CN105796563A - New application of lopinavir to medicines - Google Patents

New application of lopinavir to medicines Download PDF

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Publication number
CN105796563A
CN105796563A CN201610286809.4A CN201610286809A CN105796563A CN 105796563 A CN105796563 A CN 105796563A CN 201610286809 A CN201610286809 A CN 201610286809A CN 105796563 A CN105796563 A CN 105796563A
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China
Prior art keywords
lopinavir
group
hmgb1
diabetes
diabetic nephropathy
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CN201610286809.4A
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Chinese (zh)
Inventor
蒋王林
张广华
纪云霞
朱海波
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Binzhou Medical College
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Binzhou Medical College
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    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention provides a new application of lopinavir to medicines and in particular relates to an application of lopinavir to medicines for preventing or treating obesity, type II diabetes, diabetic nephropathy and non-alcoholic fatty liver diseases. The oral dosage of lopinavir ranges between 50mg and 2000mg in application, preferably 50-1000mg.

Description

The new medical use of Lopinavir
Technical field
The invention belongs to chemical medicine, relate to the new medical use of Lopinavir；It is specifically related to Lopinavir by suppressing high mobility group protein B 1 (highmobilitygroupprotein, HMGB1) expression, so that the relevant metabolic disturbance diseases such as prevention or treatment obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease.
Background technology
Type 2 diabetes mellitus and Adult Onset's patients with type Ⅰ DM, account for diabetics more than 90%.How fat people is for type 2 diabetes mellitus, produces insulin resistant, causes insulin sensitivity is declined.Diabetic nephropathy is the important complication of diabetes, and the diabetes later stage, nearly 40% patient can develop into diabetic nephropathy.Obesity is to consume caused body fat accumulation, a kind of unhealthy status that body weight increases owing to energy intake exceedes.The sickness rate of obesity all increases rapidly in developed country or developing country, and in becoming younger trend, it has also become the global epidemic diseases having a strong impact on health, current China has super severe one at least 2-3 hundred million people, and obesity patient breaks through 70,000,000 people.Obesity not only affects the daily life of people, and is cause type 2 diabetes mellitus, coronary heart disease, hypertension, dyslipidemia, the principal element of the diseases such as cholecystitis.Therefore, the preventing and treating of obesity has important clinical meaning.
High mobility group protein B 1 (highmobilitygroupprotein, HMGB1) is the nucleoprotein of a kind of high conservative, is distributed widely in mammalian cell.Along with the discovery of pro-inflammatory effect in its, HMGB1 becomes the focus target spot of critical care medicine research in recent years in late period.Hyperglycemia can promote the expression [VolzHC1 of HMGB1, SeidelC, LaohachewinD, KayaZ, M ü llerOJ, PlegerST, LasitschkaF, BianchiME, RemppisA, BierhausA, KatusHA, AndrassyM.HMGB1:themissinglinkbetweendiabetesmellitusand heartfailure.BasicResCardiol.2010；105(6):805-820.].HMGB1 is in close relations with obesity, especially the HMGB1 high expressed [WeisbergSP of the macrophage in fatty tissue, McCannD, DesaiM, RosenbaumM, LeibelRL, FerranteAW, Jr.Obesityisassociatedwithmacrophageaccumulationinadipos etissue.JClinInvest.2003；112(12):1796-1808.；WagnerM.Adangerousduoinadiposetissue:high-mobilitygroupbox1proteinandmacrophages.YaleJBiolMed.2014；87(2):127-133.].
Lopinavir and ritonavir share (trade name gram force sesame) for treatment that HIV/AIDS infects clinically, also can treat in the HIV of adult and more than 6 months children with other antiretroviral drugs coupling, but Lopinavir has no report in the pharmacological action of prevention or treatment obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease.By substantial amounts of research, the present inventor finds that Lopinavir can pass through to suppress HMGB1 to express thus preventing or treatment obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease.Based on this, the present inventor has invented Lopinavir by suppressing IHMGB1 to express thus suppressing obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease to develop, so that prevention or treatment obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease.
Summary of the invention
The invention provides Lopinavir application in the medicine of preparation prevention or treatment obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease.
The invention provides Lopinavir application in the medicine that preparation prevention or treatment are fat.
The invention provides Lopinavir application in the medicine of preparation prevention or treatment type ii diabetes.
The invention provides Lopinavir application in the medicine of preparation prevention or treatment diabetic nephropathy.
The invention provides Lopinavir application in the medicine of preparation prevention or treatment non-alcoholic fatty liver disease.
The invention provides Lopinavir by the application in the medicine expressed in obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease of suppression HMGB1.
The medicine that Lopinavir provided by the invention can form with pharmaceutically acceptable carrier or adjuvant, this medicine can prepare into tablet, capsule, drop pill with pharmacy conventional method, it is preferable that exists with capsule form.
The Lopinavir that invention provides is when being used for obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease, and it orally uses dosage range is 50mg～2000mg；Preferably 50～1000mg.
Detailed description of the invention
Prepared by embodiment 1 Lopinavir capsule
Weigh 50.0g Lopinavir and 150.0g carboxymethyl starch sodium is sufficiently mixed after uniformly and crosses 100 mesh sieves, add appropriate 3%PVPK30Aqueous solution is soft material processed in right amount, and 20 mesh sieves are granulated, and 60 DEG C dry 3 hours, 18 mesh sieve granulate, adds 2.0g magnesium stearate, encapsulated after mix homogeneously, regulates capsule and weighs about 200mg, to obtain final product.
Specific embodiment
The impact on ob/ob obesity mice of test example 1 Lopinavir
1.1 experiment materials
Glycolated hemoglobin measures test kit, lot number: 0590072；HMGB1 primary antibodie is bought in sigma company；Lopinavir (purity 99.5% is bought in Mei Lun bio tech ltd, Dalian)；High density lipoprotein (HDL) test kit (Beijing Zhong Sheng scientific & technical corporation, lot number: 130706), low density lipoprotein, LDL (LDL) test kit (Beijing Zhong Sheng scientific & technical corporation, lot number: 130806) and triglyceride (TG) test kit (Beijing Zhong Sheng scientific & technical corporation, lot number: 130406).
Ob/ob mice, male 50,10 week old, body weight 50～55g, buys in Nanjing model animal institute.
1.2 experimental techniques and result
Ob/ob mice 50, is randomly divided into 5 groups, namely model group, Lopinavir gastric infusion 10mg/kg, 20mg/kg, 200mg/kg, 400mg/kg group.Additionally take 10 normal ob/ob mices as a control group.Each group gives relative medicine, successive administration 4 weeks.Weigh and calculate food ration, measuring glycolated hemoglobin (HbA1c), blood glucose, high density lipoprotein (HDL), low density lipoprotein, LDL (LDL) and triglyceride (TG).Take fatty tissue, homogenate, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins to carry out dodecyl sodium sulfate polyacrylamide (SDS-PAGE) the gel denaturing electrophoretic of 10%, then go to polyvinylidene fluoride (PVDF) film, add HMGB1 primary antibodie, β-actin makes internal reference, and Westernblot detects the expression of fatty tissue HMGB1 albumen.More each administration group and the difference of model group, carry out T inspection between group.
Table 1 Lopinavir is administered the impact on ob/ob mice in 4 weeks (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 2 Lopinavir is administered 4 weeks blood biochemistry index on ob/ob mice affects (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 1, table 2 result display Lopinavir gastric infusion 10mg/kg, 20mg/kg, 200mg/kg and 400mg/kg group substantially reduce body weight and food ration, reduce blood plasma HbA1c, LDL and TG level, blood glucose is suppressed to raise, suppress fatty tissue HMGB1 to express to decline, raising HDL levels (p < 0.05 or p < 0.01).Lopinavir 200mg/kg group reduces body weight and food ration, reduces blood plasma HbA1c, LDL and TG level, it is suppressed that blood glucose raises, it is suppressed that fatty tissue HMGB1 expresses decline, and raising HDL levels compares with Lopinavir 400mg/kg group and there was no significant difference.
The impact on db/dbII patients with type Ⅰ DM mice of test example 2 Lopinavir
2.1 experiment materials
Glycolated hemoglobin measures test kit, lot number: 0590072；HMGB1 primary antibodie is bought in sigma company；Lopinavir (purity 99.5% is bought in Mei Lun bio tech ltd, Dalian)；Db/db mice, male 60,10 week old, body weight 50～55g；Buy in Nanjing model animal institute.
2.2 experimental techniques and result
Db/db mice 50, is randomly divided into 5 groups, namely model group, Lopinavir gastric infusion 10mg/kg, 20mg/kg, 200mg/kg, 400mg/kg group.Additionally take 10 normal db/db mices as a control group.Each group gives relative medicine, successive administration 4 weeks.Weigh, measure glycolated hemoglobin (HbA1c), blood glucose,.Take fatty tissue, homogenate, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins to carry out dodecyl sodium sulfate 2 polyacrylamide (SDS-PAGE) the gel denaturing electrophoretic of 10%, then go to polyvinylidene fluoride (PVDF) film, add HMGB1 primary antibodie, β-actin makes internal reference, and Westernblot detects the expression of fatty tissue HMGB1 albumen.More each administration group and the difference of model group, carry out T inspection between group.
Table 3 Lopinavir is administered the impact on db/db diabetic mice in 4 weeks (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 3 result display Lopinavir gastric infusion 10mg/kg, 20mg/kg, 200mg/kg and 400mg/kg group substantially reduce body weight, reduce blood plasma HbA1c level, it is suppressed that blood glucose raises, it is suppressed that fatty tissue HMGB1 expresses and declines (p < 0.05 or p < 0.01).Lopinavir 200mg/kg group reduces body weight, reduces blood plasma HbA1c level, it is suppressed that blood glucose raises, it is suppressed that fatty tissue HMGB1 expresses to decline to comparing with Lopinavir 400mg/kg group and there was no significant difference.
The impact on diabetic nephropathy rats of test example 3 Lopinavir
3.1 experiment materials
Lopinavir (purity 99.5% buys Mei Lun bio tech ltd, Dalian)
Benazepril, Novartis Pharma AG produces, lot number: 130106；Streptozotocin (Sigma company), blood sugar detection test kit (Beijing Zhong Sheng reagent company limited lot number: 130503)；Creatinine and blood urea nitrogen test kit (Beijing Zhong Sheng scientific & technical corporation, lot number: 130606).
Laboratory animal: SPF level SpragueDawley rat, male, body weight 150g-200g, Shandong Green Leaf Pharmaceutical Co., Ltd's Experimental Animal Center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
3.2 test methods and result
nullMale SD rat 100，After adaptability feeds 1 week，All of rat is at 10% chloral hydrate (0.35mL/100g，Ip) anesthesia，The left kidney enucleation of row，The streptozotocin solution 60mg/kg of single intravenous injection 1% after one week，Streptozotocin is with 0.1mol/L、PH is that 4.5 citric acid buffer solution dissolve，72h posterior orbit is taken a blood sample，Blood sugar detection kit measurement，Blood glucose >=16.7mmol/L is defined as modeling success，6 groups it are randomly divided into after 4 weeks，I.e. model group、Benazepril (2mg/kg) group，Lopinavir gavage 5mg/kg group，Lopinavir gavage 10mg/kg group，Lopinavir gavage 100mg/kg group，Lopinavir gavage 200mg/kg group，Additionally take 10 and be only used as Normal group.Each group successive administration 8 weeks, blood sampling measures serum creatinine and blood urea nitrogen and each group rat 24h excretion quantity of urinary protein.
Take nephridial tissue, homogenate, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins to carry out dodecyl sodium sulfate 2 polyacrylamide (SDS-PAGE) the gel denaturing electrophoretic of 10%, then go to polyvinylidene fluoride (PVDF) film, add HMGB1 primary antibodie, β-actin makes internal reference, Westernblot detects the expression of nephridial tissue HMGB1 albumen, more each administration group and the difference of model group, carry out micrography to kidney as pathological section simultaneously.
Table 4 Lopinavir is administered the impact on diabetic nephropathy rats in 8 weeks (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 5 Lopinavir is administered the impact on diabetic nephropathy coefficient and HMGB1 in 8 weeks (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 4, table 5 result show, Lopinavir gavage 5mg/kg group, Lopinavir gavage 10mg/kg group, Lopinavir gavage 100mg/kg group, Lopinavir gavage 200mg/kg group is administered 8 weeks and substantially reduces serum creatinine and blood urea nitrogen 24h excretion quantity of urinary protein, reduce the expression (comparing, p < 0.05 or 0.01) of nephridial tissue HMGB1 with model control group；Lopinavir gavage 100mg/kg group reduces serum creatinine and blood urea nitrogen and 24h excretion quantity of urinary protein, and the expression reducing nephridial tissue HMGB1 is compared with Lopinavir gavage 200mg/kg group, there was no significant difference.
Pathologic finding: rats in normal control group glomerular basement membrane is normal, has no broadening, podocytic process marshalling.Model control group Renal Glomeruli In Rats basement membrane is significantly broadening, podocytic process arrangement disorder, fusion, mesangial cell and the slight segmental hypertrophy of substrate.Lopinavir each administration group relatively model group pathological changes is light, and progressively alleviates with the increase pathology of dosage.
The impact on rats with nonalcoholic fatty liver disease of test example 4 Lopinavir
4.1 experiment materials
Lopinavir (purity 99.5% is bought in Mei Lun bio tech ltd, Dalian)
Diformin tablet (Shanghai Sine Pharmaceutical Co., Ltd., lot number: 1307231)；Free fatty (FFA) detection kit, builds up biological engineering company limited, lot number 20130715 purchased from Nanjing；Triglyceride TG (zymetology end-point method) detection kit, Whitman Biotech (Nanjing) Co., Ltd., lot number ZGY13307；T-CHOL (TC test kit (Beijing Zhong Sheng scientific & technical corporation, lot number: 130506)
Laboratory animal: SPF level SpragueDawley rat, male, body weight 150g-200g, Shandong Green Leaf Pharmaceutical Co., Ltd's Experimental Animal Center provides, and the animal quality certification number is: SYXK (Shandong) 20030020.
3.2 test methods and result
After rat adaptability raises 1 week, rat is by body weight numbering, and completely random is divided into normal group 10 and high fat modeling group 50.Normal group is given normal diet and is fed, normal feedstuff formula: flour 20%, rice flour 10%, Semen Maydis 20%, drum head 25%, bean material 20%, fish flour 2%, bone meal 2%.High fat modeling group is given high lipid food and is fed, high lipid food formula: normal feedstuff 77.6%, Adeps Sus domestica 10%, cholesterol 2.0%, cholate 0.2%, rosickyite oxygen crash throat 0.2%, yolk powder 5%, sucrose 5%.All freely drink water.Continuous modeling 8 weeks, it is divided into model group, metformin 10mg/kg, Lopinavir gastric infusion 5mg/kg, 10mg/kg, 100mg/kg, 200mg/kg group according to body weight rat, each group is continued to give high lipid food ground and gives above-mentioned relative medicine simultaneously, rat is put to death during to 16 weeks, measure body weight, calculate liver coefficient, collect blood sample, measure Serum ALT, AST, TG, T-CHOL (TC), free fatty (FFA).Take hepatic tissue, homogenate, after BCA protein determination kit (Pierce company) measures protein concentration, take 50 μ g sample proteins to carry out dodecyl sodium sulfate 2 polyacrylamide (SDS-PAGE) the gel denaturing electrophoretic of 10%, then go to polyvinylidene fluoride (PVDF) film, add HMGB1 primary antibodie, β-actin makes internal reference, and Westernblot detects the difference of the expression of hepatic tissue HMGB1 albumen, more each administration group and model group.
Table 6 Lopinavir is administered the impact on rats with nonalcoholic fatty liver disease in 8 weeks (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 7 Lopinavir is administered the impact on rats with nonalcoholic fatty liver disease in 8 weeks (n=10)
*, p < 0.05,**, p < 0.01, compares with model group
Table 6, table 7 result show, metformin 10mg/kg group, Lopinavir gavage 5mg/kg group, Lopinavir gavage 10mg/kg group, Lopinavir gavage 100mg/kg group, the administration of Lopinavir gavage 200mg/kg group substantially reduces body weight, liver coefficient and hepatic tissue HMGB1 for 8 weeks and expresses, and reduces Serum ALT, AST, TG, TC and FFA (comparing, p < 0.05 or 0.01) with model control group；Lopinavir gavage 100mg/kg group reduces body weight, liver coefficient and hepatic tissue HMGB1 and expresses, and reduction Serum ALT, AST, TG, TC and FFA compare with Lopinavir gavage 200mg/kg group, there was no significant difference.

Claims (7)

1. a new medical use for Lopinavir, is specifically related to Lopinavir application in the medicine of prevention or treatment obesity, type ii diabetes, diabetic nephropathy and non-alcoholic fatty liver disease.
2. application according to claim 1, it is characterised in that Lopinavir can prevent or treat obesity.
3. application according to claim 1, it is characterised in that Lopinavir can prevent or treat type ii diabetes.
4. application according to claim 1, it is characterised in that Lopinavir can prevent or treat diabetic nephropathy.
5. application according to claim 1, it is characterised in that Lopinavir can prevent or treat non-alcoholic fatty liver disease.
6. the application according to claim 2-5 any claim, it is characterised in that the using dosage scope of Lopinavir is 50mg～2000mg.
7. application according to claim 6, it is characterised in that the using dosage scope of Lopinavir is preferred 50～1000mg.
CN201610286809.4A 2016-05-03 2016-05-03 New application of lopinavir to medicines Pending CN105796563A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050999A2 (en) * 2004-11-15 2006-05-18 Obe Therapy Biotechnology S.A.S Methods of reducing body fat
WO2012006550A2 (en) * 2010-07-09 2012-01-12 Obetech Llc Methods and compositions for treatment of lipogenic virus related conditions
EP2965760A1 (en) * 2014-07-09 2016-01-13 Université de Montpellier Combination of antiretroviral agents for use in the prevention or treatment of chronic inflammatory diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006050999A2 (en) * 2004-11-15 2006-05-18 Obe Therapy Biotechnology S.A.S Methods of reducing body fat
WO2012006550A2 (en) * 2010-07-09 2012-01-12 Obetech Llc Methods and compositions for treatment of lipogenic virus related conditions
EP2965760A1 (en) * 2014-07-09 2016-01-13 Université de Montpellier Combination of antiretroviral agents for use in the prevention or treatment of chronic inflammatory diseases

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