EP1216050A2 - Compositions for reducing sympathomimetic-induced side effects by serenoa repens extract - Google Patents
Compositions for reducing sympathomimetic-induced side effects by serenoa repens extractInfo
- Publication number
- EP1216050A2 EP1216050A2 EP00965515A EP00965515A EP1216050A2 EP 1216050 A2 EP1216050 A2 EP 1216050A2 EP 00965515 A EP00965515 A EP 00965515A EP 00965515 A EP00965515 A EP 00965515A EP 1216050 A2 EP1216050 A2 EP 1216050A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- serenoa repens
- extract
- ephedrine
- sympathomimetic
- sympathomimetic agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/752—Citrus, e.g. lime, orange or lemon
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
Definitions
- the present invention relates to compositions containing Serenoa repens for formulation in drug, cosmetic, food, and dietary supplements.
- the present invention relates to compositions comprising Serenoa repens and agents with undesired sympathomimetic activity and the use thereof, in clinical or veterinary applications.
- the present invention relates to reducing the debilitating, untoward and undesirable side effects associated with use of agents that stimulate adrenergic receptors or display sympathomimetic activity.
- Sympathomimetic agents are widely used as pharmacologic agents to control or modulate a variety of physical conditions, including obesity, appetite, sinus congestion, body temperature, thermotolerance, asthma, alertness and physical performance.
- sympathomimetic agents are mixtures composed of caffeine and ephedrine, and/or its related alkaloids, over the counter ephedrine drugs, phenylpropanolamine, extracts and concentrates o ⁇ Ephedra species and Sida cordifolia, (plant sources of ephedrine and its related alkaloids), norephedrine (phenylpropanolamine) and pseudoephedrine, and synephrine (either synthetic or derived from plant sources).
- the sympathomimetic agent ephedrine has potent thermogenic and anti-obesity properties in both rodents and humans. The effect is markedly enhanced by caffeine, while caffeine alone has no effect.
- EC ephedrine and caffeine administered in clinically relevant doses produces acute cardiovascular effects.
- EC exerts a supra-additive synergism on thermogenesis and systolic blood pressure, without affecting diastolic blood pressure.
- EC also increases plasma glucose, insulin and C-peptide concentrations.
- EC promotes fat loss and preserves fat-free mass, which may contribute to its chronic effect on energy balance.
- EC also possesses repartitioning properties, which may be useful in the treatment of obesity.
- chronic treatment the effect of EC on energy expenditure is maintained, while side effects subside after tolerance develops to the hemodynamic and metabolic effects.
- Ephedrine has previously been described as a causative factor of vasculitis but myocarditis has only recently been associated with either ephedrine or its plant derivative Ephedra. Evidence of this is provided in a case study where a 39-year-old African
- the patient had right ventricular biopsy performed demonstrating mild myocyte hypertrophy and an infiltrate consisting predominantly of lymphocytes with eosinophils present in significantly increased numbers. Treatment for myocarditis was initiated and one month into therapy, an echocardiogram demonstrated improved left ventricular function with only mild global hypokinesis. A repeat right ventricular biopsy 2 months after the first admission showed no evidence of myocarditis. At 6 months, left ventricular ejection fraction was normal and the patient asymptomatic. Ma huang was the suspected cause of hypersensitivity myocarditis in this patient due to the temporal course of disease and its propensity to induce vasculitis.
- Adverse effects ranged in severity from tremor and headache to death in eight ephedrine users and included reports of stroke, myocardial infarction, chest pain, seizures, insomnia, nausea and vomiting, fatigue, and dizziness. Seven of the eight reported fatalities were attributed to myocardial infarction or cerebrovascular accident. Although the reports lack sufficient information to unequivocally assign causality, they suggest potential health risks may accompany the use of products containing ephedrine.
- Gutierrez M et al. (1996) describe assays of smooth muscle relaxing action of two extracts (total lipid [L] and saponifiable [S]) from Sabal serrulata (also known as Sernoa repens) fruits on smooth muscle contractions. Both extracts (0.1-1 mg/ml) relaxed the tonic contraction induced by norepinephrine (30 nM) on rat aorta and by KC1 (60 mM) on rat uterus. The Sabal extracts (0.3-1 mg/ml) also antagonized the dose- response curve of contractions induced by acetylcholine (0.1-100 microM) on urinary bladder.
- U.S. patent 5,284,873 discloses obtaining a total acid fraction obtained by alkali hydrolysis of lipid extracts of the fruit of Sabal serrulata, which were disclosed as having adrenergic antagonist action and antiinflammatory action, and useful in combatting prostate affections, in particular, benign hypertrophy of the prostate.
- Serenoa repens extracts are sold in numerous countries as lipid extracts, available in liquid or powder forms, and contain an array of fatty acids such as those described in U.S. Patent No. 5,284,873.
- Commercially available Sereno repens products include ProstaMedTM (Enzymatic Therapy, Green Bay, WI); and Saw Palmetto Extract (Nutrilite,
- Extracts of Serenoa repens berries that are commercially available include SabalSelectTM (Indena, Seattle, WA); and standardized saw palmetto extract (Euromed, Pittsburgh, PA).
- U.S. patent 6,039,950 relates to the use of compositional and activity fingerprints in processing of saw palmetto (also known as Serenoa repens) materials to produce drugs for the treatment of diseases.
- compositions comprising Serenoa repens or an extract thereof and a sympathomimetic agent.
- the Serenoa repens or extract thereof has anti-adrenergic activity, and the anti-adrenergic activity is, for example, inhibition of the adverse sympathomimetic effects of the sympathomimetic agent, wherein the adverse effects result, for example, from the effects of the sympathomimetic agent on the alpha- adrenergic receptor.
- the composition is provided in a pharmaceutically acceptable form.
- the composition optionally may comprise an extract f Serenoa repens comprising, for example, fatty acids or esters thereof, sterols and/or alcohols isolated from Serenoa repens.
- the sympathomimetic agent can be, for example, ephedrine or an ephedrine related alkaloid, alone or in combination with caffeine.
- Other sympathomimetic agents include synephrine, pseudoephedrine, and phenylpropanolamine.
- the sympathomimetic agent also may comprise ma huang or other natural sources of ephedrine or ephedrine related alkaloids, or Citrus aurantium or other natural sources of synephrine, or extracts thereof.
- ephedrine related alkaloid refers to alkaloids known in the art to have similar structure and the same sympathomimetic activity as ephedrine, such as norephedrine, and pseudoephedrine.
- methods of alleviating the side effects of a sympathomimetic agent comprising administering Serenoa repens or an extract thereof, in combination with the sympathomimetic agent, to a human or animal in need thereof.
- the Serenoa repens or extract thereof and the sympthomimetic agent are administered, for example, concomitantly, or within 1-10 minutes, within 1-60 minutes, within 1-4 hours, within 1-6 hours, within 1-24 hours or within 1-48 hours of each other.
- the Serenoa repens or extract thereof is administered prior to or after the sympathomimetic agent.
- the Serenoa repens or extract thereof is administered in an amount effective to reduce side effects, for example due to agonistic adrenergic receptor activity of the sympathomimetic agent.
- the Serenoa repens or extract thereof optionally has anti-adrenergic activity.
- the Serenoa repens may inhibit the effect of the sympathomimetic agent on the alpha-adrenergic receptor, such as binding of the sympathomimetic agent to the alpha-adrenergic receptor.
- the Serenoa repens or extract thereof, and the sympathomimetic agent may be administered in a pharmaceutically acceptable form.
- the method may comprise administering an extract of Serenoa repens comprising, for example, fatty acids or esters thereof, sterols and/or alcohols isolated from Serenoa repens.
- the invention encompasses a composition comprising Serenoa repens or extract thereof and a sympathomimetic agent.
- the Serenoa repens or extract thereof is present in an amount effective to inhibit adverse sympathomimetic effects of the sympathomimetic agent, such as binding or other effect of the sympathomimetic agent on the alpha-adrenergic receptor, upon administration.
- the adrenergic activity inhibited by the Serenoa repens or extract thereof can be inhibition of agonistic binding of the sympathomimetic agent to the alpha-adrenergic receptor.
- the invention further encompasses a composition comprising Serenoa repens or extract thereof and a pharmacologic agent having sympathomimetic activity.
- the pharmacologic agents having sympathomimetic activity include but are not limited to ephedrine and its related alkaloids, mixtures of ephedrine (and/or its related alkaloids) and caffeine, over the counter ephedrine, synephrine, pseudoephedrine, or phenylpropanolamine drugs, ma huang or other natural sources of ephedrine and its related alkaloids, Citrus aurantium or other natural sources of synephrine.
- the Serenoa repens or extract thereof optionally is present in an amount sufficient to decrease the side effects of pharmacologic agents having sympathomimetic activity.
- the Serenoa repens or extract thereof is obtained by standard botanical processing methods known in the art. Decrease of the sympathomimetic side effects is measured by methods known in the art.
- Sympathomimetic agents that can be used in the compositions and methods disclosed herein include a wide variety of agents used as pharmacologic agents to control or modulate a variety of physical conditions, including obesity, appetite, sinus congestion, body temperature, thermotolerance, asthma, alertness and physical performance.
- sympathomimetic agents include ephedrine, caffeine/ephedrine mixtures, and/or related ephedrine alkaloids, over the counter ephedrine drugs, phenylpropanolamine, extracts and concentrates of Ephedra species and Sida cordifolia, (plant sources of ephedrine and its related alkaloids), norephedrine (phenylpropanolamine), pseudoephedrine. and synephrine (either synthetic or derived from plant sources), and combinations thereof.
- the Serenoa repens or extract thereof can be provided in a composition with the symphathomimetic agent, or administered in combination with the sympathomimetic agent.
- the Serenoa repens or extract thereof is present in the composition, or is administered, in an amount effective to reduce undesirable side effects of the sympathomimetic agent.
- the side effects can be reduced by such pathways as reducing direct stimulation of adrenergic receptor activity, primarily alpha-adrenergic receptor activity, and release of neuronal norepinephrine. For example, 25 - 5,000 mg, or e.g., 50-1000 mg, or 50-500 mg of
- Serenoa repens or extract thereof can be administered or be present in a dosage amount in a composition for administration to a mammal, such as a human.
- ephedrine alone or in combination with caffeine, is provided in a composition with Serenoa repens or extract thereof, or is administered in combination with Serenoa repens or extract thereof, in order to provide, for example, thermogenic and anti-obesity effects.
- the composition in one embodiment comprises 5-50 mg ephedrine, 5-500 mg caffeine and 25 - 5,000 mg of Serenoa repens or extract thereof.
- the dosage amount of the sympathomimetic agent in the composition can vary between about 5-5,000 mg, for example, between 5- 500 mg, or between 5-100 mg or 5-50 mg.
- 5-50 mg ephedrine, 5-500 mg caffeine, 5-100 mg synephrine, 5-75 mg pseudoephedrine or 5-100 mg phenylpropanolamine drugs or combinations thereof can be used.
- Serenoa repens or extract thereof is provided in a composition together with, or is administered in combination with an herbal supplement containing Ephedra or Sida cordifolia as a source of ephedrine and guarana (for example,
- Metabolife 356TM San Diego, CA
- black tea oolong tea
- green tea coffee or cola as a source of caffeine.
- Serenoa repens also known as Sabal serrulata
- extracts are commercially available.
- Commercially available Serenoa repens products include ProstaMedTM
- Extracts of Serenoa repens berries are commercially available including SabalSelectTM (Indena, Seattle, WA); and standardized saw palmetto extract (Euromed, Pittsburgh, PA).
- Serenoa repens extracts refers to products and fractions that have been derived from Serenoa repens, for example from the fruit thereof. Methods of processing Serenoa repens have been described in the art. For example, Gutierrez et al.
- U.S. Patent No. 6,039,950 describes methods of obtaining extracts of saw palmetto wherein raw material is processed and assayed at different stages of processing. Processing methods include extraction and precipitation.
- Goepel, M. et al. (1999) discloses saw palmetto materials obtained from commercially available sources, which may be used in accordance with the present invention.
- the activity of Serenoa repens and extracts thereof on alpha-adrenoreceptor subtypes can be measured as described in the art. See, e.g., Certy et al., "Postsynaptic alpha-adrenoceptor subtypes in rabbit blood vessels and rat anococcygeus muscle studied in vitro," J Cardiovasc. Pharmacol. 3(4): 854-66, 1981. Postsynaptic alpha-adrenoceptor subtypes are investigated in vitro, employing rabbit aorta, pulmonary artery, and portal vein, and rat anococcygeus.
- phenylephrine alpha 1 -selective
- alpha- methylnoradrenaline mixed agonist
- xylazine alpha 2-selective
- prazosin alpha 1 -selective
- rauwolscine alpha 2-selective
- Serenoa repens and extracts thereof can be measured on alpha- adrenoreceptor subtypes as described in: Langer et al., "Alpha-adrenoreceptor subtypes in blood vessels: physiology and pharmacology," J. Cardiovasc Pharmacol 6(Suppl 4): S547-
- alpha-adrenoreceptors as defined by a different profile of affinity and relative order of potencies for agonists and for antagonists can be assayed.
- alpha 1 - and alpha 2-adrenoreceptor subtypes are present postsynaptically, where they mediate vasoconstriction, although the alpha 1-adrenoreceptor is the predominant receptor in vascular smooth muscle.
- compositions may be administered by a variety of routes known in the art including topical, sublingual, transdermal, oral, parenteral (including intravenous, intraperitoneal, intramuscular and subcutaneous injection as well as intranasal or inhalation administration) and implantation.
- routes known in the art including topical, sublingual, transdermal, oral, parenteral (including intravenous, intraperitoneal, intramuscular and subcutaneous injection as well as intranasal or inhalation administration) and implantation.
- parenteral including intravenous, intraperitoneal, intramuscular and subcutaneous injection as well as intranasal or inhalation administration
- implantation may be administered to humans as well as to animals for veterinary purposes.
- compositions may be provided in pharmaceutically acceptable form, and may be provided in a variety of carriers, including a range of pharmaceutically acceptible carriers available in the art.
- the carriers may include, for example, binders, lubricants, stabilizers, sugars, amino acids, and electrolytes, diluents, solvents, buffers, and solubilizers.
- compositions may include a carrier suitable for the particular route of administration selected including topical, oral, parenteral (including intravenous, intraperitoneal, intramuscular and subcutaneous injection as well as intranasal or inhalation administration) and implantation, as described in the art, for example, in “Remington: The Science and Practice of Pharmacy", Mack Publishing Company, Pennsylvania, 1995, the disclosure of which is incorporated herein by reference.
- a carrier suitable for the particular route of administration selected including topical, oral, parenteral (including intravenous, intraperitoneal, intramuscular and subcutaneous injection as well as intranasal or inhalation administration) and implantation, as described in the art, for example, in “Remington: The Science and Practice of Pharmacy", Mack Publishing Company, Pennsylvania, 1995, the disclosure of which is incorporated herein by reference.
- the effective concentration of Serenoa repens or extract thereof to reduce side effects of sympathomimetic agents is tested using methods available in the art.
- the amount of Serenoa repens or extract thereof used is in one embodiment an effective amount to act as an alpha-adrenoreceptor antagonist.
- a rat model of seminal vesicle contractility is used, wherein seminal vesicle muscular activity is pharmacologically altered by alphal -adrenergic agents. See "An In Vivo Microsurgical Animal Model of Seminal Vesicle Contractility: The
- the in vivo rat model of seminal vesicle contractility employs hypogastric nerve stimulation.
- In vivo seminal vesicle contractile function is altered by alpha adrenergic agonists and antagonists.
- the seminal vesicle is isolated in Wistar rats and cannulated microsurgically.
- Seminal vesicle luminal pressures are transduced and recorded. Central arterial and venous lines are established.
- hypogastric nerve stimulation with a microelectrode, a biphasic pressure response is measured as twitch (height, mm) and secondary (area under curve) phases.
- twitch height, mm
- secondary area under curve
- the effect of the alphal -adrenergic agents Serenoa repens or extract thereof (antagonist) and a sympathomimetic agent (agonist) on S V contractility is examined by infusing for example 1.0 mg/kg Serenoa repens or extract thereof and then for example 1.25 mg/kg sympathomimetic agent after an initial control stimulation.
- SV contractile pressures are measured after each drug is infused and expressed as percent of the control stimulation. Mean responses and measures of variance are calculated.
- Reproducible seminal vesicle contractile responses with stimulations at >10 minute intervals can be obtained.
- Alphal -adrenergic blockade from the Serenoa repens or extract thereof results in a statistically significant decrease in seminal vesicle contraction pressures.
- the effect of the sympathomimetic agent alone and with pre or co-administration of the Serenoa repens or extract thereof is compared to determine the effective concentration of
- Example 2 Activity Assay The effective concentration of Serenoa repens or extract thereof to reduce side effects of sympathomimetic agents is tested using methods available in the art.
- the amount of Serenoa repens or extract thereof used is in one embodiment an effective amount to act as an alpha-adrenoreceptor antagonist.
- Alpha-adrenoreceptor mediated contraction in rat isolated thoracic aorta is measured, as described in Hamed et al. "Pharmacological characterization of alpha- adrenoreceptor subtypes in rat isolated thoracic aorta," JAuton Pharmacol 3(4): 265-73, 1983.
- the alpha-adrenoreceptor mediated contraction in rat isolated thoracic aorta is measured using agonist (sympathomimetic agent) and antagonists (Serenoa repens or extract thereof), and by utilizing mixed agonist and antagonist interactions.
- Example 3 Activity Assay The effective concentration of Serenoa repens or an extract thereof to reduce side effects of sympathomimetic agents is tested using methods available in the art.
- the amount of Serenoa repens or extract thereof used is in one embodiment an effective amount to act as an alpha-adrenoreceptor antagonist.
- Serenoa repens or an extract thereof, used as an alpha-adrenoreceptor blocking agent, is used as administered to patients prior to or contemporaneously with administration of a sympathomimetic agent.
- Blood pressure and heart rate are measured continuously over prolonged ambulatory periods for example using an established invasive technique before and after adminstration.
- the protocol is randomised, double-blind, and double- dummy placebo controlled.
- a standardized program of physiological stress testing also is performed during each study.
- Extracts of the fruits of Serenoa repens are produced as described in European Patent 492 305.
- An extract of Serenoa repens is produced using ethanol or hexane as solvents to treat a maceration of the fruits.
- Product fractions are obtained using methods available in the art such as crystallization and chromatography.
- Another embodiment of obtaining an extract is described in French Patent No. 2 480 754, wherein Serenoa repens material is treated with polar solvents in the presence of anti-oxidants in an inert atmosphere. Active fractions are characterized as described herein and may be further purified using methods available in the art.
- Serenoa repens is described in European Patent No. 0 250 953, wherein carbon dioxide is used as the solvent under high pressure conditions, for example, at pressures ranging from 100 to 350 bars and at temperatures ranging from 30.degrees Centigrade to 50 degrees Centigrade. Active fractions are identified using assays described herein and available in the art, and may be further purified by methods available in the art.
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Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15626299P | 1999-09-27 | 1999-09-27 | |
US156262P | 1999-09-27 | ||
PCT/US2000/026752 WO2001022982A2 (en) | 1999-09-27 | 2000-09-27 | Compositions for reducing sympathomimetic-induced side effects by serenoa repens extract |
Publications (1)
Publication Number | Publication Date |
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EP1216050A2 true EP1216050A2 (en) | 2002-06-26 |
Family
ID=22558809
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00965515A Withdrawn EP1216050A2 (en) | 1999-09-27 | 2000-09-27 | Compositions for reducing sympathomimetic-induced side effects by serenoa repens extract |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1216050A2 (en) |
CN (1) | CN1376069A (en) |
AU (1) | AU7621800A (en) |
CA (1) | CA2384731A1 (en) |
WO (1) | WO2001022982A2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN105106520A (en) * | 2015-10-06 | 2015-12-02 | 常州亚当生物技术有限公司 | Healthcare product |
-
2000
- 2000-09-27 WO PCT/US2000/026752 patent/WO2001022982A2/en not_active Application Discontinuation
- 2000-09-27 EP EP00965515A patent/EP1216050A2/en not_active Withdrawn
- 2000-09-27 AU AU76218/00A patent/AU7621800A/en not_active Abandoned
- 2000-09-27 CA CA002384731A patent/CA2384731A1/en not_active Abandoned
- 2000-09-27 CN CN00813436A patent/CN1376069A/en active Pending
Non-Patent Citations (1)
Title |
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See references of WO0122982A2 * |
Also Published As
Publication number | Publication date |
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CN1376069A (en) | 2002-10-23 |
AU7621800A (en) | 2001-04-30 |
WO2001022982A2 (en) | 2001-04-05 |
CA2384731A1 (en) | 2001-04-05 |
WO2001022982A3 (en) | 2002-03-14 |
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