PDE 5-inhibitor for therapeutic use in diseases or disease conditions, which are characterized by disorders of the metabolism or of the blood circulation associated with the liver, selected from detoxification disorders, reduced or defective decomposition of medicaments and wrong decomposition of substances. PDE 5-inhibitor for use in a treatment for increasing portal blood flow in healthy liver, which is endangered by an exogenously added toxic substance that is metabolised in the liver, wherein the metabolic decomposition in the liver is click at this page. PDE 5-inhibitor for use according to claim 2, wherein the selected substance is ethyl alcohol.
PDE 5-inhibitor for use according to any of the preceding claims, wherein the medicament or the toxic substance is taken before or simultaneously with the administration of the PDE 5-inhibitor or the pharmaceutical composition comprising a PDE 5-inhibitor.
PDE 5-inhibitor for use according to any of the preceding claims, wherein the PDE 5-inhibitor is selected from the group consisting of sildenafil, tadalafil and vardenafil. The invention relates to novel therapeutic uses of PDE 5 Inhibitorl. The portal hypertension portal hypertension, ie, the high pressure in the portal veinamong others dreaded cause of bleeding from the upper gastrointestinal tract. The most common is bleeding from "oesophageal varices", ie varicose veins that develop in the esophagus because the flow of blood http://katinka-oriental.de/trophischen-geschwueren-wie-zur-behandlung-von-diabetes.php impeded by the liver and the blood seeks a "detour circulation".
Eine weitere problematische Komplikation der portalen Hypertonie sind Blutungen aus Fundusvarizen. Another problematic complication of portal hypertension are bleeding from fundal varices.
In addition, other severe or life-threatening complications of portal hypertension are known hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, ascites, spontaneous bacterial peritonitis, metabolic disorders due to reduced hepatic blood flow.
Cormack und PA Mc. Cormick, Drugs Gastroenterol Hepatol Gerade am Beispiel von Nitraten zeigt sich aber das Dilemma von Wirkstoffen, die generell vasodilatorisch wirken, wie dies aus G.
By gestörter Blutfluss in den IPC the example of nitrates, but shows the dilemma of drugs acting general vasodilator, as apparent from G. Current Opinion in Gastroenterology,19, S. This, however, which is already affected, the whole portal blood flow to the liver is even worse. Daher wurde bereits seit vielen Jahren nach Substanzen gesucht, die mehr oder weniger selektiv den Pfortaderdruck senken.
Therefore, it was gestörter Blutfluss in den IPC wanted for many years for substances that reduce the more or less selective portal vein. In particular, it is desirable to be able to apply a therapy, through which the portal blood flow of the liver may be increased without changing the arterial perfusion of the liver critical.
It comes to the problems of drug therapy should still that portal hypertension is a disease appearance with very complex and diverse etiology and is not to be equated with the pathologically defined state cirrhosis.
Different from liver cirrhosis as such may be a consequence of portal hypertension of cirrhosis, but also completely different reasons, as indicated in the following table: As chronic myeloid leukemia, myelofibrosis Lymphatische Systemerkrankungen Lymphatic system disorders Kollagenosen z. As systemic lupus erythematosus, scleroderma Kongenitale Leberfibrose Congenital hepatic fibrosis Leberfibrosen anderer Ursache Liver fibrosis from other causes M.
Rechtsherzinsuffizienz Right heart failure Trikuspidalinsuffizienz Tricuspid regurgitation Pericarditis constrictiva Constrictive pericarditis Budd-Chiari-Syndrom Thrombosen Varizen und seine Ursachen Lebervenen Budd-Chiari syndrome thrombosis of the hepatic veins Fehlbildungen der Lebervenen Abnormalities of the hepatic veins Kompression der Lebervenen z.
Die bisherigen Prophylaxe- und Therapiekonzepte gegen die portale Hypertonie weisen gestörter Blutfluss in den IPC ausreichende Erfolgsrate auf. The previous prophylactic and therapeutic approaches against portal hypertension do not have sufficient success rate. Weder die Blutungskomplikationen noch die zahlreichen anderen Krankheiten bzw. Neither the bleeding complications nor the gestörter Blutfluss in den IPC other diseases or medical complications of portal hypertension gestörter Blutfluss in den IPC be satisfactorily treated or prevented hitherto.
Komplikationen zu gestörter Blutfluss in den IPC und zu verbessern. Another object of the invention is to affect the metabolism of a substance via the liver. According to the invention, a PDE 5-inhibitor for use according to claim 1 and 2 is provided. Preferred embodiments of the present articles are defined in the gestörter Blutfluss in den IPC claims. As a basis for this new approach and improved treatment options has surprisingly been found that inhibitors of phosphodiesterase 5 are able to reduce portal pressure gestörter Blutfluss in den IPC to increase the portal vein and portal vein flow to increase significantly.
Inhibitors that are specific with respect to the phosphodiesterase type gestörter Blutfluss in den IPC PDE-5 in humans currently are 11 known types of phosphodiesteraseare known click to see more se, however, investigated for other indications than those of the present invention and in different contexts.
The best known indication field is the male erectile dysfunction MED, impotence see Fig. Gresser und CHGleiter in Eur. For a review on these and other PDE 5 inhibitors for this purpose U. Gresser and CH Gleiter in Eur. Quinazolines with cGMP phosphodiesterase-inhibiting activity are, for example, in J.
Med Chem Med Chem, The pharmaceutical formulation is described for the preparation of a medicament which might be possible to treat a number of different diseases allegedly: HA Ghofrani et al.
Ghofrani HA et al. Pulmonology 56, describe Sildenafil for treatment of pulmonary hypertension and possibly also the beginnings of heart insufficiency. S in respective abstracts on animal studies to systemic and splanchnic or portal hemodynamic effects of sildenafil in the rat. There are elected Highly artificial conditions by this substance iv or intra-arterially in the superior mesenteric artery at very high doses 0. Die artifiziellen Tierexperimente deuten auf einen unphysiologisch kurzzeitigen, generellen, dh nicht-selektiven vasodilatorischen Effekt von Sildenafil infolge direkter intravasaler Gabe bei der Ratte hin.
The artificial animal experiments suggest a non-physiological short-term and general, ie non-selective vasodilatory effect of sildenafil due to direct intravascular administration in the rat. Contrary to the animal experiments of Garcia et al. According to the invention were qualitatively and quantitatively obtain other effects in humans. Das sind in erster Linie solche Krankheiten bzw. These are primarily such diseases or disease states characterized by disturbances of metabolism or blood circulation in connection with the liver, eg detoxification disorders, decreased or impaired drug metabolism, wrong substance breakdown, build a detour circulation around the liver, immune deficiency, congestion of blood in the spleen and subsequent diseases such as gestörter Blutfluss in den IPC, thrombocytopenia, disturbance of the synthesis of coagulation factors, disorders of brain function and the like.
If a substance is metabolized in the liver, which is especially for the mentioned exogenously added substances and typically also with other endogenous or exogenous substance types is the case, gestörter Blutfluss in den IPC metabolism by increasing blood flow to the liver, which from the increased flow portal vein without pressure increase of the portal vein itself result, be influenced.
The metabolic degradation of endogenous or exogenous substance in the liver can be enhanced. Entsprechend diesem Konzept wird eine Kombinations-Medikation bzw.
According to this concept, a combination medication or -preparation for influencing the metabolism of a substance is provided, wherein, in a joint or separate application form, the following is combined: Also in this aspect of the invention, the influence of the metabolism of the substance involves an increase in portal flow and thereby advantageously an increase in hepatic blood flow.
When combined with an exogenously gestörter Blutfluss in den IPC substance, it can simultaneously with, after, or particularly before the administration gestörter Blutfluss in den IPC the PDE 5 inhibitor, or a PDE 5 inhibitor-containing pharmaceutical composition to be taken.
Especially in the ascites is a combination of a PDE 5 inhibitor with any diuretic, eg, furosemide for example, a loop diuretic or spironolactone an aldosterone antagonistparticularly suited to enhance the prophylactic or curative effect.
JP Tasu et gestörter Blutfluss in den IPC. The measurements of portal vein, portal vein and portal vein flow can be performed using known methods, eg non-invasively by Doppler sonographic measurements see eg A. Tasu JP et al. Sildenafil INN Gel und Salbe gegen Krampfadern, dh As PDE 5 inhibitors known per se from the above-mentioned documents PDE 5 inhibitors and the particular selectivity for PDE 5 against other phosphodiesterases, the following compounds suitable for use in the invention: Gresser und CHGleiter oben.
Gresser and CH Gleiter above. These also include the modified and analogous forms of these substances which are known to the skilled man and which inhibition of PDE 5 is also attributed. Important for the surprising success of the PDE 5 inhibitors as the active ingredient specifically to the indications described above is likely the observed in the context of the invention, surprisingly differentiated selectivity of action on the relevant case of portal hypertension vessels in humans be: While the vascular wie für essen of the arterial the liver vessels supplying remains unchanged or even increases and correspondingly the arterial hepatic blood flow remains the same or decreasesthe portal inflow significantly increases.
Specifically, since the physiological arterial and portal gestörter Blutfluss in den IPC blood flow are complementary - ie that the arterial blood flow decreases when the portal blood flow increases, and vice versa - is believed that due to this complementarity the selective effect on the final destination at the surprising effectiveness.
Because the effects supplement each other, a combination may be done by using, in a common or in separate formulations combination therapythe PDE 5 inhibitor in combination with another drug against portal hypertension according to the invention preferably. In particular, the combined drug can be selected from the group article source vasopressin and its analogs, such as terlipressin and somatostatin and its analogues, such as octreotide, to contribute to a synergistic increase in the arterial vascular resistance and thus the decrease of the arterial blood supply to the intestine and liver see.
The above- explained physiological complementarity of hepatic blood flow. The active ingredient or the composition may comprise a solid, semisolid, gel-like or hydrogel-like, a liquid or a similar consistency and for example the form of a solution, a suspension, a powder, a tablet, a pill, a capsule, a delay release formulation and the like take. The compositions suitably contain an effective therapeutic amount of PDE5 inhibitor together with a suitable amount of a carrier or vehicle to provide the form for proper administration to the patient.
Die Applikationsform kann eine typische Applikationsform sein, zum Beispiel oral, parenteral, insbesondere zur Injektion, ein Transdermalsystem, nasal oder zur Inhalierung. The application form can be a typical gestörter Blutfluss in den IPC form, for example orally, parenterally, in particular for injection, a transdermal, nasal or inhalation.
For application of the PDE5 inhibitor and optionally the mentioned combination drug is suitably specifically included in any of the above compositions, formulations or facilities, in an amount effective for humans for the prophylaxis or treatment of the abovementioned diseases or conditions amount.
For example, a suitable quantity, based gestörter Blutfluss in den IPC the Gel gegen Krampfadern Beinen amount, at least 0. As the dose gestörter Blutfluss in den IPC an amount of the active ingredient of at least 0. It has been shown that the effects of PDE5 inhibitor, depending on the route of administration and dosage may vary.
Surprisingly, a particularly selective action of the PDE5 inhibitor on the portal hypertension was observed when the PDE 5 inhibitor or the PDE 5 inhibitor-containing one pharmaceutical composition is administered orally, and in particular where the dose is low to moderate, for example, each administered at a dose of the PDE 5 inhibitor from 0. By comparison, a reached after such oral administration peak serum concentration of the PDE continue reading inhibitor is significantly below the serum concentration of this PDE 5 inhibitor, by an injection or infusion iv, ia or im of the PDE5 inhibitor at a concentration of 0.
It can be assumed that the most effective action of the PDE5 inhibitor for oral administration of the dosage described in a "first-pass" effect is based by the liver.
If nevertheless an injection is considered as administration form, the dose concentration should preferably be selected according to low, eg click at this page. Accordingly, in general, the dose per administration advantageously lies in a region in which a selective effect on the target vessels determinable by eg gestörter Blutfluss in den IPC in portal blood flow and a concurrently maintained or increased resistivity defined as Resistivity Index Ri is reliably ensured, eg less than 15 more preferably less than 1.
Regardless of the form of application therefore PDE 5 come suitable pharmaceutically acceptable carriers, gestörter Blutfluss in den IPC, excipients, etc. Die Herstellung eines Medikaments bzw. The specific activity of PDE 5 inhibitors for the indications listed above, special is as follows: In a pilot study, partially a significant increase in gestörter Blutfluss in den IPC diameter of the portal vein and the splenic vein was found.
The maximum flow rate of blood in the portal vein and splenic vein in the decreased only slightly. The resistance of the arterial blood supply to the liver showed almost no change, or it even increased. Due to the rapid physiologic response and the generation of the effect "reduction in portal pressure" instantly or directly after administration of PDE 5 inhibitors also a therapy of acute bleeding complications is possible.
This disease represents a deterioration of renal function with a regulatory disorder, although the kidney itself is intact. The conventional therapy, namely volume administration, administration of albumin or of terlipressin is not satisfactory. According to the invention 5 inhibitors, the blood flow is enhanced by the liver through the use of PDE, so that it is expected that blood from the portal vein supplied to the systemic circulation, and thus an improvement of the hepato-renal gestörter Blutfluss in den IPC is expected.
This disease is associated with portal hypertension and arterial oxygen desaturation.