CN101119727A - Use of cannabinoid receptor antagonists for the preparation of drugs in the treatment and prevention of type-2 diabetes - Google Patents
Use of cannabinoid receptor antagonists for the preparation of drugs in the treatment and prevention of type-2 diabetes Download PDFInfo
- Publication number
- CN101119727A CN101119727A CNA2006800052531A CN200680005253A CN101119727A CN 101119727 A CN101119727 A CN 101119727A CN A2006800052531 A CNA2006800052531 A CN A2006800052531A CN 200680005253 A CN200680005253 A CN 200680005253A CN 101119727 A CN101119727 A CN 101119727A
- Authority
- CN
- China
- Prior art keywords
- rimonabant
- purposes
- treatment
- diabetes
- prevention
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Abstract
The invention relates to the use of rimonabant, either alone or combined with another active principle, for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes or non-insulin dependent diabetes and/or the complications thereof.
Description
To be Rimonabant be used for preventing and treat the purposes of the medicine of type 2 diabetes mellitus or noninsulindependent diabetes and/or its complication in preparation to purpose of the present invention.
Type 2 diabetes mellitus is characterised in that the insulin secretion obstacle relevant with insulin sensitivity or insulin resistant sexual disorders.Insulin resistance can be worsened by the triglyceride of hyperglycemia and high-caliber circulation free fatty and storage.
Rimonabant is the international name of N-piperidino-5-(4-chlorphenyl)-1-(2, the 4-Dichlorobenzene base)-4-methylpyrazole-3 Methanamide of description in European patent 656354.
From quantitative and viewpoint qualitatively, clinical research with Rimonabant shows that it acts on dietary intake, and has reduced obese patient's body weight (G.Le Fur, 2003,35, First EuropeanWorkshop on Cannabinoid Research, Madrid, Spain, 4-5 April 2003 and Heshmati H.M. etc., Obesity Research, 2001
9(suppl.3), 70.
Have been found that at present Rimonabant has diabetes character, and it is to working with the diabetes complications associated with arterial system.
Therefore, according to the present invention, Rimonabant can be used for preparing the medicine that is used to prevent and treat type 2 diabetes mellitus and complication thereof.
Statement can be regarded as finger with the diabetes complications associated with arterial system:
-the cardiovascular disease relevant with diabetes;
-neuropathy disease is such as diabetic neuropathy, peripheral neurophaty, spontaneous cardiac nerve disease (neuropathies cardiaques autonomes);
-nephropathy is such as diabetic nephropathy, diabetic glomerulopathy;
-ophthalmic is such as diabetic retinopathy, macular edema, glaucoma;
-angiopathy: microangiopathy, macroangiopathic, coronary artery disease, peripheral arterial disease.
According to an one aspect, purpose of the present invention is that Rimonabant is used to prevent and the purposes of treatment and diabetes complications associated with arterial system, and described complication is peripheral neurophaty, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, angiopathy the most especially.
Pharmaceutical composition according to the present invention comprises effective dose Rimonabant and at least a pharmaceutically acceptable excipient.
Described excipient is to select from usual excipients well known by persons skilled in the art according to the medication of pharmaceutical dosage form and expection.
Be used for oral, Sublingual, subcutaneous, muscle, intravenous, part (topique, locale), in the trachea, in the pharmaceutical composition of the present invention of intranasal, transdermal or rectally, the unit form with the conventional medicine mixed with excipients that active component can be used for administration is administered to animal and human's class, with prevention or treatment type 2 diabetes mellitus.
The suitable unit form that is used for administration comprises the form that is used for oral administration, is used for the Sublingual, in the oral cavity, trachea, the form or the form that is used to suck of ophthalmic, intranasal administration, be used for part, transdermal, subcutaneous, intramuscular or the form of intravenous administration, the form that is used for rectally and implant, the described form of oral administration that is used for is such as tablet, Perle or hard gelatin capsule, powder, granule and oral administration solution or suspension.For local application, can use in ointment, gel, ointment or lotion according to chemical compound of the present invention.
The formation that is used for oral administration is preferred such as capsule or tablet.
More particularly, capsule or tablet are preferred, and it comprises 5 to 50mg dosage, more particularly is 10 to 30mg dosage, is in particular the Rimonabant of the dosage of 20mg.
For purposes according to the present invention, Rimonabant and the active component combination that can be selected from one of following treatment kind with another kind:
-hypolipidemic or pravastatin;
-another kind of antidiabetic drug;
-another kind of antiobesity agent.
Therefore, purpose of the present invention also is a pharmaceutical composition, and it comprises cannabinoid CB
1The antagonist of receptor and the combination of another kind of active component, described antagonist is derived from pyrazoles, be selected from Rimonabant and N-piperidino-5-(4-bromophenyl)-1-(2, the 4-Dichlorobenzene base)-4-ethyl pyrazole-3-formamide, described another kind of active component is selected from one of following treatment kind:
-hypolipidemic or pravastatin;
-another kind of antidiabetic drug.
Term hypolipidemic or pravastatin should be understood to refer to be selected from following chemical compound: the special class of chlorine shellfish, such as aluminum clofibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; Statins (HMG-CoA reductase inhibitor), such as atorvastatine, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or chemical compound, such as acipimox, aluminum nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid, cupreol, tiadenol.
Other antidiabetic drug of term should be understood to refer to: sulfonylureas, biguanide (biguanidines), alpha-glucosidase inhibitor, thiazolidinediones, the metformin class, such as acarbose, acetohexamide, ammonia sulphur butyryl, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, lattice row piperazine ketone, glybuzole, 2-benzenesulfonamido-5-(.beta.-methoxyethoxy)pyrimidine, metahexamide, metformin, miglitol, Nateglinide, pioglitazone, repaglinide, rosiglitazone (rosiglitazone), tolazamide, tolbutamide, voglibose.
According to another specific embodiment, purpose of the present invention is the pharmaceutical composition that is used for the treatment of type 2 diabetes mellitus, it comprises Rimonabant and metformin, or the combination of Rimonabant and sulfonylureas, described sulfonylureas is such as acetohexamide, invenol, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, tolazamide, tolbutamide.
According to another aspect of the present invention, the active component of Rimonabant and other combination can be simultaneously, separate (é tal é e dans le temps) administration respectively or in time.
Term " uses respectively " and should be understood to refer to the two kind chemical compounds of administration simultaneously according to compositions of the present invention, and every kind is included in the different pharmaceutical dosage forms.
Term " separately uses in time " and should be understood to refer to first chemical compound according to compositions of the present invention of administration in turn, it is included in the pharmaceutical dosage form, then administration is according to second chemical compound of compositions of the present invention, and it is included in the different pharmaceutical dosage form.
Under this situation about " separately using in time ", administration usually can be above 24 hours according to the interval between second chemical compound of same combination of the present invention according to first chemical compound and the administration of compositions of the present invention, if any chemical compound that is present in the pharmaceutical preparation allows for example administration weekly, then described interval can be longer.
Comprise or independent a kind of pharmaceutical dosage form of forming chemical compound or two kinds of chemical compound combinations according to compositions of the present invention can for example be suitable for oral, nasal cavity, non-intestinal or transdermal administration that described dosage form can used in all kinds purposes as mentioned above.
And, under the situation of " using respectively " and " separately using in time ", can design two kinds of different pharmaceutical dosage forms to be used for identical administration route or different route of administration (oral and transdermal or oral and nasal cavity or non-intestinal and transdermal etc.).
Therefore, the present invention also relates to a kind of test kit, it comprises the maybe active component of two kinds of combinations when suitable of Rimonabant and another kind of active component, wherein Rimonabant and described active component maybe when suitable the active component of two kinds of combinations in different compartments, and similar or different packings is arranged, and through design with simultaneously, separate administration respectively or in time.
Embodiment 1: Rimonabant is to the effect of the diabetics of overweight or fat type
The Rimonabant of dosage that 20mg has been compared in the Rio-Diabetes clinical research to the placebo product in weight reduction; Improve the effect in glycosylated hemoglobin (HbAlc), glucemia, insulinemia (insulin é mie) and the lipid parameter, this research has been carried out 12 months in the 1045 routine obese subjects of suffering from type 2 diabetes mellitus by monotherapy (metformin or sulfonylureas) treatment.All patients are stipulated low-calorie diet (not enough 600Kcal/ days), and before treating elementary period, 4 weeks introduced these diet.
The experimenter who handled 12 months with the Rimonabant of the dosage of 20mg demonstrates than observed more weight saving in placebo group, is 4.2 ± 0.4kg (p＜0.001).
Under the 20mg Rimonabant, aspect the level minimizing of HbAlc, observe and compare 0.7 ± 0.1% difference (p＜0.001) with placebo.This is reduced to 9th month maximum, is retained to 12nd month then, and as if the loss in weight is just stable after 6 months.
Observe glucemia minimizing 0.64 ± 1.96mmol/L under empty stomach in 20mg Rimonabant group, by comparison, it increases by 0.33 ± 2.32mmol/L (p＜0.001) in placebo group.
For the insulinemia under empty tripe, under the 20mg Rimonabant, observe it and reduce by 0.7 ± 9.9 μ IU/mL, by comparison, it increases by 0.4 ± 14.8 μ IU/mL (p=0.247) in placebo.
By Matthew D.R. etc. at Diabetologica, 1985,
28, the HOMA that describes among the 412-419 (homeostasis pattern evaluation) test evaluation insulin resistance.
By the improvement in the insulin resistance of HOMA test evaluation more objective under the 20mg Rimonabant (0.5 ± 5.7%), and placebo group is induced this insulin resistance decline.
As for the lipid feature, observe big 8.4 ± 1.2% (p＜0.001) of the increase of HDL-c level with the 20mg Rimonabant than placebo.
Compare with placebo group, the minimizing of triglyceride surpasses 16.4 ± 3.3% (p＜0.001) in the treatment group.
In this research,, observe the improvement of about 55% couple of HbAlc of weight saving and HDL-c and the not influence of improvement of the about 35% pair of triglyceride of weight saving to after wherein introducing the logarithm recurrence type analysis that is covariable weight.
And, in the patient that the Rimonabant of the dosage of using 20mg is treated, to observe systolic pressure and reduce 0.8+12.8mmHg (p=0.020), diastolic pressure reduces 1.9 ± 8.2mmHg (p=0.060).
Therefore, in the experimenter with the Rimonabant treatment, the metabolic parameter is not only relevant with weight saving such as the improvement of HbAlc, HDL-c and triglyceride, and relevant with the direct effect of described product.
Observe and no matter whether accept the antidiabetic drug treatment during studying, Rimonabant has induced significant weight to alleviate: compare with placebo group, the difference of weight saving is 4.3 ± 0.4kg (p＜0.001) in Rimonabant-metformin combination; In Rimonabant-sulfonylureas combination, it is 3.1 ± 0.5kg (p＜0.001).
No matter also observe is Rimonabant and metformin combination or Rimonabant and sulfonylureas combination, compares with placebo, observes similar result to HbAlc, and its difference that has is 0.7 ± 0.1% (p＜0.001).
Embodiment 2: Rimonabant is to the protective effect of pancreas in the obese rat
The effect that research is treated with Rimonabant long-term (12 months) in setting up fat Zucker rat.
Fa/fa be fat Zucker rat be characterised in that suffer from hyperphagia, obesity, dyslipidemia disease and type 2 diabetes mellitus.
After 12 months, show tangible pancreas hypertrophy (+38%, p＜0.05) with the fat Zucker rat of the fa/fa of vehicle treated.
By can the dose dependent mode reversing this hypertrophy with dose dependent mode administration Rimonabant: respectively 3mg/kg/ days and at 10mg/kg/ all over the world for+17% and+1%.
Embodiment 3: Rimonabant is to the effect of diabetic neuropathy model in the rat
According to B.Rudas, Arzneimittelforschung 1972; 22:830-61 induces diabetes by the streptozotocine solution (55mg/kg) of intravenous injection in citric acid buffer agent, and described buffer agent comprises 0.1M citrate, pH4.5.After five days, get blood from retro-orbital sinus, then centrifugal; Measure the concentration of glucose in every kind of animal blood slurry.8 weeks after inducing diabetes and hyperglycemia, estimate mechanical sensitivity and sensitive nerve conduction velocity (SNCV), when finishing, research measures once more.
In order to 3 or 10mg/kg oral administration Rimonabant carry out this test.Animal, the time in 7 weeks of coprocessing are handled in beginning in the 7th day every day behind the injection streptozotocine.
Determine sensitivity with Von Frey filament (anesthesia meter) by the threshold value of measuring pawl the mechanicalness noxious stimulation being recalled to mechanical stimulus.Use hard polypropylene tip to apply a power to the plantar surface of pawl.This power of replying of recalling induced in record.For every kind of animal, repeat this test 3 times, calculating mean value with about 5 minutes intervals.
According to P.De Koning etc. at Peptides:1987; 8 (3): the method for describing among the 415-22 is measured SNCV.By the pentobarbital anesthetized rat of injection 30mg/kg, by means of sciatic nerve of monopolar electrode continued stimulus and fibular nerve, described stimulation is for respectively at sciatic nerve and fibular nerve incisura (notch) (ankle).With replying of the surface electrode record arch of foot.By deducting terminal incubation period the incubation period from near-end, and remove distance between stimulating electrode and the collecting electrode with this result and calculate these and reply preclinical SNCV.
Rats with diabetes shows mechanical hyperalgesia, itself demonstrates the withdrawal threshold that pawl replys the mechanicalness noxious stimulation and has reduced about 40%.This not can by 7 weeks after processing with 3 or the Rimonabant of 10mg/kg po dosage handle fully and reverse (100%).
In identical period, compare with control rats, SNCV has reduced 22% in the diabetic rat; Ground, Rimonabant processing section with 10mg/kg has reduced (12%) described SNCV deficiency, and it is equivalent to described deficiency and has reversed 54.5%.
These results demonstrate in the rat in 8 weeks after inducing diabetes, and the oral administration Rimonabant has fully reversed the pain symptom relevant with diabetes, and have reduced SNCV deficiency in the sciatic nerve significantly.
Therefore, Rimonabant has demonstrated effect in these diabetic neuropathy transaction modules.
Embodiment 4: pharmaceutical composition
In order to be administered to the patient, Rimonabant is prepared into pharmaceutical composition, it prepares by wet granulation.
| Component | |
| Micronized Rimonabant | 20.0mg |
| Corn starch | 67.50mg |
| Lactose monohydrate | 111.66mg |
| Polyvinylpyrrolidone *(Povidone) | 5.25mg |
| Cross-linked carboxymethyl cellulose sodium | 18.75mg |
| SDS | 0.34mg |
| Microcrystalline Cellulose | 75.0mg |
| Magnesium stearate | 1.50mg |
| Final tablet, extremely | 300mg |
*Polyvinylpyrrolidone is to define at European Pharmacopoeia, and is as follows: poly-(1-(2-OXo-1-pyrrolidine base) ethylene), its 1-vinyl pyrrole alkyl-2-ketone polymer by straight chain constitutes.
Described tablet preferably uses suitable excipient coating.
Claims (11)
1. Rimonabant is used for the treatment of and prevents purposes in the medicine of type 2 diabetes mellitus and/or its complication in preparation.
2. according to the purposes of claim 1, it is used for prevention and treatment type 2 diabetes mellitus.
3. according to the purposes of claim 1, it is used to prevent and treat the complication of type 2 diabetes mellitus.
4. according to the purposes of claim 1, it is used for prevention and treatment diabetic neuropathy.
5. according to the purposes of claim 1, it is used for prevention and treatment diabetic retinopathy.
6. according to the purposes of claim 1, it is used for prevention and treatment angiopathy.
7. according to each purposes in the claim 1 to 6, wherein Rimonabant and the another kind of active component combination that is selected from one of following treatment kind:
-hypolipidemic or pravastatin;
-antidiabetic drug.
8. according to each purposes in the claim 1 to 7, wherein the dosage of used Rimonabant is 5mg to 50mg.
9. according to the purposes of claim 7, wherein Rimonabant and metformin make up.
10. according to the purposes of claim 7, wherein Rimonabant and sulfonylureas make up.
11. pharmaceutical composition comprises Rimonabant and the another kind of combination that is selected from the active component of metformin and sulfonylureas.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0501861 | 2005-02-21 | ||
| FR0501861A FR2882261B1 (en) | 2005-02-21 | 2005-02-21 | USE OF A PYRAZOLE DERIVATIVE FOR THE PREPARATION OF MEDICAMENTS USEFUL IN THE PREVENTION AND TREATMENT OF TYPE 2 DIABETES |
| FR0504942 | 2005-05-12 | ||
| FR0505228 | 2005-05-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101119727A true CN101119727A (en) | 2008-02-06 |
Family
ID=34954874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800052531A Pending CN101119727A (en) | 2005-02-21 | 2006-02-20 | Use of cannabinoid receptor antagonists for the preparation of drugs in the treatment and prevention of type-2 diabetes |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101119727A (en) |
| FR (1) | FR2882261B1 (en) |
| ZA (1) | ZA200707012B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114452831B (en) * | 2022-01-24 | 2023-04-25 | 中南大学湘雅医院 | Surface-coated extracorporeal circulation modified membrane and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2789079B3 (en) * | 1999-02-01 | 2001-03-02 | Sanofi Synthelabo | PYRAZOLECARBOXYLIC ACID DERIVATIVE, ITS PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| US20040122033A1 (en) * | 2002-12-10 | 2004-06-24 | Nargund Ravi P. | Combination therapy for the treatment of obesity |
-
2005
- 2005-02-21 FR FR0501861A patent/FR2882261B1/en not_active Expired - Fee Related
-
2006
- 2006-02-20 ZA ZA200707012A patent/ZA200707012B/en unknown
- 2006-02-20 CN CNA2006800052531A patent/CN101119727A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| FR2882261A1 (en) | 2006-08-25 |
| FR2882261B1 (en) | 2009-02-06 |
| ZA200707012B (en) | 2008-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| MASSIE et al. | Diltiazem and propranolol in mild to moderate essential hypertension as monotherapy or with hydrochlorothiazide | |
| EA015382B1 (en) | Use of roflumilast for the treatment of diabetes mellitus type 2 | |
| KR101943382B1 (en) | A pharmaceutical composition comprising SGLT-2 inhibitor and angiotensin receptor blocker | |
| CN108012527A (en) | Benzimidizole derivatives are used for the purposes of Control of Nocturnal Gastric Acid Breakthrough | |
| Plänitz | Comparison of moxonidine and clonidine HCl in treating patients with hypertension | |
| JP6499634B2 (en) | Combination of solifenacin and salivary stimulant for the treatment of overactive bladder | |
| US6613768B1 (en) | Treatment of female arousal disorder | |
| UA64761C2 (en) | Pharmaceutical compositions comprising aldose reductase inhibitor and ace inhibitor | |
| KR100709528B1 (en) | Drug composition for blood sugar control | |
| JP4786127B2 (en) | Antipigmentation treatment | |
| CN101119727A (en) | Use of cannabinoid receptor antagonists for the preparation of drugs in the treatment and prevention of type-2 diabetes | |
| KR100325793B1 (en) | Remedy for anxiety neurosis | |
| JP5117230B2 (en) | Combination medicine for type 2 diabetes treatment | |
| KR20070104913A (en) | Use of rimonabant for the preparation of medicaments that can be used in the prevention and treatment of type 2 diabetes | |
| White et al. | Chronotherapeutic delivery of verapamil in obese versus non-obese patients with essential hypertension | |
| KR100709531B1 (en) | Drug composition for prevention or inhibition of advance of diabetic complication | |
| Andersson | Improved efficacy with maintained tolerability in the treatment of primary hypertension. Comparison between the felodipine-metoprolol combination tablet and monotherapy with enalapril | |
| US7608625B2 (en) | Method for treating bruxism and bruxism-related diseases | |
| WO2005107744A1 (en) | Nerve damage | |
| JP2008530189A (en) | Use of rimonabant to prepare a medicament that can be used in the prevention and treatment of type 2 diabetes | |
| Guo-Shu et al. | Ketanserin in the treatment of hypertension: a multicentre dose-finding study in China | |
| Agent | PrRAN™-PIOGLITAZONE | |
| Agent | Pr PRO-PIOGLITAZONE | |
| Tablets et al. | Pr ACT PIOGLITAZONE | |
| Velasquez et al. | Antihypertensive Effect of Carteolol in Thiazide‐Treated Hypertensive Subjects |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1117735 Country of ref document: HK |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080206 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1117735 Country of ref document: HK |