CN1376069A

CN1376069A - Methods and compositions for reducing sympathomimetic-induced side effects

Info

Publication number: CN1376069A
Application number: CN00813436A
Authority: CN
Inventors: A·L·阿尔玛德
Original assignee: IMAGI NUTRITION Inc
Current assignee: IMAGI NUTRITION Inc
Priority date: 1999-09-27
Filing date: 2000-09-27
Publication date: 2002-10-23
Also published as: AU7621800A; WO2001022982A2; CA2384731A1; WO2001022982A3; EP1216050A2

Abstract

Provided are compositions including Serenoa repens and extracts thereof, in combination with a sympathomimetic agent, which may be used to control a variety of physical conditions, including obesity, appetite suppression, decongestion, asthma and energy stimulation. Serenoa repens, or extracts thereof, when added to dosage forms of pharmacologic agents with sympathomimetic activity, or when administered in combination with sympathomimetic agents, decreases side effects. Thus, debilitating side effects associated with use of pharmacologic agents that stimulate adrenergic receptors and display sympathomimetic effects can be reduced.

Description

The method and composition of the side effect that the minimizing sympathomimetic drug causes

Technical field

The present invention relates to be used for the compositions that contains Saw Palmetto Berries (Serenoa repens) of medicine, cosmetics, food and food supplement prescription.The present invention relates to comprise Saw Palmetto Berries and have active combination of agents thing of the sympatheticomimetic action of not expecting and the application aspect clinical and veterinary thereof.

The present invention relates to reduce with use can activate adrenoreceptor or show that the relevant health of the active reagent of sympatheticomimetic action is weak, moving difficulty and undesirable side effect.

Background technology

In the whole application, represent various publications, patent and disclosed patent application by the definite notes that draw; Whole quoting to these documents can be found in ending place of description.Publication mentioned in this article, patent and disclosed patent application are intactly in conjunction with in this manual as a reference.

Multiple physiological status is controlled or regulated to sympathomimetic extensively as pharmaceutical agent, comprises obesity, appetite, hole hyperemia, body temperature, thermostability, asthma, agility and physiology behavior.For example in fact, sympathomimetic is by caffeine and ephedrine, and/or the mixture of the alkaloid relevant composition with ephedrine, that sells has ephedrine medicine, phenylpropanolamine, the extract and a concentrate of each kind of plant of Ephedra and Sida cordifolia Linn. (Sida cordifolia), (ephedrine of plant origin and associated biomolecule alkali thereof), cathine (phenylpropanolamine) and isoephedrine, and adrianol (i.e. synthetic, also plant origin).Usually, the symptom that the use of these medicaments all can follow some not expect often is the side effect that makes health weak.The outbreak of harmful side effect may be owing to both directly activated the adrenoreceptor activity, mainly is the alpha-adrenergic receptor activity, discharges neuronal norepinephrine again.Referring to Lasagco, L. " phenylpropanolamine, summary " (1988) John Wiley and Sons, Inc.Have and the new prescription that weakens the medicament of the equal pharmacological effect of sympatheticomimetic action, effectively may have bigger improvement on the product basis now.

Sympathomimetic-ephedrine all has strong heat production and obesity performance in the rodent and the mankind, this effect can obviously be strengthened by caffeine, yet caffeine does not but have this action effect separately.Astrup etc., (1992) Int.J.Obes.Relat.Metab.Disord.16:269, the side effect that is in the news comprises: tremble, have a sleepless night and giddy.

Although ephedrine and caffeine (EC) have therapeutic efficiency, can produce acute cardiovascular response according to clinical relevant dose administration, Astrupo etc., (1993) J.Obes.Relat.Metab.Disord.1:S41-3.EC has super additional synergetic effect to calorigenic effect and systolic pressure, and does not influence diastolic pressure, and EC can also improve the glucose in the blood plasma, the concentration of insulin and C-peptide.When the energy in meals was restricted, EC can promote fat to reduce, and keeps fat free material, and this helps its long term effect to the energy balance.EC also has the characteristic of redistributing, and can be used to treatment of obesity, when carrying out long-term treatment, can keep the effect of EC to energy expenditure, and after toleration developed into hemodynamic and metabolic effect, the side effect meeting reduced.

Respectively Isomeride (DF) and EC be studies show that the two can both promote that the obese patient loses weight.Breum etc. (1994) Int.J.Obes.Relat.Metab.Disord.18:99.The side effect that is in the news comprises central nervous system's side effect, and is especially anxious, and gastrointestinal symptoms.

In the obese patient of age 18-60 year and overweight 20-80%, carried out the contrast clinical research, to two kinds of anoreticses, the prescription that contains EC (Elsinore pill) and amfepramone, compare with the action effect of placebo, Malchow-Moller etc., four patient and four patients that handle through the EC pill that handle through amfepramone of (1981) Int.J.Obes.5:183 drop by the wayside research owing to symptom excited, that tremble and have a sleepless night appears in complaint.

In order to evaluate the influence of ephedrine hydrochloride, in the outpatient service adiposis patient of picked at random, carried out double blind control research, Pasquali etc., (1985) Int.J.Obes.9:93 to losing weight.The patient who accepts ephedrine (150mg/ days) suffers obviously bigger side effect than the patient who accepts placebo.Receive an acclaim owing to having multiple use from the product that contains ephedrine of various sources gained, its purposes comprises: treat asthma, lose weight/appetite-suppressing, improve energy, strengthen the physiology behavior, sexual function improving, with the generation sense of euphoria, it is very with practical value therefore to reduce the harmful side effect that contains the ephedrine product.

(Ephedra: the source of ephedrine) and as the brazilian cocoa (guarana) in caffeine source (Metabolife 356 to containing Herba Ephedrae ^TM) a kind of medical herbs supplement carried out double blinding, 8 all experimentatioies of placebo.Nasser etc. (1999) FASEB.J.13:660.7 in 67 experimenters at random, has 7 to withdraw from experimentation before the first round finishes, and in these 7 experimenters, 5 people take supplement, and wherein hypertension takes place 1 people, and the cardiopalmus phenomenon appears in 4 people report.Take turns among 60 experimenters of experimental investigation having fed back one at least, 12 people withdraw from research before the 8th week, this 12 philtrum, and 6 people take supplement, and wherein the cardiopalmus phenomenon appears in 2 people report, and the irritability phenomenon appears in 1 people report, and 1 people develops into systolic pressure and increases.In finishing the experimenter of whole research, report has following phenomenon to increase (supplement contrast placebo): xerostomia (5: 1); Cardiopalmus (2: 2); Blood pressure (＞20pts): systolic pressure (2: 0), diastolic pressure (1: 1); Insomnia (9: 2); Constipation (1: 4) and menorrhagia (1: 2), research conclusion show that this medical herbs supplement promote to lose weight, but also can cause the side effect of not expecting in some experimenter, therefore advise that life-time service also needs further research.

For evaluation is included in the pharmacokinetic properties of the commercial ephedrine in the Herba Ephedrae extract, in normotensive health adult, studied the reaction of heart rate and blood pressure to this product.White etc., (1997) J.Clin.Pharmacol.37:116, in normotensive healthy adult people, Herba Ephedrae is indefinite to the influence of blood pressure, but can increase heart rate.

Ephedrine is considered to cause the vasculitic cause of disease already, but only to just myocarditis and ephedrine and botanical derivative Herba Ephedrae (Ephedra) thereof being connected recently, this evidence is provided by the case study to a non-descendants U.S. male of 39 years old, this man suffer from hypertension and have 1 month firmly the time carrying out property call difficulty, orthopnea, and the medical history of dependency edema, Zaacks etc. (1999) J.Toxicol.Clin.Toxicol.37:485.He takes Herba Ephedrae (Herbalife) 1-3 sheet every day, and 1 day 2 times, and took 3 months together with other vitamin replenisher, pravastatin and furosemide, find that by health check-up the patient only has slight dyspnea.By there being coronary vasodilator to studies show that according to the heart catheterization of shadow art function coronary artery is normal, left ventricle expands, the moderate pulmonary hypertension, and it is 34mmHg that the pulmonary capillary wedge is pressed.The patient is implemented the right ventricle biopsy show, slight myocyte's undue growth and sepage occur, mainly contain acidophil granules's lymphocyte in the sepage, its quantity obviously increases.Myocarditis carried out after one month the treatment, by studies show that of Echocardiogram, left ventricular function improves, and slight overall movement hypofunction is only arranged.Showing did not have myocarditic sign once more to the biopsy of right ventricle in the second month after first takes medicine the course of treatment.6th month, left ventricular ejection fraction was normal, and the patient do not have abnormal symptom, because the allergic myocarditis course of disease that the patient suffered from is short and easily cause vasculitis, was to cause this sick reason so suspect Herba Ephedrae.

In December, 1993 during the nineteen ninety-five JIUYUE, the adverse events that about 500 parts of relevant people are taken place has been received by food and drug safety office (Texas Ministry of Public Health (TDH)) when consumption contains the food supplement of ephedrine and associated biomolecule alkali (isoephedrine, norepinephrine and N-methylephedrine) report.Morb，Mortal.Wkly.Rep.(1996)45：689。All reports comprise summarizes the individual of gained and the report of confirming through epidemic diseases office (TDH) to the record at six centers that come from Texas poisoning centring system, the order of severity of adverse effect is from trembling, have a headache to the user death that causes 8 ephedrines, symptom in the report comprises: apoplexy, myocardial infarction, chest pain, epilepsy, insomnia, nauseating and vomiting, tired, and dizzy.7 cases of 8 reports that cause death are because myocardial infarction or cerebrovascular accident incident cause, though lack about clear and definite nosogenetic enough information in the report, they point out potential health risk may be accompanied by the use that contains the ephedrine product.

(1996) such as Gutierrez M the experiment to the smooth muscle relaxation of smooth muscle contraction is described to the extract (TL [L] and sponifiable body [S]) of two kinds of Saw Palmetto Berries (Sabal serrulate) (also claiming Sernoarepens) fruit.Two kinds of extracts (0.1-1mg/ml) can both relax tonic contraction that causes at rat aorta by norepinephrine (30nM) and the tonic contraction that causes at rat uterus by KCl (60mM).Serenoa repens extract (0.3-1mg/ml) can also resist the dose response curve that is caused contraction by acetylcholine (0.1-100mM) in bladder.DL-Propranolol (1mM) rather than inactive (R)-(+) Propranolol (1mM), strengthened the relaxation effect of serenoa repens extract by reducing the EC50 value, (10 milligrams/ml) effect of antagonism serenoa repens extract of actidiones, yet, actinomycetin D (5 milligrams/ml) can obviously resist the effect of TL extract, and do not change the effect of sponifiable extract.The relaxation effect of these two kinds of extracts is not subjected to the influence of tyrosine kinase inhibitor genistein (10mM) or ODC Ornithine decarboxylase inhibitor alpha-difluoromethyl-ornithine (10mM).

U.S. Pat 5,284,873 pairs of resulting total acid constituents of lipid-soluble extract by basic hydrolysis Saw Palmetto Berries (Sabal serrulata) fruit are described in detail, total acid constituents has adrenergic antagonism and antiinflammatory action, and, especially be very useful in the benign prostatauxe to resisting prostatic disorders.

Serenoa repens extract all is to sell with liquid or pulverous lipid-soluble extract form in many countries, wherein includes a series of fatty acid, as in U.S. Patent No. 5,284, and the description in 873.Commercialization Saw Palmetto Berries product comprises ProstaMed ^TM(Enzymatic Therapy, GreenBay, WI); And serenoa repens extract ((A), commercialization Saw Palmetto Berries fruit extracts has SabalSelect for Nutrilite, Buena Park ^TM(Indena, Seattle, WA); With the standardization serenoa repens extract (Euromed, Pittsburgh, PA).

United States Patent (USP) 6,039,950 relate to when processing Saw Palmetto Berries (being also referred to as Serenoa repens) material, utilize component and active fingerprint map analyzing production to be used for the treatment of the medicine of disease.

Goepel, M etc. (1999) have assessed the antagonism performance of the alpha 1 adrenergic receptor of the chemical compound of various plant origins and extract in vitro study.Cupreol preparation and thorn Herba Urticae Cannabinae, the extract of medicinal Fructus Cucurbitae moschatae and Saw Palmetto Berries obtains from several drug companies, their are suppressed [3H] Harnal is attached to the human benign prostatic alpha 1 adrenergic receptor and [3H] prazosin is attached to clone's people α 1A-and the ability of α 1B-adrenoreceptor detects, and studied the inhibitory action of clone's receptor phenylephrine activated [3H] inositol monophosphate salt formation.Up to maximum concentration that can be detected, the cupreol preparation, thorn Herba Urticae Cannabinae and the depression effect of medicinal Fructus Cucurbitae moschatae in whole experiment are inconsistent, on the contrary, all detected serenoa repens extracts suppress and bonded radioligand of people's alpha 1 adrenergic receptor and antagonist inductive [3H] inositol monophosphate salt formation.In the presence of single serenoa repens extract concentration, saturated combination experiment demonstrates noncompetitive antagonism.Relation between the recommended therapy dosage of active concentration in the experiment in vitro and serenoa repens extract than and the recommended therapy dosage of several alpha 1 adrenergic receptor antagonists of chemically determining between concern and will hang down a bit a little.The author infers that serenoa repens extract has the alpha 1 adrenergic receptor rejection, and therefore, the confirmation serenoa repens extract can be brought into play trait antiadrenergic effect.

Summary of the invention

Compositions provided by the invention comprises Saw Palmetto Berries or its extract and a kind of sympathomimetic.In a specific embodiments, Saw Palmetto Berries or its extract have antiadrenergic drug can be active, antiadrenergic drug can activity be, for example, the disadvantageous sympatheticomimetic action that suppresses sympathomimetic, wherein this adverse effect be because, for example, sympathomimetic acts on that the a-adrenoreceptor produces.

Alternatively, said composition provides with pharmaceutically acceptable form, and it can also comprise a kind of extract of Saw Palmetto Berries alternatively, for example comprises fatty acid or its ester, sterol and/or the alcohols separated from Saw Palmetto Berries.Sympathomimetic can be, for example, and ephedrine or the alkaloid relevant, individualism or exist with the caffeine combination with ephedrine.Other sympathomimetic comprises adrianol, isoephedrine, and phenylpropanolamine.

Sympathomimetic also can comprise the ephedrine or the relevant alkaloid of ephedrine of Herba Ephedrae or other natural origin, the perhaps adrianol of Citrus aurantium Linn. (Citrus aurantium) or other natural origin, or its extract." ephedrine associated biomolecule alkali " this term is meant alkaloid known in the art, has and similar structure of ephedrine and identical sympatheticomimetic action activity, as norepinephrine and isoephedrine.

In another embodiment, provide the method that alleviates the sympathomimetic side effect, comprised when using sympathomimetic administration Saw Palmetto Berries or its extract to the mankind of needs or animal.Saw Palmetto Berries or its extract and sympathomimetic co-administered, perhaps within 1-10 minute, within 1-60 minute, within 1-4 hour, within 1-6 hour, within 1-24 hour, or within 1-48 hour each self administration of medication.Alternatively, administration Saw Palmetto Berries or its extract before or after the administration sympathomimetic.Perhaps, for example because sympathomimetic has the adrenoreceptor activity of antagonism, can be according to the dosed administration Saw Palmetto Berries that can effectively reduce its side effect or its extract.

In method, Saw Palmetto Berries or its extract have trait antiadrenergic activity alternatively.For example, Saw Palmetto Berries can suppress the effect of sympathomimetic to the a-adrenoreceptor, as suppressing combining of sympathomimetic and a-adrenoreceptor.Saw Palmetto Berries or its extract, and sympathomimetic can be used pharmaceutically acceptable form administration.This method comprises a kind of extract of administration Saw Palmetto Berries, for example comprises fatty acid or its esters, sterol and/or alcohols as separating from Saw Palmetto Berries.

Implement mode of the present invention

The present invention relates to a kind of compositions that contains Saw Palmetto Berries or its extract and sympathomimetic.Alternatively, Saw Palmetto Berries or its extract are to exist with the effective dose that can suppress the disadvantageous sympatheticomimetic action of sympathomimetic after the administration, and for example combination or sympathomimetic are to other effect of a-adrenoreceptor.The adrenergic activity that Saw Palmetto Berries or its extract suppressed can be to suppress sympathomimetic to combine with the antagonism of a-adrenoreceptor.The present invention also comprises a kind of Saw Palmetto Berries or its extract and a kind of compositions with the active medicament of sympatheticomimetic action of containing.

Have the active medicament of sympatheticomimetic action and include but not limited to ephedrine and associated biomolecule alkali thereof, the mixture of ephedrine (and/or its associated biomolecule alkali) and caffeine, that sells has an ephedrine, adrianol, isoephedrine, or the phenylpropanolamine medicament, the ephedrine of Herba Ephedrae or other natural origin and associated biomolecule alkali thereof, the adrianol of Citrus aurantium Linn. or other natural origin.Saw Palmetto Berries or its extract are to exist with the enough dose that can reduce the side effect with the active medicament of sympatheticomimetic action.

Saw Palmetto Berries or its extract are that the processing method by standard botanical known in the art obtains.By methods known in the art, the side effect minimizing of sympatheticomimetic action is measured.

The sympathomimetic that can use in the compositions and methods of the invention comprises the reagent of numerous species, they can be used as pharmaceutical agent in order to control or to regulate multiple physiological status, comprise obesity, appetite, hole hyperemia, body temperature, thermostability, asthma, alertness and physiology behavior.The example of sympathomimetic comprises ephedrine, ephedrine/caffeine mixture, and/or the associated biomolecule alkali of ephedrine, sale ephedrine medicine, phenylpropanolamine arranged, the extract of ephedra and Sida cordifolia Linn. and concentrate, (ephedrine of plant origin and associated biomolecule alkali thereof), cathine (phenylpropanolamine), isoephedrine, and adrianol (both synthetic, also plant origin) and wherein several compositionss.

In compositions, Saw Palmetto Berries or its extract can be provided with sympathomimetic, or with the sympathomimetic administering drug combinations.In a specific embodiments, Saw Palmetto Berries or its extract are that the effective dose with the adverse side effect that reduces sympathomimetic exists in compositions or by administration.Be not subjected to the restriction of any theory, it is believed that can by as reduce the adrenoreceptor activity, mainly be to the active direct stimulation of a-adrenoreceptor, and discharge the such approach of neuronal norepinephrine side effect is reduced.For example, can administration 25-5,000mg, or for instance, 50-1000mg.Or the Saw Palmetto Berries of 50-500mg or its extract, perhaps be present in the compositions of using to mammal such as the mankind with dosage form.

In a specific embodiment, ephedrine, individualism or exist with caffeine combination is provided with Saw Palmetto Berries or its extract in compositions, perhaps with Saw Palmetto Berries or its extract administering drug combinations, so that provide, as the effect of heat production or obesity.For example, the compositions in a specific embodiments is by the 5-50mg ephedrine, 5-500mg caffeine and 25-5, and 000mg Saw Palmetto Berries or its extract are formed.

Therefore, the dosage of sympathomimetic can change between the 000mg at 5-5 in compositions, as, 5-500mg, or between 5-100mg or the 5-50mg.For example can use the 5-50mg ephedrine, 5-500mg caffeine, 5-100mg adrianol, the compositions of 5-75mg isoephedrine or 5-100mg phenylpropanolamine medicine or several compositions.

In another specific embodiment, Saw Palmetto Berries or its extract are provided in compositions with the medical herbs supplement, perhaps with medical herbs supplement administering drug combinations, medical herbs supplement wherein contain that (for example, Metabolife 356 as the Herba Ephedrae in ephedrine source or Sida cordifolia Linn. and as the brazilian cocoa in caffeine source ^TM, San Diego, CA), black tea, oolong tea, green tea, coffee or cola.

Saw Palmetto Berries

Saw Palmetto Berries (being also referred to as Sabal serrulata) and extract are business-like products.Business-like Saw Palmetto Berries product comprises ProstaMed ^TM(Enzymatic Therapy, Green Bay, WI); And serenoa repens extract (Nutrilite, Buena Park, CA).The extract of Saw Palmetto Berries berry is commercialization also, comprises SabalSelect ^TM(Indena, Seattle, WA); With standardized serenoa repens extract (Euromed, Pittsburgh, PA).

As used here, term " serenoa repens extract " is meant the product and the part of for example deriving and obtaining from Saw Palmetto Berries from its fruit, the processing method of Saw Palmetto Berries is all had the description of specialty, and for example Gutierrez's etc. (1996) described two kinds of extracts to the Saw Palmetto Berries fruit (TL [L] and sponifiable body [S]) separates.

U.S. Patent No. 6,039,950 have described the method for obtaining serenoa repens extract, and the different phase in the course of processing wherein need be handled and checks raw material.Processing method comprises to be extracted and precipitation.

Goepel, M. etc. (1999) describe in detail the Saw Palmetto Berries raw material that obtains from the market, and this raw material can be applied to the present invention.

Saw Palmetto Berries and extract thereof can be measured according to the description in the technical literature the action activity of alpha-adrenergic receptor hypotype, referring to, for instance, Docherty etc., " in vitro study of the postsynaptic alpha-adrenergic receptor hypotype of rabbit blood vessel and rat anus musculus caudalis meat; " J.Cardiovasc.Pharmacol.3 (4): 854-66,1981.Utilize the rabbit aorta, pulmonary artery and portal vein, and rat anus musculus caudalis meat are studied postsynaptic alpha-adrenergic receptor hypotype external.In this research, phenylephrine (α 1-selection type), Alpha-Methyl norepinephrine (mixing antagonist), and xylazine (α 2-selection type) is as agonist, prazosin (α 1-selection type) and rauwolscine (α 2-selection type) are as antagonist.

Saw Palmetto Berries and extract thereof are to the mensuration of the action activity of alpha-adrenergic receptor hypotype, as the description in Langer etc., " the alpha-adrenergic receptor hypotype of blood vessel: physiology and pharmacology, " J.Cardiovasc Pharmacol 6 (Suppl 4): S547-58,1984.For example, can detect alpha-adrenergic receptor according to the defined two kinds of hypotypes that distribute in proper order for the agonist affinity different and relative efficiency with antagonist.For example, in blood vessel, α 1-and α 2-adrenoreceptor hypotype all are present in the postsynaptic, and both can both mediate vasoconstriction, though alpha 1 adrenergic receptor is the major receptors in the vascular smooth muscle.

Carrier and medication

The administration of compositions can be undertaken by number of ways known in the art, comprise partial, the Sublingual, percutaneous, mouthful, the method for parenteral (comprise intravenous, intraperitoneal, intramuscular and subcutaneous injection also comprise intranasal or inhalation) and implantation.This compositions can be used to the people, uses in the time of also can carrying out medical treatment to animal.

Compositions can be a medicinal forms, also can pass through variety carrier, comprises that obtainable various pharmaceutically suitable carrier provide in this area.Carrier can comprise, for example, and binding agent, lubricant, stabilizing agent, sugar, aminoacid, and electrolyte, diluent, solvent, buffer agent, and solubilizing agent.Compositions can comprise a kind of carrier, this carrier is applicable to the specific administration approach selected such as partial, mouthful, parenterally (comprise intravenous, intraperitoneal, intramuscular and subcutaneous injection, also comprise intranasal or inhalation mode) and the drug delivery implant method, as the description in technical literature, for example, " Remington: medicament science with put into practice (The Science and Practice ofPharmacy) ", Mack publishing company, Pennsylvania, 1995, this civilian detailed content is incorporated herein by reference.

Publication

Publication mentioned in this article, patent and disclosed patent specification intactly are attached in the description of the present invention as a reference.

U.S. Patent No. 5,055,460 (1991)

U.S. Patent No. 5,284,873 (1994)

U.S. Patent No. 6,039,950 (2000)

Astrup, A., etc., " ephedrine/caffeine chemical compound and ephedrine, caffeine are compared effect and the safety in the energy limited meals of obese subjects with placebo.Double blind experiment " Int.J.Obes.Relat.Metab.Disord.16 (4): 269-77,1992.

Astrup, A., etc., " people to the heat production of ephedrine and caffeine, metabolism and cardiovascular response " Int.J.Obes.Relat.Metab.Disord.17 (SUPPL1): S41-S43,1993.

Breum, L., etc." relatively ephedrine/caffeine mixture and Isomeride are to the treatment of obesity.General double blinding multicenter experiment " Int.J.Obes.Relat.Metab.Disord.18 (2): 99-103,1994.

Goepel.M., U.Hecker waits " serenoa repens extract effectively and noncompetitive suppress the in vitro study of human alpha 1 adrenergic receptor " Prostate 38 (3): 208-15,1999.

Gutierrez, M., M.J.Garcia de Boto waits " the Saw Palmetto Berries fruit extract is to the relevant mechanism of the spasmolysis of smooth muscle " Gen Pharmacol 27 (1): 171-6,1996.

Malchow-Moller, A. waits " ephedrine is used as anoretics: the story of Elsinore pill " Int.J.Obes.5 (2): 183-7,1981.

Center for Disease Control (CDC).The unfortunate event relevant: Texas, in December, 1993-nineteen ninety-five JIUYUE with containing the ephedrine product.Incidence and mortality weekly 45 (32): 689-693,1996.

Nasser, J.A. etc. " the usefulness experiment of the effect of losing weight of the medical herbs supplement of Herba Ephedrae and brazilian cocoa " FASEB J 13 (5 PART 2): A874,1999.

Pasquali, R. etc. " utilize the fat control experiment of ephedrine treatment " Int.J.Obes.9 (2): 93-8,1985.

White, L.M. etc. " Herba Ephedrae (Ephedra sinica Ephedra sinica) in normotensive adult pharmacokinetics and to cardiovascular influence " J.Clin.Pharmacol.37 (2): 116-22,1997.

Zaacks, S.M. waits " hypersensitivity myocarditis and the relation of using ephedra " J.Toxicol.Clin.Toxicol.37 (4): 485-489,1999.

Embodiment

Embodiment 1: activity experiment

Utilize effective professional method to the saw palmetto that can reduce the sympathetic transmitter releasers side effect or its The valid density of extract is tested. In a specific embodiments, employed saw palmetto Or the amount of its extract is the effective dose as alpha-adrenergic aceptor antagonist.

In a specific embodiments, utilize the inotropic rat model of seminal vesicle, wherein seminal vesicle flesh The activity of meat can be carried out by alpha-adrenergic reagent the change of pharmacological. Referring to " seminal vesicle shrinks The property body in the microsurgery animal model: the effect of alpha-adrenergic reagent, " U.S.'s reproductive medicine Meeting, annual meeting in 1996, P.J.Turek, A.K.Younes, K.Aslam.Department of Urology, University of California, San Francisco, CA.

Seminal vesicle shrinkage rat model utilizes underbelly nerve stimulation to study in the body. Smart in the body The capsule contractile function changes by alpha-adrenergic activator and antagonist.

After the anesthesia, isolate the seminal vesicle of Wistar rat and insert the conduit that carries out microsurgery research. The pressure of seminal vesicle lumen is derived and record, set up maincenter artery and vein system. Utilize microelectrode to advance The underbelly nerve stimulation of row, then with spasm reaction (highly, mm) and secondary (below the curve Long-pending) phase place measures the two-phase pressure-responsive. The research that repeats nerve stimulation is with confirmatory experiment Repeatability. In addition, after initial control stimulation, by for example inject the 1.0mg/kg saw palmetto or Its extract injects the 1.25mg/kg sympathetic transmitter releasers then, to alpha-adrenergic reagent namely Saw palmetto or its extract (antagonist) and sympathetic transmitter releasers (activator) are to seminal vesicle (SV) Inotropic effect is tested. Inject after each medicine, measure the SV systolic pressure and with right Represent according to the percentage that stimulates, calculate average response and measure variance.

Utilize the stimulation at＞10 minutes intervals can obtain repeated seminal vesicle systole response. Saw palmetto Or its extract causes Alpha-Adrenergic blocking-up obviously subtracting on the statistics of seminal vesicle systolic pressure Little. To the independent medication of sympathetic transmitter releasers with before saw palmetto or its extract or medication simultaneously Action effect compares, and reduces sympathetic transmitter releasers to α-kidney to determine saw palmetto or its extract The valid density of the stimulation of upper parathyrine energy acceptor.

Embodiment 2: activity experiment

Utilize effective professional method to the saw palmetto that can reduce the sympathetic transmitter releasers side effect or its The valid density of extract is tested. In a specific embodiments, employed saw palmetto Or the consumption of its extract is the effective dose as alpha-adrenergic aceptor antagonist.

The aortic contraction of rat chest that is separated to the alpha-adrenergic receptor mediation is surveyed Fixed, such as the description " alpha-adrenergic in the rat chest main artery that is separated of Hamed etc. The pharmacological characteristics of receptor subtype, " J Auton Pharmacol 3 (4): 265-73,1983. Utilize Activator (sympathetic transmitter releasers) and antagonist (saw palmetto or its extract) and mixed by utilizing Close the interaction of activator and antagonist, to being separated of alpha-adrenergic receptor mediation The aortic contraction of rat chest is measured.

Embodiment 3: activity experiment

Before using sympathetic transmitter releasers to the patient or simultaneously, with saw palmetto or its extract, do For a kind of alpha-adrenergic receptor retarding agent, use to the patient. The unfixed period that is prolonging In, for example utilize intrusion technology continuous blood pressure measuring and the heart rate before and after administration determined. This is real The proved recipe case is at random, pseudo-placebo double blinding and two. Also carrying out in the research each time The standardization program test of physical stress. In 24 hours periods, to the variation of blood pressure level and pattern, With to the test of side effect such as hypotensive physiology, and to dynamically and the reaction of isometric exercise survey Examination is to determine that saw palmetto or its extract are to reducing the shadow of the side effect that is caused by sympathetic transmitter releasers Ring, wherein side effect comprises excitement, gastrointestinal symptoms, insomnia, hypertension, palpitaition, irritability, height Blood sugar, dry, blood pressure, systolic pressure, diastolic pressure, constipation and menorrhagia.

Embodiment 4: the production of serenoa repens extract

The method of describing such as European patent 492 305 is produced the extract of saw palmetto fruit, with ethanol or Hexane is that solvent is processed softening fruit, utilizes this area effective method such as crystallization and chromatography to obtain Get the product fraction. In another embodiment, method such as the France of acquisition extract are special The description of sharp No.2 480 754 wherein utilizes polar solvent pair in antioxidant and inert gas The saw palmetto raw material is processed, and characterizes then the characteristic of active component according to method described herein, And can utilize effective professional method that it is further purified. Another kind of acquisition serenoa repens extract Method is described and is seen European patent No.0 250 953, wherein under high pressure utilizes carbon dioxide as molten Agent, pressure limit from 100 to 350 bar for example, temperature range is from 30 ℃ to 50 ℃. Utilize this paper The detection method of describing and effective professional method are identified active component, and can be utilized effectively Professional method it is further purified.

Claims

1. compositions that contains Saw Palmetto Berries (Serenoa repens) or its extract and sympathomimetic.

2. compositions as claimed in claim 1, it is active that wherein Saw Palmetto Berries or its extract have the antiadrenergic drug energy.

3. compositions as claimed in claim 2, wherein antiadrenergic drug can activity be to suppress and the bonded agonist of alpha-adrenergic receptor.

4. compositions as claimed in claim 1, wherein said composition is pharmaceutically acceptable form.

5. compositions as claimed in claim 1, the serenoa repens extract that it comprises comprise isolated chemical compound from Saw Palmetto Berries, and described chemical compound is selected from fatty acid, fatty acid ester, alcohols and sterol.

6. compositions as claimed in claim 1, wherein sympathomimetic comprises the associated biomolecule alkali of ephedrine or ephedrine.

7. compositions as claimed in claim 1, wherein sympathomimetic comprises the associated biomolecule alkali of ephedrine or ephedrine and the mixture of caffeine.

8. compositions as claimed in claim 1, wherein sympathomimetic is selected from adrianol, isoephedrine and phenylpropanolamine.

9. compositions as claimed in claim 1, wherein sympathomimetic is the ephedrine or the associated biomolecule alkali of Herba Ephedrae or other natural origin, or the adrianol of Citrus aurantium Linn. (Citrus aurantium) or other natural origin.

10. method that alleviates the sympathomimetic side effect, this method comprises human or animal's administration Saw Palmetto Berries that these needs are arranged or its extract, and sympathomimetic;

Wherein Saw Palmetto Berries or its extract are the amount administrations with the side effect that can effectively reduce sympathomimetic.

11. method as claimed in claim 10, it is active that wherein Saw Palmetto Berries or its extract have the antiadrenergic drug energy.

12. method as claimed in claim 11, wherein antiadrenergic drug can activity be to suppress and the bonded agonist of alpha-adrenergic receptor.

13. method as claimed in claim 10, wherein Saw Palmetto Berries or its extract are with pharmaceutically acceptable form administration.

14. method as claimed in claim 10 comprises a kind of serenoa repens extract of administration, this extract comprises isolated chemical compound from Saw Palmetto Berries, and described chemical compound is selected from fatty acid, fatty acid ester, sterol and alcohols.

15. method as claimed in claim 10, wherein sympathomimetic comprises the associated biomolecule alkali of ephedrine or ephedrine.

16. method as claimed in claim 10, wherein sympathomimetic comprises the associated biomolecule alkali of ephedrine or ephedrine and the mixture of caffeine.

17. method as claimed in claim 10, wherein sympathomimetic is selected from adrianol, isoephedrine and phenylpropanolamine.

18. method as claimed in claim 10, wherein sympathomimetic is ephedrine or its associated biomolecule alkali of Herba Ephedrae or other natural origin, or the adrianol of Citrus aurantium Linn. or other natural origin.

19. method as claimed in claim 10, wherein the administration of Saw Palmetto Berries or its extract is carried out before about 24 hours at the administration sympathomimetic at least.