US20130053411A1 - Pharmaceutical composition and method for treating hypertension - Google Patents

Pharmaceutical composition and method for treating hypertension Download PDF

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US20130053411A1
US20130053411A1 US13/695,628 US201113695628A US2013053411A1 US 20130053411 A1 US20130053411 A1 US 20130053411A1 US 201113695628 A US201113695628 A US 201113695628A US 2013053411 A1 US2013053411 A1 US 2013053411A1
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dextromethorphan
effective amount
pharmaceutical composition
amlodipine
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Jaw-Wen Chen
His-Chieh Wang
Shin-Yi Juang
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TSH BIOPHARM CORP Ltd
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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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Hypertension is a public health problem that affects more than 25% of the adult population worldwide.
  • [1,2] Hypertension has been identified as the leading risk factor for mortality and ranks as the third-leading cause of disability-adjusted life-years.
  • [1,3] Despite the availability of numerous antihypertensive agents, the diagnosis, management, and control of hypertension are far from ideal, with control rates of 6% to 30% in different communities worldwide.
  • Nonadherence to antihypertensive treatment has been associated with lower rates of blood pressure (BP) control and higher rates of cardiovascular events.
  • BP blood pressure
  • Administration of a once-daily fixed-dose combination (FDC) therapy with >2 classes of antihypertensive agents is a strategy adopted for improving adherence and BP control. This strategy has been described in the recent guidelines, even as an initial therapeutic option.
  • FDC once-daily fixed-dose combination
  • NADPH oxidases have recently been shown to contribute to the pathogenesis of hypertension. See Williams et al., 2007 , J. Cardiovasc Pharmacol., 50:9-16 and references therein. It has been suggested that specific inhibitors of these enzymes may have potential therapeutic use in hypertensive disease. Two of the most specific inhibitors, gp91ds-tat and apocynin, have been shown to decrease blood pressure in animal models of hypertension.
  • inhibitors including diphenylene iodonium, aminoethyl benzenesulfono fluoride, 517834, PR39, protein kinase C inhibitors, and VAS2870, have shown promise in vitro, but their in vivo specificity, pharmacokinetics, and effectiveness in hypertension remains to be determined.
  • the currently available antihypertensive agents, angiotensinconverting enyzme inhibitors and angiotensin receptor blockers also effectively inhibit NADPH oxidase activation.
  • the cholesterol-lowering agents, statins have been shown to attenuate NADPH oxidase activation.
  • Dextromethorphan is a dextrorotatory morphinan and is widely used as a nonopioid cough suppressant in a variety of over-the-counter remedies. [17] It is an NMDA receptor antagonist. The exact mechanism of action of its antitussive activity, however, remains unclear. Studies using animal models of cerebral ischemia and hypoglycemic neural injuries have demonstrated that DM possesses neuroprotective activity. [18-23] DM effectively inhibited the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced production of reactive oxygen species (ROS).
  • MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • ROS reactive oxygen species
  • DM reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice through the direct inhibition of NADPH oxidase and that it also decreases superoxide production in the aorta and carotid artery of apolipoprotein E (apoE)-deficient mice. Liu et al., 2009 , Cardiovascular Research, 82:161-169.
  • CBs Calcium channel blockers
  • Amlodipine is a CCB with antihypertensive properties prescribed as monotherapy. It is one of a series of dihydropyridine calcium antagonists. It has been found to be well tolerated even in high-risk patients, such as those with coronary disease, heart failure, or multiple risk factors for cardiovascular events. [12-16] Amlodipine has a generally slower onset and longer duration of action than, for example, nifedipine. (Jensen, H. et al., J. Hum. Hypertens., 42(5): 541-45, 1990). The metabolites of amlodipine apparently do not possess significant calcium channel blocking activity, while the parent drug offers a biological half-life of some 35-40 hours, prompting a once-daily dosage regimen.
  • dextromethorphan not only is effective to lower blood pressure in a subject suffering from hypertension, but also acts synergistically with a calcium channel blocker to result in a major improvement in the treatment of hypertension, with no or little adverse effects.
  • embodiments of the present invention relate to a method of treating hypertension or a symptom associated therewith in a subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of dextromethorphan and a pharmaceutically acceptable carrier.
  • embodiments of the present invention relate to a method of treating hypertension or a symptom associated therewith in a subject.
  • the method comprises administering to the subject an effective amount of dextromethorphan and an effective amount of a calcium channel blocker.
  • embodiments of the present invention relate to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject, comprising an effective amount of dextromethorphan, an effective amount of a calcium channel blocker, and a pharmaceutically acceptable carrier.
  • the present invention relates to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject, which comprises an effective amount of dextromethorphan, an effective amount of amlodipine, and a pharmaceutically acceptable carrier.
  • embodiments of the present invention relate to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject, comprising an effective amount of a calcium channel blocker, an effective amount of a NADPH oxidase inhibitor, and a pharmaceutically acceptable carrier.
  • aspects of the present invention relate to methods of treating hypertension or a symptom associated therewith in a subject, comprising administering to the subject an effective amount of a calcium channel blocker, such as amlodipine, and an effective amount of a NADPH oxidase inhibitor, such as dextromethorphan.
  • a calcium channel blocker such as amlodipine
  • a NADPH oxidase inhibitor such as dextromethorphan.
  • FIG. 1 a - FIG. 1 d illustrate the blood pressure lowing effect of dextromethorphan (DM) in an animal model for hypertension, i.e., spontaneous hypertensive rats (SHR), at three dosage levels, 1 mg/kg/day, 5 mg/kg/day, and 25 mg/kg/day:
  • DM dextromethorphan
  • FIG. 1 a changes of systolic blood pressure (SBP) after DM treatment
  • FIG. 1 b changes of diastolic blood pressure (DBP) after DM treatment
  • FIG. 1 c changes of heart rate (HR) after DM treatment.
  • FIG. 1 d changes of mean blood pressure (MBP) after DM treatment
  • FIG. 2 a - FIG. 2 d illustrate the blood pressure lowing effect of amlodipine (AM) in SHR, at two dosage levels, 1 mg/kg/day and 5 mg/kg/day:
  • AM amlodipine
  • FIG. 2 a changes of SBP after AM treatment
  • FIG. 2 b changes of DBP after AM treatment
  • FIG. 2 c changes of HR after AM treatment
  • FIG. 2 d changes of MBP after AM treatment
  • FIG. 3 a - FIG. 3 d illustrate the blood pressure lowing effect of the combination of DM and
  • FIG. 3 a changes of SBP after DM+AM treatment
  • FIG. 3 b changes of DBP after DM+AM treatment
  • FIG. 3 c changes of HR after DM+AM treatment.
  • FIG. 3 d changes of MBP after DM+AM treatment
  • FIG. 4 a - FIG. 4 d illustrate the blood pressure lowing effect of different treatment regimens in SHR, expressed as percentage change of blood pressure or heart rate:
  • FIG. 4 a percentage changes of SBP after different treatment regimens
  • FIG. 4 b changes of DBP after different treatment regimens
  • FIG. 4 c changes of HR after different treatment regimens.
  • FIG. 4 d changes of MBP after different treatment regimens
  • FIG. 5 a and FIG. 5 b show the comparison of blood pressure lowering effect of single and combination treatments in SHR as percentage changes of SBP and DBP:
  • FIG. 5 a percentage changes of SBP and DBP after single treatment with DM at 1 mg/kg/day, single treatment with AM at 5 mg/kg/day, and combined treatment with DM at 1 mg/kg/day and AM at 5 mg/kg/day;
  • FIG. 5 b percentage changes of SBP and DBP after single treatment with DM at 5 mg/kg/day, single treatment with AM at 5 mg/kg/day, and combined treatment with DM at 5 mg/kg/day and AM at 5 mg/kg/day;
  • FIG. 6 is a flow chart showing the different time points when blood pressure were measured and blood sampling were taken in the animal study.
  • the name of a compound can encompass all possibly existing isomeric forms (e.g., optical isomer, enantiomer, diastereomer, racemate or racemic mixture), esters, prodrugs, metabolite forms, pharmaceutically acceptable salts, pharmaceutically acceptable esters, pharmaceutically acceptable amides, and protected derivatives, of the compound.
  • isomeric forms e.g., optical isomer, enantiomer, diastereomer, racemate or racemic mixture
  • esters e.g., prodrugs, metabolite forms, pharmaceutically acceptable salts, pharmaceutically acceptable esters, pharmaceutically acceptable amides, and protected derivatives, of the compound.
  • pharmaceutically acceptable salt(s) means those salts of a compound of interest that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds.
  • the acidic or basic groups can be organic or inorganic.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • Certain compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids, e.g., lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris, and other salts which are currently in widespread pharmaceutical use and are listed in sources well known to those of skill in the art, such as The Merck Index.
  • Any suitable constituent can be selected to make a salt of an active drug discussed herein, provided that it is non-toxic and does not substantially interfere with the desired activity.
  • a “NADPH oxidase inhibitor” is a drug or a natural substance that inhibits, decreases or reduces the enzymatic activity of a NADPH oxidase, i.e., nicotinamide adenine dinucleotide phosphate-oxidase.
  • the NADPH oxidase generates superoxide by transferring electrons from NADPH and coupling the electrons to molecular oxygen to produce superoxide, a reactive free-radical that can generate reactive oxygen species (ROS).
  • a “NADPH oxidase inhibitor” is effective in preventing, decreasing or reducing the production of the superoxide, thus ROS, in blood vessels of a subject.
  • NADPH oxidase inhibitors examples include, but are not limited to, dextromethorphan, gp91ds-tat, apocynin, diphenylene iodonium, aminoethyl benzenesulfono fluoride, 517834, PR39, protein kinase C inhibitors, VAS2870, angiotensinconverting enyzme inhibitors, angiotensin receptor blockers and statins.
  • DM refers to the compound (+)-3-methoxy-17-methyl-9 ⁇ ,13 ⁇ ,14 ⁇ -morphinan, which is also named (+)-3-methoxy-N-methylmorphinan, and any pharmaceutically acceptable salt thereof.
  • dextromethorphan can be in a pharmaceutically acceptable salt form selected from the group consisting of salts of free acids, inorganic salts, salts of sulfate, salts of hydrochloride, and salts of hydrobromide. Dextromethorphan is commonly available as the monohydrated hydrobromide salt.
  • Dextromethorphan is the dextrorotatory (d) enantiomer.
  • a pharmaceutical composition according to embodiments of the present invention comprises substantially optically pure dextromethorphan or is substantially free of the levorotary (l) enantiomer of DM.
  • substantially optically pure dextromethorphan or “substantially free of the levorotary (l) enantiomer of DM” means that the pharmaceutical composition contains a greater proportion or percentage of DM in relation to its 1 enantiomer.
  • the pharmaceutical composition preferably contains about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%, by weight of DM, wherein the percentage is based on the total amount of DM and its 1 enantiomer in the pharmaceutical composition.
  • Dextromethorphan can be synthesized and optically purified using methods known in the art, for example as described in U.S. Pat. No. 2,676,177, the content of which is hereby incorporated by reference. It is also available from various commercial sources.
  • calcium channel blockers refers to a class of drugs and natural substances that disrupt the calcium (Ca 2+ ) conduction of calcium channels. They block voltage-gated calcium channels (VGCCs) in cardiac muscle and blood vessels and decrease blood pressure.
  • VGCCs voltage-gated calcium channels
  • the term “calcium channel blockers” encompasses any class of CCBs that can be used for treating hypertension in a subject, such as the class of dihydropyridine, phenylalkylamine, benzothiazepine, and the nonselective CCBs.
  • amlodipine or “AM” refers to the compound 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate, and any optical isomer, enantiomer, diastereomer, racemate or racemic mixture, pharmaceutically acceptable salts, or pharmaceutically acceptable esters, of the compound.
  • amlodipine can be in a pharmaceutically acceptable salt form of inorganic and organic acids.
  • Such acids are selected from the group consisting of acetic, benzene-sulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
  • Particularly preferred are besylate, hydrobromic, hydrochloric, phosphoric and sulfuric acids. (See Campbell, S. F. et al., U.S. Pat. No. 4,806,557).
  • Amlodipine can also be a pharmaceutically acceptable ester of amlodipine, particularly lower alkyl esters.
  • Amlodipin is a chiral compound.
  • a pharmaceutical composition according to embodiments of the present invention can comprise a racemate, i.e., 1:1 mixture of (R)-(+)- and (S)-( ⁇ )-amlodipine or a racemic mixture of the (R)-(+)- and (S)-( ⁇ )-amlodipine at different ratios.
  • the pharmaceutical composition can also comprise isolated (R)-(+)-amlodipine or (S)-( ⁇ )-amlodipine that is substantially free of the other stereoisomer.
  • composition according to embodiments of the present invention comprises substantially optically pure (S)-( ⁇ )-amlodipine or is substantially free of (R)-(+)-amlodipine.
  • substantially optically pure (S)-( ⁇ )-amlodipine or “substantially free of (R)-(+)-amlodipine” means that the pharmaceutical composition contains a greater proportion or percentage of (S)-( ⁇ )-amlodipine in relation to (R)-(+)-amlodipine.
  • the pharmaceutical composition preferably contains about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%, by weight of (S)-( ⁇ )-amlodipine, wherein the percentage is based on the total amount of (R)-(+)-amlodipine and (S)-( ⁇ )-amlodipine in the pharmaceutical composition.
  • the chemical synthesis of the racemic mixture of amlodipine can be performed using methods known in the art, e.g., as described in Arrowsmith, J. E. et al., J. Med. Chem., 29: 1696-1702 (1986). It is also available from various commercial sources. Separation of the amlodipine isomers from the racemic mixture can be performed by methods known in the art, such as those illustrated in U.S. Pat. No. 6,448,275 or U.S. Pat. No. 7,482,464. The contents of the references are hereby incorporated by reference.
  • the term “pharmaceutical composition” is intended to encompass a product or composition comprising the specified ingredient in the specified amount, as well as any product which results, directly or indirectly, from combinations of the specified ingredient in the specified amount.
  • the term “subject” means any animal, preferably a mammal, most preferably a human, to whom will be or has been administered compounds or pharmaceutical compositions according to embodiments of the invention.
  • the term “mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans etc., more preferably, a human.
  • a subject is in need of, or has been the object of observation or experiment of, treatment or prevention of hypertension and symptoms associated therewith.
  • treating hypertension or a symptom associated therewith means to elicit an antihypertensive effect, such as by providing a normalization to otherwise elevated systolic and/or diastolic blood pressure, and by so doing providing relief from one or more possible symptoms or other hemodynamic effects caused by the elevated blood pressure.
  • treating refers to an amelioration, prophylaxis, or reversal of a disease or disorder, or at least one discernible symptom thereof, for example, treating hypertension or a symptom associated therewith by lowering the elevated systolic and/or diastolic blood pressure.
  • treating refers to an amelioration, prophylaxis, or reversal of at least one measurable physical parameter related to the disease or disorder being treated, not necessarily discernible symptom in or by the mammal, for example, treating hypertension or a symptom associated therewith by decreasing ROS in the vessels.
  • treating refers to inhibiting or slowing the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, physiologically, e.g., stabilization of a physical parameter, or both.
  • treating refers to delaying the onset of a disease or disorder or reduce of the risk of acquiring a disease or disorder, such as hypertension or a symptom associated therewith.
  • the specified pharmaceutical compositions are administered as a preventative measure to a subject having a predisposition to hypertension, even though symptoms of hypertension are absent or minimal.
  • the term “effective amount” of a compound refers to the amount of the compound that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the effective amount of a compound is sufficient to treat, improve the treatment of, or prophylactically prevent, hypertension or a symptom associated therewith, but is insufficient to cause significant adverse effects associated with administration of the compound.
  • the prophylactic or therapeutic treatment of the above identified conditions is expected to be achieved via administration of dosage levels of the active ingredients in amounts from about 0.01 mg/kg to about 100 mg/kg, 0.03 mg/kg to about 75 mg/kg, 0.05 mg/kg to about 50 mg/kg body weight per day, or from about 0.1 mg/kg to about 10 mg/kg of body weight per day.
  • dosage levels of the active ingredients in amounts from about 0.01 mg/kg to about 100 mg/kg, 0.03 mg/kg to about 75 mg/kg, 0.05 mg/kg to about 50 mg/kg body weight per day, or from about 0.1 mg/kg to about 10 mg/kg of body weight per day.
  • the dosage can be formulated to be delivered in a substantially continuous fashion, as may be provided by sustained and/or controlled release dosage forms, or by a transdermal patch.
  • cardiovascular effects including tachycardia and diminished contractility of the heart
  • edema of the extremities headache, dizziness, flushing, fatigue, vertigo, muscle cramps, hallucination, diarrhea, fever, urinary retention, vomiting, body rash/itching, etc.
  • dextromethorphan is effective to lower blood pressure in a subject suffering from hypertension, either alone or in combination with another antihypertensive agent. It is further discovered that dextromethorphan, a NADPH oxidase inhibitor, and amlodipine, a CCB, act synergistically in lowering blood pressure in a subject suffering from hypertension. This synergistic effect is unexpected. Novel and more effective pharmaceutical compositions and methods for treating hypertension or a symptom associated therewith are thus developed based on the present discoveries.
  • the present invention relates to a method of treating hypertension or a symptom associated therewith in a subject.
  • the method comprises administering to the subject a pharmaceutical composition comprising an effective amount of dextromethorphan and a pharmaceutically acceptable carrier.
  • any of the pharmaceutically acceptable salt of dextromethorphan can be used in the pharmaceutical compositions and methods according to embodiments of the present invention.
  • a substantially optically pure dextromethorphan such as a substantially optically pure dextromethorphan hydrobromide, is used in the present invention.
  • dextromethorphan is rapidly absorbed from the gastrointestinal tract and converted into the less active metabolite, dextrorphan, in the liver by the cytochrome P450 enzyme CYP2D6 Inhibiting the enzymatic activity of CYP2D6 would increase the stability of dextromethorphan and prolong its half life in the subject, resulting in more effective treatment with more consistent and predictable result.
  • a method according to an embodiment of the present invention can further comprise administering to the subject a CYP2D6 inhibitor.
  • CYP2D6 inhibitors that can be used in the present invention include, but are not limited to, quinidine.
  • the CYP2D6 inhibitors can be administered together with DM in the same pharmaceutical composition, or separately from DM in a different pharmaceutical composition, so long as the dosing schedules of DM and the CYP2D6 inhibitor overlap in time so that the administered CYP2D6 inhibitor is effective to prolong the half life of dextromethorphan in the subject.
  • embodiments of the present invention relate to a method of treating hypertension or a symptom associated therewith in a subject, comprising administering to the subject an effective amount of dextromethorphan and an effective amount of a calcium channel blocker (CCB).
  • CCB calcium channel blocker
  • any of the CCBs effective for treating hypertension in a subject can be used in the present invention, including, but not limited to, amlodipine, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, perhex
  • the CCB is amlodipine.
  • Any of the optical isomer, enantiomer, diastereomer, racemate or racemic mixture, pharmaceutically acceptable salts, or pharmaceutically acceptable esters, of amlodipine can be used in the present invention.
  • a racemic mixture of amlodipine or (R,S)-amlodipine is used in the present invention.
  • a substantially optically pure (S)-( ⁇ )-amlodipine such as a substantially optically pure (S)-( ⁇ )-amlodipine besylate, (S)-( ⁇ )-amlodipine mesylate or S)-( ⁇ )-amlodipine maleate, is used in the present invention.
  • dextromethorphan and the CCB can be administered together in the same pharmaceutical composition, or separately in different pharmaceutical compositions, so long as the dosing schedules of DM and the CCB overlap in time.
  • the CCB and DM are administered in a dosage ratio of CCB:DM as 1:0.5 to 1:100, e.g., 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100, in the same pharmaceutical composition, e.g., a dosage form comprising both CCB and DM, or in separate pharmaceutical compositions, e.g., a separate dosage form for each of CCB and DM.
  • Another general aspect of the present invention relates to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject, which comprises an effective amount of dextromethorphan, an effective amount of a calcium channel blocker, and a pharmaceutically acceptable carrier.
  • Embodiments of the present invention also relate to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject, which comprises an effective amount of a calcium channel blocker, an effective amount of a NADPH oxidase inhibitor, and a pharmaceutically acceptable carrier.
  • CCBs effective for treating hypertension in a subject such as those described above, can be used in the present invention.
  • NADPH oxidase inhibitor examples include, but are not limited to, gp91ds-tat, apocynin, diphenylene iodonium, aminoethyl benzenesulfono fluoride, S17834, PR39, protein kinase C inhibitors, VAS2870, angiotensinconverting enyzme inhibitors, angiotensin receptor blockers, statins, and dextromethorphan.
  • compositions according to embodiments of the present invention can optionally comprise other therapeutically active ingredients, such as another class of antihypertensive agent.
  • Embodiments of the present invention also relate to methods of treating hypertension or a symptom associated therewith in a subject.
  • the methods comprising administering to the subject an effective amount of a NADPH oxidase inhibitor, such as dextromethorphan, and an effective amount of a CCB, such as amlodipine.
  • a NADPH oxidase inhibitor such as dextromethorphan
  • a CCB such as amlodipine
  • the NADPH oxidase inhibitor and the CCB can be administered together in a single pharmaceutical composition, separately at approximately the same time, or separately on separate dosing schedules. All that is required is that the dosing schedules of the NADPH oxidase inhibitor and the CCB overlap in time and thus are being followed concurrently.
  • the methods according to embodiments of the present invention can optionally comprise administering to the subject other therapeutically active ingredients, such as another class of antihypertensive agent.
  • the therapeutic active ingredient can be administered by any known route of administration, including, orally, topically, parenterally (including subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion administration techniques), by inhalation spray or rectally in dosage units or pharmaceutical compositions containing conventional pharmaceutically acceptable carriers and any such dosage units or pharmaceutical compositions are within the scope of the present invention.
  • compositions adapted for oral administration include solid forms such as pills, tablets, caplets, and hard or soft capsules (each including immediate release, timed release, and sustained release formulations) as well as lozenges and dispersible powders or granules.
  • Liquid forms of pharmaceutical compositions adapted for oral administration include solutions, syrups, elixirs, emulsions, and aqueous or oily suspensions. Any of these dosage forms may be prepared according to any method or compounding technique known in the art for the manufacture of pharmaceutical compositions.
  • compositions adapted for oral administration may further include one or more sweetening agents, flavoring agents, coloring agents, or preserving agents in order to provide attractive or palatable preparations.
  • the dosage form is a tablet or pill
  • it may either be uncoated or coated, and if coated, may be coated by any known technique.
  • the coating if desirably provided, can be formulated or applied by known techniques so that the coating can delay disintegration of the tablet or pill, and thus, absorption of the active ingredient, thereby providing a controlled and/or sustained release dosage form capable of providing sustained therapeutic or prophylactic effect over a longer period.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • An enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass substantially intact into the duodenum or to be delayed in release can separate the two components.
  • enteric layers or coatings including a number of polymeric acids, shellac, cetyl alcohol and cellulose acetate.
  • enteric layers or coatings including a number of polymeric acids, shellac, cetyl alcohol and cellulose acetate.
  • tablets, pills or capsules may be formulated as osmotic pump dosage forms by any known method.
  • compositions adapted for oral administration may also be presented as hard or soft gelatin capsules, wherein the active ingredient may be mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin in the case of the former or with water or miscible solvents such as propylene glycol, PEG's and ethanol, or an oil medium such as peanut oil, liquid paraffin, or olive oil in the case of the latter.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin in the case of the former or with water or miscible solvents such as propylene glycol, PEG's and ethanol, or an oil medium such as peanut oil, liquid paraffin, or olive oil in the case of the latter.
  • Aqueous suspensions can be prepared that contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia, dextran, polyvinyl-pyrrolidone or gelatin; and dispersing or wetting agents such as lecithin, polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyethylene sorbitan monooleate.
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl, p-hydroxybenzoate; one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharine or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil, such as cottonseed, olive, sesame or coconut oil, or in a mineral oil, such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • Such oily suspensions may be preserved by the inclusion of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for the preparation of an aqueous suspension suitable for oral administration can provide the active ingredient(s) in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives, all of which have been discussed above.
  • a dispersing or wetting agent suspending agent
  • preservatives all of which have been discussed above.
  • Sweetening, flavoring, or coloring agents may also be present, if desired.
  • compositions suitable for oral administration may also be presented in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable or mineral oil, such as those described above, or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, such as soy bean, lecithin, sorbitan monooleate, or polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening or flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring or coloring agents.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring or coloring agents.
  • compositions may be further provided in a form adapted for parenteral administration, i.e., by injection or infusion.
  • injectable aqueous or oleaginous suspensions are desirably sterile and may be formulated according to known methods using suitable dispersing, wetting and suspending agents as mentioned above.
  • a parenterally-acceptable diluent or solvent may also be utilized, such as 1,3-butanediol, water, Ringer's solution, and isotonic sodium chloride.
  • Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as solvents or suspending mediums in injectable or infusible solutions, and these may include any bland fixed oil, such as any of the synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid also may be utilized in the preparation of injectable or infusible solutions.
  • the pharmaceutical composition may also be presented in the form of a suppository.
  • Suppositories can be formulated by mixing the active ingredient(s) and any additional desired therapeutic agent(s) with a suitable non-irritating excipient that is solid at room temperature but molten at body temperature, thereby releasing the active ingredient(s).
  • suitable materials include cocoa butter and polyethylene glycols.
  • Topical use creams, ointments, gels, solutions or suspensions containing the active ingredient(s) may be prepared.
  • topical use includes mouth washes and gargles.
  • Topical formulations may include cosolvents, emulsifiers, penetration enhancers, preservatives, emollients, and the like.
  • the active ingredients according to embodiments of the present invention can also be provided in a pharmaceutical composition in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, phophatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyl dimethylammonium propanes, and stearylamine, neutral lipids such as triglycerides, and combinations thereof. They may either contain cholesterol or may be cholesterol-free.
  • amphipathic lipids such as phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, phophatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphat
  • compositions according to embodiments of the present invention are formulated for oral administration.
  • the pharmaceutical compositions may be conveniently presented in dosage form, and prepared by any of the methods known in the art of pharmacy in view of the present disclosure.
  • the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • compositions will generally include from about 0.01 mg to about 1000 mg, from about 0.1 mg to 500 mg, from about 1 mg to about 100 mg, or from about 10 mg to about 100 mg, of the active ingredients.
  • each dosage form for oral administration such as a pill, a tablet, a caplet, a hard or soft capsule, comprises about 10 mg to about 100 mg of an NADPH oxidase inhibitor, such as DM.
  • Each of the dosage form can further comprise 10 mg to about 100 mg of a CYP2D6 inhibitor, such as quinidine.
  • Each of the dosage form can additionally comprise about 0.5 mg to about 10 mg of a CCB, such as AM.
  • each dosage form for oral administration such as a pill, a tablet, a caplet, a hard or soft capsule, comprises a ratio of a CCB (such as AM): a NADPH oxidase inhibitor (such as DM) of 1:0.5 to 1:100, e.g., 1:1, 1:5, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90 or 1:100.
  • a CCB such as AM
  • a NADPH oxidase inhibitor such as DM
  • a suitable dosage range of a NADPH, such as dextromethorphan, for use in the present invention is from about 0.1 mg to about 500 mg total daily dose, given as a once daily administration in the morning or in divided doses if required.
  • a dose range of between about 1 mg to about 300 mg is given as a once daily administration or in divided doses if required, and most preferably a dose range of from between about 10 mg to about 100 mg, or a dose range of from between about 20 mg to about 50 mg is given as a once daily administration or in divided doses if required.
  • Patients may be upward titrated from below to within this dose range to a satisfactory control of symptoms or blood pressure as appropriate.
  • a suitable dosage range of a CCB, such as amlodipine, for use in the present invention is from about 0.01 mg to about 100.0 mg total daily dose, given as a once daily administration in the morning or in divided doses if required.
  • a dose range of between about 0.5 mg to about 20.0 mg is given as a once daily administration or in divided doses if required, and most preferably a dose range of from between about 0.5 mg to about 10.0 mg is given as a once daily administration or in divided doses if required.
  • Patients may be upward titrated from below to within this dose range to a satisfactory control of symptoms or blood pressure as appropriate.
  • Untreated WKY and SHR were compared with SHR treated with amlodipine (1, 5 mg/kg/day) or dextromethorphan (1, 5, 25 mg/kg/day) and fix dose combination (AM+DM) using a matrix combination of above doses for 4 weeks. All the treatment groups are listed in Table 1, including G1 ⁇ G12 for SHR and G0 for WKY as a control.
  • Treatment groups Treatment* A0 A1 A2 D0 G1 G5 G9 D1 G2 G6 G10 D2 G3 G7 G11 D3 G4 G8 G12 *A0: no drug; A1: 1 mg/kg/day; and A2: 5 mg/kg/day of amlodipine treatment.
  • rats were divided into several experimental groups as follows:
  • Control rats received 1% solution of methylcellulose (1 ml/kg) by a gavage as a vehicle.
  • AM and DM were suspended in 1% solution of methylcellulose and administered by a gavage in a 1 ml/kg volume. All compounds were administered for 4 weeks.
  • Arterial blood pressure measurement and blood sampling were carried out before treatment, and after the second and forth week of drug administration.
  • Arterial blood pressure was measured in conscious rats with an automatic sphygmomanometer, using tail-cuff method. Before the measurements, the animals were placed inside a warming chamber (about 34° C.) for 30 min. The aim of the procedure is to calm the animals and dilate the tail blood vessels. Arterial blood pressure was measured at least three times for each animal. Changes in pressure are expressed as the percentage of baseline values.
  • Total cholesterol, LDL-cholesterol, ALT, AST and Creatinine are measured by using automatic biochemical analyzers (SpotchemTM SP 4410 Kyoto Daiichi Kagaku Co. Ltd.).
  • the oxidant systems include enzymes such as superoxide dismutase, catalase, and glutathionine peroxidase, macromolecules such as albumin, ceruloplasmin and ferritin, small molecules such as ascorbic acid, ⁇ -tocopherol, ⁇ -carotene, reduced gluthionine, uric acid and bilirubin.
  • the sum of the endogenous and food-derived antioxidants represents the total antioxidant activity of the system.
  • the total antioxidant capacity or total antioxidant status (TAS, mmol/L) of plasma, serum, urine, saliva, or cell lysates can be measured using commercially available kits, such as Antioxidant Assay Kit (Cat No. 709001, Cayman) or Total Antioxidant Status, Randox Lab Ltd), with results expressed as mmol/L, following the kit's protocol.
  • serum peroxynitrate (3-nitrotyrosine, 3-NT), 8-Hydroxydeoxyguanosine(8-OHdG), endothelin-1 (ET-1), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities are also assessed.
  • Nitrotyrosine is formed in presence of the active metabolite NO.
  • Various pathways including the formation of peroxinitrite lead to nitrotyrosine production.
  • nitrotyrosine is a stable end product of peroxynitrite oxidation, assessment of its plasma concentration may be useful as a marker of NO-dependent damage in vivo.
  • the presence of nitrotyrosine has been detected in various inflammatory processes including atherosclerotic plaques, celiac disease, rheumatoid arthritis, chronic renal failure and septic shock.
  • Nitrotyrosine has also been identified as a marker of inflammation. In normal plasma low, undetectable, levels of nitrotyrosine are present.
  • Quantitative determination of nitrotyrosine in plasma and other biological samples can be performed using commercially available kits, such as Nitrotyrosine ELISA kit (Hycult Biotech, HK501)
  • 8-OHdG is produced by oxidative damage of DNA by reactive oxygen and nitrogen species and serve as an established marker of oxidative stress. Increased 8-OH-dG are associated with hypertension, as well as aging process and a number of other conditions, such as cancer and diabetes. Quantitative determination of 8-OHdG in plasma and other biological samples can be performed using commercially available kits, such as 8-hydroxy-2-deoxy Guanosine EIA Kit (Cayman, Cat No. 589320 or 589321)
  • ET-1 Endothelin-1
  • L Endothelin-1 Assay Kit
  • the 3-NT, 8-OhdG, ET-1 can also be measured in duplicate with commercially available enzyme-linked immunosorbent assay kits (Quantikine, R&D Systems, USA) according to the manufacturer's instructions.
  • TBA thiobarbituric acid
  • the organic phase is analyzed spectrophotometrically at 532 nm, using 1,1,3,3-tetramethoxypropane as an external standard. The results are expressed as ⁇ mol/L of MDA.
  • Arterial blood pressure and blood sampling will be measured before treatment, and after the second and forth week of drug administration ( FIG. 6 ).
  • Results are expressed as mean ⁇ SD.
  • the normality of distribution was checked by means of Kolmogorov-Smirnov test with Lilliefors test.
  • the statistical evaluation was performed using analysis of variance (ANOVA) and post hoc comparisons were performed by means of Least Significant Differences (LSD) test. If the data were not normally distributed, statistical evaluation was performed by using ANOVA (Kriskall-Wallis) and Mann-Whitney U test. Differences were considered significant when p ⁇ 0.05.
  • Table 2 lists the blood pressure measurements of the control groups, i.e., WKY and SHR, measured before and after the rats were given with the blank treatment (1% solution of methylcellulose). As shown in Table 2, the blood pressure measurements generally stayed the same at the two measure points.
  • the blood pressure lowering effect of DM and AM is greater than the additive effect of DM and AM alone separately. This indicates that DM and AM act synergistically in lowering the blood pressure.
  • the mechanism of the blood pressure lowering effect of dextromethorphan or its synergistic action with a calcium channel blocker in the treatment of hypertension is studied by an endothelium-dependent vasorelaxation study, which measures isometric tension of rat aortic ring in response to drugs.
  • the effect of the testing drug e.g., dextromethorphan, amlodipine, or a combination of dextromethorphan and amlodipine on high KCl-induced contractions are studied, e.g., by measuring the cumulative concentration-response curves to the endothelium-dependent and endothelium-independent relaxant agonists acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, or to the 1-receptor agonist phenylephrine (PE).
  • the testing drug e.g., dextromethorphan, amlodipine, or a combination of dextromethorphan and amlodipine
  • ACh endothelium-dependent and endothelium-independent relaxant agonists acetylcholine
  • SNP sodium nitroprusside
  • PE 1-receptor agonist phenylephrine
  • the rats are anaesthetized with pentobarbital (60 mg kg-1 of body weight, i.p.), descending thoracic aorta is dissected, cut into small rings (3-5 mm in width) and suspended in a 5 ml organ bath containing normal Krebs physiological salt solution (KPSS) of the following compositions (mM): NaCl 118.2, KCl 4.7, CaCl 2 . 2H 2 O 2.5, KH 2 PO 4 1.2, MgCl 2 1.2, glucose 11.7, NaHCO 3 25.0, and EDTA 0.026.
  • KPSS normal Krebs physiological salt solution
  • the bathing solution is gassed continuously with 95% oxygen and 5% carbon dioxide at 37° C. (pH 7.4).
  • Isometric tension (g) is measured using a force displacement transducer connected to a Mac Lab recording system (ADI Instruments, Australia). Aortic rings are then progressively stretched to an optimal basal tension of 1 g and allowed to equilibrate for 45 min. During this period, the bathing solution is replaced every 15 min and, if needed, the basal tone is readjusted to 1 g.
  • Aortic rings are then repeatedly stimulated with KCl solution (high K + , 80 mM) for 5 min at 10 min intervals until two consecutive equal contractions are attained—evidence of tissue stability.
  • the aortic rings are incubated for 20 min with the testing drug, e.g., dextromethorphan, amlodipine, or a combination of dextromethorphan and amlodipine or its vehicle (control), and cumulative concentration-response curves to the endothelium-dependent and endothelium-independent relaxant agonists acetylcholine (ACh, 10 ⁇ 10 to 10 ⁇ 5 M) and sodium nitroprusside (SNP, 10 ⁇ 11 to 10 ⁇ 6 M), respectively, or to the 1-receptor agonist phenylephrine (PE, 10 ⁇ 10 to 10 ⁇ 5 M) are then measured. To test the relaxation responses to ACh and SNP, the aortic rings are pre-contracted with PE (1 ⁇ M).
  • the testing drug e.g., dextromethorphan, amlodipine, or a combination of dextromethorphan and amlodipine or its vehicle (control
  • the concentrations of the testing drug are chosen based on the physiologically achievable plasma concentrations of the drug.
  • the aortic rings are exposed to various pharmacological agents for 5 min before the incubation with the drug or its vehicle.
  • endothelium is removed by gently rubbing the intimal surface of the vessel with the blunted forceps.
  • the endothelium is considered effectively removed if ACh (1 ⁇ M) caused less than 10% relaxation of aortic rings pre-contracted with PE.
  • the concentration-response curves to ACh are measured in aortic rings incubated with and in continued presence of N-nitro-1-arginine methyl ester (L-NAME, 10 ⁇ M)—an eNOs inhibitor, indomethacin (10 ⁇ M)—a cyclooxygenase inhibitor, and methylene blue (10 ⁇ M)—a cyclic GMP inhibitor, respectively.
  • L-NAME N-nitro-1-arginine methyl ester
  • 10 ⁇ M an eNOs inhibitor
  • indomethacin (10 ⁇ M) a cyclooxygenase inhibitor
  • methylene blue (10 ⁇ M) a cyclic GMP inhibitor
  • the aortic rings are partially depolarized by increasing concentration of KCl in the KPSS (4.8-20 mM), and the concentration-response curves to ACh is then performed.
  • EDHF endothelium-derived hyperpolarizing factor
  • K+ potassium
  • the contractile responses of aortic rings to graded concentrations of PE are expressed as percentages of the maximum contractile effect of high K + in respective tissues.
  • vasodilator effect of increasing concentrations of ACh or SNP are expressed as percent decrease of the peak PE (10 ⁇ 6 M) contraction.
  • concentration-response curve for each experimental condition is plotted and from it are deduced the values of maximal contraction (Cmax) or maximal relaxation (Rmax) and the concentration of the testing drug (expressed as negative log molar) producing 50% of maximum contraction or relaxation (pEC50) recorded (Prism Version 2.0, GraphPad Software, USA).

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US9744165B2 (en) 2017-08-29
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BR112012028153A2 (pt) 2018-08-07
RU2571284C2 (ru) 2015-12-20
CN102869360A (zh) 2013-01-09
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AU2011250485B2 (en) 2016-07-07
US20160235741A1 (en) 2016-08-18

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