WO2007010337A2 - Utilisation d'inhibiteurs de phosphodiesterase type 5 pour la prevention et le traitement de maladies ou de troubles, et systemes d'administration associes - Google Patents

Utilisation d'inhibiteurs de phosphodiesterase type 5 pour la prevention et le traitement de maladies ou de troubles, et systemes d'administration associes Download PDF

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WO2007010337A2
WO2007010337A2 PCT/IB2006/001013 IB2006001013W WO2007010337A2 WO 2007010337 A2 WO2007010337 A2 WO 2007010337A2 IB 2006001013 W IB2006001013 W IB 2006001013W WO 2007010337 A2 WO2007010337 A2 WO 2007010337A2
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use according
inhibitors
inhibitor
medicament
increased
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PCT/IB2006/001013
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German (de)
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WO2007010337A3 (fr
WO2007010337A8 (fr
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Thomas Ley
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Proxomed Medizintechnik Gmbh
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Priority to EP06744566A priority Critical patent/EP1909793A2/fr
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Publication of WO2007010337A3 publication Critical patent/WO2007010337A3/fr
Publication of WO2007010337A8 publication Critical patent/WO2007010337A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to the use of phosphodiesterase (PDE) type 5 inhibitors or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention and / or treatment of diseases or disorders associated with an overgrowth of adipose tissue in the body.
  • diseases or disorders include obesity, hyperlipidemia, hyperlipoproteinemia and Type 2 diabetes mellitus.
  • the invention provides for specific delivery systems for vaginal or subcutaneous administration.
  • Obesity is a condition in which abnormal or excessive fat accumulation in adipose tissue is detrimental to health, and is defined in adults by a body mass index (BMI) above 30 (kg / m 2 ). Obesity is one of the most visible, but until recently mostly neglected public Health problems and is now understood as a chronic health disorder. It is based on a polygenetic predisposition, is associated with a high concomitant and consequential morbidity and requires a long-term treatment and care concept.
  • BMI body mass index
  • BMI Body Mass Index
  • Another problem of overweight is the disease of diabetes mellitus, especially type 2 diabetes. Originally known as non-insulin-dependent diabetes, type 2 diabetes occurred only in the elderly and middle-aged. Recently, the number of people affected has risen sharply in all age groups and more and more young people are diagnosed with diabetes, mainly in overweight and overweight adolescents and children. This applies to both industrialized and developing countries. This increase is cause for concern, because children should not actually be affected and the disease could be prevented by preventive measures such as weight reduction.
  • Beta blockers block, for example, the ß3 receptors that are important for lipolysis and thus contribute to obesity.
  • Hyperlipidaemia means the elevation of serum lipids and is a generic term for hypercholesterolemia (increased serum cholesterol concentration), hypertriglyceridemia (increased serum triglycerides concentration) and hyperlipoproteinemia.
  • Hyperlipoproteinemia is also a lipid metabolism disorder with increased concentration of lipoproteins in the serum and possibly a shift in lipoprotein levels.
  • primary hyperlipoproteinemia can be divided into types IV, with type I, III and V very rare.
  • Type IV (the so-called endogenous hyperlipidemia) is the most common type.
  • the secondary Hyperlipoproteinemia occurs in diabetes mellitus, obesity, pancreatitis or medically caused eg by contraceptives.
  • Object of the present invention is concentrated and user-friendly to reduce or eliminate the obesity in adolescents and adults. Further, by reducing body fat and body weight, the present invention is intended to reduce or minimize or prevent obesity and other disorders or disorders associated with increased fat tissue. Furthermore, this invention is intended to prevent or reduce the risk of myocardial infarction and stroke.
  • PDE phosphodiesterase
  • PDE phosphodiesterase
  • type 5 also abbreviated to PDE5 inhibitors in the following
  • PDE5 inhibitors have been used mainly for the treatment of hypertension and erectile dysfunction in all forms.
  • PDE5 inhibitors specific for cyclic guanosine monophosphate are PDE5 inhibitors specific for cyclic guanosine monophosphate (cGMP). These are selective inhibitors of the cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase (cGMP PDE) type 5, which can increase the concentration of cGMP, leading to an anti-vasospastic and vasodilatatorischen efficacy and potentiation the effect of the endothelium-derived relaxation factor (EDRF) and of nitrovasodilators.
  • EDRF endothelium-derived relaxation factor
  • the PDE5 inhibitors or their pharmaceutically acceptable salts as an active ingredient of the medicament are preferably used in combination with a used pharmaceutically acceptable carrier.
  • a carrier any conventional carrier material can be used.
  • the carrier material may be an organic or inorganic inert carrier material suitable, for example, for oral or topical administration.
  • Suitable carriers include, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum and the like.
  • the active ingredients may be administered in any pharmaceutically acceptable and convenient dosage form.
  • the medicament of the invention may be prepared for oral, transmucosal (e.g., buccal or nasal), transdermal and subcutaneous administration.
  • Examples of oral forms are tablets, capsules, pills, powders, granules or solutions, drops, suspensions or emulsions.
  • Examples of transmucosal forms, especially for buccal or nasal administration are tablets, effervescent tablets, sprays, drops or gels, suppositories are suitable for rectal administration.
  • transdermal forms e.g. Creams, ointments, pastes, lotions or liniments.
  • a particular aspect of the invention is to provide a subcutaneous and / or a vaginal therapeutic system for the use of PDE5 inhibitors or their pharmaceutically acceptable salts, avoiding the disadvantages not only of the oral dosage form and for optimal treatment and to prevent obesity and reduce body fat and body weight.
  • PDE5 inhibitors or their pharmaceutically acceptable salts as a solid, liquid, as krem- or gel-like system are absorbed so effectively subcutaneously or via the mucous membranes of the vagina, that a therapeutically effective blood plasma level is achieved without one Irritation of the skin or vaginal membranes. Due to the well-tolerated and complete absorption via the skin or vaginal membranes, the same therapeutic effect as in the other dosage forms, but in a much more appropriate form and much better comfort, especially for a longer period of therapy before.
  • the reduction in the concentration of guanosine tri- or diphosphates GTP or GDP in the mitochondria of hepatocytes of the liver via PDE5 inhibitors is completely ineffective.
  • the desired reduction of GTP and GDP promotes H + permeability of the inner mitochondrial membrane and its thermogenesis, thus favoring lipolysis and fat loss. Due to the mentioned effects, oral administration is not very effective.
  • the liver breaks down 50% of the PDE5 inhibitor drug without any effect, and on the other hand, the hepatocytes do not support the increase of H-permeability by PDE5 inhibitors.
  • the mechanism of the proton electrochemical gradient (delta p) of the mitochondrial membrane is described, for example, in Brand MD et al., 1994.
  • Mitochondria play the most important role in lipolysis and dither-free thermogenesis: they are cell organelles that release the chemical energy contained in glucose or fatty acids as redox energy and regenerate adenosine triphosphate (oxidative phosphorylation) or Use heat generation.
  • Particularly preferred application systems for vaginal and subcutaneous administration are, for example, delivery systems which have a ring, ellipse, multiple ring or multiple ellipse shape or are in the form of an, for example, pin or cylindrical implant.
  • delivery systems which have a ring, ellipse, multiple ring or multiple ellipse shape or are in the form of an, for example, pin or cylindrical implant.
  • the vaginal administration system for example, the European patent EP 0 876 81 5 B1.
  • Such application systems as well as pin-shaped implants are already used for contraceptives, but are also particularly suitable for the present invention.
  • active ingredient of the present invention are preferably the known PDE5 inhibitors Sildenafil, Tadalafil and Vardenafil or their pharmaceutically acceptable salts such. their citrates, halides, hydrochlorides, phosphates, sulfates, acetates, maleates, succinates, ascorbates, carbonates or the like. Particularly preferred are the citrates.
  • the pharmaceutically active preparations may contain other pharmaceutically active agents or agents.
  • the active ingredient e.g. a PDE5 inhibitor
  • CYP cytochrome P450
  • the concentration in the blood plasma is greatly increased and the degradation or excretion delayed.
  • L-arginine and specific and unspecific lipase enzyme inhibitors and also aggregation inhibitors may be mentioned.
  • a particularly preferred lipase enzyme inhibitor is orlistat (a tetrahydrolipstatin capable of inhibiting lipases for a long time).
  • Preferred examples of aggregation inhibitors are acetylsalicylic acid or ticlopidine.
  • a contraceptive can be used as additional active ingredient.
  • the combination of a PDE5 inhibitor with a contraceptive is therefore particularly advantageous since contraceptives can be known to lead both to secondary hyperlipoproteinemia and to obesity.
  • Particularly preferred in this context is an application system in the form of a vaginal ring which comprises both a PDE5 inhibitor and a contraceptive.
  • NO is formed on a synthetic route from L-arginine. Therefore, it is advantageous to use L-arginine as an additional active ingredient, since any nitrogen source bottlenecks are thereby avoided. NO is again used for cGMP synthesis. Finally, cGMP relaxes the smooth muscle and supports lipolysis as a result of the mechanisms mentioned here.
  • the combination of PDE5 inhibitor and L-arginine is therefore particularly advantageous and can potentiate cGMP genesis.
  • Orlistat causes no lipolysis and thus no fat loss, but reduces the absorption of fat by about 30%. Therefore, a combination of, in particular, PDE5 inhibitors and orlistat is particularly suitable for the treatment of obesity and for the reduction of body weight.
  • Obesity e.g. Obesity, type 2 diabetes mellitus, hyperlipidemia and hyperlipoproteinemia. All diseases can be treated in all mammals, including humans.
  • the invention enables effective prevention of coronary heart disease, myocardial infarction and / or stroke, which are well known as consequent risks of obesity.
  • additives such as absorption enhancers, solubilizers, antioxidants, preservatives, stabilizers, humectants, gelling agents, emulsifiers, lubricants, flavoring and flavoring agents, buffers, and the like can be added to the medicaments in accordance with generally accepted pharmaceutical manufacturing practices.
  • absorption enhancers can be mono- and / or polyhydric aliphatic, cycloaliphatic and / or aromatic-aliphatic alcohols each having up to eight carbon atoms, for example: ethanol, 1, 2-propanediol, dexpanthenol and / or Polyethylene glycol; Alcohol / water mixtures; saturated and / or unsaturated fatty alcohols each having 8-1 8 carbon atoms; Natriumdeoxychlorat; sodium caprylate; sodium caproate; sodium lauryl sulfate; Poloyxylen-9-lauryl ether; Sodium taurocholate, glucuronic acid, succinic acid, tartaric acid and sodium salicylate.
  • solubilizer for example, glycol, ethanol, isopropanol, propylene glycol, polyethylene glycol, transcutol, medium-chain glycerides, surfactants, cyclodextrin and labrosol can be used.
  • antioxidants e.g. Sodium metabisulfate, sodium bisulfate and tocopherol can be added in small amounts for drug stabilization.
  • glycerol, sorbitol, dextran and mannitol may be added as humectants to prevent mucosal irritation.
  • a lubricant e.g. Methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, carbopol, gelatin, agar-agar, alginate, tragacanth, xanthan and polyvinyl alcohol.
  • flavor oils and flavorings may be added, e.g. Cyclamate, saccharin, aspartame, peppermint oil and fennel oil.
  • the pH is preferably between 3 and 8, in particular between 4.5 and 6.5.
  • the osmotic pressure of a solution containing the active ingredient is preferably between 150 and 850 milliosmoles (mOsm), more preferably between 200-40 mOsm.
  • a transmucosal therapeutic system for buccal administration may more preferably be in the form of sprays (solution and suspension), lozenges, pastilles and chewing gums.
  • the same ingredients are usually used as in a nasal spray, preservatives is largely dispensed with and the pH or the presence of an isotonic solution is not so relevant.
  • preservatives is largely dispensed with and the pH or the presence of an isotonic solution is not so relevant.
  • the addition of flavor enhancers and aroma oils or flavorings is the rule.
  • the remaining buccal dosage forms contain predominantly the additives customary in the prior art.
  • transmucosal therapeutic system used for rectal administration may be in the form of suppositories, in particular the prior art additives.
  • the transmucosal system preferably has an active ingredient content of between 5-40 mg drug / dose.
  • active ingredients that are not administered by the oral route and are not metabolized by the liver, in an amount up to max. 0.25 mg / kg body weight should be administered. Higher amounts would lower the peripheral vascular resistance too much and cause circulatory collapse.
  • liver metabolizes approx. 50% of the active ingredient, when administered via the oral route approx. Twice, ie max. about 0.5 mg / kg administered.
  • the preferred amount for an adult is generally about a daily maximum oral dose of about 20 mg.
  • body fat depends on body weight, physical activity, sex, basal metabolism and the amount of dose administered per time, so that treatment of overweight persons can take from days to weeks.
  • administration of the preparation during treatment over a prolonged period of days to weeks requires more rigorous discipline of dose compliance and regular intake, taking into account consistent and safe bioavailability of the drug to minimize side effects and cost, with concomitant outcome effectiveness.
  • Fig. 1 shows the relative change of the glucose level and the heart-time volume
  • FIG. 2 shows the relative change in the functional capillary density (FCD) in FIG. 1
  • Fig. 3 shows the relative change of the erythrocyte velocity in
  • FCD metabolically active alveolar capillaries
  • FCD metabolically active capillary capillaries
  • Fig. 8 shows the velocity distribution of the erythrocytes in the vascular bed of the metabolically active peripheral capillaries after 30 minutes with and without PDE5 inhibitor, based on the diameter of the vessels.
  • insulin One of the most important biological effects of insulin is the rapid acceleration of glucose uptake in muscle and fat cells. Insulin also induces glycogen synthesis and storage in liver and muscle, triglyceride synthesis in liver and adipose tissue, and the storage of amino acids in muscle. At the same time, insulin inhibits hepatic gluconeogenesis and is therefore one of the most important regulators of glucose metabolism. Another key function of the peptide hormone insulin is the regulation of cell growth and proliferation by activating the transcription of genes. In summary, insulin promotes the transport of glucose to all cells, in the fat cells it activates enzymes needed to convert glucose into fat, inhibits the breakdown of fat, and has a growth-promoting effect.
  • the feeling of hunger arises when insulin has lowered the level of sugar after ingestion.
  • the sugar level due to the increased lipolysis is maintained at a level where the feeling of hunger is not unpleasant by maintaining the blood plasma glucose concentration by degrading the adipocytes.
  • Fig.1 glucose level regeneration.
  • a chain of surprising microhemodynamic and analogous metabolic mechanisms is responsible for the phenomenon.
  • One of the surprising effects is the increase in microhemodynamics in additively recruited capillaries ( Figures 2, 5), which results in a cascade of more extensive and surprising effects.
  • the PDE-5 inhibitor significantly relaxes the fibril bundles of precapillary sphincters ( Figures 2 and 5), which differ markedly from smooth muscle histologically, and, secondly, this phenomenon necessarily results in a significantly higher capillary volume of the expanded perfused tissue mass multiplies the metabolic surface and thereby forces an increased glucose supply of the erythrocytes.
  • the required energy or glucose is finally provided via the oxidation of free fatty acids via lipolysis, as can be seen in Fig. 1 after 20 minutes without administration of substitutions in vivo.
  • the prior art has three types of capillaries. These are subdivided into so-called arteriovenous anastomoses, maternal arterioles and true capillaries (diameter 4-8 ⁇ m), whereby the arteriovenous anastomoses can in turn be divided into three other types of capillaries, depending on the morphology.
  • the present invention activates the precapillary sphincter of true capillaries that are involved in the metabolism, but also the other capillaries. At rest, the true capillaries are inactive. By increasing the CO (FIG. 1) alone, a significantly higher recruitment of the true capillaries is not achieved, since the arteriovenous anastomoses, which usually run parallel, serve as a short circuit.
  • the second messenger cyclic guanosine 3 ', 5'-monophosphate is responsible for their relaxation in smooth muscle cells.
  • cGMP The second messenger cyclic guanosine 3 ', 5'-monophosphate
  • a PDE5 inhibitor lowers the concentration of GTP, otherwise there would be an imbalance between GTP and cGMP.
  • the acute energy consumption in the form of ATP consumption is significant within the first minutes in FIG.
  • the phosphodiesterase type 5 causes the degradation of the cGMP. If a phosphodiesterase type 5 (PDE5) inhibitor is added to the process, the degradation of cGMP is slowed because the synthesis of phosphodiesterase type 5 is inhibited and vasodilation is assisted by ATP consumption.
  • cAMP PDE cyclic adenosine 3 ', 5'-monophosphate phosphodiesterase
  • the effect of the present invention is based essentially on the increase of the cGMP (not the cAMP as in WO 01/35979 by PDE3 and PDE4 inhibitors) to the detriment of the GTP or GDP concentration, which is deliberately lowered.
  • PDE3 and PDE4 inhibitors are certainly a potential component of adipose cell lipolysis, they are a very ineffective in vivo as also disclosed by Enoksson et al., Diabetologia (1 998) 41: 560-568. It is well known that the adipose tissue is inhomogeneously distributed, especially as a result of differentiated and insufficient vascular supply. Adipose tissue is therefore often located where there is a reduced vascular and circulatory situation. The most important component in the removal of fatty tissue is not the fact of lipolysis alone, but the amount of Fat mass, which is stimulated to thermogenesis and achieved, ie, the effectiveness of lipolysis / fat mass.
  • WO 01/35979 does not show how or how effectively the already insufficiently perfused adipose tissue should be achieved (eg with oxygen or norepinephrine) in order finally to develop the O2 supply, PDE3 and PDE4 inhibition and norepinephrine action at the adipose site , PDE5 inhibitors represent the optimal vascular dilator of the peripheral bloodstream pathway, in particular the flow pathway, which is significantly involved in the metabolism and thermogenesis, ie in particular the additively recruited capillaries (FIGS. 2, 5).
  • the mechanism of capillary recruitment by the relaxation of the fibril bundles of precapillary sphincters has already been described in this invention and is significantly seen in Figs.
  • PDE5 inhibitors recruit the metabolically important and active capillaries that carry the active fat burning or thermogenesis at all or except for the generated and described CO increase.
  • thermogenesis is the O2 analogue of pCh saturation (Example 1).
  • the pulmonary capillary recruitment shown here in FIG. 2 additionally produces an improved lung perfusion and thereby an increased oxygen uptake into the circulation, which is absolutely necessary for the thermogenesis by the oxidation of the fatty acids in the mitochondria.
  • lipolysis is one of the factors of fat loss and reduction of obesity, it is not the only one, as shown in the publication by P. Schonfeld, The Zither-Free Thermogenesis, (2002) Chemistry in Our Time, 36th ed., No. 1 becomes. A chain of additional parameters is needed for optimal thermogenesis.
  • thermogenesis is free fatty acids, which activate the H - permeability of the inner mitochondrial membrane.
  • Thermogenin, a decoupling protein UCP1 (uncoupling proteins - UCPs), as well as UCP2 and UCP3 are potent H-transponders that are activated by fatty acids and inhibited by purine nucleotides such as GDP or GTP.
  • PDE5 inhibitors lower the concentration of GDP and thus increase the H transportability and consequently the thermogenesis, which ultimately convert the fat to heat under oxygen consumption.
  • the effect of GDP on UCP2 is not effective in hepatocytes of the liver, so oral PDE5 inhibitor applications are not particularly effective.
  • the transvaginal, transcutaneous or rectal route is preferred. PDE5 inhibitor therefore accompanies a completely different mechanism, which has a much improved effectiveness of the effect.
  • the recruitment of metabolically active capillaries is a much more important factor.
  • it activates and allows for increased perfusion or perfusion of the adipose tissue and its supply of oxygen, as well as the active agent itself and on the other hand it causes additional expression of norepinephrine due to Köpertemperatursenkung (Example 1), which in turn arises from the spontaneously increased perfusion volume via capillary recruitment (Example 1 and Example 2).
  • People experience the application of PDE5 inhibitors in 2 phases. First, by hot flashes caused by the increased lipolysis due to thermogenesis, then by a cold wave via cold receptors by the increased perfused body volume.
  • the cold is reported to the hyopthalamus, which in turn activates norepinephrine through the sympathetic nervous system.
  • the free fatty acids already described activate the H-permeability of the inner mitochondrial membrane via the ß3-adreno-zeptors of the hypo- cytes, increase the thermogenesis under oxygen consumption and counteract the cooling.
  • the sympathetic nervous system response to lipolysis is disclosed by Dulloo AG, Samec S. in "Uncoupling Proteins: Do They Have a Role in Body Weight Regulation?", News Physiol., 2000; 1, 5, 31, 3-318.
  • PDE5 inhibitors show extremely effective recruitment of metabolically active capillaries or their controlling relaxation of the fibril bundles of precapillary sphincters.
  • the PDE5 inhibitors simultaneously relax the fibril bundles of alveolar precapillary sphincters, which enforce increased lung perfusion and cause increased circulation of oxygen in the bloodstream.
  • the increase in O2 saturation in turn optimizes the oxidation of fatty acids in the mitochondria and was measured in Example 1 with an osmotic oxygen pressure increase from 268 mmHg to 353 mmH.
  • the cGMP supports the dilatation of the afferent vessels containing the smooth muscle, thus supporting the supply of the spontaneously recruited capillaries, and is therefore only secondarily involved in the lipolysis process in vivo.
  • the thereby simultaneously increased HZV supplies the main vessels with the necessary and increased volume, whereby it consumes at the same time increased energy.
  • PDE5 inhibitors are the most effective smooth muscle dilators, for example in M. Humbert et al., (2004) Treatment of Pulmonary Arterial Hypertension New England J. Med. 351; 14 or WR Clarke (2004).
  • the measured glucose level drop ( Figure 1) indicates an acute glucose consumption of the myocardium and smooth muscle. A regeneration process is now triggered.
  • FCD functional capillary density
  • phosphodiesterase type 5 inhibitors or their pharmaceutically acceptable salts in the treatment and prevention of obesity and lowering of body weight and body or tissue fats, wherein the tissue both the internal organs, vessels, all skin layers as well as any musculoskeletal and tissue type in humans and mammals, can be effective and useful.
  • Both groups were intubated under anesthesia and thoracotomized.
  • the lung surface was examined microscopically in vivo at regular time intervals under respiratory controlled conditions. At the same time, the microcirculation of the lung surface was recorded, as was hemodynamics. The respiratory ventilation parameters were kept constant throughout the course.
  • the experimental group was each administered 0, 16 mg / kg tadalafil (PDE5 inhibitor) in the pulmonary circulation. This was followed by a continuous follow-up of 35 minutes. Before and after the application of the PDE5 inhibitor, a blood analysis was additionally carried out at regular time intervals. Results:
  • the positive end-expiratory pressure was fixed at 3 mmHg, the respiratory rate at 1 2 paces / min, and the minute ventilation at 5, 1 L / min.
  • the heart rate remained statistically unchanged, however, the increase in cardiac output was significant after about 5-1 5 minutes, Fig.1.
  • the arterial partial oxygen pressure p ⁇ 2 increased from 268 mmHg to 353 mmH after 6 minutes (p ⁇ 0.05).
  • the erythrocyte velocity increased 5 minutes after administration of tadalafil from 263 ⁇ 56 [// m / s] to 313 + 62 U / m / s] (p ⁇ 0.001) in the vascular interval 4-17 ⁇ m in diameter.
  • the control group showed no microcirculatory and hemodynamic changes over the entire experimental course and no statistically significant changes in the parameters in the analogous course of the period under identical experimental conditions.
  • the cGMP level in the blood falls, the forerunner of which is the decreasing functional capillary density (FCD) in FIG. 2, followed by the declining CO and the decreasing blood velocity in FIG. 3.
  • FCD functional capillary density
  • a second experiment demonstrates the effect of vardenafil as a PDE5 inhibitor in the peripheral capillaries.
  • the capillary recruitment with a single dose of 0.33 mg / kg vardenafil increased on average from 28 ⁇ m / ⁇ m 2 to 61 ⁇ m / ⁇ m 2 [length of the functional or perfused peripheral capillaries per observed tissue surface] 30 minutes after oral administration.
  • a capillary density recruitment factor averaged 2.1.
  • the observation or measurement of the capillary parameters was performed microscopically sublingually and non-invasively.
  • the mere ingestion of PDE5 inhibitors increases the HZV due to the resistance minimization peripheral pathway.
  • the increase in end-diastolic filling volume is used to increase the work to be done by the heart as well as the heart-time volume (CO) and to increase energy expenditure.
  • the energy-producing process results from ATP (adenosine triphosphate) regeneration from adenosine monophosphate (AMP) + 2 phosphate (P) or adenosine diphosphate (ADP) + 1 phosphate (P).
  • ATP adenosine triphosphate
  • P adenosine monophosphate
  • ADP adenosine diphosphate
  • P adenosine diphosphate
  • FIG. 8 The oxygen supply and the oxygen transport to the adipose body regions take over the erythrocytes with increased speed (FIG. 8), in order to ensure the energy recovery or ATP regeneration there.
  • Figure 7 shows the increase in recruitment of metabolically active capillaries in the 4-8 range microns.
  • the peripheral capillaries were recorded microscopically in humans sublingually and statistically evaluated.
  • the evaluation of 2048 capillaries is shown in FIG. 7 before and after taking vardenafil, a PDE5 inhibitor.
  • metabolically active capillaries are located in the interval 4-8 microns. Recruitment depends on physical condition, age, nicotine consumption, vascular status, and gender of the patient.
  • Hot flushes occur as a result of increased lipolysis. Additional capillaries of the peripheral and pulmonary flow path are recruited or activated (FIG. 7, recruitment of peripheral capillaries after administration of PDE5 inhibitors, recorded microscopically sublingually in humans). The metabolism is accelerated and extended to the adipose tissue. More fat mass is achieved and supplied by additive capillary recruitment, with ATP regeneration or oxidative phosphorylation requiring more oxygen for thermogenesis. It is also surprising in example 2 that the oxygen transport is transported faster (from the pulmonary) into the pheripheral tissue by the increased speed of the oxygen-carrying erythrocytes.
  • the relaxation of the fibril bundles of precapillary sphincters via PDE5 inhibitors promotes capillary recruitment in obese areas and accelerates the transport of, on the one hand, oxygen and, on the other hand, catecholamines (norepinephrine as the most important factor in lipolysis), ie more tissue or fat mass Achieved relaxation of the fibril bundles of precapillary sphincters and "forced" to thermogenesis, causing temperature increases (hot flashes) occur.
  • PDE5 inhibitors increase the concentration of cGMP and decrease the concentration of GTP. This leads to activation of the UCP class and thus to thermogenesis via the transmembrane H + line and therefore also to energy consumption.
  • norepinephrine favors the splitting of fats into glycerol and fatty acid residues.
  • This fatty acid residue is the activator of the UCP by the displacement of the GTP or GDP at the UCP. This step actively contributes to fat reduction by taking PDE5 inhibitors.
  • the activated UCP associate again with GTP and deactivate it.
  • the norepinephrine shake results from the relaxant effect of the PDE5 inhibitors on the precapillary sphincters, or by regular physical exertion.
  • People experience the application of PDE5 inhibitors in the described 2 phase as a cold wave via cold receptors by the increased perfused body volume.
  • the cold is reported to the hyopthalamus, which in turn activates norepinephrine through the sympathetic nervous system.
  • the already described free fatty acids activate the H + conduction and consequently the thermogenesis, which counteracts the cold wave or the cold stimulus.

Abstract

L'invention concerne l'utilisation d'inhibiteurs de phosphodiestérase (PDE) type 5 ou de leurs sels pharmaceutiquement compatibles, pour la production d'un médicament destiné à la prévention et/ou au traitement de maladies ou de troubles qui sont liés avec une multiplication excessive du tissu adipeux dans le corps humain. L'invention concerne en particulier l'utilisation d'inhibiteurs de phosphodiestérase type 5 pour la prévention et le traitement de l'adiposité. L'invention concerne en outre des systèmes d'administration particuliers, convenant pour l'administration vaginale et sous-cutanée d'inhibiteurs PDE5.
PCT/IB2006/001013 2005-07-15 2006-04-25 Utilisation d'inhibiteurs de phosphodiesterase type 5 pour la prevention et le traitement de maladies ou de troubles, et systemes d'administration associes WO2007010337A2 (fr)

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WO2009099807A2 (fr) * 2008-02-01 2009-08-13 Medtronic Vascular Inc. Utilisation de la phosphodiestèrase en tant que composant de dispositifs médicaux implantables
WO2013057205A1 (fr) 2011-10-20 2013-04-25 Technische Universitaet Wien Dérivés de diazabicycloalcane et de diazaspiroalcane comme inhibiteurs de la phosphodiestérase-5
US20150359798A1 (en) * 2011-09-06 2015-12-17 Jansfat Biotechnology Co., Ltd. Piperazinyl derivative reduces high-fat diet-induced accumulation of fat in the livers, therapeutically
WO2021237322A1 (fr) * 2020-05-29 2021-12-02 Luiz Peracchi Edson Implant sous-cutané réabsorbable de longue durée à libération prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de la dysfonction érectile et de l'hyperplasie bénigne de la prostate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009099807A2 (fr) * 2008-02-01 2009-08-13 Medtronic Vascular Inc. Utilisation de la phosphodiestèrase en tant que composant de dispositifs médicaux implantables
WO2009099807A3 (fr) * 2008-02-01 2010-11-04 Medtronic Vascular Inc. Utilisation de la phosphodiestèrase en tant que composant de dispositifs médicaux implantables
US20150359798A1 (en) * 2011-09-06 2015-12-17 Jansfat Biotechnology Co., Ltd. Piperazinyl derivative reduces high-fat diet-induced accumulation of fat in the livers, therapeutically
WO2013057205A1 (fr) 2011-10-20 2013-04-25 Technische Universitaet Wien Dérivés de diazabicycloalcane et de diazaspiroalcane comme inhibiteurs de la phosphodiestérase-5
WO2021237322A1 (fr) * 2020-05-29 2021-12-02 Luiz Peracchi Edson Implant sous-cutané réabsorbable de longue durée à libération prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de la dysfonction érectile et de l'hyperplasie bénigne de la prostate
EP4159206A4 (fr) * 2020-05-29 2024-04-24 Peracchi Edson Luiz Implant sous-cutané réabsorbable de longue durée à libération ?prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de la dysfonction érectile et de l'hyperplasie bénigne de la prostate

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