LT5475B - Use of 2,5-dihidroxybenzenesulfonic compounds for the treatment of disorders based on an impairment of no production and/or of regulation of edhf function - Google Patents
Use of 2,5-dihidroxybenzenesulfonic compounds for the treatment of disorders based on an impairment of no production and/or of regulation of edhf function Download PDFInfo
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- LT5475B LT5475B LT2006026A LT2006026A LT5475B LT 5475 B LT5475 B LT 5475B LT 2006026 A LT2006026 A LT 2006026A LT 2006026 A LT2006026 A LT 2006026A LT 5475 B LT5475 B LT 5475B
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- Prior art keywords
- use according
- medicament
- general formula
- compounds
- treatment
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Abstract
Description
Šis išradimas yra susijęs su 2,5-dihidroksibenzensulfoninių junginių panaudojimu gamyboje vaisto, skirto reguliuoti azoto oksido (NO) sintezę ir (arba) EDHF (endotelio kilmės hiperpoliarizuojančiam faktoriui) reguliuoti diabetinių pacientų endotelyje, kur šis vaistas yra skiriamas vartoti <500 mgThe present invention relates to the use of 2,5-dihydroxybenzenesulfonic compounds in the manufacture of a medicament for the control of nitric oxide (NO) synthesis and / or EDHF (endothelial-derived hyperpolarizing factor) in the endothelium of diabetic patients for administration to <500 mg.
2,5-dihidroksibenzensulfoninių junginių, kurių bendroji formulė I, dienos doze.Daily dosage of 2,5-dihydroxybenzenesulfonic compounds of the general formula I.
Azoto oksidas (NO) turi ypatingai svarbias ir įvairias funkcijas širdies kraujagyslių sistemoje. NO gaminimosi ir (arba) funkcijos susilpnėjimas vaidina pagrindinį vaidmenį daugelyje širdies ir kraujagyslių sutrikimų ir su diabetu arba impotencija susijusių sutrikimų (Nitric Oxide: A New Paradigm for Second Messengers”, James F. Kenwin Jr. et ai., Journal of Medicinai Chemistry, 1995, Volume 38, Number 22, 4343-4362; “Conseųuencies of reduced production of NO on vascular reactivity of porcine coronary arteries after angioplasty: importance of EDHF”, Thollon et ai., British Journal of Pharmacology, 2002,136,1153-1161).Nitric oxide (NO) has extremely important and diverse functions in the cardiovascular system. Impairment of NO production and / or function plays a key role in many cardiovascular disorders and diabetes or impotence-related disorders (James F. Kenwin Jr. et al., Journal of Medical Chemistry, 1995, Volume 38, Number 22, 4343-4362; "Consequences of reduced production of NO on vascular reactivity of porous coronary arteries after angioplasty: importance of EDHF", Thollon et al., British Journal of Pharmacology, 2002,136,1153- 1161).
VVO97/37647 aprašomas 2,5-dihidroksibenzensulfoninių junginių panaudojimas vaistų, skirtų endotelio funkcijai normalizuoti, lytinės funkcijos sutrikimui gydyti, diabeto sukeltų kraujagyslių komplikacijoms ir endotelinės kilmės kraujagyslių sutrikimams gydyti. Tačiau pagal ankstesnius pasiekimus, norint gauti norimą naudingą poveikį tokio gydymo reikalingam pacientui 2,5dihidroksibenzensulfoninių junginių reikia skirti palyginus dideles dienos dozes, ty. iki 2000 mg per dieną.WO97 / 37647 describes the use of 2,5-dihydroxybenzenesulfonic compounds for the treatment of endothelial function, sexual dysfunction, diabetes-induced vascular complications and endothelial-derived vascular disorders. However, according to the prior art, relatively high daily doses, i.e., 2.5dihydroxybenzenesulfonic compounds should be administered to the patient in need of such treatment to obtain the desired beneficial effect. up to 2000 mg per day.
Vaisto, turinčio 2,5-dihidroksibenzensulfoninių junginių vartojimas didelėmis dozėmis yra pavojingas dėl daugelio priežasčių. Nors ir retais atvejais, yra žinomi šių junginių šalutiniai poveikiai, tokie kaip žarnyno deformacijos, odos reakcijos, karščiavimas, sąnarių skausmai arba kraujo vaizdo pokyčiai.High doses of a drug containing 2,5-dihydroxybenzenesulfonic compounds are dangerous for many reasons. Although rare, side effects of these compounds are known, such as bowel deformities, skin reactions, fever, joint pain or changes in the blood picture.
Be to, daugumai pacientų poreikis gerti didelį vaisto kiekį yra rimta psichologinė problema. Taigi, bendra tokio vaisto dozė yra paprastai suskaidoma į keletą mažesnių dozių, kurios sugirdomos pacientui per keletą kartų per dieną. Tačiau tai reikalauja, kad pacientas laikytųsi tikslios vaisto priėmimo schemos, dažnai lydimos paciento nepasitenkinimo.In addition, for most patients, the need to drink large amounts of the drug is a serious psychological problem. Thus, the total dose of such a drug is usually broken down into a number of smaller doses, which are given to the patient several times a day. However, this requires the patient to follow an accurate medication admission schedule, often accompanied by patient dissatisfaction.
Todėl šio išradimo tikslas yra pateikti vaistą azoto oksido (NO) sintezės reguliavimui diabetinių pacientų endotelyje, kuris leistų išvengti žinomų šioje srityje vaistų trūkumų. Pageidautina, kad vaistas taip pat galėtų būti naudojamas EDHF (endotelio kilmės hiperpoliarizuojančio faktoriaus) svarbiausio faktoriaus nuo endotelio priklausančios kraujagyslių relaksacijos reguliavimui, kas aprašyta, pvz., “Human coronary arteriolar dilation to arachidonic acid dependes on cytochrome P-450 monooxygenase and Ca2+activated K+ chanels H. Miura, DD. Guterman, Čir. Res., 83, 501-507,1998; “Endothelium-derived hyperpolarizing factor. Identification and mechanisms of action in human subcutaneous resistance arteries”, Coats et ai., Circulation,It is therefore an object of the present invention to provide a medicament for the regulation of nitric oxide (NO) synthesis in the endothelium of diabetic patients, which would overcome the known shortcomings of the drugs known in the art. Preferably the medicament may also be used for the regulation of EDHF (Endothelium-origin hiperpoliarizuojančio Factor), a prime factor in vascular endothelium-dependent relaxation to adjust, as described, for example., Human coronary arteriolar dilation to arachidonic acid Depends on cytochrome P-450 monooxygenase and Ca 2+ activated K + chanels H. Miura, DD. Guterman, Chir. Res., 83, 501-507, 1998; Endothelium-derived hyperpolarizing factor. Identification and Mechanisms of Action in Human Subcutaneous Resistance Arteries ”, Coats et al., Circulation,
103, 1702-1708, 2001; “Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation”, Halcox et ai.,103, 1702-1708, 2001; "Characterization of endothelium-derived hyperpolarizing factor in human forearm microcirculation", Halcox et al.
Am. J. Physiol. Heart Circ. Physiol., 280, H2470-H2477, 2001; “Endotheliumdependent hyperpolarization as a remote anti-atherogenic mechanism”, S. Salemidis, Thomas M. Cocks, Trends in Phamnacological Science Vol.23,Am. J. Physiol. Heart Circ. Physiol., 280, H2470-H2477, 2001; "Endothelium-Dependent Hyperpolarization as a Remote Anti-atherogenic Mechanism," by S. Salemidis, Thomas M. Cocks, Trends in Phamnacological Science Vol.23,
NO.5, 213.2002). Minėti literatūros šaltiniai yra pridedami kaip nuorodos ir yra šio aprašymo dalis.NO.5, 213.2002). The above references are incorporated by reference and are part of this description.
Dabar netikėtai buvo rasta, kad mažesnė nei 500 mg vieno arba daugiau 2,5-dihidroksibenzensulfoninių junginių, kurių žemiau duota bendroji formulė I, dienos dozė yra pakankama azoto oksido (NO) sintezei reguliuoti diabetinių pacientų endotelyje.It has now been unexpectedly found that a daily dose of less than 500 mg of one or more 2,5-dihydroxybenzenesulfonic compounds of the general formula I below is sufficient to regulate nitric oxide (NO) synthesis in the endothelium of diabetic patients.
Be to, buvo rasta, kad žemiau duotos I bendrosios formulės 2,5dihidroksibenzensulfoniniai junginiai taip pat tinka EDHF (endotelinės kilmės hiperpoliarizuojančiam faktoriui) reguliuoti, kai jie yra vartojami mažesne nei 500 mg dienos dozeIn addition, the 2,5-dihydroxybenzenesulfonic compounds of general formula I below have also been found to be useful in the regulation of EDHF (endothelial-derived hyperpolarizing factor) when administered at a daily dose of less than 500 mg.
Taigi, vienas šio išradimo aspektas yra bent vieno iš 2,5dihidroksibenzensulfoninių junginių, kurių bendroji formulė I,Thus, one aspect of the present invention is the use of at least one of the 2,5-dihydroxybenzenesulfonic compounds of general formula I,
kuriojein which
R reiškia H arba SO3',R represents H or SO 3 ',
B reiškia bent vieną katijoną, n reiškia 1 arba 2, m reiškia 1 arba 2, kuris gali būti farmaciniu požiūriu priimtino solvato formos, panaudojimas gamyboje vaisto, skirto diabetinių pacientų azoto oksido (NO) sintezės reguliavimui ir (arba) EDHF (endotelio kilmės hiperpoliarizuojančio faktoriaus) reguliavimui diabetinių pacientų endotelyje, kur šis vaistas yra skiriamas vartoti kasdien, įvedant <500 mg 2,5-dihidroksibenzensulfoninių junginių, kurių bendroji formulė I, dozę.B represents at least one cation, n represents 1 or 2, m represents 1 or 2, which may be in the form of a pharmaceutically acceptable solvate, for the preparation of a medicament for regulating nitric oxide (NO) synthesis in diabetic patients and / or EDHF (endothelial-derived hyperpolarizing factor) in the endothelium of diabetic patients, wherein the drug is administered daily by administering a dose of <500 mg of 2,5-dihydroxybenzenesulfonic compounds of general formula I.
Katijonas B I bendrosios formulės 2,5-dihidroksibenzensulfoniniuose junginiuose gali būti bet koks fiziologiniu požiūriu priimtinas kationas, žinomas šios srities specialistams, pvz. iš P. Heinrich Stahl, Camille G. VVermuth (Editors), “Handbook of Pharmaceutical Salts - Properties, Selections and Ūse”, Verlag Helvetica Chimica Actą, Zūrich, Svvitzerland, Wiley-VCH, VVeinheim, Germany, 2002, kuris pridedamas kaip nuoroda ir yra šio aprašymo dalis. Specialistai supras, kad katijonas B turi būti pasirinktas tokiu būdu, kad bendras I formulės 2,5-dihidroksibenzensulfonių junginių krūvis turi būti neutralus.Cation B in the 2,5-dihydroxybenzenesulfonic compounds of the general formula I may be any physiologically acceptable cation known to those skilled in the art, e.g. from P. Heinrich Stahl, Camille G. Vermuth (Editors), "Handbook of Pharmaceutical Salts - Properties, Selections and Use", Verlag Helvetica Chimica Act, Zurich, Svvitzerland, Wiley-VCH, Veinheim, Germany, 2002, which is incorporated by reference and is part of this description. It will be appreciated by those skilled in the art that cation B should be selected such that the total charge of the compounds of formula I 2,5-dihydroxybenzenesulfones should be neutral.
Šis išradimas apima mažiausiai dviejų aukščiau minėtų I bendrosios formulės 2,5-dihidroksibenzensulfoninių junginių mišinio panaudojimą o taip pat šių junginių mišriųjų druskų, t.y. junginius su skirtingais katijonais B ir (arba) skirtingomis 2,5-dihidroksibenzensulfoninėmis liekanomis.The present invention encompasses the use of a mixture of at least two of the aforementioned 2,5-dihydroxybenzenesulfonic compounds of the general formula I as well as the mixed salts of these compounds, i.e. compounds with different cation B and / or different 2,5-dihydroxybenzenesulfonic residues.
Geriau, kai I bendrosios formulės 2,5-dihidroksibenzensulfoninių junginių katijonas(-ai) yra parinkti iš grupės, susidedančios iš Ca2+, Mg2+, Na+, K+ ir [NH4-xRx]+, kur x yra 0,1,2, 3 arba 4, o R reiškia šakotąjį arba nešakotąjį Cm4 alkilo radikalą. Jeigu x yra didesnis už 1, t.y. jeigu du arba daugiau alkilo radikalų yra [NH4-XRX]+ katijone, jie gali būti vienodi arba skirtingi, bet tinkamesni yra vienodi alkilo radikalai.Preferably, the cation (s) of the 2,5-dihydroxybenzenesulfonic compounds of general formula I is selected from the group consisting of Ca 2+ , Mg 2+ , Na + , K + and [NH 4 - x R x] + , wherein x is 0 , 1,2, 3 or 4, and R represents a branched or unbranched Cm4 alkyl radical. If x is greater than 1, that is, if two or more alkyl radicals are present in the [NH 4 -X R X ] + cation, they may be the same or different, but the same alkyl radicals are more suitable.
Pageidautina, kad vaiste būtų vienas arba daugiau junginių, pasirinktų iš grupės, susidedančios iš kalcio 2,5-dihidroksibenzensulfonato (kalcio dobesilato), dietilamino 2,5-dihidroksibenzensulfonato (etamsilato) ir bis(dietilamino)-2,5-dihidroksibenzen-1,4-disulfonato (persilato). Pagal šį išradimą vaisto gamyboje ypatingai tinka naudoti kalcio 2,5dihidroksibenzensulfonatą (kalcio dobesilatą.Preferably, the drug comprises one or more compounds selected from the group consisting of calcium 2,5-dihydroxybenzenesulfonate (calcium dobesylate), diethylamine 2,5-dihydroxybenzenesulfonate (etamsylate) and bis (diethylamino) -2,5-dihydroxybenzene-1, 4-disulfonate (persilate). Calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate) is particularly suitable for use in the manufacture of the medicament according to the present invention.
Išradime naudojami I bendrosios formulės 2,5dihidroksibenzensulfonatiniai junginiai taip pat gali būti solvatų, ypatingai hidratų formos. I bendrosios formulės 2,5-dihidroksibenzensulfonatinius junginius bei jų solvatus galima pagaminti naudojant šios srities specialistams žinomus reagentus ir metodus.The 2,5-dihydroxybenzenesulfonate compounds of the general formula I used in the invention may also be in the form of solvates, in particular hydrates. The 2,5-dihydroxybenzenesulfonate compounds of general formula I and their solvates can be prepared using reagents and methods known to those skilled in the art.
Kalcio 2,5-dihidroksibenzensulfonato (kalcio dobesilato) ir dietilamino 2,5-dihidroksibenzensulfonato (etamsilato) gamyba yra žinoma, pavyzdžiui, iš “The Merck lndex”-13th edition, Merck & Co., R. Rahway, N.J., USA. 2001. Minėtas literatūros aprašymas yra čia pridėtas kaip literatūros šaltinis ir yra išradimo aprašymo dalis. Bis(dietilamino)-2,5-dihidroksibenzen-1,4disulfonato (persilato) gamyba yra žinoma, pavyzdžiui, iš Prancūzijos patento FR 73/17709 (Publication No.2,201,888). Atitinkamas aprašymas čia pridėtas kaip literatūros šaltinis ir yra išradimo aprašymo dalis.Calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate) and diethylamine 2,5-dihydroxybenzenesulfonate (etamsylate) production is known, for example, from "The Merck lndex" -13 th edition, Merck & Co., R. Rahway, NJ, USA. 2001. The foregoing literature is incorporated herein by reference and is part of the disclosure. The production of bis (diethylamino) -2,5-dihydroxybenzene-1,4-disulfonate (persilate) is known, for example, from French patent FR 73/17709 (Publication No.2,201,888). The relevant description is incorporated herein by reference and is part of the disclosure.
Buvo rasta, kad I bendrosios formulės 2,5-dihidroksibenzensulfoniniai junginiai reguliuoja azoto oksido (NO) sintezę, o taip pat EDHF (endotelinės kilmės hiperpoliarizuojančio faktoriaus) funkciją diabetinių pacientų endotelyje, naudojant bendrą <500 mg dienos dozę.2,5-Dihydroxybenzenesulfonic compounds of general formula I have been found to regulate nitric oxide (NO) synthesis as well as EDHF (endothelial-derived hyperpolarizing factor) function in the endothelium of diabetic patients at a total daily dose of <500 mg.
Šie I bendrosios formulės 2,5-dihidroksibenzensulfoniniai junginiai taip pat gali būti skiriami pacientams mažesnėmis dienos dozėmis, pvz., nuo 100 iki <500 mg, geriau nuo 150 iki 450 mg, geriausia nuo 200 iki 400 mg.These 2,5-dihydroxybenzenesulfonic compounds of the general formula I may also be administered to patients in lower daily doses, e.g., from 100 to <500 mg, preferably from 150 to 450 mg, preferably from 200 to 400 mg.
Vartojant šiuos I bendrosios formulės 2,5-dihidroksibenzensulfoninius junginius bendra <500 mg dienos doze nepageidaujamų šalutinių poveikių dažnis ir laipsnis taip pat gali būti sumažintas. Vaisto priėmimo dažnis gali būti sumažintas iki dviejų kartų per dieną, geriau vieną kartą per dieną, tuo pačiu sumažinant paciento nepasitenkinimą.The use of these 2,5-dihydroxybenzenesulfonic compounds of the general Formula I at a total daily dose of <500 mg may also reduce the incidence and severity of side effects. The frequency of admission may be reduced to twice a day, preferably once a day, while reducing patient dissatisfaction.
Kadangi I bendrosios formulės 2,5-dihidroksibenzensulfoniniai junginiai reguliuoja azoto oksido (NO) sintezę, o taip pat EDHF funkciją diabetinių pacientų endotelyje, jie tinka gaminti vaistui, skirtam sutrikimų, susijusių su azoto oksido (NO) gaminimosi pablogėjimu ir (arba) EDHF funkcijos susilpnėjimu, profilaktikai ir (arba) gydymui (“Calcium Dobesilate: Pharmacology and Future Approaches”, T. Tejerina, E. Ruiz, Gen. Pharmac. Vol.31, No.3, 357-360, 1988).Because 2,5-dihydroxybenzenesulfonic compounds of the general formula I regulate nitric oxide (NO) synthesis as well as EDHF function in the endothelium of diabetic patients, they are suitable for the manufacture of a drug for the treatment of disorders associated with nitric oxide (NO) production and / or EDHF function. prophylaxis and / or treatment (Calcium Dobesilate: Pharmacology and Future Approaches, T. Tejerina, E. Ruiz, Gen. Pharmac. Vol.31, No.3, 357-360, 1988).
Geriausiai aukščiau minėti I bendrosios formulės 2,5dihidroksibenzensulfoniniai junginiai gali būti naudojami gamyboje vaisto, skirto mikrocirkuliacinių sutrikimų, labiausiai diabetinės retinopatijos, lytinės funkcijos sutrikimo, ypatingai erekcijos sutrikimo “Pharmacological Aspects of Erectile Dysfunction”, John A. Thomas, Jpn. J. Pharmacol. 89, 101-112, 2002), inkstų sutrikimų, vainikinių mikrocirkuliacinių sutrikimų ir (arba) periferinių arterijų mikrocirkuliacijos sutrikimų profilaktikai ir (arba) gydymui.The aforementioned 2,5-dihydroxybenzenesulfonic compounds of general formula I may be used in the manufacture of a medicament for microcirculatory disorders, most notably diabetic retinopathy, sexual dysfunction, in particular erectile dysfunction Pharmacological Aspects, John A. Thomas, Jpn. J. Pharmacol. 89, 101-112, 2002), for the prevention and / or treatment of renal disorders, coronary microcirculatory disorders and / or peripheral arterial microcirculatory disorders.
Priklausomai nuo konkretaus įgyvendinimo varianto, šio išradimo vaistas, kaip papildomas sudedamąsias dalis, taip pat gali turėti įprastų šios srities specialistams žinomų papildomų medžiagų.Depending on the particular embodiment, the medicament of the present invention, as an additional ingredient, may also contain conventional additional substances known to those skilled in the art.
Vaistai pagal šį išradimą gali būti gaminami panaudojant standartines šios srities specialistams žinomas metodikas, pvz. iš “Pharmaceutics: the Science of Dosage Forms”, Second Edition, Aulton, M.E. (Ed.) Churchil Livingstone, Edinburgh (2002) turinyje esančių lentelių; “Encyclopedia of Pharmaceutical Technology”, Second Edition, Svvarbrick, J. and Boylan J.C. (Eds.), Marcei Dekker, Ine. New York (2002);”Modern Pharmaceutics”, Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcei Dekker, Ine. New York 2002 ir “The Theory and Practice of Industrial Pharmacy”, Lachman L., Liebemnan H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). Atitinkami aprašymai čia pridėti kaip literatūros šaltiniai ir yra išradimo aprašymo dalis.The medicaments of the present invention may be prepared using standard techniques known to those skilled in the art, e.g. from Pharmaceutics: The Science of Dosage Forms, Second Edition, Aulton, M.E. (Ed.) Churchil Livingstone, Edinburgh (2002) Tables in Content; Encyclopedia of Pharmaceutical Technology, Second Edition, Svvarbrick, J. and Boylan J.C. (Eds.), Marcei Dekker, Ine. New York (2002), Modern Pharmaceutics, Fourth Edition, Banker G.S. and Rhodes C.T. (Eds.) Marcei Dekker, Ine. New York 2002 and The Theory and Practice of Industrial Pharmacy, Lachman L., Liebemnan H. and Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). Relevant descriptions are incorporated herein by reference and are part of the disclosure.
Geriausiame šio išradimo įgyvendinimo variante vaistas yra tinkamas peroraliniam vartojimui.In a preferred embodiment of the present invention, the medicament is suitable for oral administration.
Jeigu vaistas yra tinkamas peroraliniam vartojimui, geriausia, kai jis yra tabletės, kapsulės arba suspensijos formos.If the drug is suitable for oral administration, it is preferably in the form of a tablet, capsule or suspension.
Šio išradimo vaistas taip pat gali būti multidalelių formos, ypatingai plokštelių arba granulių, esant reikalui supresuotų į tabletę, supiltų į kapsulę arba suspenduotų tinkamame skystyje. Tinkami skysčiai yra žinomi šios srities specialistams.The medicament of the present invention may also be in multiparticulate form, in particular in the form of tablets or granules, if necessary compressed into a tablet, encapsulated or suspended in a suitable liquid. Suitable fluids are known to those skilled in the art.
Tinkamiausiame šio išradimo įgyvendinimo variante vaistas turi bent vieno I bendrosios formulės 2,5-dihidroksibenzensulfoninio junginio, kuris gali būti solvato formos ir bent dalinai yra prolonguoto išsiskyrimo formos.In a preferred embodiment of the present invention, the medicament comprises at least one 2,5-dihydroxybenzenesulfonic compound of general formula I, which may be in the form of a solvate and at least in part is a sustained release form.
Įdėjus vieną arba daugiau I bendrosios formulės 2,5dihidroksibenzensulfoninių junginių, kurie gali būti solvato formos, bent dalinai arba pilnai į prolonguoto išsiskyrimo formą, galima pratęsti jo poveikio trukmę, leidžiant pasireikšti tokios prolonguotos formos naudingiems efektams, pvz., palaikant optimalią terapinę koncentraciją plazmoje arba audinyje.The addition of one or more of the 2,5-dihydroxybenzenesulfonic compounds of general formula I, which may be in the form of a solvate, at least partially or wholly in the sustained release form, may extend the duration of action by allowing beneficial effects of such prolonged form, e.g. in the cloth.
Tinkamos prolonguoto išsiskyrimo formos bei medžiagos ir jų pagaminimo būdai yra žinomi šios srities specialistams, pvz. iš “ModifiedRelease Drug Delivery Technology”, Rathbone, M.J.. Hadgraft, J. and Roberts, M.S. (Eds.), Marcei Dekker, Ine., New York (2002) turinyje esančių lentelių; “Handbook of Pharmaceutical Controlled Release Technology”, Wise, D.L. (Ed.), Marcei Dekker, Ine. New York (2002);”Controlled Drug Delivery”, Vol.1, Basic Concepts, Bruck, S.D. (Ed.) CRC Press Ine., Boca Raton (1983) ir iš Taakada, K. and Yoshikavva, H., “Orai Drug Delivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Ine., New York (1999), Vol.2, 728-742; Fix, J., “Orai drug delivery, small intestine and colon”, Encyclopedia of Controlled Drug Delivery, Mathiovvitz, E. (Ed.), John Wiley & Sons, Ine., New York (1999), Vol.2, 698-728. Atitinkami aprašymai čia pridėti kaip literatūros šaltiniai ir yra išradimo aprašymo dalis.Suitable forms and materials for sustained release and methods for their preparation are known to those skilled in the art, e.g. from ModifiedRelease Drug Delivery Technology, Rathbone, M.J .. Hadgraft, J. and Roberts, M.S. (Eds.), Marcei Dekker, Ine., New York (2002) Table of Contents; Handbook of Pharmaceutical Controlled Release Technology, Wise, D.L. (Ed.), Marcei Dekker, Ine. New York (2002); Controlled Drug Delivery, Vol.1, Basic Concepts, Bruck, S.D. (Ed.) CRC Press Ine., Boca Raton (1983) and from Taakada, K. and Yoshikavva, H., "Weather Drug Delivery," in Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Ine., New York (1999), Vol.2, 728-742; Fix, J., "Weather Drug Delivery, Small Intestine and Colon," in Encyclopedia of Controlled Drug Delivery, Mathiovvitz, E. (Ed.), John Wiley & Sons, Ine., New York (1999), Vol.2, 698. -728. Relevant descriptions are incorporated herein by reference and are part of the disclosure.
Jeigu šio išradimo vaiste yra bent vienas I bendrosios formulės 2,5dihidroksibenzensulfoninis junginys, bent dalinai esantis prolonguoto išsiskyrimo formoje, geriausia šį prolonguotą išsiskyrimą pasiekti naudojant bent vieną dangą arba paruošiant matricą, turinčią bent vieną uždelsto išskyrimo medžiagą. Atitinkami aprašymai čia pridėti kaip literatūros šaltiniai ir yra išradimo aprašymo dalis.If the medicament of the present invention contains at least one of the 2,5-dihydroxybenzenesulfonic compounds of general formula I, at least partially in sustained release form, it is preferable to achieve this sustained release using at least one coating or by preparing a matrix containing at least one delayed release agent. Relevant descriptions are incorporated herein by reference and are part of the disclosure.
Geriau, kai uždelsto išskyrimo medžiaga yra galimai modifikuotas, natūralus, pusiau sintetinis polimeras arba gamtinis, pusiau sintetinis arba sintetinis vaškas arba riebalų alkoholis arba riebalų rūgštis, arba bent jau dviejų aukščiau minėtų komponentų mišinys.Preferably, the delayed-release material is a potentially modified, natural, semi-synthetic polymer or natural, semi-synthetic or synthetic wax or fatty alcohol or fatty acid, or a mixture of at least two of the above components.
Geriausi vandenyje netirpūs polimerai, naudojami prolonguoto išskyrimo medžiagai gauti, yra polimerai akrilo dervos pagrindu, kurią geriausia parinkti iš poli(met)akrilatų; ypatingai geri yra poli(Ci-4)alkil(met)akrilatai, poli(Cr 4)dialkilamino(Ci-4)alkil(met)akrilatai ir (arba) kopolimerai arba jų mišiniai, o ypatingai pageidautini etilakrilato ir metilakrilato kopolimerai, kuriuose monomerų santykis 2:1 (Eudragit NE30D®), etilakrilato, metilmetakrilato ir trimetilamonio etilmetakrilato chlorido kopolimerai, kurio monomerų santykis yra 1:2:0,1 (Eudragit RS®), etilakrilato, metilmetakrilato ir trimetilamonio etilmetakrilato chlorido kopolimerai, kurių monomerų santykis 1:2:0,2 (Eudragit RL®) arba mišinys bent dviejų iš aukščiau minėtų kopolimerų. Šios padengimo medžiagos yra gaunamos iš prekybininkų kaip 30 masės % vandeninio latekso dispersijos, ty. kaip Eudragit RS30D®, Eudragit NE30D® arba Eudragit RL30D® ir taip pat gali būti naudojamos kaip medžiagos padengimo tikslams.The best water-insoluble polymers used to prepare the sustained release material are acrylic resin based polymers, which are preferably selected from poly (meth) acrylates; especially preferred are poly (C 1-4) alkyl (meth) acrylates, poly (C 1-4) dialkylamino (C 1-4) alkyl (meth) acrylates and / or copolymers or mixtures thereof, and ethyl acrylate and methyl acrylate copolymers containing monomer copolymers of 2: 1 (Eudragit NE30D®), ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate chloride with a monomer ratio of 1: 2: 0.1 (Eudragit RS®), copolymers of ethyl acrylate, methyl methacrylate and trimethylammonium ethyl methacrylate: 2: 0.2 (Eudragit RL®) or a mixture of at least two of the above copolymers. These coating materials are commercially available as 30% by weight dispersion of aqueous latex, ie. such as Eudragit RS30D®, Eudragit NE30D® or Eudragit RL30D® and may also be used as coating agents.
Kitame įgyvendinimo variante prolonguoto išskyrimo medžiaga yra paremta vandenyje netirpiais celiuliozės dariniais, geriausia alkilceliuliozėmis, ypatingai gerai tinka etilceliuliozė, arba celiuliozės esteriai, pvz. celiuliozės acetatas. Vandeninės etilceliuliozės dispersijos yra prekyboje, pavyzdžiui, jos turi Aquacoat® arba Surelease® prekių ženklus.In another embodiment, the sustained release material is based on water-insoluble cellulose derivatives, preferably alkylcelluloses, ethylcellulose being particularly suitable, or cellulose esters, e.g. cellulose acetate. Aqueous dispersions of ethyl cellulose are commercially available, for example, under the trademarks Aquacoat® or Surelease®.
Kaip gamtiniai, pusiau sintetiniai arba sintetiniai vaškai, riebalai arba riebalų alkoholiai, prolonguoto išskyrimo medžiagos gali būti paremtos kamaubo vašku, bičių vašku, glicerolio monostearatu, glicerolio monobehenatu, glicerolio ditripalmitostearatu, mikrokristaliniu vašku, cetilo alkoholiu, cetilstearilalkoholiu arba mažiausiai dviejų šių komponentų mišiniu.As natural, semi-synthetic or synthetic waxes, fatty or fatty alcohols, sustained release agents may be based on kamauba wax, beeswax, glycerol monostearate, glycerol monobehenate, glycerol ditripalmitostearate, microcrystalline wax, cetyl alcohol, cetyl alcohol or cetyl alcohol.
Į aukščiau minėtų prolinguoto išskyrimo polimerų mišinius taip pat gali įeiti įprasti, fiziologiniu požiūriu priimtini plastifikatoriai šios srities specialistams žinomais kiekiais.Mixtures of the above-mentioned proliferative release polymers may also contain conventional physiologically acceptable plasticizers in amounts known to those skilled in the art.
Tinkamų plastifikatorių pavyzdžiais yra C6-C40 alifatinių arba aromatinių dikarboksirūgščių ir C1.C4 alifatinių alkoholių diesteriai, pvz., dibutilftalatas, dietilftalatas, dibutilsebacatas arba dietilsebacatas, hidrofiliniai arba lipofiliniai citrinų rūgšties esteriai, pvz., trietilcitratas, tributilcitratas, acetiltributilcitratas arba acetiltrietilcitratas, polietilenglikoliai, propilenglikoliai, glicerolio esteriai, pvz., triacetinas, Myvacet® (acetilinti mono- ir digliceridai, nuo C23H44O5 iki C25H47O7), vidutinio grandinės ilgio trigliceridai (Migliol®), oleino rūgštis arba bent jau dviejų minėtų plastifikatorių mišiniai. Geriau, kai vandeninėse Eudragit RS® arba esant reikalui Eudragit RL® dispersijose yra trietilcitrato. Prolonguoto išskyrimo medžiaga gali turėti vieną arba daugiau plastifikatorių, kurių kiekiai yra, pavyzdžiui, 5-50 %, skaičiuojant nuo naudojamo polimero(ų) kiekio.Examples of suitable plasticizers are di-esters of C6-C40 aliphatic or aromatic dicarboxylic acids and C1-C4 aliphatic alcohols, e.g. propylene glycols, glycerol esters such as triacetin, Myvacet® (acetylated mono- and diglycerides, C23H44O5 to C25H47O7), medium chain triglycerides (Migliol®), oleic acid, or mixtures of at least two of the above plasticizers. Preferably, the aqueous dispersions of Eudragit RS® or, if desired, Eudragit RL® contain triethyl citrate. The prolongated release material may contain one or more plasticizers in amounts of, for example, 5 to 50%, based on the amount of polymer (s) used.
Prolonguoto išskyrimo medžiaga taip pat gali turėti šios srities specialistams žinomų kitų įprastų pagalbinių medžiagų, pvz. tepalų, spalvotų pigmentų arba paviršinio aktyvumo medžiagų.The prolongated release material may also contain other conventional excipients known to those skilled in the art, e.g. lubricants, colored pigments, or surfactants.
Šio išradimo vaistas taip pat gali turėti bent vieną enterinę dangą, kuri ištirpsta priklausomai nuo pH. Dėl šios dangos vaistas gali pereiti per skrandį neištirpęs ir I bendrosios formulės junginiai išsiskiria tik virškinimo trakte. Pageidautina, kad enterinė danga ištirptų esant pH tarp 5 ir 7,5.The medicament of the present invention may also have at least one enteric coating that dissolves in a pH-dependent manner. Due to this coating, the drug can pass through the stomach undissolved and the compounds of the general formula I are excreted only in the gastrointestinal tract. Preferably, the enteric coating dissolves at a pH between 5 and 7.5.
Enterinė danga gali būti bet kokios specialistams žinomos medžiagos pagrindu, pvz., metakrilo rūgšties/metilmetakrilato kopolimerai, kurių monomerų molių santykis yra 1:1 (Eudragit L®), metakrilo rūgšties/metilmetakrilato kopolimerai, kurių monomerų molių santykis yra 1:2 (Eudragit S®), metakrilo rūgšties/etilakrilato kopolimerai, kurių monomerų molių santykis yra 1:1 (Eudragit L30D-55®), metakrilo rūgšties/metilakrilato/metilmetakrilato kopolimerai, kurių monomerų molių santykis yra 7:3:1 (Eudragit FS®), šelakas, hidroksipropilmetilceliuliozės acetato sukcinatai, celiuliozės acetato ftalatai arba bent jau dviejų iš šių komponentų mišiniai, kurie, esant reikalui, gali būti naudojami derinyje su aukščiau minėtais vandenyje netirpiais poli(met)akrilatais, geriausia derinyje su Eudragit NE30D® ir (arba) Eudragit RL®, ir (arba) Eudragit RS®.The enteric coating may be based on any material known to those skilled in the art, e.g., methacrylic acid / methyl methacrylate copolymers having a 1: 1 molar monomer ratio (Eudragit L®), methacrylic acid / methyl methacrylate copolymers having a 1: 2 molar monomer ratio (Eudragit S®), methacrylic acid / ethyl acrylate copolymers 1: 1 (Eudragit L30D-55®), methacrylic acid / methyl acrylate / methyl methacrylate copolymers 7: 3: 1 (Eudragit FS®), shellac, hydroxypropylmethylcellulose acetate succinates, cellulose acetate phthalates, or mixtures of at least two of these components, optionally in combination with the above water-insoluble poly (meth) acrylates, preferably in combination with Eudragit NE30D® and / or Eudragit RL ®, and / or Eudragit RS®.
Šio išradimo vaisto dangos gali būti uždedamos panaudojant įprastus specialistams žinomus būdus, pvz., iš Johnson, J.L., “Pharmaceutical tablet coating, Coatings Technology Handbook (Second Edition), Šatas, D. and Tracton, A.A. (Eds), Marcei Dekker, Ine. New York, (2001), 863-866; Carstensen, T., “Coating Tablets in Advanced Pharmaceutical Solids,The drug coatings of the present invention can be applied using conventional techniques known to those skilled in the art, e.g., Johnson, J.L., "Pharmaceutical tablet coating, Coatings Technology Handbook (Second Edition), Schath, D. and Tracton, A.A. (Eds), Marcei Dekker, Ine. New York, (2001), 863-866; Carstensen, T., Coating Tablets in Advanced Pharmaceutical Solids,
Svvarbrick, J. (Ed.), Marcei Dekker, Ine. New York, (2001), 455-468; Leopold, C.S., “Coated dosage forms for colon-specific drug delivery”, Pharmaceutical Science & Technology Today, 2(5), 197-204 (1999), Rhodes, C.T. and Porter, S.C., Coatings, in Encyclopedia of Controlled Drug Delivery. Mathiovvitz, E. (Ed.), John Wiley & Sons, Ine., New York (1999), Vol.1, 299-311. Atitinkami aprašymai yra pridedami kaip literatūros šaltiniai ir yra šio aprašymo dalis.Svvarbrick, J. (Ed.), Marcei Dekker, Ine. New York, (2001), 455-468; Leopold, C.S., "Coated Dosage Forms for Colon-Specific Drug Delivery," Pharmaceutical Science & Technology Today, 2 (5), 197-204 (1999), Rhodes, C.T. and Porter, S.C., Coatings, in Encyclopedia of Controlled Drug Delivery. Mathiovvitz, E. (Ed.), John Wiley & Sons, Ine., New York (1999), Vol.1, 299-311. Relevant descriptions are included as references and are part of this description.
Kitame įgyvendinimo variante šio išradimo vaistas turi vieną arba daugiau I bendrosios formulės 2,5-dihidroksibenzensulfoninių junginių ne tik prolonguoto išsiskyrimo formoje, bet taip pat ir neuždelstoje formoje. Derinant su betarpiško išsiskyrimo forma, gali būti pasiekta didelė pradinė dozė, kad būtų pasiektas greitas naudingas poveikis. Tada lėtas išsiskyrimas iš uždelsto išsiskyrimo formos apsaugos nuo naudingo poveikio mažėjimo.In another embodiment, the medicament of the present invention contains one or more 2,5-dihydroxybenzenesulfonic compounds of general formula I, not only in sustained release form, but also in immediate release form. In combination with the immediate release form, a high initial dose may be achieved to achieve a rapid beneficial effect. Slow release from the delayed release form will then protect against a reduction in beneficial effects.
Tai gali būti pasiekiama, pavyzdžiui, panaudojant vaistą, turintį bent vieną betarpiško išskyrimo dangą, kurioje yra bent vienas iš I bendrosios formulės 2,5-dihidroksibenzensulfoninių junginių, kad būtų galima gauti greitą naudingo poveikio pasireiškimą kai tik jis įvedamas pacientui.This may be achieved, for example, by the use of a medicament comprising at least one immediate release coating containing at least one of the 2,5-dihydroxybenzenesulfonic compounds of general formula I to provide a rapid onset of beneficial effect upon administration to the patient.
Farmakologiniai metodai:Pharmacological methods:
NO sintezės reguliavimas 2,5-dihidroksibenzensulfoniniais junginiais gali būti įvertintas specialistams žinomais būdais, pvz., iš “Effects of calcium dobesilate on the synthesis of endothelium-dependent relaxing factors in rabbit isolated aorta”, T. Tejerina et ai., British Journal of Pharmacology (1997), 121, 711-716, Ίη vitro Effects of Calcium Dobesilate on the Responsiveness of Spontaneously Diabetic Rat Aorta”, T. Tejerina et ai., Jpn. J. Pharmacol., 78, 391-394 (1998) ir “Dobesilate enhances endothelial nitric oxide synthase-activity in maero- and microvascular endothelial cells”, Christoph Suschek et ai., British Journal of Pharmacology (1997), 122, 15021508. Atitinkami aprašymai čia pridėti kaip literatūros šaltiniai ir yra išradimo aprašymo dalis.The regulation of NO synthesis by 2,5-dihydroxybenzenesulfonic compounds can be evaluated by methods known to those skilled in the art, e.g., T. Tejerina et al., British Journal of Effects of calcium dobesilate on the synthesis of endothelium-dependent relaxing factors. Pharmacology (1997) 121, 711-716, "In vitro Effects of Calcium Dobesilate on the Responsiveness of Spontaneously Diabetic Rat Aorta", T. Tejerina et al., Jpn. J. Pharmacol., 78, 391-394 (1998) and "Dobesilate enhances endothelial nitric oxide synthase activity in maero- and microvascular endothelial cells", Christoph Suschek et al., British Journal of Pharmacology (1997) 122, 15021508. Relevant descriptions are incorporated herein by reference and are part of the disclosure.
Toliau duodamuose metoduose EDHF (endotelinės kilmės hiperpoliarizuojančio faktoriaus) įnašui į žmogaus varpos lygiojo raumens sugebėjimo susitraukti reguliavimą, I bendrosios formulės 2,510 dihidroksibenzensulfoninių junginių poveikiui į nuo endotelio priklausomai varpos lygiojo raumens relaksacijai nustatyti, o taip pat šių junginių poveikiui į erekcijos atsakus, yra aprašomas modelis in vivo bandyme su žiurkėmis.The following methods describe the contribution of EDHF (endothelial-derived hyperpolarizing factor) to the contraction of human penile smooth muscle, the effect of 2,510 dihydroxybenzenesulfonic compounds of general formula I on endothelium-dependent penile smooth muscle relaxation, and their effect on erectile responses. in an in vivo rat study.
Rezistentiškų varpos arterijų vaskuliarinis reaktyvumasVascular reactivity of resistant penile arteries
Kruopščiai pašalinus įsiskverbusius trabekulės audinius, buvo atskirtos varpos mažosios arterijos, spiralinės arterijos (kraujagyslės spindis 150-400 pm), kurios yra giliųjų varpos arterijų galinės šakos, ir po to arterijų žiedinės atkarpos (2 mm ilgio) buvo įtaisytos ant dviejų 40 pm vielų prie mikrovaskuliarinių dvigubų Halpern-Mulvany miografų (J.P. Trading, Aarhus, Denmark) izometrinio tempimo registravimams. Kraujagyslių segmentai buvo laikomi 30 min., kad pasiektų pusiausvyrą, fiziologiniame druskos tirpale (PSS), kurio sudėtis (kiekvienas komponentas nurodytas mM): 119 NaCI, 4,6 KCI, 1,5 CaCI2, 1,2 MgCI2, 24,9 NaHCO3, 11 gliukozės, 1,2 KH2PO4, 0,027 EDTA 37 °C temperatūros vandenyje, per kurį nepertraukiamai burbuliukais leidžiamas 95 %O2 ir 5 % CO2 mišinys, palaikant pH 7,4. Buvo nustatytas kraujagyslių segmentų pasyvus įtempimas ir vidinis perimetras, kai atpalaiduojama in situ, esant 100 mm Hg (L100) slėgiui per sienelę. Po to buvo nureguliuoti kraujagyslių segmentų vidiniai perimetrai, atitinkamai 90 % L100, kai jėgos išaugimas yra artimas maksimaliam, kaip aprašyta Mulvany MJ, Halpern W., “Contractile properties of small resistance arteries in spontaneously hypertensive and normotensive rats”, Circ. Res., 41, 19-26, 1977. Atitinkamas aprašymas yra pridedamas kaip literatūros šaltinis ir yra išradimo aprašymo dalis.After careful removal of the penetrated trabecular tissue, penile small arteries, spiral arteries (vascular radius 150-400 pm), which are the terminal branches of deep penile arteries, were separated, and then circular sections of arteries (2 mm long) were mounted on two 40 pm wires. for isometric stretch recording of microvascular double Halpern-Mulvany myographs (JP Trading, Aarhus, Denmark). Vascular segments were stored for 30 min to equilibrate in saline (PSS) containing (each component expressed as mM): 119 NaCl, 4.6 KCl, 1.5 CaCl 2 , 1.2 MgCl 2 , 24, 9 NaHCO 3 , 11 glucose, 1.2 KH 2 PO 4 , 0.027 EDTA in water at 37 ° C, bubbling 95% O 2 and 5% CO 2 continuously at pH 7.4. Passive tension and internal circumference of the vascular segments when released in situ at a wall pressure of 100 mm Hg (L100) was determined. Subsequently, the internal circumferences of the vascular segments were adjusted to 90% L100, respectively, at a force close to maximum as described by Mulvany MJ, Halpern W., "Contractile Properties of Small Resistance Arteries in Spontaneously Hypertensive and Normotensive Rats", Circ. Res., 41, 19-26, 1977. The corresponding description is incorporated by reference and is part of the description of the invention.
Tada šie preparatai buvo sudėti į 125 mM K+ (KPSS, ekvimolinis NaCI pakeitimui kiekis KCI PSS buferyje) ir matuojamas susitraukiamumo atsakas. Arterijos buvo sutraukiamos 1 μΜ norepinefrinu (apytikriai 80 % KPSS sukelto susitraukimo), o relaksaciniai atsakai buvo įvertinti panaudojant junginių kaupiamąjį pridėjimą į kameras. Arteriniai segmentai, laikomi kaip neturintys funkcinio endotelio, neatsipalaiduoja iki 10 μΜ acetilcholino.These preparations were then added to 125 mM K + (KPSS, equimolar amount of NaCl for substitution in KCI PSS buffer) and the shrinkage response was measured. Arteries were constricted with 1 μΜ of norepinephrine (approximately 80% contraction induced by KPSS), and relaxation responses were evaluated using cumulative addition of compounds to the chambers. Arterial segments, considered as having no functional endothelium, do not relax to 10 μΜ acetylcholine.
Tyrimai organų kamerojeOrgan chamber studies
Siauros akytkūnio audinio juostelės (3x3x7 mm) buvo įmerktos į 8 ml organų kameroje esančio PSS, laikoma 37 °C temperatūroje ir aeruojama 95 % O2 ir 5 % CO2 mišiniu, palaikant pH 7,4. Kiekviena audinio juostelė buvo tempiama palaipsniui didinant tempimą iki optimalaus izometrinio įtempimo, kaip nustatyta pagal maksimalų susitraukiamumo atsaką iki 1 μΜ fenilefrino, kaip aprašyta Saenz de Tejada et ai., “A Nitric Oxide-like factor mediates nonadrenergenic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth musele”, J. Clin. Invest. 88, 112-118. Atitinkamas aprašymas yra pridedamas kaip literatūros šaltinis ir yra išradimo aprašymo dalis.Narrow cellular tissue strips (3x3x7 mm) were immersed in 8 mL of PSS in the organ chamber, stored at 37 ° C, and aerated with a mixture of 95% O2 and 5% CO2 at pH 7.4. Each tissue strip was stretched by gradually increasing the stretch to the optimum isometric tension as determined by the maximal contraction response to 1 μΜ phenylephrine as described by Saenz de Tejada et al., A Nitric Oxide-like Factor Mediates Nonadrenergic-Noncholinergic Neurogenic Relaxation of Penile Corpus Cavern smooth musele, ”J. Clin. Invest. 88, 112-118. The corresponding description is incorporated by reference and is part of the description of the invention.
Audiniai buvo sutraukti panaudojant 0,5-3 pm fenilefrino (80 % KPSS sukelti susitraukimo ir atsipalaidavimo atsakai buvo įvertinti panaudojant kaupiamąjį junginių pridėjimą [kameras.Tissues were contracted using 0.5 to 3 pm phenylephrine (80% KPSS-induced contraction and relaxation responses were evaluated using cumulative addition).
Erekcijos atsakai į akytkūnio nervo stimuliaciją bandyme su anestezuotomis žiurkėmisErectile responses to porous nerve stimulation in anesthetized rats
Genetiškai diabetinių žiurkių patinėliai (BB/wor žiurkės, Molegaard Breeding and Research, Svvensved, Denmark) buvo anestezuoti ketaminu (60 mg/kg). Chirurginė procedūra susidėjo iš atskyrimo ir dešiniojo akytkūnio nervo izoliavimo, padarius pjūvį per pilvo vidurinę liniją ir išėmus į paviršių varpos kojytę per skersinį tarpvietės įpjovimą. Intraakytkūninis slėgis (ICP) buvo matuojamas įvedant į dešiniąją kojytę 23 dydžio adatą sujungtą su vienkartiniu slėgio perdavikliu (Abbott, Sligo, Ireland) ir duomenų surinkimo sistema (AD/Instruments, castle Hill, Australia). Į kairiąją miego arteriją ir dešiniąją išorinę jungo veną buvo įstatyti kateteriai atitinkamai pastoviam kraujospūdžio matavimui ir fiziologinio tirpalo arba vaisto infuzijai. Elektrinis stimuliavimas buvo daromas mažyčiu platinos bipoliniu kabliuko pavidalo elektrodu, sujungtu su stimuliatoriumi ir srovės stiprintuvu (Cibertec, Madrid, Spain). Elektrinio stimuliavimo parametrai susidėjo iš 1 ms trukmės ir 1,5 mA srovės stiprumo impulsų 1 min. Dažnio-atsako kreivės buvo gautos naudojant 1,3 ir 10 Hz stimuliavimą 3 min. intervalais.Genetically diabetic male rats (BB / wor rats, Molegaard Breeding and Research, Svvensved, Denmark) were anesthetized with ketamine (60 mg / kg). The surgical procedure consisted of dissection and isolation of the right coronary nerve by means of an incision through the abdominal median line and removal of the penis foot through a transverse peritoneal incision. Intracellular pressure (ICP) was measured by inserting into the right foot a 23-gauge needle connected to a disposable pressure transducer (Abbott, Sligo, Ireland) and a data acquisition system (AD / Instruments, Castle Hill, Australia). Catheters were inserted into the left carotid artery and the right external jugular vein, respectively for continuous blood pressure measurement and saline or drug infusion. Electrical stimulation was performed with a tiny platinum bipolar hook electrode coupled to a stimulator and a current amplifier (Cibertec, Madrid, Spain). Electrical stimulation parameters consisted of pulses of 1 ms duration and 1.5 mA current for 1 min. Frequency-response curves were obtained using 1.3 and 10 Hz stimulation for 3 min. intervals.
Norint įvertinti ūmius I bendrosios formulės 2,5dihidroksibenzensulfoniniųjunginių poveikius įerekcijos atsakus, buvo atliktas kontrolinis stimuliavimas, esant 1, 3 ir 10 Hz, ir po stabilizacijos laikotarpio buvo suleista į veną atitinkamo junginio (10 mg/kg), ištirpinto 20 % hidroksipropil-p-ciklodekstrine (HPpCD), arba vien tik tirpiklis. Stimuliavimas buvo pakartotas praėjus 60 min. po atitinkamo junginio arba tirpiklio suleidimo.To evaluate the acute effects of the 2,5-dihydroxybenzenesulfonic compounds of the general formula I on control response, control stimulation at 1, 3 and 10 Hz was performed and after the stabilization period the corresponding compound (10 mg / kg) dissolved in 20% hydroxypropyl-p- was injected. cyclodextrin (HPpCD), or solvent alone. Stimulation was repeated 60 min later. after administration of the appropriate compound or solvent.
Toliau šis išradimas yra iliustruojamas pavyzdžiais. Šios iliustracijos yra duotos vien tik kaip pavyzdžiai ir neriboja šio išradimo pagrindinės prasmės.The invention is further illustrated by the following examples. These illustrations are given by way of example only and are not intended to limit the scope of the present invention.
Bendra masė 0,3500 gTotal weight 0.3500 g
Aukščiau minėti kiekiai kalcio dobesilato, kukurūzų krakmolo, laktozės, povidono K-30, citrinų rūgšties monohidrato, magnio stearato ir natrio rūgščiojo sulfito kruopščiai sumaišomi įprastu maišikliu ir po to presuojami tabletėmis įprastu tabletavimo presu.The above amounts of calcium dobesilate, corn starch, lactose, povidone K-30, citric acid monohydrate, magnesium stearate and sodium bisulfite are thoroughly mixed in a conventional blender and then compressed into tablets using a conventional tabletting press.
Farmakologiniai metodai:Pharmacological methods:
Vaistai ir medžiagos:Medicines and substances:
Fenilefrinas, norepinefrinas (arterenolis), acetilcholinaas, indometacinas, NG-nitro-L-argininas (L-NNA), apaminas, charybdotoksinas ir hidroksipropil-βciklodekstrinas (HPpCD) buvo gauti iš Sigma Chemical Co. (St. Louis, MO, USA). Mikonazolis buvo gautas iš RBI (Natic, MA, USA). Kalcio dobesilatas (kalcio dihidroksi-2,5-benzensulfonatas, Doxium®) buvo gautas iš Dr. Esteve Laboratories (Barcelona, Spain).Phenylephrine, norepinephrine (arterenol), acetylcholine, indomethacin, N G -nitro-L-arginine (L-NNA), apamine, charybdotoxin, and hydroxypropyl-β-cyclodextrin (HPpCD) were obtained from Sigma Chemical Co. (St. Louis, MO, USA). Miconazole was obtained from RBI (Natic, MA, USA). Calcium dobesilate (calcium dihydroxy-2,5-benzenesulfonate, Doxium®) was obtained from Dr. Esteve Laboratories (Barcelona, Spain).
Duomenų analizė:Data Analysis:
Relaksacijos atsakai yra išreikšti procentais nuo bendros relaksacijos (tonuso praradimo), sukeltos, pridėjus 0,1 M papaverino HCI į kamerą eksperimento gale. Visi duomenys išreikšti kaip vidurkis ± standartinė paklaida. Buvo gautos pilnos koncentracija-atsakas arba dažnis-atsakas kreivės ir palygintos panaudojant dvifaktorinės variacinės analizės (ANOVA) statistinį testą naudojant StatView programą Apple kompiuteriui. Erekcijos atsakai buvo nustatyti matuojant intraakytkOninio slėgio ploto po kreive (AUC) padidėjimus į žiurkių akytkūnio nervo stimuliavimą, normalizuotą pagal vidurkines arterinio slėgio reikšmes. Pilnos dažnio-atsako kreivės buvo lyginamos pagal dvifaktorin į ANOVA testą.Relaxation responses are expressed as percentages of total relaxation (tone loss) induced by the addition of 0.1 M papaverine HCl to the chamber at the end of the experiment. All data are expressed as mean ± standard error. Complete concentration-response or frequency-response curves were obtained and compared using a two-factor analysis of variance (ANOVA) using StatView for Apple. Erectile responses were determined by measuring the increase in intra-curative pressure area (AUC) to stimulation of rat porous nerve, normalized to mean arterial pressure values. Complete frequency-response curves were compared by two-way ANOVA.
EDHF vaidmuo nuo endotelio priklausančioje žmogaus akytkūnio trabekulinių juostelių relaksacijoje ir žmogaus varpos rezistentinėms arterijoms (HPRA):Role of EDHF in endothelium-dependent relaxation of human porous trabecular strips and human penile arteries (HPRA):
Trabekulinio audinio juostelėse acetilcholinas (ACh; nuo 1 nM iki 10 μΜ) davė nuo koncentracijos priklausančią relaksaciją, kuri buvo beveik panaikinta, paveikiant NO sintetazės (NOS) inhibitoriaus - NG-nitro-L-arginino (L-NNA; 100 μΜ) - ir ciklooksigenazės (COX) inhibitoriaus - indometacino (5 μΜ) - deriniu. Atvirkščiai, varpos arterijų atveju, nors veikimas L-NNA (100 μΜ) ir indometacinu (5 μΜ) žymiai sumažino ACh sukeltą relaksaciją, svarbus šių arterijų relaksacijos komponentas išliko. Šios ACh sukeltos relaksacijos, esant NOS ir COX inhibicijai, buvo panaikintos, sutraukiant HPRA didele ekstraląstelinio K+ koncentracija (35 mM) arba veikiant šias arterijas nuo Ca2+ priklausančiais K+-kanalų blokatorių, apamino (APA; 100 nM) ir charibdotoksino (CTX; 100 nM) deriniu.In trabecular tissue strips, acetylcholine (ACh; 1 nM to 10 μΜ) gave a concentration-dependent relaxation that was almost abolished by exposure to the NO synthase (NOS) inhibitor, N G -nitro-L-arginine (L-NNA; 100 μΜ), and a cyclooxygenase (COX) inhibitor indomethacin (5 μΜ). Conversely, in the case of penile arteries, although exposure to L-NNA (100 μΜ) and indomethacin (5 μΜ) significantly reduced ACh-induced relaxation, an important component of the relaxation of these arteries remained. These ACh-induced relaxations in the presence of NOS and COX inhibition were abolished by inhibition of HPRA by high concentrations of extracellular K + (35 mM) or by the action of these arteries on Ca 2+ -dependent K + channel blockers, apamine (APA; 100 nM) and charibdotoxin ( CTX; 100 nM).
Kalcio dobesilato poveikiai į nuo endotelio priklausančią žmogaus varpos lygiųjų raumenų relaksaciją:Effects of calcium dobesylate on endothelium-dependent relaxation of human penile smooth muscle:
Kalcio dobesilatas (10 μΜ) labai stiprina ACh sukeltą HPRA relaksaciją.Calcium dobesylate (10 μΜ) greatly enhances ACh-induced HPRA relaxation.
Šio stiprinimo kalcio dobesilatu (10 μΜ) žymiai neveikia NOS ir COX suderintas inhibavimas, bet jis yra panaikinamas, jeigu arterijos yra pamerktos į didelę kalio koncentraciją (35 mM).This enhancement by calcium dobesilate (10 μΜ) is not significantly affected by NOS- and COX-coordinated inhibition, but is abolished if arteries are dipped in high potassium concentration (35 mM).
HPRA buvimas APA (100 nM) ir CTX (100 nM) derinyje, kuris blokuoja ACh sukeltą relaksaciją rezistentišką NOS ir COX inhibicijai, panaikina stiprinančius kalcio dobesilato poveikius. Pagaliau, mikonazolas (0,3 mM) žymiai sumažina kalcio dobesilato rezistentiškos NOS ir COX inhibicijai HPRA ACh sukeltos relaksacijos stiprinančius efektus.The presence of HPRA in the combination of APA (100 nM) and CTX (100 nM), which blocks ACh-induced relaxation resistant to NOS and COX inhibition, abolishes the potentiating effects of calcium dobesylate. Finally, miconazole (0.3 mM) significantly reduces the enhancement effects of HPRA ACh-induced relaxation by inhibition of calcium dobesylate-resistant NOS and COX.
Kalcio dobesilato poveikiai į anestezuotų diabetinių žiurkių erekcinius atsakus:Effects of calcium dobesilate on erectile responses in anesthetized diabetic rats:
Akytkūnio nervo elektrinis stimuliavimas anestezuotoms žiurkėms davė nuo dažnio priklausomą intraakytkūninio slėgio (ICP) padidėjimus, kurie nebuvo pakeisti veikiant tirpikliu (20 % HPpCD). Suleidus į veną kalcio dobesilato (10 mg/kg), žymiai padidėjo erektilūs atsakai į akytkūnio nervo stimuliaciją.Electrical stimulation of the porous nerve in anesthetized rats gave a frequency-dependent increase in intraocular pressure (ICP) that was not altered by solvent exposure (20% HPpCD). Intravenous administration of calcium dobesilate (10 mg / kg) significantly increased erectile responses to the stimulation of the porous nerve.
Aukščiau minėti rezultatai rodo, kad EDHF dalyvauja nuo endotelio priklausančioje žmogaus varpos rezistentiškų arterijų relaksacijoje. Parodytas EDHF reguliavimas kalcio dobesilatu.The above results indicate that EDHF is involved in endothelium-dependent relaxation of human penile resistant arteries. The regulation of EDHF by calcium dobesilate is shown.
Šiuose aukščiau aprašytuose in vitro eksperimentuose kalcio dobesilato koncentracija yra koncentracijos plazmoje ribose, pasiekiamose vartojant <500 mg peroralinę dozę. Net ir ši maža kalcio dobesilato dozė duoda padidintus erekcijos atsakus.In these in vitro experiments described above, the concentration of calcium dobesylate is within the plasma concentration range achieved with an oral dose of <500 mg. Even this low dose of calcium dobesilate produces increased erectile responses.
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| JAMES F ET AL.: "Nitric Oxide: A New Paradigm for second Messengers", J MED CHEM., 1995, pages 4343 - 4362, XP001073968, DOI: doi:10.1021/jm00022a001 |
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