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WO2011037467A1 - Atazanavir pour le traitement de maladies inflammatoires - Google Patents

Atazanavir pour le traitement de maladies inflammatoires Download PDF

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Publication number
WO2011037467A1
WO2011037467A1 PCT/NL2010/050628 NL2010050628W WO2011037467A1 WO 2011037467 A1 WO2011037467 A1 WO 2011037467A1 NL 2010050628 W NL2010050628 W NL 2010050628W WO 2011037467 A1 WO2011037467 A1 WO 2011037467A1
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WIPO (PCT)
Prior art keywords
atazanavir
disease
treatment
inflammation
bilirubin
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Ceased
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PCT/NL2010/050628
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English (en)
Inventor
Frank Antoine Damiaan Theodorus George Wagener
Paul Anthonius Bernardus Maria Smits
Douwe Dekker
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Radboud Universiteit Nijmegen
Original Assignee
Stichting Katholieke Universiteit
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Publication of WO2011037467A1 publication Critical patent/WO2011037467A1/fr
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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
    • A61K31/435—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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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

Definitions

  • the invention relates to Atazanavir for use as a medicament for preventing, delaying and/or treating an inflammation-mediated or -associated disease and/or a disease wherein oxidative stress occurs.
  • Type 2 diabetes mellitus and cardiovascular disease related T2DM are herein taken as an example of an inflammation-mediated or -associated disease.
  • T2DM is characterized by the combination of insulin resistance and a relative defect in insulin secretion resulting in hyperglycemia. Besides hyperglycemia, the majority of patients with T2DM suffer from dyslipidemia and hypertension. Cardiovascular complications are the leading cause of morbidity and mortality associated with the disease. Extensive research is performed to unravel the underlying process and to subsequently develop new treatment strategies.
  • endothelial activation 1"4 It can be demonstrated early in the disease, even before the occurrence of hyperglycemia, and is strongly related to the development of atherosclerosis and the resulting cardiovascular risk.
  • endothelial switch of phenotype which is crucial and completely physiologic during acute inflammation.
  • the change of phenotype temporarily enables endothelial cells to regulate the inflammatory process by adjusting vascular tone, improving endothelial adhesion of leukocytes and stimulating coagulation.
  • adverse triggers related to diabetes chronically activate this pro -inflammatory phenotype, causing detrimental effects on the vascular system.
  • ROS reactive oxygen species
  • ROS and RNS can cause activation of and damage to the vascular endothelium which is considered an important factor in the patho-physiology of a multitude of diseases and conditions, including atherosclerosis, sepsis, rheumatoid arthritis, ischemia-reperfusion injury and sepsis.
  • vascular hyporeactivity known to occur in human endotoxemia experiments was attenuated after the administration of high dose vitamin C or N-acetylcysteine 9 ' 10 . Therefore antioxidant therapy could represent a promising intervention in septic patients to prevent vascular hyporeactivity and other forms of organ damage.
  • Atazanavir or a related compound preferably as disclosed in EP 900 210 for use as a medicament for preventing, treating and/or delaying oxidative stress and / or an inflammation-mediated or -associated disease.
  • Atazanavir is a medicament marketed under the trade name ReyatazTM by Bristol Myers, (formerly known as BMS-232632).
  • Atazanavir is an antiretroviral drug of the protease inhibitor (PI) class. Like other anti-retrovirals, it is used to treat infection of human immunodeficiency virus (HIV).
  • PI protease inhibitor
  • the name "Atazanavir” may be replaced by its s t r u c t u r a l fo r mu l a : m e t hy l N-[(lS) - ⁇ [(25,3S)-3-hydroxy-4-[(2S)-2- [(methoxycarbonyl)amino]-3,3-dimethyl-N'- ⁇ [4-(pyridin-2- yl)phenyl]methyl ⁇ butanehydrazido]- 1 -phenylbutan-2-yl] carbamoyl ⁇ -2,2- dimethylpropyl] carbamate.
  • This structural formula is also depicted in figure 1.
  • European patent application EP 900 210 discloses several compounds related to Atazanavir and methods for producing them. We expect that each of the compounds related to Atazanavir as disclosed in EP 900 210 may be used instead of Atazanavir. Atazanavir is however the most preferred compound of use in the present invention.
  • a compound used in the invention i.e Atazanavir or a related compound is said to be functional when said compound is able to induce a detectable increase of the bilirubine and/or is able to delay oxidative stress after at least one day of treatment. Such increase of bilirubine may be assessed using HPLC, or spectrophotometric techniques.
  • a medicament is synonymous of a pharmaceutical composition.
  • an "inflammation-mediated disease” may also be replaced by an “inflammation-associated disease”. This is a disease wherein inflammation is involved at a stage of the disease. Inflammation may be involved and detectable at the onset of the disease: in this case inflammation could be seen as partly causing the development of the disease.
  • An "inflammation-mediated disease” may also be a disease wherein inflammation will develop and therefore will be detectable in a later stage of the disease. Inflammation may also be detectable during the whole period wherein a subject has been diagnosed as having said inflammation mediated disease. Inflammation may be diagnosed using techniques known to the skilled person.
  • Inflammation may be diagnosed by quantifying the presence of a pro-inflammatory cytokine, such as TNFa(500 - 2000 pg/mL) 11 , IL- ⁇ (10 - 200 pg/mL), IL-6 (1 - 10 ng/niL), IFNy (10 - 200 pg/mL) and/or MCP-1 (Monocyte Chemotactic protein 1) (0,5 - 10 ng/niL) and/or the presence of an anti- inflammatory cytokine, such as IL-10 (10 - 200 pg/mL) and/or IL-IRa (10 - 300 pg/mL).
  • C-reactive protein (CRP) is a further marker of inflammation.
  • the presence of each of these cytokines or markers may be assessed using various assays, preferably by ELISA as exemplified in the experimental part. Inflammation may also be assessed by leukocyte count by techniques known to the skilled person.
  • Oxidative stress may be diagnosed using techniques known to the skilled person. Oxidative stress may be diagnosed by quantifying the presence of or a certain quantity of malondialdehyde (normal level 0,6 - less than 1.5 nmol/mL, elevated level > 1,5 nmol/mL) (ALPCO diagnostics Malondialdehyde HPLC kit).
  • an inflammation-mediated disease is a disease wherein oxidative stress occurs.
  • Any disease as identified in table 1 is encompassed within the present invention.
  • said disease is selected from: T2DM (Type 2 Diabetes), cardiovascular disease related to T2DM, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), sepsis, atherosclerosis, and systemic sclerosis .
  • a disease wherein oxidative stress occurs is not an inflammation-mediated disease.
  • Such disease includes cancer.
  • an organism or an individual or a subject may be an animal or a human being.
  • the organism is a human being.
  • an organism treated is suspected to have a high risk of developing a inflammation mediated disease or a disease wherein oxidative stress occurs, due for example to physiological factors (genetic predisposition, age) and/or to the environment of the subject and/or to the lifestyle of a subject (for example nutritional habit and/or to the absence of physical activity).
  • Atazanavir does not reduce the body fat content or the body weight and/or does not have a neuroprotective effect.
  • prevention shall be understood to include complete prevention, prophylaxis, as well as lowering the individual's risk of falling ill with said disease or condition.
  • the term shall also be understood to include alleviation of a symptom known to be associated with an inflammation-mediated disease or a symptom known to be associated with a disease wherein oxidative stress occurs .
  • Prevention may also mean that a parameter or marker known to be associated with an inflammation mediated disease stays within values which are associated to the absence of said disease. The same holds for a disease wherein oxidative stress occurs.
  • a symptom associated with an inflammation-mediated disease or a disease wherein oxidative stress occurs may depend on the disease itself.
  • a symptom may be hyperglycemia .
  • the presence of such a symptom may be assessed using a glucose meter for measurement of capillary blood.
  • a symptom may be cardiac angina on exertion.
  • the presence of such a symptom may be assessed using an electrocardiogram (EKG) produced during exertion.
  • EKG electrocardiogram
  • a symptom may be hypotension.
  • the presence of such symptom may be assessed using intra-arterial blood pressure monitoring.
  • a symptom may be hypoalbuminaemia.
  • the presence of such a symptom may be assessed by clinical chemistry on a venous blood sample.
  • a symptom may be joint swelling.
  • a symptom may be skin thickening and hardening (sclerosis), The presence of such symptom may be assessed during physical examination.
  • Alleviation of a symptom known to be associated with an inflammation-mediated or - associated disease or associated with a disease wherein oxidative stress occurs preferably means that said symptom is no longer detectable in a subject after at least two consecutive days of treatment with at least 10, 50, 70, 100 or 150 or 200 or 300 mg of Atazanavir per day or twice daily or at least three consecutive days, or at least four consecutive days, or at least one seven consecutive days, or at least one month of continuous or intermittent treatment, or at least six months of continuous or intermittent treatment, or at least one year of continuous or intermittent treatment or longer.
  • Delaying used herein means administration of Atazanavir to an organism, i.e. a patient being in a pre-stage of the condition to be treated in which patients a pre- form of the corresponding condition is diagnosed by methods known in the art. "Delaying” may mean that the apparition of any symptom or the value of a parameter known to be associated with an inflammation mediated disease or associated with a disease wherein oxidative stress occurs is delayed for at least one week, one month, six months, one year or more. In a preferred embodiment, oxidative stress is delayed for at least one week, one month, six months, one year or more.
  • treatment means the management and care of a patient for the purpose of combating the inflammation-mediated or -associated disease, condition, or disorder or the disease wherein oxidative stress occurs .
  • Treating may mean that a symptom associated with an inflammation mediated disease or a disease wherein oxidative stress occurs will be alleviated and/or a value of a parameter known to be associated with an inflammation-mediated or -associated disease or a disease wherein oxidative stress occurs will be modulated to rejoin a physiological level (decreased or increased) after at least two consecutive days of treatment with Atazanavir or at least three consecutive days, or at least four consecutive days, or at least one seven consecutive days, or at least one month of continuous or intermittent treatment, or at least six months of continuous or intermittent treatment, or at least one year of continuous or intermittent treatment or longer.
  • modulation and “regulating” is art-recognized and refers to up regulation (i.e., activation or stimulation or increase), or down regulation (i.e., inhibition or suppression or decrease) of a value of a parameter known to be associated with an inflammatory associated disease or with a disease wherein oxidative stress occurs.
  • An increase or decrease of said value of a parameter is preferably defined as being a detectable change of the value of said parameter as compared to the value of the same parameter in a control subject.
  • a control subject is preferably a healthy or a subject which has not yet been treated with Atazanavir.
  • an increase of the value of a parameter means an increase of at least 5% of the value of said parameter. More preferably, an increase of the value of said parameter means an increase of at least 10%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, at least 150% or more.
  • a decrease of the value of a parameter means a decrease of at least 5% of the value of said parameter. More preferably, a decrease of the value of said parameter means a decrease of at least 10%, even more preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 70%, at least 90%, at least 150% or more.
  • a parameter as identified herein may be a parameter which is specific for a given inflammation-mediated or -associated disease or a disease wherein oxidative stress occurs.
  • a parameter may be HbAl c level in venous blood.
  • the value of said parameter is ranged between 6.5 and 1 1.0 %, it is indicative of the presence of said disease.
  • the value of said parameter is ranged between 4.0 and less than 6.5, it is indicative of the absence of said disease.
  • Said parameter may be assessed by clinical chemistry on a venous blood sample 12 .
  • a parameter may be high sensitivity C-reactive protein plasma levels.
  • the value of said parameter is ranged between 2.0 and 6.5 mg/litre, it is indicative of the presence of said disease.
  • the value is ranged between 1.0 and less than 2.0 mg/litre, it is indicative of the absence of said disease.
  • Said parameter may be assessed by clinical chemistry on a venous blood sample. 13
  • a parameter may be C-reactive protein plasma level.
  • the value of said parameter is ranged between 10.0 and 500.0 mg/litre, it is indicative of the presence of said disease.
  • the value of said parameter is ranged between 1.0 and 10 mg/liter, it is indicative of the absence of said disease.
  • Said parameter may be assessed by clinical chemistry on a venous blood sample.
  • a parameter may be albumin plasma level.
  • the value of said parameter is ranged between 12.0 and 35.0 g/litre, it is indicative of the presence of said disease.
  • the value of said parameter is more than 35.0 and up to 50.0 g/litre, it is indicative of the absence of said disease.
  • Said parameter may be assessed by clinical chemistry on a venous blood sample.
  • a parameter may be the erythrocyte sedimentation rate (ESR).
  • ESR erythrocyte sedimentation rate
  • a parameter may be assessed using venous blood sampling.
  • a parameter may be the modified Rodnan skin score (mRss). 11 The value of said parameter is ranged between 0 and 51. The higher the score, the greater the extent and severity of the disease. Said parameter may be assessed by physical examination.
  • said parameter may be a parameter which is known to be indicative of inflammation or of oxidative stress as earlier defined herein.
  • values of said parameters which are known to be associated with the presence/absence of inflammation will be considered as values which are indicative for the presence/absence of said inflammation mediated disease.
  • values of said parameters which are known to be associated with the presence/absence of oxidative stress will be considered as values which are indicative for the presence/absence of said disease wherein oxidative stress occurs.
  • a medicament or a pharmaceutical composition will usually comprise a pharmaceutical carrier in addition to Atazanavir.
  • the formulation of a composition depends on the intended mode of administration and (therapeutic) application of Atazanavir.
  • a pharmaceutical carrier can be any compatible, non toxic substance suitable to deliver Atazanavir to a subject. E.g. sterile water, or inert solids or excipient may be used as the carrier usually complemented with pharmaceutically acceptable adjuvants, buffering agents, dispersing agents, and the like.
  • Compositions will either be in liquid, or in solid and/or in dry form.
  • Atazanavir can be administered in a solid dosage form, such as a capsule, tablet, and powder, or in a liquid dosage form, such as an elixir, a syrup, and a suspension.
  • a composition comprising Atazanavir may be liquid solid or semi solid.
  • Atazanavir may be formulated in a solid phase as powder, optionally in a capsule or tablet.
  • a solution of Atazanavir, and also a suspension, and especially an isotonic aqueous solution or suspension is preferably used, it being possible, for example in the case of a lyophilised composition that comprise Atazanavir alone or together with a carrier, for example mannitol, for such solutions or suspensions to be made up prior to use.
  • a pharmaceutical composition may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, or acids, for example citric acid, and are prepared In a manner known per se, for example by means of conventional dissolving or lyophilising processes.
  • the said solutions or suspensions may comprise viscosity-increasing substances, such as so dium carboxymethylcellu-lose, carboxymethylcellulose, hydroxypropylmethylcellulose (e.g. cellulose HPM603), silica gel, dextran, polyvinylpyrrolidone or gelatin.
  • viscosity-increasing substances such as so dium carboxymethylcellu-lose, carboxymethylcellulose, hydroxypropylmethylcellulose (e.g. cellulose HPM603), silica gel, dextran, polyvinylpyrrolidone or gelatin.
  • a suspension in oil comprises as the oil component the vegetable, synthetic or semisynthetic oils customary for injection purposes.
  • liquid fatty acid esters that contain as acid component a long-chained fatty acid having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, -carntene or 3,5-di-tert-butyl- 4-hydroxytoluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palpitate, "Labrafil M 2375” (polyoxy ethylene glycerol trioleate, Gattefoss , Paris), "Miglyol 812” (triglyceride of saturated fatty acids with a chain length of Ce to C12, Hills AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, soybean oil and more especially groundnut oil and sesame oil.
  • vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, soybean oil and more especially groundnut oil and sesame oil.
  • An injection composition is prepared in customary manner under sterile conditions; the same applies also to introducing said composition into an ampoule or vial and sealing the containers.
  • a pharmaceutical composition for oral administration can be obtained by combining Atazanavir with a solid carrier, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of an appropriate excipient, into a tablet, dragee cores or capsule. It is also possible to incorporate Atazanavir into a plastics carrier that allow it to diffuse or be released in a controlled amount, i.e. a so-called controlled release formulation.
  • a suitable carrier is especially a filler, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also a binder, such as a starch paste using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
  • a filler such as sugars, for example lactose, saccharose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates for example tricalcium phosphat
  • An excipient is especially a flow conditioner and/or a lubricant, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • Dragee cores may be provided with a suitable, optionally enteric, coating, there being used inter alia concentrate d sugar so lutions which may compri s e gum arab ic , talc , polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulos e prep arati ons , such a s ethyl c e l lulo s e p hth al ate or hydroxypropylmethylcellulose phthalate.
  • a capsule may be a hard gelatin capsule or a soft, sealed capsule made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • a hard gelatin capsule may comprise Atazanavir in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with a stabiliser.
  • Atazanavir is preferably dissolved or suspended in a suitable oily excipient, such as a fatty oil, paraffin oil or liquid polyethylene glycols, it likewise being possible for a stabilizer and/or an antibacterial agent to be added.
  • oils especially liquid fatty acid esters that contain as acid component a long-chained fatty acid, for example having from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid, or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, - carotene or 3,5-di-tert-butyl-4-hydroxy- toluene.
  • antioxidants for example vitamin E, - carotene or 3,5-di-tert-butyl-4-hydroxy- toluene.
  • the alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially ethylene or propylene glycol and glycerol.
  • fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375 " (polyoxy ethylene glycerol trioleate, Gattefoss , Paris), UMiglyol 812” (triglyceride of saturated fatty acids with a chain length of C8 to C12, Hulls AG, Germany), but especially vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, groundnut oil, soybean oil and more especially sesame oil. Paraffin oil is also possible.
  • a stabiliser such as an emulsifiers, wetting agent or surfactant, binder, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose (preferred), sodium carboxymethylcellulose, cyclodextrin(s) and/or polyvinylpyrrolidone, and/or antibacterial agents may be added.
  • binder such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose (preferred), sodium carboxymethylcellulose, cyclodextrin(s) and/or polyvinylpyrrolidone, and/or antibacterial agents may be added.
  • a suitable emulsifier is especially oleic acid, non-ionic surfactants of the fatty acid polyhydroxy alcohol ester type, such as sorbitan monolaurate, monooleate, monostearate or monopalmitate, sorbitan tristearate or trioleate, polyoxy ethylene adducts of fatty acidpolyhydroxy alcohol esters, such as polyoxy ethylene sorbitan monolaurate, mono-oleate, monostearate, monopalmitate, tristearate or trioleate, polyethylene glycol fatty acid esters, such as polyoxyethyl stearate, polyoxyethylene glycol (300 or 400) stearate, poly-ethylene glycol 2000 stearate, especially ethylene oxide/propylene oxide block polymers of the E)Pluronic type (Wyandotte Them.
  • non-ionic surfactants of the fatty acid polyhydroxy alcohol ester type such as sorbitan monolaurate, monooleate, monostearate or monopalmitate
  • Atazanavir is not soluble in the mentioned oils it is present in the form of a suspension, for example having a particle size of approximately from 1 to 100 mm. Such a suspension may also be used as such, that is to say without capsules.
  • a colouring or a pigment may be added to a tablets or a dragee coating or to a capsule wall, for example for identification purposes or to indicate different doses of Atazanavir.
  • a preferred mode of administration is oral administration using a capsule or a tablet as earlier identified herein.
  • Commercially available forms of Atazanavir are tablets of 200 mg.
  • Several formulations of Atazanavir are disclosed in patent application EP 900 210. The dose of Atazanavir used depends on the species of subject, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.
  • a dose of at least 10, 50, 70, 100 or 200 or 300 mg of Atazanavir is administered twice daily during at least two consecutive days to a subject, or a dose of at least 10, 50, 70, 100 or 200 or 300 mg of Atazanavir is administered twice daily during at least three or four consecutive days to a subject, or at least seven consecutive days, or at least one month, or at least two month, or at least three month, or at least four month, or at least five month, or at least six months, or at least one year or longer.
  • Atazanavir may be administered in a continuous (i.e. each day during the treatment) or intermittent treatment.
  • Atazanavir is administered in a continuous treatment. In a treatment of more than one month, Atazanavir is preferably administered daily, more preferably at least 50 mg twice daily.
  • Atazanavir may be used in combination with another active ingredient known to be active against an inflammation-mediated or -associated disease or against a disease wherein oxidative stress occurs. Therefore, the invention further encompasses a medicament comprising Atazanavir and a further active ingredient.
  • Other active ingredients in a medicament or in a pharmaceutical composition may be an ingredient which is normally classically used for preventing, delaying and/or treating an inflammation-mediated an or -associated disease or a disease wherein oxidative stress occurs in a subject.
  • Preferred active ingredients include an antioxidant especially when the inflammation mediated disease is sepsis.
  • Preferred antioxidants include vitamin c and/or N-acetylcysteine.
  • Atazanavir may be administered simultaneously or sequentially with another active ingredient.
  • Atazanavir for the manufacture of a medicament as defined earlier herein.
  • Methods for the manufacture of a medicament as defined earlier herein.
  • the verb "to comprise” and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
  • the verb "to consist” may be replaced by "to consist essentially of meaning that a medicament or a pharmaceutical composition as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention.
  • reference to an element by the indefinite article “a” or “an” does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements.
  • the indefinite article “a” or “an” thus usually means “at least one”.
  • Figure 1 structural formula of Atzanavir.
  • Figure 2 protocol for plethysmography
  • Figure 3 Effect of placebo and atazanavir treatment on acetylcholine (0.5, 2.0 and 8.0 ⁇ / ⁇ ) and nitroglycerine (0.125, 0.250 and 0.500 ⁇ / ⁇ 1/ ⁇ ) induced change in forearm blood flow (FBF, ml/dl/min, mean + SE), expressed as a ratio of forearm flow and preceding baseline (dose/baseline saline).
  • bilirubin is one of the effector molecules of heme oxygenase (HO), which breaks down heme into carbon monoxide (CO), iron (Fe) and biliverdin.
  • HO heme oxygenase
  • CO carbon monoxide
  • Fe iron
  • BVR biliverdin reductase
  • UGT1A1 UDP glucuronosyl transferase
  • FIG. 5 the vasodilator response to acetylcholine (ACh) and to nitroglycerin (NTG) were consecutively assessed. Both vasodilators were administered in three increasing doses. Dosages were adjusted to forearm volume (depicted as ⁇ g/min/dL forearm volume). A 30 minute pause (equilibration period) was made prior to each agent. S, saline.
  • Figure 6 increase of FBF in response to the three increasing dosages of acetylcholine (ACh) and nitroglycerin (NTG), depicted as percentage from baseline. Error bars indicate standard errors of the mean. Black columns represent placebo treatment, white columns atazanavir treatment. Statistical analysis was performed on the log- transformed data depicted in table 3. Examples
  • Example 1 Treatment of Type 2 diabetes mellitus
  • Study design (see table 2 2): Single-centre, randomized, double blind, placebo- controlled, cross-over study.
  • Forearm blood flow was assessed by venous occlusion strain gauge plethysmography on days 4 and 32.
  • HO activity was quantified by several means on days 1, 4, 29 and 32. mRNA levels, protein levels and in vitro activity will be determined using isolated peripheral mononuclear blood cells (PMBC's) acquired by venapuncture. In addition, plasma levels of heme, bilirubin and ferritin will be determined. Finally, HO activity will be quantified by the measurement of end tidal CO levels.
  • PMBC's peripheral mononuclear blood cells
  • statins were necessary as some statins interact with atazanavir (see IB) and statins additionally have shown to influence the HO system in vitro. 14 This cessation was temporary, starting four weeks before the first treatment period and ending immediately after the second. For the justification of statin withdrawal, see 'Treatment of subjects'.
  • Study population patients with T2DM, aged 18 - 70 years.
  • the research population consisted of T2DM patients of all ethnic backgrounds, both sexes and age between 18 and 70. Subjects were not allowed to use anti-hypertensive medication or suffer from cardiovascular co-morbidity.
  • Type 2 diabetes mellitus treated with diet, oral medication and/or insulin.
  • Subject has a Quetelet Index (Body Mass Index) of 18 to 35 kg/m 2 .
  • results of haematology and biochemistry testing should be within the laboratory's reference ranges.
  • Determinants of renal and hepatic function should be within twice the upper limit of normal range. Abnormalities in lipid profile are permitted.
  • Cardiac conduction abnormalities consisting of a 2 nd degree atrioventricular block or a complex bundle branch block.
  • Subjects with Gilbert Syndrome which is suggested by an unconjugated hyperbilirubinemia (total bilirubin level above 10 ⁇ /L and a normal direct bilirubin level) and has to be confirmed by genetic testing.
  • Intervention Four day treatment with atazanavir (300 mg twice daily) in a placebo- controlled, randomized and double blinded cross-over design with a washout period of three weeks.
  • the normally prescribed dosage of atazanavir is 400 mg once daily. Bilirubin levels obtained with this dosage, were monitored during a former study of the department of pharmacy. In the 48 healthy subjects without the Gilbert syndrome, bilirubin levels reached a mean of 36,1 ⁇ /L (13,7 - 94,1 ⁇ /L, SD 16,6) on the seventh day of treatment.
  • Atazanavir The half life of atazanavir is quite short (8,6 hrs). The usual once-daily regimen therefore causes large concentration swings. Unfortunately, the half life of bilirubin is even shorter; the plasma level following an intravenously administered bolus was shown to be halved in less than an hour. 16 Consequently, we expected large swings of bilirubin parallel to the swings of atazanavir. As we aimed at the protective effect of bilirubin, these presumably large swings were fairly undesirable. We therefore suggested to prescribe atazanavir in a dosage of 300 mg twice daily. This regimen had been used in a pharmacokinetic study before and had not been associated with an increase of side effects.
  • VCAM-1 soluble vascular adhesion molecules
  • ICAM-1 ICAM-1
  • E-selectin E-selectin
  • von Willebrand Factor soluble vascular adhesion molecules
  • cytokines IL-6, IL-10 and/or TNF-a
  • Both treatment periods consisted of 4 consecutive days. Pill intake was observed on day 1 and 4 of both treatment periods. During all these visits blood was collected by venapuncture (hematology, biochemistry, adhesion molecules and PBMC isolation). End tidal CO levels were determined on day 1 and 4 of each treatment period. On the last treatment day, endothelial function was assessed by measurement of the forearm blood flow, a technique which is described in detail below.
  • Vasodilating agents were administered in three increasing doses during 5 minutes a dose. The agents were considered to have reached a stable concentration within 3 minutes. Forearm blood flow (FBF) was therefore assessed during the last 2 minutes of each dose. A 30 minute pause was made prior to each agent, to ensure proper baseline measurements. Blood flow to the hands was occluded by inflation of the wrist cuffs to 300 mm Hg and restored during NaCl infusion. The upper arm cuffs were repeatedly inflated by a Hokanson rapid cuff inflator (Hokanson, Belllevue, US) to a pressure of 40 mg Hg to occlude venous return for 10 seconds during FBF registration. One cycle of FBF measurements consisted of approximately 8 measurements a dose. The total procedure took approximately three hours. Results
  • Example 2 Experimental hyperbilirubinemia improves endothelial function in patients with type 2 diabetes mellitus.
  • Subjects with T2DM were recruited through local advertising and were not allowed to have a positive history of smoking, drug abuse or macrovascular complications of diabetes. Subjects had to be at least 18 and no older than 70 years of age. The body mass index was allowed to range from 18 to 35 kg/m 2 . All hyperglycemia treatment regimens including diet, oral medication and insulin therapy were accepted. Subjects were prohibited from using vasoactive medication, aspirin or anti-oxidant vitamin supplements, as these drugs could influence endothelial function. To avoid pharmacokinetic interactions with atazanavir, any use of gastric acid suppressive medication and statins was discontinued during participation starting four weeks prior to the first treatment period. Subjects were enrolled only if they accepted such treatment interruption during participation. All subjects gave written informed consent prior to the screening visit.
  • the regular dose regimen of atazanavir in HIV patients was modified to an alternative regimen of 300 mg twice daily to be taken with food. If reflected by the area under the curve, the exposure to atazanavir caused by this dose regimen does not exceed the exposure associated with both regular dose regimens. 17
  • forearm blood flow was assessed by venous occlusion strain gauge plethysmography.
  • a time schedule of these flow assessments is provided in figure 4. All experiments were performed in the morning after an overnight fast in a temperature-controlled room (23° C) with the subjects in supine position. If needed, dose adjustments of hypoglycaemic agents were recommended during the evening and early morning prior to the assessments. Capillary glucose levels were monitored. The brachial artery of the non-dominant arm was cannulated with a 27-gauge needle (kindly supplied by B.
  • FBF was recorded simultaneously on both the infusion and the control arm by venous occlusion plethysmography using mercury-in-silastic strain gauges (Hokanson EC4, Hokanson, Inc., Washington, USA).
  • the upper arm cuffs were inflated using a rapid cuff inflator (Hokanson E-20, DE Hokanson). Wrist cuffs were inflated to 220 mm Hg during each series.
  • blood pressure in supine position was assessed with an aneroid sphygmomanometer.
  • venous blood was drawn. Hematological parameters were assessed using an AD VIA 120 Hemalog (Bayer Diagnostic, Tarrytown, N.Y., USA) and chemical parameters including bilirubin levels were determined using an Aeroset (Abbott Laboratories, Abbott Park, IL, U.S.A.). In addition, plasma samples were stored at -80° C for determination of atazanavir plasma levels, anti-oxidant capacity and biomarkers of vascular inflammation. Atazanavir plasma levels were determined using a modification of a validated HPLC method with UV detection as published previously. 16 Plasma anti-oxidant capacity was assessed by means of the ferric reducing ability of plasma (FRAP) assay, according to the method of Benzie and Strain.
  • FRAP ferric reducing ability of plasma
  • FRAP values were obtained using a seven-point calibration curve of known amounts of Fe 2+ and expressed in mmol Fe 2+ /L.
  • concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule- 1 (sICAM-1) were determined by a multiplex assay (Bio-plex cytokine assay, BioRad, Hercules, CA, USA at Luminex 100, Luminex Corporation, the Netherlands).
  • the concentration of von Willebrand factor (vWF) was determined by ELISA (Progen biotechnik, Heidelberg, Germany and R&D systems, Minneapolis, U.S. A). To enable the determination of bilirubin levels after deblinding of the study one additional lithium heparin plasma sample was stored at -80°C in a brown Eppendorf tube.
  • Figure 6 displays the original data in terms of percentage from baseline.
  • the log-transformed data used for analysis are presented in table 5.
  • the data discussed in the text are medians instead of averages of the original flow data to approximate the effect of logarithmic transformation. Statistical significance was accepted at the 95% confidence level (P ⁇ 0.05).
  • the results of FBF experiments are depicted in figure 6 and table 5. Baseline flow after placebo treatment was comparable to baseline flow after atazanavir treatment (1.8 and 1.5 mL/min/dL tissue in the intervention arm and 1.6 and 1.7 mL/min/dL in the control arm respectively). Neither acetylcholine infusion nor nitroglycerin infusion affected the blood flow of the contralateral forearm (data not shown).
  • Intra arterial infusion of acetylcholine induced an increase in FBF at all three doses after both placebo and atazanavir treatment.
  • atazanavir treatment was accompanied by a significantly enhanced vasodilator response to acetylcholine.
  • FBF amounted to median levels of 19.9 and 21.9 mL/min/dL following placebo and atazanavir treatment respectively.
  • a 12 percent increase of FBF was observed without relevant differences between the three acetylcholine dosages.
  • acetylcholine response was not influenced by the atazanavir level, the bilirubin level following atazanavir treatment, the glycated hemoglobin level at baseline or the duration of diabetes prior to inclusion (based on po st ho c analysis) .
  • Intra-arterial infusion of nitroglycerin also induced a significant increase of FBF at all dosages. Contrary to acetylcholine, the extent of vasodilator response to nitroglycerin was not influenced by our intervention with atazanavir. At the highest nitroglycerin dose, 0.5 ⁇ g/min/dL, FBF amounted to median levels of 7.3 and 7.1 mL/min/dL following placebo and atazanavir treatment respectively.
  • Endothelial dysfunction is strongly related to the development of atherosclerosis and the resulting cardiovascular risk. 19 Central in the pathogenesis of endothelial dysfunction is the decreased availability of endothelial nitric oxide (NO). 20 One of the key factors leading to limited NO availability is the increase of intracellular oxidative stress. A substantial part of the production of reactive oxygen species (ROS) is supposed to stem from NADPH oxidase activity. 21 Addressing the mechanistic importance of oxidative stress, several groups have studied the effect of anti-oxidant treatment strategies among which intra-arterial infusion of ascorbate.
  • ROS reactive oxygen species
  • HIV protease inhibitors are commonly connoted for their contribution to cardiovascular complications in HIV patients. 31 In contrast to several other protease inhibitors however, atazanavir does not affect glucose tolerance, plasma cholesterol level or endothelial function in healthy volunteers at a dosage of 400 mg once daily. 32 Consistently, we did not observe changes in plasma glucose or plasma cholesterol levels at a twice daily dosage of 300 mg nor did we find a relation between atazanavir plasma levels and the observed improvement of endothelial function.
  • Table 1 List of examples of inflammation-mediated and associated diseases that may be treated by atazanavir treatment. inflammation related to: Examples of disorders and conditions
  • headache disorders such as migraine, cluster headache and
  • neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis (Lou Gehrig's disease).
  • cerebrovascular disease such as transient ischemic attack and stroke.
  • demyelinating diseases of the central nervous system such as multiple sclerosis
  • peripheral nervous system such as Guillain-Barre syndrome and chronic inflammatory
  • CIDP demyelinating polyneuropathy
  • spinal cord disorders -infections trauma, malformations (e.g., myelocele, meningomyelocele, tethered cord)
  • Table 2 overview of study activity in the trial dedicated to T2DM.
  • Data are given as mean (SD, range), frequency of treatment regimens are given as number of subjects.
  • SD body mass index
  • HbAlc average glycated hemoglobin
  • SU sulphonyl urea derivates.
  • LDL low-density lipoprotein
  • FRAP ferric reducing ability of plasma
  • vWF von Willebrand factor
  • sVCAM-1 soluble vascular cell adhesion molecule- 1
  • sICAM- 1 soluble interstitial cellular adhesion molecule- 1.
  • Reported P-values are the result of paired t-tests.
  • AChl-3 acetylcholine dosage of 0.5, 2.0 and 8.0 ⁇ g/min/dL respectively; NTGl-3, nitroglycerin dosage of 0.125, 0.250 and 0.500 ⁇ g/min/dL respectively.
  • standard errors of the mean In parenthesis standard errors of the mean.
  • Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996; 97(l):22-28. van Etten RW, de Koning EJ, Verhaar MC, Gaillard CA, Rabelink TJ. Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate. Diabetologia 2002; 45(7): 1004-1010.
  • Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 1997 June 17;95(12):2617-22. dei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998 June 9;97(22):2222-9. HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA.
  • Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin- dependent diabetes mellitus. J Clin Invest 1996 January l ;97(l):22-8. imi FK, Ting HH, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with insulin- dependent diabetes mellitus. J Am Coll Cardiol 1998 March l;31(3):552-7. arty MF. "Iatrogenic Gilbert syndrome"- A strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. Med Hypotheses 2007;69(5):974-94. nger R, Yamashita K, Bilban M et al.
  • Bilirubin and biliverdin treatment of atherosclerotic diseases Cell Cycle 2007 January l ;6(l):39-43. dberg RB. Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab 2009 September;94(9):3171-82. ashi S, Takamiya R, Yamaguchi T et al. Induction of heme oxygenase- 1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme. Circ Res 1999 October 15;85(8):663-71.

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Abstract

L'invention porte sur l'atazanavir destiné à être utilisé comme médicament pour empêcher, traiter et/ou retarder une maladie à médiation par inflammation ou associée à une inflammation et/ou une maladie dans laquelle un stress oxydatif se produit.
PCT/NL2010/050628 2009-09-28 2010-09-28 Atazanavir pour le traitement de maladies inflammatoires Ceased WO2011037467A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104055770A (zh) * 2014-07-03 2014-09-24 滨州医学院 利托那韦在制备预防或治疗缺血性心脑血管疾病的药物中的应用
CN104083366A (zh) * 2014-07-08 2014-10-08 滨州医学院 硫酸阿扎那韦在制备预防或治疗缺血性心脑血管疾病的药物中的应用
CN115887454A (zh) * 2022-12-01 2023-04-04 清华大学 阿扎那韦用于调节gpr119受体活性的用途
WO2024113305A1 (fr) * 2022-12-01 2024-06-06 清华大学 Utilisation d'atazanavir pour réguler l'activité du récepteur gpr119

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0900210A1 (fr) 1996-04-22 1999-03-10 Novartis AG Derives d'azahexane heterocycliques a activite antivirale
WO2006050999A2 (fr) * 2004-11-15 2006-05-18 Obe Therapy Biotechnology S.A.S Compositions pharmaceutiques et procedes de reduction de la graisse corporelle
WO2006108666A1 (fr) * 2005-04-13 2006-10-19 Proteosys Ag Mefloquine, nelfinavir et saquinavir utilises comme nouveaux agents dans les maladies neurodegeneratives et (neuro)inflammatoires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0900210A1 (fr) 1996-04-22 1999-03-10 Novartis AG Derives d'azahexane heterocycliques a activite antivirale
WO2006050999A2 (fr) * 2004-11-15 2006-05-18 Obe Therapy Biotechnology S.A.S Compositions pharmaceutiques et procedes de reduction de la graisse corporelle
WO2006108666A1 (fr) * 2005-04-13 2006-10-19 Proteosys Ag Mefloquine, nelfinavir et saquinavir utilises comme nouveaux agents dans les maladies neurodegeneratives et (neuro)inflammatoires

Non-Patent Citations (39)

* Cited by examiner, † Cited by third party
Title
ACOSTA EP; KENDALL MA; GERBER JG ET AL.: "Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily", ANTIMICROB AGENTS CHEMOTHER, vol. 51, no. 9, September 2007 (2007-09-01), pages 3104 - 10
BENZIE IF; STRAIN JJ: "The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay", ANAL BIOCHEM, vol. 239, no. 1, 15 July 1996 (1996-07-15), pages 70 - 6
BERGERSEN BM: "Cardiovascular risk in patients with HIV Infection: impact of antiretroviral therapy", DRUGS, vol. 66, no. 15, 2006, pages 1971 - 87
CHEN H; KARNE RJ; HALL G ET AL.: "High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance", AM JPHYSIOL HEART CIRC PHYSIOL, vol. 290, no. 1, January 2006 (2006-01-01), pages H137 - H145
CHOWIENCZYK PJ; BRETT SE; GOPAUL NK ET AL.: "Oral treatment with an antioxidant (raxofelast) reduces oxidative stress and improves endothelial function in men with type II diabetes", DIABETOLOGIA, vol. 43, no. 8, 2000, pages 974 - 977
COLAFIGLI M ET AL: "Cardiovascular risk score change in HIV-1-infected patients switched to an atazanavir-based combination antiretroviral regimen.", HIV MEDICINE MAR 2008, vol. 9, no. 3, March 2008 (2008-03-01), pages 172 - 179, XP002558687, ISSN: 1464-2662 *
DARKO D; DORNHORST A; KELLY FJ; RITTER JM; CHOWIENCZYK PJ: "Lack of effect of oral vitamin C on blood pressure, oxidative stress and endothelial function in Type II diabetes", CLIN SCI (LOND), vol. 103, no. 4, October 2002 (2002-10-01), pages 339 - 44
DEANFIELD JE; HALCOX JP; RABELINK TJ: "Endothelial function and dysfunction: testing and clinical relevance", CIRCULATION, vol. 115, no. 10, 13 March 2007 (2007-03-13), pages 1285 - 95
DEANFIELD JE; HALCOX JP; RABELINK TJ: "Endothelial function and dysfunction: testing and clinical relevance", CIRCULATION, vol. 115, no. 10, 2007, pages 1285 - 1295
DUBE MP; SHEN C; GREENWALD M; MATHER KJ: "No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial", CLIN INFECT DIS, vol. 47, no. 4, 15 August 2008 (2008-08-15), pages 567 - 74
FORSTERMANN U; MUNZEL T: "Endothelial nitric oxide synthase in vascular disease: from marvel to menace", CIRCULATION, vol. 113, no. 13, 4 April 2006 (2006-04-04), pages 1708 - 14
FURST DE; CLEMENTS PJ; STEEN VD ET AL.: "The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis", J RHEUMATOL, vol. 25, no. 1, 1998, pages 84 - 88
GAO L; MANN GE: "Vascular NAD(P)H oxidase activation in diabetes: a double- edged sword in redox signalling", CARDIOVASC RES, vol. 82, no. 1, 1 April 2009 (2009-04-01), pages 9 - 20
GOLDBERG RB: "Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications", J CLIN ENDOCRINOL METAB, vol. 94, no. 9, September 2009 (2009-09-01), pages 3171 - 82
HAMILTON SJ; CHEW GT; WATTS GF: "Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus", DIAB VASE DIS RES, vol. 4, no. 2, 2007, pages 89 - 102
HAYASHI S; TAKAMIYA R; YAMAGUCHI T ET AL.: "Induction of heme oxygenase-1 suppresses venular leukocyte adhesion elicited by oxidative stress: role of bilirubin generated by the enzyme", CIRC RES, vol. 85, no. 8, 15 October 1999 (1999-10-15), pages 663 - 71
KOLLS JK: "Oxidative stress in sepsis: a redox redux", J CLIN INVEST, vol. 116, no. 4, 2006, pages 860 - 863
KWAK JY; TAKESHIGE K; CHEUNG BS; MINAKAMI S: "Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system", BIOCHIM BIOPHYS ACTA, vol. 1076, no. 3, 15 February 1991 (1991-02-15), pages 369 - 73
LEE TS; CHANG CC; ZHU Y; SHYY JY: "Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection", CIRCULATION, vol. 110, no. 10, 2004, pages 1296 - 1302
LITTLE RR; SACKS DB: "HbAlc: how do we measure it and what does it mean?", CURR OPIN ENDOCRINOL DIABETES OBES, vol. 16, no. 2, 2009, pages 113 - 118
MCCARTY MF: ""Iatrogenic Gilbert syndrome"- A strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin", MED HYPOTHESES, vol. 69, no. 5, 2007, pages 974 - 94
OLLINGER R; YAMASHITA K; BILBAN M ET AL.: "Bilirubin and biliverdin treatment of atherosclerotic diseases", CELL CYCLE, vol. 6, no. 1, 1 January 2007 (2007-01-01), pages 39 - 43
PLEINER J; MITTERMAYER F; SCHALLER G; MARSIK C; MACALLISTER RJ; WOLZT M: "Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress", J AM COLL CARDIOL, vol. 42, no. 9, 2003, pages 1656 - 1662
PYRKO, PETER ET AL: "HIV-1 Protease Inhibitors Nelfinavir and Atazanavir Induce Malignant Glioma Death by Triggering Endoplasmic Reticulum Stress", CANCER RESEARCH , 67(22), 10920-10928 CODEN: CNREA8; ISSN: 0008-5472, 2007, XP002558686 *
RASK-MADSEN C; KING GL: "Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes", NAT CLIN PRACT ENDOCRINOL METAB, vol. 3, no. 1, 2007, pages 46 - 56
ROBERTS WL; MOULTON L; LAW TC ET AL.: "Evaluation of nine automated high- sensitivity C-reactive protein methods: implications for clinical and epidemiological applications", CLIN CHEM, vol. 47, no. 3, 2001, pages 418 - 425
SCHALKWIJK CG; STEHOUWER CD: "Vascular complications in diabetes mellitus: the role of endothelial dysfunction", CLIN SCI (LOND), vol. 109, no. 2, 2005, pages 143 - 159
SCHALLER G; PLEINER J; MITTERMAYER F; POSCH M; KAPIOTIS S; WOLZT M: "Effects of N-acetylcysteine against systemic and renal hemodynamic effects of endotoxin in healthy humans", CRIT CARE MED, vol. 35, no. 8, 2007, pages 1869 - 1875
SORIANO, VINCENT ET AL: "Efficacy and safety of replacing lopinavir with atazanavir in HIV-infected patients with undetectable plasma viremia: final results of the SLOAT trial", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY , 61(1), 200-205 CODEN: JACHDX; ISSN: 0305-7453, 2008, XP002558685 *
TADDEI S; VIRDIS A; GHIADONI L; MAGAGNA A; SALVETTI A: "Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension", CIRCULATION, vol. 97, no. 22, 9 June 1998 (1998-06-09), pages 2222 - 9
TIMIMI FK; TING HH; HALEY EA; RODDY MA; GANZ P; CREAGER MA: "Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus", JAM COLL CARDIOL, vol. 31, no. 3, 1 March 1998 (1998-03-01), pages 552 - 7
TING HH; TIMIMI FK; BOLES KS; CREAGER SJ; GANZ P; CREAGER MA: "Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus", J CLIN INVEST, vol. 97, no. 1, 1 January 1996 (1996-01-01), pages 22 - 8
TING HH; TIMIMI FK; BOLES KS; CREAGER SJ; GANZ P; CREAGER MA: "Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus", J CLIN INVEST, vol. 97, no. 1, 1996, pages 22 - 28
TING HH; TIMIMI FK; HALEY EA; RODDY MA; GANZ P; CREAGER MA: "Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia", CIRCULATION, vol. 95, no. 12, 17 June 1997 (1997-06-17), pages 2617 - 22
VAN ETTEN RW; DE KONING EJ; VERHAAR MC; GAILLARD CA; RABELINK TJ: "Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate", DIABETOLOGIA, vol. 45, no. 7, 2002, pages 1004 - 1010
VERA T; GRANGER JP; STEC DE: "Inhibition of bilirubin metabolism induces moderate hyperbilirubinemia and attenuates ANG 11-dependent hypertension in mice", AM J PHYSIOL REGUL INTEGR COMP PHYSIOL, vol. 297, no. 3, September 2009 (2009-09-01), pages R738 - R743
VITEK L; OSTROW JD: "Bilirubin chemistry and metabolism; harmful and protective aspects", CURR PHARM DES, vol. 15, no. 25, 2009, pages 2869 - 83
VON BERGMANN G; EILBOTT W: "Funktionsprufung der Leber mittels Bilirubinbelastung", ZEITSCHRIFT FUR KLINISCHE MEDIZIN, vol. 106, 1927, pages 520 - 560
XU J; ZOU MH: "Molecular insights and therapeutic targets for diabetic endothelial dysfunction", CIRCULATION, vol. 120, no. 13, 29 September 2009 (2009-09-29), pages 1266 - 86

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104055770A (zh) * 2014-07-03 2014-09-24 滨州医学院 利托那韦在制备预防或治疗缺血性心脑血管疾病的药物中的应用
CN104083366A (zh) * 2014-07-08 2014-10-08 滨州医学院 硫酸阿扎那韦在制备预防或治疗缺血性心脑血管疾病的药物中的应用
CN115887454A (zh) * 2022-12-01 2023-04-04 清华大学 阿扎那韦用于调节gpr119受体活性的用途
WO2024113305A1 (fr) * 2022-12-01 2024-06-06 清华大学 Utilisation d'atazanavir pour réguler l'activité du récepteur gpr119

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