rashes, and urinary retention.
- Short and long acting inhaled /32 adrenergic agonists achieve short-term bronchodilation and provide some symptomatic relief in COPD patients, but show no meaningful maintenance effect on the progression of the disease.
- Short acting ⁇ l adrenergic agonists improve symptoms in subjects with COPD, such as increasing exercise capacity and produce some degree of bronchodilation, and even an increase in lung function in some severe cases.
- the maximum effectiveness of the newer long acting inhaled ⁇ l adrenergic agonists was found to be comparable to that of short acting ⁇ l adrenergic agonists.
- Salmeterol was found to improve symptoms and quality of life, although only producing modest or no change in lung function. In asthmatics, however, ⁇ l adrenergic agonists have been linked to an increased risk of death, worsened control of asthma, and deterioration in lung function.
- ipratropium to a standard dose of inhaled ⁇ l adrenergic agonists for about 90 days, however, produces some improvement in stable COPD patients over either drug alone.
- Anti-cholinergic agents were found to produce greater bronchodilation than ⁇ l adrenergic agonists in people with COPD.
- Ipratropium bromide given to patients without bronchodilator therapy produced an improvement of the functional effective volume of the patient's lungs that was greater when administered in conjunction with an anti-cholinergic agent than with a ⁇ l adrenergic agonist, given the residual effect of the anti- cholinergic drug.
- Theophyllines have a small bronchodilatory effect in COPD patients whereas they have some common adverse effects, and they have a small therapeutic range given that blood concentrations of 15-20 mg 1 are required for optimal effects.
- Adverse effects include nausea, diarrhea, headache, irritability, seizures, and cardiac arrhythmias, and they occur at highly variable blood concentrations and, in many people, they occur within the therapeutic range.
- the theophyllines' doses must be adjusted individually according to smoking habits, infection, and other treatments, which is cumbersome.
- Inhaled corticosteroids have been found to have no real short-term effect in airway hyper-responsiveness to histamine, but a small long-term effect on lung function, e.g., in pre-bronchodilator functional effective volume. Fluticasone treatment of COPD patients showed a significant reduction in moderate and severe (but not mild) exacerbations, and a small but significant improvement in lung function and six minute walking distance. Oral prednisolone, inhaled beclomethasone or both had no effects in COPD patients, but lung function improved oral corticosteroids. Mucolytics have a modest beneficial effect on the frequency and duration of exacerbations but an adverse effect on lung function.
- N-acetylcysteine nor other mucolytics have a significant effect in people with severe COPD (functional effective volume ⁇ 50%) in spite of evidencing greater reductions in frequency of exacerbation.
- N- acetylcysteine produced gastrointestinal side effect.
- Long-term oxygen therapy administered to hypoxaemic COPD and congestive cardiac failure patients had little effect on their rates of death for the first 500 days or so, but survival rates in men increased afterwards and remained constant over the next five years. In women, however, oxygen decreased the rates of death throughout the study. Continuous oxygen treatment of hypoxemic COPD patients (functional effective volume ⁇ 70% predicted) for 19.3 years decreased overall risk of death.
- COPD chronic obstructive pulmonary disease
- Bronchodilators form one of the mainstays of therapy in COPD patients. The judicious use of these agents increases airflow and reduces dyspnea in patients with COPD. Patients often experience a reduction in symptoms and improvement in their quality of life.
- bronchodilators available for the treatment of COPD, each with specific clinical benefits: anticholinergics, short-acting beta 2 agonists, combination anticholinergic and short-acting beta 2 agonist, long-acting beta 2 agonists and methylxanthines.
- Anticholinergics such as ipratropium
- Ipratropium bromide has been used concomitantly with other bronchodilators for the treatment of patients with COPD.
- Ipratropium bromide is a quaternary anticholinergic bronchodilator that is commonly used to treat obstructive lung disease.
- ipratropium is not usually employed as a first-line bronchodilator to treat chronic asthma, it has been used extensively in hospital emergency departments as adjunctive therapy for the emergency treatment of acute asthma exacerbation.
- 0 ARDS' most common symptoms are labored, rapid breathing, nasal flaring, cyanosis blue skin, lips and nails caused by lack of oxygen to the tissues, breathing difficulty, anxiety, stress, tension, joint stiffness, pain and temporarily absent breathing.
- ARDS is currently diagnosed by mere symptomatic signs, e. g. chest auscultation with a stethoscope that may reveal abnormal symptomatic breath sounds, and confirmed with chest X-rays and the 5 measurement of arterial blood gas.
- ARDS in some instances, appears to be associated with other diseases, such as acute myelogenous leukemia, acute tumor lysis syndrome (ATLS) developed after treatment with, e.g. cytosine arabinoside, etc.
- ATLS acute tumor lysis syndrome
- ARDS is associated with traumatic injury, severe blood infections such as sepsis or other systemic illness, high-dose radiation therapy and chemotherapy, and inflammatory responses which lead to multiple organ failure and in many cases death.
- premature babies premature babies
- the lungs are not quite developed 0 and, therefore, the fetus is in an anoxic state during development.
- lung surfactant a material critical for normal respiration, is generally not yet present in sufficient amounts at this early stage of life; however, premies often hyper-express the adenosine Al receptor and/or underexpress the adenosine A2a receptor and are, therefore, susceptible to respiratory problems including bronchoconstriction, lung inflammation and ARDS, among others.
- RDS Respiratory Distress Syndrome
- BPD bronchopulmonary dysplasia
- Rhinitis may be seasonal or perennial, allergic or non-allergic.
- Non-allergic rhinitis may be induced by infections, such as viruses, or associated with nasal polyps, as occurs in patients with aspirin idiosyncrasy. Medical 0 conditions such as pregnancy or hypothyroidism and exposure to occupational factors or medications may cause rhinitis.
- NARES syndrome is a non-allergic type of rhinitis associated with eosinophils in the nasal secretions, which typically occurs in middle-age and is accompanied by some loss of sense of smell. When cholinergic pathways are stimulated they produce typical secretions that are identified by their glandular constituents so as to implicate neurologic stimulation.
- saline sprays are generally used to relieve mucosal irritation or dryness associated with various nasal conditions, minimize mucosal atrophy, and dislodge encrusted or thickened mucus. If used immediately before intranasal corticosteroid dosing, saline sprays may help prevent drug-induced local irritation.
- Anti-histamines such as terfenadine and astemizole, two non-sedating anti-histamines, are also employed to treat this condition, but have been associated with a ventricular arrhythmia known as Torsades de Points, usually in interaction with other medications such as ketoconazole and erythromycin, or secondary to an underlying cardiac problem.
- Loratadine, another non-sedating anti-histamine, and cetirizine have not been associated with an adverse impact on the QT interval, or with serious adverse cardiovascular events. Cetirizine, however, produces extreme drowsiness and has not been widely prescribed.
- Non-sedating anti-histamines e.g.
- Claritin may produce some relieving of sneezing, runny nose, and nasal, ocular and palatal itching, but have not been tested for asthma or other more specific conditions.
- Terfenadine, loratadine and astemizole exhibit extremely modest bronchodilating effects, reduction of bronchial hyper-reactivity to histamine, and protection against exercise- and antigen-induced bronchospasm. Some of these benefits, however, require higher-than-currently-recommended doses.
- the sedating-type anti-histamines help induce night sleep, but they cause sleepiness and compromise performance if taken during the day. When employed, anti-histamines are typically combined with a decongestant to help relieve nasal congestion.
- Sympathomimetic medications are used as vasoconstrictors and decongestants.
- the three commonly prescribed systemic decongestants, pseudoephedrine, phenylpropanolamine and phenylephrine cause hypertension, palpitations, tachycardia, restlessness, insomnia and headache.
- the interaction of phenylpropanolamine with caffeine, in doses of two to three cups of coffee, may significantly raise blood pressure.
- medications such as pseudoephedrine may cause hyperactivity in children.
- Topical decongestants nevertheless, are only indicated for a limited period of time, as they are associated with a rebound nasal dilatation with overuse.
- Anti-cholinergic agents are given to patients with significant rhinorrhea or for specific conditions such as "gustatory rhinitis", usually caused by ingestion of spicy foods, and may have some beneficial effects on the common cold.
- Cromolyn for example, if used prophylactically as a nasal spray, reduces sneezing, rhinorrhea, and nasal pruritus, and blocks early- and late-phase hypersensitivity responses, but produces sneezing, transient headache, and even nasal burning.
- Topical corticosteroids such as Vancenase are somewhat effective in the treatment of rhinitis, especially for symptoms of congestion, sneezing, and runny nose.
- corticosteroid nose sprays may cause irritation, stinging, burning, or sneezing, as well.
- Local bleeding and septal perforation can also occur sometimes, especially if the aerosol is not aimed properly.
- Topical steroids generally are more effective than cromolyn sodium, particularly in the treatment of NARES, and also to reduce some symptoms of rhinitis.
- Their side effects limit their usefulness except for temporary therapy in patients with severe symptoms. These agents are sometimes used for shrinking nasal polyps when local therapy fails.
- Immunotherapy while expensive and inconvenient, often provides benefits, especially for inpatients who experience side effects from other medications.
- This effect is useful in IgE-mediated diseases, e.g., hypersensitivity in atopic patients with recurrent middle ear infections.
- IgE-mediated diseases e.g., hypersensitivity in atopic patients with recurrent middle ear infections.
- a runny nose is more than a nuisance.
- the disorder often results in impaired quality of life and sets the stage for more serious ailments, including psychological problems.
- rhinitis is mostly treated with propranolol, verapamil, and adenosine, all of which have Food and Drug Administration-approved labeling for acute termination of supraventricular tachycardia (SVT).
- SVT supraventricular tachycardia
- the non-glucocorticoid steroids of this invention are believed to be substantially free of the listed detrimental effects of those steroids currently in use.
- pulmonary fibrosis and other interstitial lung diseases may vary, they all affect parts of the lung.
- bronchiolitis When inflammation involves the walls of the bronchioles (small airways) it is called bronchiolitis, when it involves the walls and air spaces of the alveoli (air sacs) it is called alveolitis, and when it involves the small blood vessels (capillaries) of the lungs it is called vasculitis.
- the inflammation may heal, or it may lead to permanent scarring of the lung tissue, in which case it is called pulmonary fibrosis.
- This fibrosis or scarring of the lung tissue results in permanent loss of its ability to breathe and carry oxygen, and the amount of scarring determines the level of disability a person experiences because of the destruction by the scar tissue of the air sacs and lung tissue between and surrounding the air sacs and the lung capillaries. When this happens, oxygen is generally administered to help improve breathing.
- Pulmonary fibrosis is caused by, or takes the form of, occupational and environmental exposure to irritants such as asbestos, silica and metal dusts, bacteria and animal dusts, gases and fumes, asbestosis and silicosis, infections that produce lung scarring, of which tuberculosis is one example, connective tissue or collagen diseases such as Rheumatoid Arthritis, Systemic Sclerosis and Systemic Lupus Erythematosis, idiopathic pulmonary fibrosis and, although not as common, pulmonary fibrosis of genetic/familial origin and certain medicines.
- irritants such as asbestos, silica and metal dusts, bacteria and animal dusts, gases and fumes, asbestosis and silicosis, infections that produce lung scarring, of which tuberculosis is one example, connective tissue or collagen diseases such as Rheumatoid Arthritis, Systemic Sclerosis and Systemic Lupus Erythematosis, idiopathic pulmonary
- IPF pulmonary fibrosis
- familial idiopathic pulmonary fibrosis whose main symptom is shortness of breath, which is difficult to diagnose since many lung diseases show this symptom.
- the shortness of breath may first appear during exercise, eventually resulting in shortness of breath even at rest.
- Other symptoms may include dry cough (without sputum), and clubbing of the fingertips.
- Glucocorticosteroids are usually administered to treat pulmonary fibrosis inflammation with inconclusive results. Other drugs, however, are not usually added until it is clear that the steroids are not effective in reversing the disease.
- Glucocorticosteroids are also used in combination with other drugs when diagnosis is first established, e.g. oxygen therapy that is prescribed in severe cases.
- influenza and pneumococcal pneumonia vaccines are often recommended in pulmonary fibrosis and more generally for all lung diseases to prevent infection.
- the treatment and management of pulmonary fibrosis often requires a lung biopsy to assess the unpredictable response of patients to glucocorticosteroids or other immune system suppressants. Lung transplants are sometimes an ultimate option in severe cases of pulmonary fibrosis and other lung diseases.
- Pulmonary fibrosis may also be caused by other specific diseases, such as sarcoidosis, a disease whose cause is unknown, that is characterized by the formation of granulomas or areas of inflammatory cells. This disease may attack any organ of the body, but most frequently attacks the lungs, and is generally diagnosed when a chest X-ray shows enlarged lymph glands in the center of both lungs or evidence of lung tissue thickening. For many, sarcoidosis is a minor problem, and symptoms including dry cough, shortness of breath, mild chest pain, fatigue, weakness and weight loss-may appear infrequently and stop even without medication. For others, it is a disabling disease.
- sarcoidosis a disease whose cause is unknown, that is characterized by the formation of granulomas or areas of inflammatory cells. This disease may attack any organ of the body, but most frequently attacks the lungs, and is generally diagnosed when a chest X-ray shows enlarged lymph glands in the center of both lungs or evidence of lung tissue thickening
- Histiocytosis X also associated with pulmonary fibrosis, seems to begin in the bronchioles or small airways of the lungs and their associated arteries and veins, and is generally followed by destruction of the bronchioles and narrowing and damaging of small blood vessels. Symptoms of this disease include dry cough (without sputum), breathlessness upon exertion, and chest pain, and may be chronic with loss of lung function. Glucocorticosteroid therapy is often prescribed, although there is no evidence that it is effective. Histiocytosis X is associated with cigarette smoking, and with jobs, such as mining and may be caused by inhalation of small particulate matter, e. g.
- Neutrophilic inflammation is gaining increasing recognition as an important component of chronic persistent asthma, and is frequently associated with cases of fatal asthma. Neutrophilic inflammation is also considered to be the principal component of COPD. None of the currently available steroids are capable of attenuating neutrophilic inflammatory reactions, and may in fact contribute to them by delaying neutrophil apoptosis. DHEA-S has been shown to be effective in three different models of human asthma: the allergic rabbit, the allergic mouse, and the allergic primate. These effects included decreased magnitude of both early phase and late stage responses following allergen challenge, and dramatic reduction in eosinophilic and neutrophilic inflammation.
- DHEA-S was found to be at least equivalent to budesonide, with respect to reduction of eosinophilic inflammation, and far superior to it with respect to neutrophilic inflammation. With respect to reduction of eosinophilic inflammation, DHEA-S was found to be at least equivalent to budesonide (Pulmicort) and far superior to it with respect to neutrophilic inflammation. Very few putative asthma therapeutics show evidence of activity in multiple animal models. DHEA and DHEA-S are naturally occurring steroids found in all tissues of the body of both males and females. Low dose inhalation therapy with the steroids of this invention is therefore well tolerated.
- DHEA-S DHEA-S in humans
- the present steroidal compounds are believed to work by a mechanism of action different from glucocorticoid steroids; that is these compounds do not appear to activate the glucocorticoid receptor.
- One of its demonstrated effects is the reduction of pulmonary adenosine, a potentially critical feature in view of the role of adenosine in pulmonary inflammation, and the fact that the lungs of asthma contain excessive amounts of this autocoid.
- glucocorticoid steroids e.g., mucositis, skin thickening, exopthalmia, reductions in bone growth (children) or/and mineralization (adults).
- Preclinical toxicology studies show that even at doses as high as 2mg/kg/day in dogs and 1 lmg/kg day in rats, a maximum tolerated dose is not achieved. These doses are substantially in excess of the clinical dose in either asthma or COPD patients.
- a first active agent selected from dehydroepiandrosterones, analogues or their pharmaceutically or veterinarily acceptable salts
- a second active agent selected from anti-muscarinic agents, alone or in conjunction with anti-histamines, anti- sense oligonucleotides, leukdtriene inhibitors, theophyllines, B2 adrenergic agents, and/or mucolytics, among others.
- the first and second agents are administered in therapeutic or prophylactic amounts that are effective to inhibit, delay or control symptoms of the treated diseases or conditions, particularly those associated with lung vasoconstriction, bronchoconstriction, lung inflammation, lung allergies, changes in lung _ tissues, immune cell accumulation, e.g., neutrophils and eosinophils, fibrosis, cancerous tissue development, and others.
- the pharmaceutical or veterinary composition of the invention comprises a first active agent selected from a non- glucocorticoid steroid having the chemical formula I shown below: wherein the broken line represents a single or a double bond; R is hydrogen or a halogen; the H at position 5 is present in the alpha or beta configuration or the compound of chemical formula I comprises a racemic mixture of both configurations; and R 1 is hydrogen or S0 2 OM, wherein M is selected from the group consisting of H, Na, sulfatide -S0 2 0-CH 2 CHCH 2 OCOR 3 ; and phosphatide
- R 2 and R 3 which may be the same or different, are straight or branched (CJ-CH) alkyl or glucuronide
- R preferably is halogen e.g., bromo, chloro, or fluoro
- Ri is H
- the double bond is present
- the compound of formula (I) is 16-alpha-fluoro epiandrosterone in a preferred embodiment of the compound of formula (I)
- R is H
- Ri is S0 2 OM
- M is a sulphatide group and the double bond is present
- the compound of formula (I) is the dehydrated form of dehydroepiandrosterone sodium sulphate (DHEA-S -2H 2 0) of chemical formula (II) shown below:
- non-glucocorticoid steroid has the chemical formula III, and IV shown below:
- RI is A-CH(OH)-C(0)-
- A is H or (C1-C22) alkyl, alkenyl, or alkynyl, each of which may be substituted with one or more (C1-C4) alkyl, halogen, HO, or phenyl which may be substituted with , one or more halogen, HO, CH 3 , or CH 3 O.
- the hydrogen atom at position 5 of the chemical formula I may be present in the alpha or beta configuration, or the DHEA compound may be provided as a mixture of compounds of both configurations.
- Compounds illustrative of chemical formula I above are included, although not exclusively, are DHEA, wherein R and R 1 are each hydrogen, containing a double bond; 16- alpha bromoepiandrosterone, wherein R is Br, R 1 is H, containing a double bond; 16- alpha-fluoro epiandrosterone, wherein R is F, R 1 is H, containing a double bond; Etiocholanolone, wherein R and R 1 are each hydrogen lacking a double bond; and Dehydroepiandrosterone sulphate, wherein R is H, R 1 is S0 2 OM and M is a sulphatide group as defined above, lacking a double bond.
- preferred compounds of formula I are those where R is halogen, e.g. bromo, chloro, or fluoro, where RI is hydrogen, and where the double bond is present.
- R is halogen, e.g. bromo, chloro, or fluoro
- RI is hydrogen
- a most preferred compound of formula I is 16-alpha-fluoro epiandrosterone.
- Other preferred compounds are DHEA and DHEA salts, such as the sulfate salt (DHEA-S).
- DHEA-S sulfate salt
- One most preferred composition and treatment involves DHEA-S and Ipratropium Bromide, and another involves DHEA-S and Tiotropium Bromide.
- non-glucocorticoid steroid and the anti-muscarinic agents potentiate each other's anti-inflammatory effects whether administered orally, topically or through the respiratory tract.
- Other preferred combinations involves analogues of DHEA shown in the chemical formulas provided above and one or more of the anti-muscarinic agents.
- Other DHEA analogues and derivatives suitable for use in this invention are non-glucocorticoid steroid of the chemical formula
- R20 and R21 are independently OH, pharmaceutically acceptable ester or pharmaceutically acceptable ether;
- R22 is H, (halogen)m (Cl-ClO) alkyl or (Cl- C10) alkyl; n is 0, 1 or 2; and m is 1, 2 or 3; or pharmaceutically or veterinarily acceptable salts thereof.
- non-glucocorticoid steroids such as those of formulas (I), (II), (III), (IV) and (V), their derivatives and their salts are administered in a dosage of about 0.05, about 0.1, about 1, about 5, about 20 to about 100, about 500, about 1000, about 1500 about 1,800, about 2500, about 3000, about 3600 mg kg body weight.
- Other dosages are also suitable and are contemplated within this patent.
- the first active agent of formula I, III and IV may be made in accordance with known procedures, or variations thereof that will be apparent to those skilled in the art. See, for example, U.S. Patent No. 4,956,355; UK Patent No. 2,240,472; EPO Patent Application No.
- the dehydroepiandrosterone and its salts may be administered with the second agent for e.g. ipratropium bromide, and optionally a non-glucocorticoid steroid of formula (I), (II), (III), (IV) or (V), and/or other bioactive agents, separately and concurrently, before or after one another, or in the same composition.
- the second agent for e.g. ipratropium bromide, and optionally a non-glucocorticoid steroid of formula (I), (II), (III), (IV) or (V), and/or other bioactive agents, separately and concurrently, before or after one another, or in the same composition.
- the dosage lends itself to simultaneous administration, either in the same composition or separately for example once a day.
- bioactive agents preferred is the administration of any of the currently prescribed drugs for asthma, COPD, allergic rhinitis, etc.
- ⁇ -2 adrenergic agonists such as ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol and seretide, among others; other anti-cholinergic agents; anti-histaminic agents; adenosine Al, A2b and A3 receptor antagonists such as anti-sense oligos, among others; adenosine A2a agonists; and glucocorticosteroids.
- ⁇ -2 adrenergic agonists such as e
- the phrase "concurrently administering", as used herein, means that the anti-inflammatory steroid or its salt and the anti-muscarinic agents are administered either simultaneously in time (preferably by formulating the two together in a common pharmaceutical carrier), or at different times during the course of a common treatment schedule. In the case where both DHEA and anti-muscarinic agents are administered, they may be administered at times sufficiently close or simultaneously to enhance their anti-inflammatory effects.
- the anti-muscarinic agent and the non-glucocorticoid steroid or their salts may be formulated individually with a pharmaceutically acceptable carrier, or with the second active agent.
- the non-glucocorticoid steroid, and its salts and the anti-muscarinic agent may be administered systematically, topically, or directly into the respiratory tract of the subject.
- the composition may be formulated by any of the techniques set forth in this patent and others as an artisan would know.
- the anti-muscarinic agent(s) is(are) administered in a therapeutic amount for treating the targeted disease or condition, and/or an amount effective to reduce or inhibit undesirable symptoms in the lungs of the subject, and the dosage will vary depending upon the condition of the subject, other agents being administered, the type of formulation employed, and the route of administration.
- the anti-muscarinic agents may be administered in amounts known in the art.
- the anti-muscarinic receptor agent may be administered once, or several times, a day.
- non-glucocorticoid steroid, anti-muscarinic agents, and any other optional drugs, anti-sense oligos to adenosine receptors or other targets, used to treat respiratory, lung and neoplastic diseases, and other agents listed below, may be administered per se or in the form of pharmaceutically acceptable salts, as discussed aboye, all being referred to as "active compounds or agents.”
- active compounds or agents may be administered either systemically or topically, as discussed below.
- anti-muscarinic agents examples include ipratropium bromide, tiotropium bromide, troventol, and others known in the art.
- a recent publication by Yahgmurov reported improvement in pulmonary function with enhancement of airway conductance in large and middle bronchi in COPD patients after treatment with troventol. In bronchial asthma (BA) patients, a lesser effect on airway resistance was observed, which appeared more noticeable in small bronchi.
- the administration of troverifol by inhalation to patients afflicted with chronic obstructive pulmonary disease (COPD) was reported in the same publication to result in a reduction in the generation of reactive oxygen species by phagocytes in blood and bronchoalveolar lavage (BAL).
- COPD chronic obstructive pulmonary disease
- troventol When troventol was compared with atrovent (ipratropium bromide) and atropine, the author reports that cell incubation with troventol for 5 min inhibited histamine release by 47%, and no distinction was observed between placebo and atropine or atrovent effects.
- the histamine release from mast cells is explained as having been caused by an abrupt increase in the concentration of cytosolic calcium ion.
- the speed of passive calcium ion uptake was decreased by troventol (56.3%) and by atrovent (28%), but not by atropine.
- troventol unlike atrovent and atropine, appears to inhibit histamine secretion by reducing the cell membrane permeability of calcium ions.
- bronchodilating agents other than anti-muscarinic agents are ubiquinones, glucocorticoids, adenosine receptor antagonists such as theophyllines, anti-cholinergics, and ⁇ l adrenergic agonists.
- leukotrienes are zyflo, an inhibitor of the enzyme 5-lipoxygenase (5-LO), zafirlukast (Accolate®), montelukast (Singulair®), and others known in the art.
- Leukotriene receptor antagonists inhibit the effects of the cysteinyl leukotrienes, which represent 3 of a large number of chemical mediators of asthma. Leukotrienes are released by several types of cells and can cause bronchoconstriction and inflammation. The cysteinyl leukotrienes are particularly important mediators in patients with aspirin-sensitive asthma (characterized by chronic severe asthma symptoms, nasal polyps, and aspirin-induced bronchospasm). LTRAs competitively block leukotriene receptors on bronchial smooth muscle and elsewhere.
- ⁇ l adrenergic agonists examples include ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salmeterol, pirbuterol, formoterol, biloterol, bambuterol, salbutamol, and seretide, among others.
- glucocorticosteroids such as beclomethasone, corticoid 21-sulfopropionates, (16 alpha) - 16, 17 - alkylidene bis (oxy) - 3 - arylpregna - 2, 4 - trien - 20 - ones, hydrocortisone esters, cyproterone thiopivalate (CTP), hydrocortisone, dexamethasone trimethyl acetate, alkane sulfonic acids of decinine, ⁇ -hydroxyprednisolone, 18,18-difluorosteroids, preparing 17.alpha.-hydroxy corticoid 21 -phosphate, 21 -phosphate corticords having unprotected hydroxyl radicals at least at the 17.
- beclomethasone corticoid 21-sulfopropionates, (16 alpha) - 16, 17 - alkylidene bis (oxy) - 3 - arylpregna - 2, 4
- the daily dosage of the anti-muscarinic agent and the non-glucocorticoid steroid to be administered to a subject will vary with the overall treatment programmed, the agent employed, the type of formulation, the route of administration and the state of the patient.
- Anti-muscarinic agents and anti-inflammatory steroids are known in the art, and are commercially available.
- Examples 16 to 26 show aerosolized preparations in accordance with the invention for delivery with a device for respiratory or nasal administration, or administration by inhalation. For intrapulmonary administration, liquid preparations are preferred.
- bioactive agents there exist FDA recommended amounts for supplementing a person's dietary intake with additional bioactive agents, such as in the case of vitamins and minerals.
- the pharmacopeia's recommendations cover a ve'fy broad range of dosages, from which the medical artisan may draw guidance. Amounts for the exemplary agents described in this patent may be in the range of those currently being recommended for daily consumption, below or above those levels.
- the treatment may typically begin with a low dose of an anti-muscarinic agent in combination with a non-glucocorticoid steroid, and optionally a glucocorticoid steroid or other bioactive agent as appropriate, and then a titration up of the dosage for each patient.
- the dosage of each of the agents should be adjusted downwards to begin therapy until a dosage is reached that is adequate for the patient. It is recommended that, when possible, a once-a-day dose be administered to maintain a continuous blood level of the agent.
- Preferable ranges for the first, second and other agents employed here will vary depending on the route of administration and type of formulation employed, as an artisan will appreciate and manufacture in accordance with known procedures arid components.
- the active compounds may be administered as one dose (once a day) or in several doses (several times a day).
- compositions and method of preventing and treating respiratory and neoplastic diseases may be used to treat adults, children and infants, as well as non-human animals afflicted with the described conditions.
- the present invention is concerned primarily with the treatment of human subjects, it may also be employed, for veterinary purposes in the treatment of other mammalian subjects, such as dogs and cats as well as for large domestic and wild animals.
- this treatment helps regulate (titrate) the patient in a custom tailored manner.
- an agent such as the non-glucocorticoid steroid in accordance with this invention may reduce inflammation and bronchoconstriction
- the further administration of an anti-muscarinic agent will improve the subject's respiration in a short period of time.
- agents that may be incorporated into the present composition or administered in conjunction with this therapy are one or more of a variety of therapeutic agents that are administered to humans and animals.
- agents suitable are analgesics, pre-menstrual medications, menopausal agents, anti-aging agents, anti- anxyolytic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schyzophrenic agents, anti- cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti-angyogenic agents, cytokines, growth factors, anti- metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphor
- hormones are female and male sex hormones such as premarin, progesterone, androsterones and their analogues, thyroxine and glucocorticoids, among the libido altering agents are Viagra and other NO-level modulating agents, among the analgesics are over-the-counter medications such as ibuprofen, oruda, aleve and acetaminofen and controlled substances such as morphine and codeine, among the anti-depressants are tricyclics, MAO inhibitors and epinephrine, ⁇ mino butyric acid (GABA), dopamine and serotonin level elevating agents, e.g.
- Prozac, Amytryptilin, Wellbutrin ancPZoloft, among the skin renewal agents are Retin-A
- hair growth agents such as Rogaine
- anti-inflammatory agents are non-steroidal anti-inflammatory drugs (NSAIDs) and steroids
- soporifics are melatonin and sleep inducing agents such as diazepam
- cytoprotective, anti-ischemic and head injury agents such as enadoline, and many others.
- agents in the different groups are provided in the following list.
- analgesics are Acetominophen, Anilerdine, Aspirin, Buprenorphine, Butabital, Butorpphanol, Choline Salicylate, Codeine, Dezocine, Diclofenac, Diflunisal, Dihydrocodeine, Elcatoninin, Etodolac, Fenoprofen, Hydrocodone, Hydromorphone, Ibuprofen, Ketoprofen, Ketorolac, Levorphanol, Magnesium Salicylate, Meclofenamate, Mefenamic Acid, Meperidine, Methadone, Methotrimeprazine, Morphine, Nalbuphine, Naproxen, Opium, Oxycodone, Oxymorphone, Pentazocine, Phenobarbital, Propoxyphene, Salsalate, Sodium Salicylate, Tramadol and Narcotic analgesics in addition to those listed above.
- anti-anxiety agents include Alprazola , Bro azepam, Buspirone, Chlordiazepoxide, Chlormezanone, Clorazepate, Diazepam, Halazepam, Hydroxyzine, Ketaszolam, Lorazepam, Meprobamate, Oxazepam and Prazepam, among others.
- anti-anxiety agents associated with mental depression are Chlordiazepoxide, Amitriptyline, Loxapine Maprotiline and Perphenazine, among others.
- anti-inflammatory agents are non-rheumatic Aspirin, Choline Salicylate, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Floctafenine, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Magnesium Salicylate, Meclofenamate, Mefenamic Acid, Nabumetone, Naproxen, Oxaprozin, Phenylbutazone, Piroxicam, Salsalate, Sodium Salicylate, Sulindac, Tenoxicam, Tiaprofenic Acid, Tolmetin.
- anti-inflammatories for ocular treatment are Diclofenac, Flurbiprofen, Indomethacin, Ketorolac, Rimexolone (generally for post-operative treatment).
- anti-inflammatories for non-infectious nasal applications are Beclomethaxone, Budesonide, Dexamethasone, Flunisolide, Triamcinolone, and the like.
- soporifics anti-insomnia sleep inducing agents
- soporifics such as those utilized for treatment of insomnia
- Alprazolam Bromazepam, Diazepam, Diphenhydramine, Doxylamine, Estazolam, Flurazepam, Halazepam, Ketazolam, Lorazepam, Nitrazepam, Prazepam Quazepam, Temazepam, Triazolam, Zolpidem and Sopiclone, among others.
- sedatives are Diphenhydramine, Hydroxyzine, Methotrimeprazine, Promethazine, Propofol, Melatonin, Trimeprazine, and the like.
- Examples of sedatives and agents used for treatment of petit mal and tremors are Amitriptyline HCl, Chlordiazepoxide, Amobarbital, Secobarbital, Aprobarbital, Butabarbital, Ethchiorvynol, Glutethimide, L-Tryptophan, Mephobarbital, MethoHexital Na, Midazolam HCl, Oxazepam, Pentobarbital Na, Phenobarbital, Secobarbital Na, Thiamylal Na, and many others.
- Agents used in the treatment of head trauma include Enadoline HCl (e.g.
- cytoprotective agents and agents for the treatment of menopause and menopausal symptoms are Ergotamine, Belladonna Alkaloids and Phenobarbitals.
- agents for the treatment of menopausal vasomotor symptoms are Clonidine, Conjugated Estrogens and Medroxyprogesterone, Estradiol, Estradiol Cypionate, Estradiol Valerate, Estrogens, conjugated Estrogens, esterified Estrone, Estropipate and Ethinyl Estradiol.
- agents for treatment of symptoms of Pre Menstrual Syndrome are Progesterone, Progestin, Gonadotrophic Releasing Hormone, oral contraceptives, Danazol, Luprolide Acetate and Vitamin B6.
- agents for the treatment of emotional/psychiatric treatments are Tricyclic Antidepressants including Amitriptyline HCl (Elavil), Amitriptyline HCl, Perphenazine (Triavil) and Doxepin HCl (Sinequan).
- Examples of tranquilizers, anti-depressants and anti-anxiety agents are Diazepam (Valium), Lorazepam (Ativan), Alprazolam (Xanax), SSRI's (selective Serotonin reuptake inhibitors), Fluoxetine HCl (Prozac), Sertaline HCl (Zoloft), Paroxetine HCl (Paxil), Fluvoxamine Maleate (Luvox), Venlafaxine HCl (Effexor), Serotonin, Serotonin Agonists (Fenfluramine), and other over the counter (OTC) medications.
- Examples of anti-migraine agents are Imitrex and the like.
- the active agents of this invention are provided within broad amounts of the composition.
- the active agents may be contained in the composition in amounts of about 0.001%, about 1%; about 2%, about 5%, about 10%), about 20%, about 40%, about 90%, about 98%, about 99.999% of the composition.
- the amount of each active agent may be adjusted when, and if, additional agents with overlapping activities are included as discussed in this patent.
- the dosage of the active compounds may vary depending on age, weight, and condition of the subject. Treatment may be initiated with a small dosage, e.g.
- the first active agent of the invention be it a non-glucocorticoid steroid or n anti-muscarinic agent that is administered first, and optionally other bioactive agents described above. This may be similarly done with the second active agent, until a desirable level is attained. Or vice versa, for example in the case of multivitamins and/or minerals, the subject may be stabilized at a desired level of these products and then administered the first active compound. The dose may be increased until a desired and or optimal effect under the circumstances is reached.
- the active agent is preferably administered at a concentration that will afford effective results without causing any unduly harmful or deleterious side effects, and may be administered either as a single unit dose, or if desired in convenient subunits administered at suitable times throughout the day.
- the second therapeutic or diagnostic agent(s) is (are) administered in amounts which are known in the art to be effective for the intended application. In cases where the second agent has an overlapping activity with the principal agent, the dose of one of the other or of both agents may be adjusted to attain a desirable effect without exceeding a dose range that avoids untoward side effects.
- analgesic and anti- inflammatory agents when added to the composition, they may be added in amounts known in the art for their intended application or in doses somewhat lower that when administered by themselves.
- Pharmaceutically acceptable salts should be pharmacologically and pharmaceutically or veterinarily acceptable, and may be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts. Organic salts and esters are also suitable for use with this invention.
- the active compounds are preferably administered to the subject as a pharmaceutical or veterinary composition, which includes systemic and topical formulations.
- the compositions may conveniently be presented in single or multiple unit dosage forms as well as in bulk, and may be prepared by any of the methods which are well known in the art of pharmacy. The actual preparation and compounding of these different formulations is known in the art and need not be detailed here.
- the active compounds may be administered once or several times a day.
- the composition of the invention may also be provided in the form of a kit, whether already formulated or where the active agents are separately provided along with other ingredients, and instructions for its formulation and administration regime.
- the kit may also contain other agents, such as those described in this patent and, for example, when for parenteral administration, they may be provided with a carrier in a separate container, where the carrier may be sterile.
- the present composition may also be provided in lyophilized form, and in a separate container, which may be sterile, for addition of a liquid carrier prior to administration. See, e.g. US Patent No. 4,956,355; UK Patent No. 2,240,472; EPO Patent Application Serial No.
- Formulations suitable for respiratory, nasal, intrapulmonary, and inhalation administration are preferred, as are topical, oral and parenteral formulations. All methods of preparation include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into desired formulations.
- compositions suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
- Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier.
- the compositions of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
- a tablet may be prepared by compressing or molding a power or granules containing the active compound, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing. ⁇ n a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and or surface active/dispensing agent(s).
- Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
- a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose to which may also be added any accessory ingredient(s).
- Such accessory ingredient(s) may include flavorings, suitable preservatives, an agent to retard crystallization of the sugar, and an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol.
- Compositions for oral administration may optionally include enteric coatings known in the art to prevent degradation of the compositions in the stomach and provide release of the drug in the small intestine.
- Compositions suitable for buccal or sub-lingual administration include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth and pastilles comprising the compound in an inert base such as gelation and glycerin or sucrose and acacia.
- compositions suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the compositions isotonic with the blood of the intended recipient.
- Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
- the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried or lyophilized condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Nasal and instillable formulations comprise purified aqueous solutions of the active compound with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.
- Formulations for rectal or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids.
- Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye.
- Otical formulations are generally prepared in viscous carriers, such as oils and the like, as is known in the art, so that they may be easily administered into the ear without spilling.
- compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
- Carriers which may be used include Vaseline, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
- Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
- Compositions suitable for transdermal administration may also be delivered by iontophoresis. See, for example, Pharmaceutical Research 3:318 (1986), and typically take the form of an optionally buffered aqueous solution of the active compound.
- Topical formulations comprise the active compound dissolved or suspended in one or more media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical formulations.
- Cosmetic formulations may be in the form of solid or liquid preparations, for spreading on a subject's skin, including skin base, pancake, suntan, self-tanning and sun blocking lotions and oils. These formulations may additionally contain other cosmetic ingredients as are known in the art. Examples of these formulations are lotions, creams, oils, and other ointments, e.g. suntan lotions containing sunscreens and other protective ingredients, facial make-up and cleansing formulations, shampoos, hair and skin conditioners, and many more known in the art and commercially available.
- accessory ingredient(s) selected from diluents, buffers, flavoring, coloring and aromatizing agents, binders, disintegrants, surface active agents, thickeners, lubricants, emulsifiers, surfactants, emollients, preservatives (including anti-oxidants), and the like.
- accessory ingredient(s) selected from diluents, buffers, flavoring, coloring and aromatizing agents, binders, disintegrants, surface active agents, thickeners, lubricants, emulsifiers, surfactants, emollients, preservatives (including anti-oxidants), and the like.
- Other ingredients may also be utilized as is known in the art.
- the active compounds disclosed herein may be administered into the respiratory system either by inhalation, respiration, nasal administration or intrapulmonary instillation (into the lungs) of a subject by any suitable means, and are preferably administered by generating an aerosol or spray comprised of powdered or liquid nasal, intrapulmonary, respirable or inhalable particles.
- the respirable or inhalable particles comprising the active compound are inhaled by the subject, i.e, by inhalation or by nasal administration or by instillation into the respiratory tract or the lung itself.
- the formulation may comprise respirable or inhalable liquid or solid particles of the active compound that, in accordance with the present invention, include respirable or inhalable particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and continue into the bronchi and alveoli of the lungs.
- respirable or inhalable particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and continue into the bronchi and alveoli of the lungs.
- particles ranging from about 0.05, about 0.1, about 0.5, about 1, about 2 to about 4, about 6, about 8, about 10 microns in size. More particularly, about 0.5 to less than about 5 microns in size, are respirable or inhalable.
- Particles of non- respirable size which are included in an aerosol or spray tend to deposit in the throat and be swallowed. The quantity of non-respirable particles in the aerosol is, thus, preferably minimized.
- a particle size in the range of about 8, about 10, about 20, about 25 to about 35, about 50, about 100, about 150, about 250, about 500 ⁇ m is preferred to ensure retention in the nasal cavity or for instillation and direct deposition into the lung.
- Liquid formulations may be squirted into the respiratory tract (nose) and the lung, particularly when administered to newboms and infants.
- Liquid pharmaceutical compositions, of active compound for producing an aerosol may be prepared by combining the active compound with a stable vehicle, such as sterile pyrogen free water.
- Solid particulate compositions 5. containing respirable dry particles of micronized active compound may be prepared by grinding dry active compound with a mortar and pestle, and then passing the micronized composition through a 400 mesh screen to break up or separate out large agglomerates.
- a solid particulate composition comprised of the active compound may optionally contain a dispersant that serves to facilitate the formation of an aerosol.
- a suitable dispersant is lactose, which may be blended with the active compound in any suitable ratio, e.g., a 1 to 1 ratio by weight.
- Aerosols of liquid particles 0 comprising the active compound may be produced by any suitable means, such as with a nebulizer. See, e.g. US Patent No. 4,501,729.
- Nebulizers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation.
- Suitable compositions for use in nebulizer consist of the active ingredient in liquid carrier, the active ingredient comprising up to 40% w/w composition, but preferably 5 less than 20% w/w carrier being typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example sodium chloride.
- Optional additives include preservatives if the composition is not prepared sterile, for example, methyl hydroxybenzoate, anti-oxidants, flavoring agents, volatile oils, buffering agents and surfactants. Aerosols of solid particles comprising the active compound may likewise be produced with any sold particulate medicament aerosol generator.
- Aerosol generators for administering solid 0 particulate medicaments to a .subject product particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a medicament at a rate suitable for human administration.
- aerosol generators include metered dose inhalers and insufflators.
- DHEA dehydroepiandrosterone
- s means seconds
- mg means milligrams
- kg means kilograms
- kw means kilowatts
- Mhz means megahertz
- nmol means nanomoles.
- Tissue adenosine was extracted, derivatized to 1, N6-ethenoadenosine and analyzed by high performance liquid chromatography (HPLC) using spectrofluorometric detection according to the method of Clark and Dar (J. of Neuroscience Methods 25:243 (1988)). Results of these experiments are summarized in Table 1 0 below. Results are expressed as the mean ⁇ SEM, with K p ⁇ 0.05 compared to control group, and ⁇ p ⁇ 0.05 compared to DHEA or methyltestosterone-treated groups. Table 1: In vivo Effect of DHEA, b -1 -methyltestosterone &
- Methyltestosterone 8.3 ⁇ 1.0 16.5 ⁇ 0.9 N.D. 0.42 ⁇ 0.06
- Folinic acid administered alone induce increase in adenosine levels for all organs studied.
- Example 3 Preparation of the Experimental Model Cell cultures, HT-29 SF cells, which represent a subline of HY-29 cells (ATCC, Rockville, Md.) and are adapted for growth in completely defined serum-free PC-1 medium (Ventrex, Portland, Me.), were obtained. Stock cultures were maintained in this medium at 37° (in a humidified atmosphere containing 5% C0 2 ). At confluence cultures were replated after dissociation using trypsin/EDTA (Gibco, Grand Island, N.Y.) and re-fed every 24 hours. Under these conditions, the doubling time for HT-29 SF cells during logarithmic growth was 24 hours.
- Example 4 Flow Cytometry
- Cells were plated at 10 s /60-mm dish in duplicate. For analysis of cell cycle distribution, cultures were exposed to either 0, 25, 50, pr 200 ⁇ M DHEA. For analysis of reversal of cell cycle effects of DHEA, cultures were exposed to either 0 or 25 ⁇ -v ⁇ DHEA, and the media were supplemented with MVA, CH, RN, MVA plus CH, or MVA plus CH plus RN or were not supplemented. Cultures were trypsinized following 0, 24, 48, or 74 hours and fixed and stained using a modification of a procedure of Bauer et al., Cancer Res., 46, 3173-3178 (1986).
- cells were collected by centrifugation and resuspended in cold phosphate-buffered saline. Cells were fixed in 70% ethanol, washed, and resuspended in phosphate-buffered saline.
- DHEA AKZO, Basel, Switzerland
- Figure 1 illustrates the inhibition of growth for HT-29 cells by DHEA. Points refer to numbers of cells, and bars refer to SEM. Each data point was performed in quadruplicate, and the experiment was repeated three times.
- FIG. 2 illustrates the effects of DHEA on cell cycle distribution in HT-29 SF cells.
- cells were harvested, fixed in ethanol, and stained with propidium iodide, and the DNA content/cell was determined by flow cytometric analysis.
- the percentage of cells in Gi, S, and G 2 M phases was calculated using the Cellfit cell cycle analysis program. S phase is marked by a quadrangle for clarity. Representative histograms from duplicate determinations are shown. The experiment was repeated three times.
- the cell cycle distribution in cultures treated with 25 or 50 ⁇ M DHEA was unchanged after the initial 24 hours. However, as the time of exposure to DHEA increased, the proportion of cells in S phase progressively decreased, and the percentage of cells in Gi, S and G 2 M phases was calculated using the Cellfit cell cycle analysis program. S phase is marked by a quadrangle for clarity. Representative histograms from duplicate determinations are shown. The experiment was repeated three times. The cell cycle distribution in cultures treated with 25 or 50 ⁇ M DHEA was unchanged after the initial 24 hours. However, as the time of exposure to DHEA increased, the proportion of cells in S phase progressively decreased and the percentage of cells in Gi phase was increased after 72 hours. A transient increase in G 2 M phase cells was apparent after 48 hours.
- DHEA-containing medium supplemented with mevalonic acid ("MVA"; mM) squalene (SQ; 80 ⁇ M), cholesterol (CH; 15 ⁇ g/ml), MVA plus CH, ribonucleosides (RN; uridine, cytidine, adenosine, and guanosine at final concentrations of 30 ⁇ M each), deoxyribonucleosides (DN; thymidine, deoxycytidine, deoxyadenosine and deoxyguanosine at final concentrations of 20 ⁇ M each).
- MVA mevalonic acid
- RN ribonucleosides
- DN deoxyribonucleosides
- DN deoxyribonucleosides
- RN plus DN or MVA plus CH plus RN, or medium that was not supplemented. All compounds were obtained from Sigma Chemical Co. (St. Louis, Mo.) Cholesterol was solubilized in ethanol immediately before use. RN and DN were used in maximal concentrations shown to have no effects on growth in the absence of DHEA.
- Figure 3 illustrates the reversal of DHEA-induced growth inhibition in HT-29 SF cells.
- the medium was supplemented with 2 ⁇ M MVA, 80 ⁇ M SQ, 15 ⁇ g/ml CH, or MVA plus CH (MVA+CH) or was not supplemented (CON).
- the medium was supplemented with a mixture of RN containing uridine, cytidine, adenosine, and guanosine in final concentrations of 30 ⁇ M each; a mixture of DN containing thymidine, deoxycytidine, deoxyadenosine and deoxyguanosine in final concentrations of 20 ⁇ M each; RN plus DN (RN+DN); or MVA plus CH plus RN (MVA+CH+RN).
- Cell numbers were assessed before and after 48 hours of treatment, and culture growth was calculated as the increase in cell number during the 48 hour treatment period. Columns represent cell growth percentage of untreated controls; bars represent SEM. Increase in cell number in untreated controls was 173,370"6518. Each data point represents quadruplicate dishes from four independent experiments. Statistical analysis was performed using Student's t test K p ⁇ 0.01; p ⁇ , 0.001; compared to treated controls. Note that supplements had little effect on culture growth in absence of DHEA.
- HT-29 SF cells were treated with 25 FM DHEA in combination with a number of compounds, including MVA, CH, or RN, to test their ability to prevent the cell cycle-specific effects of DHEA.
- Cell cycle distribution was determined after 48 and 72 hours using flow cytometry.
- Figure 4 illustrates reversal of DHEA-induced arrest in HT-29 SF cells. Cells were plated (10 5 cells/60 mm dish) and 48 hours later treated with either 0 or 25 FM DHEA.
- the medium was supplemented with 2 FM MVA; 15 Fg/ml CH; a mixture of RN containing uridine, cytidine, adenosine, and guanosine in final concentrations of 30 FM; MVA plus CH (MVA+CH); or MVA plus CH plus RN (MVA+CH+RN) or was not supplemented.
- Cells were harvested after 48 or 72 hours, fixed in ethanol, and stained with propidium iodine, and the DNA content per cell was determined by flow cytometric analysis. The percentage of cells in G], S, and G 2 M phases were calculated using the Cellfit cell cycle profile analysis program. S phase is marked by a quadrangle for clarity. Representative histograms from duplicative determinations are shown.
- DHEA in vitro exposure of HT-29 SF human colonic adenocarcinoma cells to concentrations of DHEA known to deplete endogenous mevalonate results in growth inhibition and Gi arrest and that addition of MVA to the culture medium in part prevents these effects.
- DHEA produced effects upon protein isoprenylation which were in many respects similar to those observed for specific 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors such as lovastatin and compactin.
- DHEA mediates its effects upon cell cycle progression and cell growth in a pleiotropic manner involving ribo-and deoxyribonucleotide biosynthesis and possibly other factors as well.
- Example 10 Ipratropium Bromide 0.03% (IB) & Beclomethasone Dipropionate Comparison Thirty-three children with non-allergic perennial rhinitis (NAPR) and 113 with allergic perennial rhinitis
- APR APR were randomly assigned to either IB or BDP for 6 months in a single-blind, multicenter protocol in which the physicians were blinded to treatment.
- patients and physicians rated symptom control of rhinorrhea, nasal congestion, and sneezing.
- Patients also completed quality of life questionnaires at baseline and after 6 months of therapy. Both treatments showed a significant improvement in control of rhinorrhea, congestion, and sneezing compared with baseline over the 6 months of treatment (P ⁇ .05). Only for the control of sneezing was BDP consistently better than IB (P ⁇ .05).
- Ipratropium bromide was safe and effective in controlling rhinorrhea and diminishing the interference by rhinorrhea in school attendance, concentration on school work, and sleep. Ipratroprium bromide was as effective as BDP in the control of rhinorrhea and showed a relatively good effect on congestion. Patient and physician assessment favored BDP in the control of sneezing. Milgrom et al. Ann. Allergy Asthma Immunol. 83(2): 105-11(1999).
- micronized DHEA and micronized anti-muscarinic agent are added in the proportions given below either dry or after predispersal in a small quantity of stabilizer, disodium dioctylsulphosuccinate, lecithin, oleic acid or sorbitan trioleate/trichloro-fluoromethane solution to a suspension vessel containing the main bulk of the trichlorofluoromethane solution.
- the resulting suspension is further dispersed by an appropriate mixing system using, for example, a high shear blender, ultrasonics or a microfluidiser until an ultrafine dispersion is created.
- the suspension is then continuously recirculated to suitable filling equipment designed for cold fill or pressure filling of dichlorodifluoromethane.
- the suspension may be also prepared in a suitable chilled solution of stabilizer, in trichlorofluoromethane/dichloro-difluoromethane.
- nebulized ipratropium/beta2 -agonist combination therapy was associated with a pooled 7.3% improvement in forced expiratory volume in 1 sec (95% confidence interval (CI), 3.8-10.9%), and a 22.1% improvement in peak expiratory flow (95% CI, 11.0-33.2%), when compared with patients who received only beta 2- agonist without ipratropium.
- CI confidence interval
- peak expiratory flow 95% CI, 11.0-33.2%
- Tiotropium bromide is a new long-lasting anticholinergic drug which, like ipratropium bromide, is a quaternary ammonium derivative. It binds with high affinity to muscarinic receptors but dissociates very slowly from M(l)- and M(3)-muscarinic receptors. Pharmacology studies have demonstrated a prolonged protective effect against cholinergic agonists and cholinergic nerve stimulation in animal and human airways. In Phase II studies single inhaled doses of tiotropium bromide have a bronchodilator and bronchoprotective effect in asthmatic and chronic obstructive pulmonary disease (COPD) patients of over 24 h.
- COPD chronic obstructive pulmonary disease
- Example 13 Ipratropium & Albuterol Effect on COPD Patients
- PFT pulmonary function test
- Ipratropium bromide 36 microg qid
- albuterol base 180 microg qid
- an equivalent combination of ipratropium bromide and albuterol sulfate 42 microg and 240 microg qid, respectively.
- MEASUREMENTS AND. RESULTS PFT response rates were analyzed using 12% and 15% increases in FEVl compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEVl was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p ⁇ 0.05; all comparisons within 30 min).
- Antimuscarinic treatment of airway disease is used as an effective bronchodilator in chronic obstructed pulmonary disease (COPD) as well as an antisecretory drug for watery rhinorrhea (Allergic Rhinitis).
- COPD chronic obstructed pulmonary disease
- Allergic Rhinitis an antisecretory drug for watery rhinorrhea
- Present formulations are limited to ipratropium bromide, a safe and effective respiratory therapeutic. Ipratropium has been documented by spirometry, ai an effective bronchodilator both alone and in combination with albuterol. The evidence suggests that anticholinergics can affect other important aspects of COPD, such as dynamic hyperinflation.
- the active ingredients are micronized and bulk blended with lactose in the proportions given above.
- the blend is filled into hard gelatin capsules or cartridges or into specifically constructed double foil blister packs (Rotadisks blister packs, Glaxo® to be administered by an inhaler such as the Rotahaler inhaler (Glaxo®) or in the case of the blister packs with the Diskhaler inhaler (Glaxo®).
- the study includes 6 animals studied under a crossover design with a minimum of 4 weeks rest between study arms.
- the treatment with DHEA-S led to the following changes in the disease status of the animals: Lung compliance improved during the early phase response. See, Figure 4.3.1.1.
- the treatment with DHEA-S attenuated the drop in airway compliance following allergen challenge by 87% as compared to saline treatment.
- Lung resistance improved during the early phase response. See, Figure 4.3.1.2.
- Treatment with DHEA-S tended to decrease the total number of leukocytes migrating into the BALF 48 hours after allergen challenge.
- Leukocytes rose from 31.4 x 10 4 to 54.9 x 10 4 cell/ml with saline treatment versus a rise from 34.5 x 10 4 to 39.4 x 10 4 cell/ml in the DHEA-S treatment group.
- the percentage of eosinophils in the saline treated group increased after allergen exposure, the percentage of eosinophils in the DHEA- S treated animals was not significantly different before and after allergen challenge.
- Eosinophil numbers (cells/ml) in the BALF 48 hours after allergen challenge were approximately 64% less following treatment with DHEA-S (1.6 + 0.8 x 10 4 cells/ml) compared to treatment with saline (4.3 + 1.7 x 10 4 cells/ml), but the differences did not reach significance.
- DHEA-S treatment attenuated the neutrophil influx to a level that was not significantly higher than pre-challenge levels. See, Figure 4.3.1.3.
- the absolute number of neutrophils (cells/ml) in the saline group increased to 22.0 ⁇ 10.3 x 10 4 cells/ml while they raised to only 9.7 ⁇ 2.2 x 10 4 cells/ml with DHEA-S treatment.
- Example 25 DHEA-S Effect on Allergen-induced Airway Obstruction & Pulmonary Inflammation This study defines the effect of 7 days of treatment with DHEA-S on allergen-induced bronchial hyperresponsiveness (BHR), early and late phase responses, and pulmonary inflammation in dust mite-sensitized rabbits. Baseline BHR and inflammation were first determined. The following week, allergen challenge, pulmonary function testing and BALF were performed on the untreated rabbits. Histamine sensitivity was determined 24 hours post allergen challenge. Rabbits were rested for 3 weeks then baseline values were re-established.
- BHR allergen-induced bronchial hyperresponsiveness
- DHEA-S (5 mg day) was delivered once a day for 7 days via an infratracheal powder injector through the endotracheal tube of the anesthetized rabbit.
- allergen challenge 24 hrs after the last treatment, allergen challenge, pulmonary function testing and BALF were performed as previously.
- a histamine challenge was performed.
- the drug was not micronized prior to use thus only a portion of the administered dose was expected to reach the deep lung.
- the study includes 4 animals studied under a crossover design. The treatment with DHEA-S led to changes in the disease status of the animals that are described in the following paragraph.
- Pulmonary Function P o for adenosine in the 4 animals ranged from 0.55 to 4.56 mg/ml with mean of 2.5 mg/ml.
- dust mite exposure decreased peak compliance recorded during the early phase by 45% relative to saline, and 28% in the late phase compared to saline, respectively.
- Dust mite exposure increased maximum airway resistance by 234% and 290% during the early and late phase responses, respectively.
- DHEA-S reduced the airway resistance changes in the 6 hours after aerosol dust mite challenge by over 200%.
- the total AUC for the control and treatment groups was 1069 vs. 495. However, due to variability within the small number of animals statistical significance was not reached.
- Treatment with DHEA-S shifted the hyperresponsiveness response to histamine. The histamine response in the saline treated group was greater after dust mite and more variable than in the DHEA-S treatment group.
- Inflammatory cell migration into the BAL fluid was reduced by DHEA-S treatment.
- Animals treated with DHEA-S exhibited lower numbers of eosinophils (2.0 vs. 3.2 x 10 4 cells/ml) and macrophages (17.8 vs. 24.1 x 10 4 cells/ml) in BALF 24 hours after allergen challenge compared to the control group.
- neutrophils 1.3 vs. 10.2 x 10 4 cells/ml
- macrophages (19.4 vs. 29.6 x 10 4 cells/ml) 15 minutes after dust mite challenge. This reduction persisted through the 6 hours time point but was less pronounced. It should be noted that this 24 hour post-dust mite time point was 48 hours after the last treatment with DHEA-S.
- Example 26 DHEA-S Effect on Allergen-induced Airway Obstruction & Pulmonary Inflammation
- This study defines the effect of 7 days of treatment with DHEA-S on allergen-induced bronchial hyperresponsiveness (BHR), early and late phase responses, and pulmonary inflammation in dust mite-sensitized rabbits.
- Baseline BHR and inflammation were first determined.
- DHEA-S (5 mg ml, 2 ml nebulized) or an equivalent volume of vehicle was delivered once per day via nebulization through a pediatric facemask covering the nose and mouth on days 1 through 7.
- allergen challenge, pulmonary function testing and BALF were performed.
- 24 hours after allergen challenge a histamine challenge was performed and the lungs removed for histology.
- the study includes 5 animals studied under a crossover design. There was a 3 week resting period between study arms and lungs were taken during the second treatment arm only.
- the treatment witrh DHEA-S led to the changes in the disease status of the animals described in the following paragraph.
- Dust mite challenge induced a significant increase in the number of eosinophils, neutrophils, and macrophages in the BAL fluid six hours after aerosol administration of allergen.
- the percentage of eosinophils also increased from less than 0.2% to 8% six hours after dust mite challenge in the vehicle control animals confirming that the allergen induced migration of eosinophils into the airways.
- PC 0 for adenosine in the 5 animals ranged from 2.0 to 8.4 mg/ml with mean of 4.5 mgml.
- dust mite exposure decreased peak compliance recorded during the early phase by 32% relative to saline, and 21% in the late phase compared to saline, respectively. Dust mite exposure increased maximum airway resistance by 64% and 82% during the early and late phase responses, respectively.
- Effects on airway obstruction were measured by changes in dynamic compliance and total lung resistance in response to allergen challenge. Rabbits were monitored for 6 hours following allergen challenge and the values plotted against time. Changes in dynamic compliance were determined by the % change in compliance as compared to the animal's initial saline value recorded prior to challenge. Changes in response to allergen and/or treatment were calculated using the AUC where an AUC unit is defined as % change x hour. Treatment with DHEA-S attenuated the drop in airway compliance following allergen challenge by 62% as compared to vehicle treatment. Following allergen alone the total AUC was -99 units compared to +38 units for animals treated with DHEA-S.
- DHEA-S had no significant effect on airway resistance changes in the 6 hours after aerosol dust mite challenge.
- the total AUC for the control and treatment groups was 315 vs. 377.
- DHEA-S had little effect upon resistance in this study. This may be due to particular aspects of the allergic rabbit model, which was designed to study compliance, or to the crossover design. It is worth pointing out that currently available steroids in use for asthma or COPD administered under similar circumstances would not be expected to correct allergen-induced increases in resistance.
- treatment with DHEA-S did not improve hyperresponsiveness to histamine.
- the PC 50 for control and DHEA-S treated animals was 0.84 vs. 0.86 mg/ml. It should be noted that the histamine response was measured 48 hours after the last administration of DHEA-S.
- Inflammatory cell migration into the BAL fluid was reduced by DHEA-S treatment.
- Animals treated with DHEA-S exhibited lower numbers of eosinophils, neutrophils, and macrophages in BALF 6 hours after allergen- challenge compared to the vehicle control group, at p ⁇ 0.01, when analyzed by ANOVA and Fisher's test for LSD.
- the BAL fluid from vehicle- and drug-treated animals contained 8 x 10 4 vs. 4 x 10 4 eosinophils/ml, 94 x 10 4 vs. 29 x 10 4 neutrophils/ml, 37 x 10 4 vs. 12 x 10 4 respectively. The effect was not significant 24 hours after dust mite challenge.
- this 24 hours post-dust mite time point was 48 hours after the last treatment with DHEA-S. Histology Effects on interstitial inflammation were evaluated by histology. A veterinary pathologist evaluated hemotoxylin and eosin stained sections in a blinded manner. Sections were scored for inflammatory parameters using a scale of 0 to 4 with 0 representing no finding and 4 representing severe. Lung sections from animals treated with DHEA-S exhibited less inflammation associated with the airways.
- DHEA-S Prior to DHEA-S treatment serum samples exhibited DHEA and DHEA-S concentrations of 0.9 ng/ml and 4.7 ⁇ g/dl, respectively. Twenty-four hours after the last of seven daily treatments, DHEA and DHEA-S concentrations were 1.1 ng/ml and 4.9 ⁇ g/dl, respectively. DHEA-S was not detectable in BAL fluid. DHA concentrations could be measured, but no correlation with treatment was apparent. Observations of DHEA-S Effects
- Example 27 Effects of Inhaled DHEA-S, Pulmicort® & Saline on Allergen-Induced Airway Obstruction & Inflammation
- 2- DHEA-S tended to decrease the number of eosinophils 6 hours after allergen challenge, while Pulmicort reduced the number of eosinophils at 24 hours post-allergen ( Figure 4.3.4.1).
- DHEA-S and Pulmicort decreased pavementing as compared to saline, tended to decrease necrotizing bronchitis, and tended to increase monocyte phagocytic hyperplasia, but only the effect on pavementing was statistically significant.
- DHEA-S and Pulmicort attenuated inflammation and the decline in pulmonary function normally induced by aeroallergen challenge.
- DHEA-S was equivalent to Pulmicort in its ability to decrease histamine responsiveness and reduce histological indicators of inflammation 24 hours after allergen exposure, and superior in its reductions of inflammatory cells, especially neutrophils, 6 hours after allergen exposure.
- the differences observed between DHEA-S and Pulmicort in both cell types affected and time course of response suggest the drugs work through dissimilar mechanisms.
- the composite histamine dose-response graph for the saline control group exhibited an upward shift of the resistance curve following dust mite challenge ( Figure 4.3.4.2). This provides evidence that dust mite challenge increases bronchial hyperresponsiveness in these animals. These data confirm that the animals in the study responded to the relevant antigen with airway inflammation and altered pulmonary function.
- DHEA-S inhibits allergen-induced eosinophilic and neutrophilic inflammation.
- the effects produced by DHEA-S were different than those demonstrated by Pulmicort. Unlike Pulmicort, DHEA-S caused a dramatic reduction in neutrophilic inflammation.
- DHEA-S 's anti- inflammatory effect was maximal at an earlier time point as compared to Pulmicort. The effect on bronchial hyperresponsiveness 24 hours after dust mite was similar for both DHEA-S and Pulmicort.
- DHEA-S has both the standard properties of the glucocorticoid steroids (e.g., ability to inhibit allergen-induced eosinophilia), and additional properties not shared by the glucocorticoids.
- DHEA-S demonstrated the ability to inhibit neutrophilic inflammation, a unique property that would enable DHEA-S to offer increased benefits in both asthma and COPD as compared to glucocorticoids.
- Example 28 DHEA-S Effect on Bronchial Hyper-responsiveness & Inflammation
- mice This study demonstrates the ability of DHEA-S to reduce bronchial hyperresponsiveness to methacholine challenge in ragweed-sensitized mice.
- Two groups of mice were sensitized with two intraperitoneal injections and one intranasal administration of ragweed allergen (Ambrosia artemisiifolid) on days 0, 4 and 11 respectively.
- a third group was treated similarly with saline to serve as non-allergic controls.
- DHEA-S delivered as an aerosol (5 mg/ml suspension in saline, 2 ml nebulized) using the whole-body plethysmograph system (Buxco Electronics, Inc., Sharon, CT) and a DeVilbiss ultrasonic nebulizer. Twenty-four hours " after the last drug exposure, mice where challenged with increasing concentrations of methacholine to determine bronchial hyperresponsiveness and then lavaged to determine relative changes in cell populations in BAL fluid. DHEA-S treatment led to the following changes in the disease status of the animals:
- the populations of cells in the non-allergic saline control and allergic ragweed group are strikingly different following methacholine challenge.
- Ragweed sensitization results in a significant increase in the percent eosinophils, lymphocytes, and neutrophils compared to the saline control mice (P ⁇ 0.05).
- Treatment of allergic mice with DHEA-S twenty-four hours prior to challenge results in a shift of cellular populations from the allergic profile towards one more similar to the non-allergic mice.
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US20050038004A1 (en) * | 2003-07-31 | 2005-02-17 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anticholinergic bronchodilator for treatment of asthma or chronic obstructive pulmonary disease |
US20050026882A1 (en) * | 2003-07-31 | 2005-02-03 | Robinson Cynthia B. | Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease |
US7923455B2 (en) * | 2005-01-28 | 2011-04-12 | Boehringer Ingelheim International Gmbh | Medicaments for the prevention or treatment of heart failure comprising administration of an anticholinergic |
BRPI0614394A2 (en) * | 2005-08-06 | 2011-03-29 | Boehringer Ingelheim Int | use of tiotropium salts |
US20090062326A1 (en) * | 2006-03-17 | 2009-03-05 | Spindel Eliot R | M3 muscarinic receptor antagonists for treatment of m3 muscarinic receptor-expressing tumors |
AU2008214359B2 (en) * | 2007-02-05 | 2014-01-16 | Apellis Pharmaceuticals, Inc. | Local complement inhibition for treatment of complement-mediated disorders |
US8815258B2 (en) | 2009-05-29 | 2014-08-26 | Pearl Therapeutics, Inc. | Compositions, methods and systems for respiratory delivery of two or more active agents |
AU2015201037C1 (en) * | 2009-05-29 | 2017-07-27 | Pearl Therapeutics, Inc. | Respiratory delivery of active agents |
KR20170070274A (en) * | 2009-05-29 | 2017-06-21 | 펄 테라퓨틱스 인코포레이티드 | Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems |
JP6454323B2 (en) | 2013-03-15 | 2019-01-16 | パール セラピューティクス,インコーポレイテッド | Method and system for conditioning particulate crystalline materials |
WO2019182745A1 (en) | 2018-03-19 | 2019-09-26 | Bryn Pharma, LLC | Epinephrine spray formulations |
CA3112210A1 (en) * | 2018-09-07 | 2020-03-12 | Allied Mineral Products, Llc | Dry refractory compositions with reduced levels of respirable crystalline silica |
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