CN1205634A - Use of PDE inhibitors in manufacture of medicament for treatment of bladder diseases - Google Patents
Use of PDE inhibitors in manufacture of medicament for treatment of bladder diseases Download PDFInfo
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- CN1205634A CN1205634A CN 96197169 CN96197169A CN1205634A CN 1205634 A CN1205634 A CN 1205634A CN 96197169 CN96197169 CN 96197169 CN 96197169 A CN96197169 A CN 96197169A CN 1205634 A CN1205634 A CN 1205634A
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Abstract
The present invention pertains to the use of inhibitors of phosphodiesterase I for the treatment of urinary bladder diseases, in particular the use of vincamine, vinpocetine (ethyl apovincamin-22-oate), and/or modified compounds of the said inhibitors having inhibiting properties for PDE I, as well as pharmacologically compatible salts thereof, in local and systemic administration.
Description
The present invention relates to utilize Phosphodiesterase I (PDE I) inhibitor to treat bladder disease.
The influence that the physiology transmission of the loose information of smooth muscle cell is subjected to blood (hormone) or neural (neurotransmitter) to transmit matter (courier).These couriers or neurotransmitter cause cyclic nucleotide in the smooth muscle cell " cyclic adenosine monophosphate " (cAMP) and " cyclic guanosine monophosphate " (cGMP) content increase, thereby cause loose.CAMP and cGMP itself is by phosphodiesterase (PDEs) hydrolysis.The PDEs inhibitor reduces the hydrolysis of cAMP and cGMP conversely again, thereby these molecules in the cell are increased and so loose smooth muscle cell.For example, the mechanism of this effect is by C.D.Nicholson, R.A.Challiss and M.Shadid:Pulm.Pharmacol.7 (1) (1994), 1-17, with T.J.Torphy etc.: J.Pharmacol.Exp.Ther.265 (3) (1993), 1213-23 described.
From these publications and W.J.Thompson:Pharmacol.Ther.51 (1991), 13-33 and J.Beavo exist: J.Beavo and M.D.Housley (eds.): cyclic nucleotide phosphodiesterase: structure, adjust and drug effect, Chichester, New YorkBrisbaneToronto-Singapore, Wiley, among the 1990:3-15, further know, the characteristic of many PDEs isozymes can be used for distinguishing different PDEs (I-V), and described PDEs is different and according to its different different activity that have that distribute in the distribution of each organ and tract.In above-mentioned publication, also discussed in each tissue, different isozymes have a situation.
The important target site that utilizes PDE isozyme selective depressant is the urethra than the lower end, because with conventional substances by method of pharmacy treatment bladder function obstacle usually seldom effectively and be subjected to side effects limit.Therefore, by the important PDE isozyme of inhibition on function, thereby the targeting that produces bladder muscle obviously is superior to the pharmacological treatment method of having set up.
The present invention is surprised to find that in medication preparation, phosphodiesterase can be used for treating bladder disease.In claim 1-4, relate to the preferred embodiment that the present invention uses.Claim 5 relates to the method for the treatment of bladder disease by the PDE I inhibitor of the patient's q.s that needs treatment.Preferably give with the suitable dosage form of Green (galenic) medical science.
The present invention discloses the method for identification and classification PDE I inhibitor by utilizing PDE I inhibitor as the competitor Journal of Sex Research that is at war with.
Be surprised to find that now in human bladder flesh, the PDE I has special importance: this isozyme of targeting inhibitor will cause the loose of bladder muscle, even give very low dose of inhibitor, for example, and PDE I inhibitor vinpocetine, its dosage is 10
-5Mol/l (Fig. 2) under this dosage, does not have tangible effect to other organ, particularly blood vessel.Therefore, in the treatment bladder disease, has excellent efficacies and effectiveness.
Therefore, the objective of the invention is to utilize PDE I inhibitor to treat bladder disease, particularly so-called urine is urged syndrome (urge symptoms), frequent micturition, urinary incontinence, the unstability of involuntary urination and bladder muscle (detrusor instability (di)), and the inhibitor of the present invention application that is used for the object of the invention medicine and contains the medicine of PDE I inhibitor in preparation.
Preferred PDE I inhibitor is:
Vincamine, vinpocetine (apovincamine-22-acetoacetic ester (ethyl apovincamin-22-oate)), and/or have PDE I modified compound rejection characteristic, described inhibitor, and the pharmacology goes up suitable salt.
Obtain salt suitable on the pharmacology similarly by method with inorganic or organic acid neutralization bases.For example, spendable mineral acid comprises hydrochloric acid, sulphuric acid, phosphoric acid or hydrobromic acid, and for example, organic acid comprises carbonic acid, sulfonic acid, as acetic acid, tartaric acid, lactic acid, propanoic acid, glycolic, malonic acid, maleic acid, fumaric acid, tannic acid, succinic acid, alginic acid, benzoic acid, the 2-phenoxy benzoic acid, the 2-acetoxy-benzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, the 3-aminosallcylic acid, ascorbic acid, pamoic acid, nicotinic acid, the .gamma.-pyridinecarboxylic acid, oxalic acid, aminoacid, methanesulfonic acid, ethyl sulfonic acid, the 2-isethionic acid, second-1, the 2-disulfonic acid, benzenesulfonic acid, 4-toluene sulfonic acide, or naphthalene 2-sulfonic acid.
Be used for the treatment of in the medicine of above-mentioned disease in preparation, except common excipient.Outside carrier and the additive, use PDE I inhibitor or its salt of effective dose.Dosage depends on species, body weight, age, concrete disease and administration type.
Possible application form is oral, intravenous, intramuscular, subcutaneous, and intracavity (for example intravesical) preparation.Especially, the latter is solution and the preparation that is used for parenterai administration.
Non-intestinal drug delivery agent per unit dosage contains 0.05 μ g-100mg, and preferred 1mg-50mg above-claimed cpd and independently unit dosage form existence are as ampoule or bottle.Preferably, use the solution of active component, more preferably aqueous solution, and be mainly isosmotic solution, but also can be suspension.These injection forms can be the i.e. dosage forms of usefulness, perhaps, can be only before use, by with compounds effective, the lyophilization thing that for example contains or do not contain other solid carrier mixes with needed solvent or suspension medium to be prepared.
For oral administration, use conventional Green's medical preparation, as tablet, the capsule of tablet, coating, dispersible powder, granule, aqueous or oily suspensions, syrup, aqueous solution or drop.
Solid preparation can comprise inert excipient, additive and carrier, as silicic acid, silicone oil, polymer fatty acid (as stearic acid), gelatin, the agar of calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate or aluminum, methylcellulose, Pulvis Talci, high degree of dispersion, or plant or Animal fat oil, solid high molecular polymer (as Polyethylene Glycol); The preparation that is used for oral administration can comprise or not contain other flavoring and/or sweeting agent.
Liquid preparation can be sterilization and/or can contain or not contain additive, as antiseptic, stabilizing agent, wetting agent, penetrating agent, emulsifying agent, spreading agent, solubilizing agent, be used to regulate osmotic pressure or be used for buffered salt, and/or viscosity modifier.
For example, this additive is tartrate and citrate buffer agent, ethanol, chelating agent (as ethylenediaminetetraacetic acid and non-toxic salt thereof).
In order to regulate viscosity, can use high molecular polymer, for example Ye Tai poly(ethylene oxide), carboxymethyl cellulose, polyvinylpyrrolidone, glucosan or gelatin.For example, solid carrier is starch, lactose, mannitol, methylcellulose, the silicic acid of Pulvis Talci, high degree of dispersion, polymer fatty acid (as stearic acid), gelatin, agar.Calcium phosphate, magnesium stearate, animal and plant fat, solid high molecular polymer (as Polyethylene Glycol).
The oily suspensions that is used for non-intestinal or part (for example using in the capsule) administration can comprise vegetable oil, synthetic or semisynthetic oil, ester as liquid fat acid, wherein, in described fatty acid chain, contain 8-22 carbon atom, as Palmic acid, lauric acid, tridecanoic acid, heptadecanoic acid, stearic acid, Oleum Arachidis hypogaeae semen, myristic acid behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassidic acid, erucic acid or oleic acid, can be with the monobasic with 1-6 carbon atom or trihydroxylic alcohol with described acid estersization, as methanol, ethanol, propanol, butanols, amylalcohol or its isomer, glycol, or glycerol.For example, the ester of described fatty acid is the commercial miglyols that buys, isopropyl myristate, isopropyl palmitate, isopropyl stearate, 6-capric acid PEG ester, the caprylate/decanoin of saturated fatty alcohol, polyoxyethylene-triolein, ethyl oleate, wax shape fatty acid ester are as fatty acid ester of synthetic duck uropygial fat, ellipse seed oil isopropyl fatty acid ester, oleic acid oil base ester, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol etc.Also use the silicone oil or the aliphatic alcohol of various viscosity, as different tridecyl alcohol, 2-octyldodecanol, cetyl octadecanol or oleyl alcohol, fatty acid is as oleic acid.In addition, can use vegetable oil, as Oleum Ricini, almond oil, olive oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen or Oleum Glycines.Above-mentioned substance has the characteristic of spreading agent in addition, and good especially auxilliary malleability promptly will be arranged on skin.
As solvent, gellant and cosolvent, can make water or water-miscible solvent, for example pure, as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, Polyethylene Glycol, phthalic acid derivatives, adipic acid derivant, propylene glycol, glycerol, dipropylene glycol or tripropylene glycol, wax, methyl cellosolve, cellosolve, ester, morpholine, diox, dimethyl sulfoxide, dimethyl formamide, oxolane, Ketohexamethylene etc.
Form agent as film, can use cellulose ether, their solubilized or swelling form a kind of film in water and organic solvent and after drying, as hydroxypropyl cellulose, methylcellulose, ethyl cellulose or soluble starch.Also can use blended gellant and film to form agent.If like this, so mainly use the ion macromole, as sodium carboxymethyl cellulose, polyacrylic acid, polymethylacrylic acid and salt thereof, Sodium amylopectine semiglycolate, alginic acid or propylene glycol sodium salt, arabic gum, xanthan gum, guar gum or chondrus ocellatus Holmes.
As other formulation adjuvant, can use: glycerol, have the paraffin of different viscosities, triethanolamine, collagen, allantoic acid, novantisolic acid, aromatic oil.
For preparation, also can use surfactant, emulsifying agent or wetting agent, for example, sodium lauryl sulphate, the Oleum Ricini of fatty acid ether sulfate, N-dodecyl β-imino group disodium beclomethasone, polyoxyethyleneization or single oleic acid Isosorbide Dinitrate, monostearate sorbitan fat, hexadecanol, lecithin, glyceryl monostearate, Myrj 45, alkyl phenol polyglycol ether, cetyltrimethylammonium chloride or the former mono phosphoric acid ester ethanolamine salt of monoalkyl/dialkyl group polyglycol ether.
Stabilizing agent, as be used for stable emulsion or be used to prevent montmorillonites or the collodial silica that active substance decomposes, as antioxidant, for example tocopherol or fourth hydroxyanisol, perhaps antiseptic, for example p-Hydroxybenzoate also can be used for preparing needed preparation.
In order to promote infiltration, preferably contain the organic solvent of highly compatible in the capsule with preparation, as ethanol, methyl pyrrolidone, Polyethylene Glycol, oleyl alcohol, capryl alcohol, linoleic acid, glyceryl triacetate, propylene glycol, glycerol, Solketal or dimethyl sulfoxide.
Using preparation under antibacterial or the sterilising conditions, filling or seal formulation.For part or transdermal application, preferably, with preparation packing in wieldy independently unit dose, if for causes for stable, as the parenterai administration form, also can pack respectively containing or do not contain the active component of solid carrier or its compositions such as lyophilization thing and needed solvent etc.Embodiment 1-injection
The 50mg vinpocetine is dissolved in the distilled water with 750mg NaCl, pH is transferred to 3.7 with 1NHCl, add distilled water again, and solution is divided in the 0.5ml ampoule to cumulative volume 100ml.Embodiment 2-is used for the solution of topical
With the 500mg vinpocetine, the 2ml isopropyl myristate becomes to be used for the solution of topical with the 10ml ethanol preparation and with the packing of 2ml unit dosage form.
By effect and the effectiveness of following pharmacological research proof according to the medicine of the technology of the present invention preparation.
The fresh human bladder flesh that collects in the operation process is cut into little (about 3 * 3 * 6mm).Then, in order to ensure the survival of this organ bar, place it in the organ that contains nutritional solution molten in.By the organ bar is connected on the measuring device, can writes down the variation of organ bar length and dynamics, and therefore can measure the effect that is added to chemical compound in the organ bath nutritional solution by the variation (increase or reduce) of organ bar length and dynamics.In on-test, with suitable n-compound (for example carbachol) the organ bar is shunk, after the organ bar shrinks and finishes, with the dosage (10 of Phosphodiesterase I inhibitor to increase progressively
-9, 10
-8, 10
-7Deng mol/l) be added in the organ liquid, measure the relaxation effect that is triggered thus.Because the employed people of being organizes, therefore resulting result is applicable to whole machine body basically, and in whole machine body, the metabolic process of being studied is carried out sooner, and therefore, chemical compound will play a role more significantly.
The result of these organ bath tests of Fig. 1-6 explanation.
Fig. 1 shows is that the non-specific phosphodiesterase inhibitor papaverine of cumulative rises concentration is in advance with the relaxation effect of little of the detrusor of 1 μ m carbachol contraction.Curve display be the meansigma methods of measurement result on little of 12 detrusors.This inhibitor is not a medicine, because it and all PDEs interact, thereby causes serious adverse.
Fig. 2 shows be the PDE I inhibitor vinpocetine of cumulative rises concentration in advance with the relaxation effect of little of people's detrusor of 1 μ M carbachol contraction, curve display be the meansigma methods of measurement result on little of 12 detrusors.
Fig. 3 shows is that the PDE III inhibitor milrinone of cumulative rises concentration is in advance with the relaxation effect of little of people's detrusor of 1 μ M carbachol contraction.Curve display be the meansigma methods of little measurement result of 10 detrusors.
Fig. 4 shows be the PDE IV inhibitor rolipram of cumulative rises concentration in advance with the relaxation effect of little of people's detrusor of 1 μ M carbachol contraction, curve display be the meansigma methods of little measurement result of 8 detrusors.
Fig. 5 shows is the relaxation effect of the PDE V inhibitor zaprinast of cumulative rises concentration to little of people's detrusor of shrinking with l μ M carbachol in advance.Curve display be the meansigma methods of little measurement result of 10 detrusors.
Fig. 6 shows is that the PDE V inhibitor dipyridamole of cumulative rises concentration is in advance with the relaxation effect of little of people's detrusor of 1 μ M carbachol contraction.Curve display be the meansigma methods of little measurement result of 10 detrusors.Therefore up to the present also do not know PDE II inhibitor and can not test.
By known method, as according to Galwan etc., Arch.Pharmacol.1990,342,221-227; Or Nicholson, Br.J.Pharmacol.1989,79, whether the method described in the 889-897 for example, proves according to following conventional method whether chemical compound is applicable to the object of the invention, that is, be PDE I inhibitor.
Flesh tissue homogenize and ultracentrifugation that intra-operative is obtained.Then, leach supernatant, shift out and chromatography with pipet.As M.Truss etc.: Urology45157:893-901, carry out the mensuration of PDE isozyme described in 1995.Measure the activity that radioactive amount can be used for calculating enzyme, represent with Pmol/ml/min.Draw activity curve and can be used for distinguishing the wherein extra high fraction of phosphodiesterase activity.With regard to the activity of different substrates, the activity of phosphodiesterase shows different components during each peak value.The phosphodiesterase activity of this special component can be used for determining phosphodiesterase isoenzyme (PDE).If a kind of material suppresses the necessary concentration (IC of 50% substrate hydrolysis
50) in containing each peak value fraction of corresponding phosphodiesterase isoenzyme than in other peak value fraction, hanging down 20 times at least, this material can be regarded the PDE inhibitor as so.For this reason, as mentioned above, carry out enzyme preparation research once more.Yet, now, before enzymatic mixture is cultivated in the peak fraction, add test compound.Then, measure and draw the enzymatic activity curve once more and can be used for determining material as the phosphodiesterase isoenzyme inhibitor of above-mentioned definition.
Claims (6)
1. the Phosphodiesterase I inhibitor is used for the treatment of application in the medicine of bladder disease in preparation.
2. the application of claim 1 is used for the treatment of the short syndrome of urine, the unstability of frequent micturition, urinary incontinence, involuntary urination and bladder muscle (detrusor instability (di)).
3. the application of claim 1, wherein, the Phosphodiesterase I inhibitor is a vincamine, and vinpocetine (apovincamine-22-acetoacetic ester) and/or the modified compound of described inhibitor and pharmacology thereof with Phosphodiesterase I rejection characteristic go up suitable salt, are used for the treatment of claim 1.
4. the application of arbitrary claim among the claim 1-2 is used for part or whole body administration.
5. by being chosen wantonly, the Phosphodiesterase I inhibitor of q.s gives the method that required patient treats bladder disease with the Galenicals form.
6. Journal of Sex Research is identified and the method for the Phosphodiesterase I inhibitor of classifying by following compounds is at war with as the Phosphodiesterase I competitive inhibitor, wherein said chemical compound is a vincamine, vinpocetine (apovincamine-22-acetoacetic ester) and/or have the modified compound Phosphodiesterase I rejection characteristic, described inhibitor, and on the pharmacology suitable salt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96197169 CN1205634A (en) | 1995-08-08 | 1996-08-01 | Use of PDE inhibitors in manufacture of medicament for treatment of bladder diseases |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19529102.6 | 1995-08-08 | ||
| CN 96197169 CN1205634A (en) | 1995-08-08 | 1996-08-01 | Use of PDE inhibitors in manufacture of medicament for treatment of bladder diseases |
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| CN1205634A true CN1205634A (en) | 1999-01-20 |
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| CN 96197169 Pending CN1205634A (en) | 1995-08-08 | 1996-08-01 | Use of PDE inhibitors in manufacture of medicament for treatment of bladder diseases |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104997775A (en) * | 2015-06-30 | 2015-10-28 | 浙江大学 | Applications of vinpocetine in preparation of drugs used for treating pulmonary fibrosis |
| CN105287537A (en) * | 2014-05-26 | 2016-02-03 | 和光学 | Vinpocetine pharmaceutical composition and application of vinpocetine pharmaceutical composition to prevention and treatment of stress urinary incontinence and urinary urgency |
-
1996
- 1996-08-01 CN CN 96197169 patent/CN1205634A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105287537A (en) * | 2014-05-26 | 2016-02-03 | 和光学 | Vinpocetine pharmaceutical composition and application of vinpocetine pharmaceutical composition to prevention and treatment of stress urinary incontinence and urinary urgency |
| CN104997775A (en) * | 2015-06-30 | 2015-10-28 | 浙江大学 | Applications of vinpocetine in preparation of drugs used for treating pulmonary fibrosis |
| CN104997775B (en) * | 2015-06-30 | 2018-07-27 | 浙江大学 | Application of the vinpocetine in preparing anti-fibrosis drug |
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