WO2004091632A1 - A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor - Google Patents

A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor Download PDF

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Publication number
WO2004091632A1
WO2004091632A1 PCT/HU2004/000036 HU2004000036W WO2004091632A1 WO 2004091632 A1 WO2004091632 A1 WO 2004091632A1 HU 2004000036 W HU2004000036 W HU 2004000036W WO 2004091632 A1 WO2004091632 A1 WO 2004091632A1
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WO
WIPO (PCT)
Prior art keywords
effect
digitalis
pharmaceutical composition
phosphodiesterase inhibitor
active ingredient
Prior art date
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PCT/HU2004/000036
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English (en)
French (fr)
Inventor
János EGRI
Original Assignee
SynoSens Kutató és Fejlesztő Kft.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SynoSens Kutató és Fejlesztő Kft. filed Critical SynoSens Kutató és Fejlesztő Kft.
Priority to CA002522143A priority Critical patent/CA2522143A1/en
Priority to EP04727332A priority patent/EP1648470A1/en
Priority to JP2006506247A priority patent/JP2006523667A/ja
Priority to YUP-2005/0775A priority patent/RS20050775A/sr
Publication of WO2004091632A1 publication Critical patent/WO2004091632A1/en

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the invention refers to a cardiotonic pharmaceutical composition having enhanced therapeutical width of effect. Active ingredients having the effect of digitalis has been used for a very long time as a cardiotonic drug in cases when the heart function is weak, the activity of the myocardium is
  • a drawback of the administration of the active ingredients having the effect of digitalis resides in the fact that it can easily result in arrhythmia. This symptom is due to partly the reduction of the refractoriness of the ventricle myofibrils, partly
  • the arrhythmias are separated ventricular extrasystoles, at first bigeminy, later severe ventricular tachycardia develops.
  • the active ingredients having the effect of digitalis are characterized by a rather narrow therapeutical width, i.e. the difference between the
  • the aim of the invention is to provide a cardiotonic pharmaceutical composition having an enhanced therapeutical width, thus, the administration of the composition eliminates the development of arrhythmia. It was found that the above aim is achieved by the pharmaceutical composition of the invention comprising (a) an active ingredient having the effect of digitalis and (b) a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor and one or more conventional carrier(s).
  • cGMP cyclic guanosine monophosphate
  • the invention is based on the recognition that in the presence of a cGMP phosphodiesterase inhibitor the cGMP phosphodiesterase enzyme fails to decompose the cyclic guanosine monophosphate present, and in this way the effect of nitrogen monoxide (NO) that forms continuously in the human organism is, as a matter of fact, amplified since the cGMP activates the NO synthase enzyme producing the nitrogen monoxide.
  • NO nitrogen monoxide
  • the higher amount of the produced nitrogen monoxide results in both vasodilation and an enhanced therapeutical width of the active ingredients having the effect of digitalis.
  • glycosides that can be obtained from plants of the Digitalis family (e.g. Digitalis purpurea, Digitalis lanata, Digitalis lutea etc.) or digitaloides i.e. glycosides of similar effect which can be obtained from plants of the Strophantus family (e.g. Strophantus gratus, Strophantus kombe etc.) or from other plants (e.g. Scilla maritima, Convallaha majalis etc.) are meant.
  • the term Huaweiglycosides includes a pure glycoside, a mixture of glycosides as well as products that can be prepared by the chemical transformation of said glycosides.
  • Examples of the active ingredient having the effect of digitalis are digoxin, digitoxin, lanatoside A, lanatoside B, lanatoside C, lanatoside D, K-strophanthin, G- strophanthin (ouabain), scillaren, convallatoxin etc.
  • Preferred active ingredients having the effect of digitalis are digoxin, digitoxin and ouabain.
  • a ..cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor an agent inhibiting the metabolism of the cyclic guanosine monophosphate is meant.
  • said agent inhibits the various isoenzymes of cGMP phosphodiesterase. The task of these isoenzymes is to decompose cGMP.
  • cGMP phosphodiesterase inhibitors examples include cicletanine [chemical name: ( ⁇ )-3-(4-chlorophenyl)-1 ,3 ⁇ dihydro ⁇ 6-methylfuro-[3,4-c]pyridin-7-ol] or a pharmaceutically suitable acid addition salt thereof, a known antihypertensive [US-P No. 4,383,998], vinpocetine [chemical name: (3 ⁇ ,16 ⁇ )-eburnamenine-14- carboxylic acid ethyl ester], a known cerebral vasodilator [US-P No.
  • sildenafil [chemical name: 1-[3-(4,7-dihydro-1-methyI-7-oxo-3- propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl- su!fonyl]-4-methylpiperazine] or a pharmaceutically suitable acid addition salt thereof, a known active agent for the treatment of impotence, zaprinast [chemical name: 1 ,4-dihydro-5-(2-propoxyphenyl)- 7/-/-1 ,2,3-triazolo[4,5-d]pyrimidin-7-one] or a pharmaceutically suitable acid addition salt thereof, a known antiallergic, ibudilast [chemical name: 2-methyl-1-[2-(1-methylethyl)- pyrazolo[1 ,5-a]pyridin-3-yl]-1-propanone] or a pharmaceutically suitable acid addition salt thereof, a known antiallergic, anti
  • rolipram chemical name: 4-[3-cyclopenty!oxy)-4-(methoxy- phenyl)]-2-pyrrolidinone] or a pharmaceutically suitable acid addition salt thereof
  • a known antidepressant US-P No. 4,193,926
  • pimobendan chemical name: 4,5-dihydro-6-[2-(4-methoxy- phenyl)-1 H-b ⁇ nzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone] or a pharmaceutically suitable acid addition salt thereof
  • a known cardiotonic US-P No.
  • vesnarinone chemical name: 1-(3,4-dimethoxybenzoyl)-4- (1 ,2,3,4-tetrahydro-2-oxo-6-quinolinyl)-piperazine] or a pharmaceutically suitable acid addition salt thereof, a known cardiotonic [US-P No. 4,415,572],
  • ODQ chemical name: 1 H-[ . ,2,4]oxadiazolo[4,3-a]quinoxaline- 1-one] or a pharmaceutically suitable acid addition salt thereof
  • WIN-58237 chemical name: 1 -cyclopentyl-3-methyl-6-(4- pyridyI)pyrazolo[3,4-d]pyrimidin-4-(5H) ⁇ one] or a pharmaceutically suitable acid addition salt thereof
  • ONO-1505 chemical name: 4-[2-(2-hydroxyethoxy)ethyl- amino]-2-(1 H-imidazol-1-yl)-6-methoxyquinazoline methane sulfonate] and
  • DMPPO [1 ,3-dimethyl-6-(2-propoxy-5-methanesulfonylamido- phenyl)pyrazolo[3,4-d]pyrimidin-4-(5f7')-one] or a pharmaceutically suitable acid addition salt thereof.
  • Preferred cGMP phosphodiesterase inhibitors of the invention are the following ones: cicletanine or a pharmaceutically suitable acid addition salt thereof, vinpocetine, sildenafil or a pharmaceutically suitable acid addition salt thereof and zaprinast or a pharmaceutically suitable acid addition salt thereof.
  • An especially preferred cGMP phosphodiesterase inhibitor of the invention is cicletanine or a pharmaceutically suitable acid addition salt thereof, suitably the hydrochloride.
  • the pharmaceutical composition of the invention comprises the active ingredient having the effect of digitalis and the cGMP phosphodiesterase inhibitor, in general, in a weight ratio of (1-500)-(500-1 ), preferably (1-200): (200-1 ).
  • the active ingredient having the effect of digitalis or the cGMP phosphodiesterase inhibitor can be present in the pharmaceutical composition of the invention in the form of a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof.
  • the pharmaceutical composition of the invention is a solid or liquid preparation suitable for peroral or parenteral administration.
  • the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
  • binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.
  • filling agents such as lactose, glucose, starch, calcium phosphate etc.
  • auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.
  • wetting agents such as sodium laurylsulfate etc. as the carrier.
  • the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl p- hydroxybenzoate etc. as the carrier.
  • suspending agents such as gelatine, carboxymethylcellulose etc.
  • emulsifiers such as sorbitane monooleate etc.
  • solvents such as water, oils, glycerol, propylene glycol, ethanol etc.
  • preservatives such as methyl p- hydroxybenzoate etc. as the carrier.
  • Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general.
  • the pharmaceutical composition of the invention is prepared by admixing the active ingredient to one or more carher(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se.
  • Dosage forms listed above as well as other dosage forms and the preparation thereof, furthermore the useful carriers are known from the literature, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
  • the pharmaceutical composition contains dosage unit, in general.
  • a preferred pharmaceutical composition of the invention contains an active ingredient having the effect of digitalis, for example digoxin, and cicletanine, vinpocetine, sildenafil, zaprinast, ibudilast, rolipram, pimobendan, vesnarinone, ODQ, WIN-58237, ONO-1505 or DMPPO or, if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof in addition to one or more conventional carrier(s).
  • An especially preferred pharmaceutical composition of the invention contains an active ingredient having the effect of digitalis, for example digoxin, and cicletanine, vinpocetine, sildenafil, zaprinast or if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof in addition to one or more conventional carrier(s).
  • an active ingredient having the effect of digitalis for example digoxin, and cicletanine, vinpocetine, sildenafil, zaprinast or if desired and chemically possible, a pharmaceutically suitable acid addition salt or a salt formed with a pharmaceutically suitable base thereof in addition to one or more conventional carrier(s).
  • a most preferred pharmaceutical composition of the invention contains digoxin and cicletanine or cicletanine hydrochloride in addition to one or more conventional carrier(s).
  • the favourable therapeutical effect of the pharmaceutical composition of the invention was studied in the following tests.
  • solitary ventricular ectopic beats bigeminy (BG), accelerated indioventricular rhythm (AIVR), ventricular tachycardia (VT), ventricular fibrillation (VF), and finally cardiac arrest.
  • BG bigeminy
  • AIVR accelerated indioventricular rhythm
  • VT ventricular tachycardia
  • VF ventricular fibrillation
  • Table 2 The cumulative ouabain doses required to produce BG, AIVR, VT and VF in the absence and presence of cicletanine are given in Table 2.
  • the results of the above tests indicate that the cGMP phosphodiesterase inhibitors enhance the therapeutical width of digitalis glycosides as shown by the reduction of the dose required for cardiotonic therapy and the increase of dose eliciting arrhythmogenic side-effects.
  • the invention includes a use of a cGMP phosphodiesterase inhibitor for the preparation of a pharmaceutical composition enhancing the therapeutical width of an active ingredient having the effect of digitalis.
  • a pharmaceutical composition is administered to a patient being treated with an active ingredient having the effect of digitalis, the aim of the invention i.e. the enhanced therapeutical width of the active ingredient having the effect of digitalis is also achieved.
  • the invention includes a method for enhancing the therapeutical width of an active ingredient having the effect of digitalis in which a patient being in need of a cardiotonic treatment with an active ingredient having the effect of digitalis is treated, in addition to the active ingredient having the effect of digitalis, also with a cGMP phosphodiesterase inhibitor.
  • the daily dose of the active ingredient having the effect of digitalis e.g. digoxin is usually 0.05 to 0.75 mg for an adult person, while the daily dose of the cGMP phosphodiesterase inhibitor such as cicletanine hydrochloride is, in general, 1 to 100 mg/kg body weight, preferably 1 to 20 mg/kg.
  • the invention is further illustrated by means of the following
  • One capsule contains 0.07 mg of digoxin, 200 mg of cicletanine hydrochloride and 250 mg of microcrystalline cellulose. The ingredients are mixed and filled into hard gelatine capsules.
  • Example 2 Preparation of tablets
  • One tablet contains 0.1 mg of digoxin, 400 mg/kg of cicletanine hydrochloride, 9.9 mg of silica, 50 mg of carboxy- methyl cellulose, 30 mg of microcrystalline cellulose and 10 mg of magnesium stearate.
  • the ingredients are admixed and compressed to tablets of 0.5 g.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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PCT/HU2004/000036 2003-04-15 2004-04-14 A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor WO2004091632A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002522143A CA2522143A1 (en) 2003-04-15 2004-04-14 A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor
EP04727332A EP1648470A1 (en) 2003-04-15 2004-04-14 A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor
JP2006506247A JP2006523667A (ja) 2003-04-15 2004-04-14 ジギタリス作用を有する活性成分及びｃＧＭＰホスホジエステラーゼ阻害剤を含有する医薬組成物
YUP-2005/0775A RS20050775A (en) 2003-04-15 2004-04-14 A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0300985 2003-04-15
HU0300985A HUP0300985A2 (hu) 2003-04-15 2003-04-15 Megnövelt hatásszélességű gyógyászati készítmény

Publications (1)

Publication Number Publication Date
WO2004091632A1 true WO2004091632A1 (en) 2004-10-28

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PCT/HU2004/000036 WO2004091632A1 (en) 2003-04-15 2004-04-14 A pharmaceutical composition containing an active agent having the effect of digitalis and a cgmp phosphodiesterase inhibitor

Country Status (7)

Country Link
EP (1) EP1648470A1 (hu)
JP (1) JP2006523667A (hu)
CA (1) CA2522143A1 (hu)
ES (1) ES2363087T3 (hu)
HU (1) HUP0300985A2 (hu)
RS (1) RS20050775A (hu)
WO (1) WO2004091632A1 (hu)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128035A2 (en) * 2005-05-26 2006-11-30 Navitas Pharma, Inc. Enantiomeric compositions of cicletanine, in combination with other agents, for the treatment of hypertension
EP2849792A4 (en) * 2012-05-18 2015-12-16 Luoda Pharma Pty Ltd LIQUID FORMULATION

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BUKOSKI, R. D. ET AL.: "Vascular actions of cicletanine", ARCHIVES DES MALADIES DU COEUR ET DES VAISSEAUX, vol. 82, no. 4, 1989, pages 45 - 50, XP008033902 *
CLEMENT, D. L. ET AL.: "Lack of Effect of Cicletanine on Plasma Digoxin Levels", INTERNATIONAL JOURNAL OF CLINICAL PHARMACOLOGY RESEARCH, vol. 8, no. 1, 1988, pages 9 - 11, XP008033838 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006128035A2 (en) * 2005-05-26 2006-11-30 Navitas Pharma, Inc. Enantiomeric compositions of cicletanine, in combination with other agents, for the treatment of hypertension
WO2006128035A3 (en) * 2005-05-26 2009-04-16 Navitas Pharma Inc Enantiomeric compositions of cicletanine, in combination with other agents, for the treatment of hypertension
EP2849792A4 (en) * 2012-05-18 2015-12-16 Luoda Pharma Pty Ltd LIQUID FORMULATION
US9808529B2 (en) 2012-05-18 2017-11-07 Luoda Pharma Pty Ltd Liquid formulation
US10413610B2 (en) 2012-05-18 2019-09-17 Luoda Pharma Limited Liquid formulation
US11357855B2 (en) 2012-05-18 2022-06-14 Luoda Pharma Limited Liquid formulation

Also Published As

Publication number Publication date
EP1648470A1 (en) 2006-04-26
HUP0300985D0 (en) 2003-06-28
RS20050775A (en) 2007-12-31
ES2363087T3 (es) 2011-07-20
CA2522143A1 (en) 2004-10-28
JP2006523667A (ja) 2006-10-19
HUP0300985A2 (hu) 2005-07-28

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