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Diazoxide for use in the treatment of a central nervous system (CNS) autoimmune demyelinating disease

A demyelinating disease, the technology of diazoxide, which is applied in the application field of diazoxide in the treatment or prevention of autoimmune demyelinating diseases of the central nervous system

Inactive Publication Date: 2012-11-07
NEUROTEC PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lenzser G etc. showed that when 20mg / kg (120mg / m 2 ) to rats, diazoxide pretreatment can alleviate the blood-brain barrier permeability caused by global cerebral ischemia, but at 6mg / kg (36mg / m 2 ) has no effect (Lenzser G et al., Brain Research.2005,1051:72-80)

Method used

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  • Diazoxide for use in the treatment of a central nervous system (CNS) autoimmune demyelinating disease
  • Diazoxide for use in the treatment of a central nervous system (CNS) autoimmune demyelinating disease
  • Diazoxide for use in the treatment of a central nervous system (CNS) autoimmune demyelinating disease

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Experimental program
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Effect test

specific Embodiment

[0096] Experiments carried out in mice in the present invention show that diazoxide at most 12mg / m 2 It is effective at different daily doses per day.

[0097] The dose of diazoxide can be expressed as mg diazoxide per kg body weight or mg diazoxide per square meter of roller body surface. The article "Dose translation from animal to human studies revisited" by Reagan-Shaw S. (FASEB J 2007,22:659-661) provides a method for converting mg / kg to mg / m 2 standard conversion factor.

[0098] Dose (mg / kg) x K m = dose (mg / m 2 )

[0099] The article also explains that this conversion is the basis for converting the dose in the first animal species to the dose in the second animal species (dose conversion for body size variation). Thus, a mg / kg animal dose (AD) can be converted to a mg / kg human equivalent dose (HED) by the following formula:

[0100]

[0101] Among them, the Km of each species is shown in Table I (data selected from Reagan-Shaw S. Dose translation from animal ...

Embodiment 1

[0107] Example 1: Low doses of diazoxide do not cause hyperglycemia in mice

[0108] To determine the in vivo effect of very low doses of diazoxide on blood glucose, mice receiving daily doses of diazoxide were monitored. Eleven-week-old female C57BL / 6J mice, purchased from Charles River, were maintained on a 12:12-h light:dark cycle with standard food and water ad libitum. Experiment begins at 11:00. Diazoxide (Sigma-Aldrich, St. Louis, Mo, USA) was administered orally by gavage (p.o.) daily at a dose of 1 mg / kg (3 mg / m 2 ) ( figure 1 A) and 0.05mg / kg (0.15mg / m 2 ) ( figure 1 B) (n=6 / group). This period of time is necessary to generate a steady state of plasma diazoxide concentration. Blood glucose levels were measured every 3-4 days during the 30-day treatment period starting on day 4. Measurements were taken immediately before dosing (time 0) and at 60 minutes. Obtain a blood sample from the saphenous vein and measure blood glucose levels using a glucometer and bl...

Embodiment 2

[0109] Example 2: Low-dose diazoxide improves experimental autoimmune encephalomyelitis in mice

[0110] Female C57BL / 6J mice aged 8-10 weeks, purchased from Harlan Laboratories, were maintained on a 12:12 hr light:dark cycle with standard food and water ad libitum. EAE was induced by immunization with >95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (rat MOG 35-55 , Sequence: MEVGWYRSPFSRVVHLYRNGK; EspiKem Srl, Florence, Italy). Mice were injected subcutaneously on one flank with 100 μl of a solution containing 150 μg of rat MOG (Sigma-Aldrich, St Louis, Mo, USA) in complete Freund's adjuvant and 5 mg / ml of Mycobacterium tuberculosis H37RA (Difco Laboratories, Detroit, MI, USA). Mice also received one intraperitoneal injection of 150 ng pertussis toxin (Sigma-Aldrich, St. Louis, Mo, USA) in 100 μl PBS

[0111] Mice were scored daily for EAE symptoms on a scale of 0-6, according to the following principles: 0, no clinical symptoms; 1: distal tail weakne...

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Abstract

The invention relates to the use of diazoxide or a pharmaceutically acceptable salt thereof at low doses to treat a CNS autoimmune demyelinating disease selected from selected from multiple sclerosis (MS), clinically isolated syndrome (CIS), tumefactive (tumor-like) MS, Marburg's acute MS, Bal?s's concentric sclerosis, acute disseminated encephalomyelitis (ADEM), post-vaccinal encephalitis (PVE), post-infectious encephalomyelitis (PIE) and neuromyelitis optica (NMO).

Description

technical field [0001] The present invention relates to the use of low doses of diazoxide and pharmaceutically acceptable salts thereof in the treatment or prevention of multiple sclerosis (MS), its variants and other central nervous system (CNS) autoimmune demyelinating diseases, and also It relates to compositions comprising low doses of diazoxide for use in the treatment of mammals infected with these diseases. Background technique [0002] Multiple sclerosis (MS) is an autoimmune, chronic inflammatory demyelinating central nervous system (CNS) disease that occurs in genetically predisposed individuals and involves immune factors such as antibodies, complement, and the innate immune response Transmitter. [0003] MS is classified as an idiopathic inflammatory demyelinating disease and is the most common cause of neurological impairment in young adults after trauma and epilepsy (Noseworthy JH et al., Multiple sclerosis. N Engl J Med 2000, 343 :938-52). [0004] MS is ch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/549A61P25/00
CPCA61K31/549A61P25/00A61P35/00A61P37/06A61P43/00
Inventor 马可·普列塞乔塞特-妮可·梅伊盖海妮曼努埃尔·罗德里格斯阿吕胡安弗朗西斯科·埃斯皮诺萨帕里利亚诺埃米·维尔吉利特雷泽尔斯皮拉尔·曼塞拉阿罗卡安德烈·帕斯坦萨莫拉诺
Owner NEUROTEC PHARMA
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