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Crf2 ligands in combination therapy

A technology of CRF2 and CRF1, which is applied in the field of CRF2 ligands for combination therapy, can solve problems such as confusion, decline, oligonucleotide toxicity and side effects, and body weight

Inactive Publication Date: 2004-06-02
BRISTOL MYERS SQUIBB PHARMA CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reg. Peptides71, 15-21, 1997), CRF 2 Receptors were only reduced by 15-20%, while the oligonucleotides used produced toxic side effects (significant weight loss), a result that confounded the results of scientific experiments

Method used

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  • Crf2 ligands in combination therapy
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  • Crf2 ligands in combination therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Synthesis and purification of oligonucleotides for in vivo experiments

[0130] Oligonucleotides were synthesized with an automated ABI 394 RNA / DNA synthesizer using standard synthesis protocols. The antisense and mismatch oligonucleotides used in the experiments shown in Figures 3 and 4 consisted of the following sequences:

[0131] Antisense: TGA CGC agc ggc acC AGA CC

[0132] Mismatches: TGA GGC acc gga acC ACA CC

[0133] Wherein, uppercase letters indicate 2'-methoxyribonucleoside phosphodiester residues, while lowercase letters indicate 2'-deoxyribonucleoside phosphorothioate residues. 2'-Methoxyribonucleoside phosphoimidate was purchased from Chem Genes, propynyl and 5-methylcytidine phosphoimidate were obtained from Glen Research, and 2'-fluoro phosphoimido Esters were obtained from NeXstar. Beaucage reagent for synthesis of phosphorothioate linkages and fluorescein phosphoramidite for 5' labeling of oligonucleotides were purchased from Glen Research. Th...

Embodiment 2

[0136] Animals and Surgery

[0137] Male Sprague Dawley rats (Charles River) weighing 320-360 grams at the time of surgery were housed individually in stainless steel cages and provided free access to food and water. After a 4-day acclimatization period, under anesthesia with Rompun (100 mg / kg) and ketamine (9 mg / kg), long-term 26-gauge catheters were implanted bilaterally in the rats, with the catheters positioned in the lateral ventricle . Orientation coordinates were: incision line 3.3 mm below the interauricular line; 0.2 mm posterior to the brine; ±2.7 mm lateral to the midline; 3.8 mm ventral to the skull surface, and an angle of 24°. A syringe (33 gauge) protruded 0.5 mm beyond the catheter tip. The animals were subjected to daily acclimatization controls beginning 2 days after surgery.

[0138] All animal care used published methods approved by the Institutional Animal Care and Use Committee (IACUC). DuPont Pharmaceutical Research Laboratories is accredited by th...

Embodiment 3

[0140] oligonucleotide administration

[0141] Oligonucleotide infusions were started on day 8 after surgery when the rats weighed approximately 20 grams higher than the weight at surgery. Fresh oligonucleotide solutions were prepared daily by dissolving lyophilized oligonucleotide particles in sterile saline. Rats were weighed daily at 9 am prior to infusion with oligonucleotides. 1 microliter of the solution was injected into each ventricle over 2 minutes using a microprocessor controlled syringe pump (Stoelting). The syringes for each rat were rinsed with ethanol and sterile water and dried between daily injections.

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PUM

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Abstract

This invention relates to antisense oligonucleotides directed against the mRNA of the corticotropin releasing factor subtype-2 (CRF2) receptor which substantially reduce expression of CRF2 receptors in the rodent brain and the use of antisense oligonucleotides in in vivo CNS studies of gene function and to treat a wide range of psychiatric disorders including anxiety, obsessive-compulsive disorder, panic disorders, post-traumatic stress disorder, phobias and depression.

Description

field of invention [0001] The present invention relates to containing CRF 1 Receptor Ligands and CRFs 2 Pharmaceutical compositions of receptor ligands or pharmaceutically acceptable salts or prodrugs thereof; and relating to the treatment of CRF 1 and CRF 2 A method for a disease associated with receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of CRF 1 Receptor Ligands and CRFs 2 A receptor ligand or a pharmaceutically acceptable salt or prodrug thereof, wherein the CRF receptor ligand of the present invention is an agonist or antagonist of the CRF receptor. In addition to the drug targets of the present invention as CRF receptors, the present invention also relates to the targeting of CRF 1 and CRF 2 Pharmaceutical preparations of receptor mRNA. Background of the invention [0002] Numerous studies have demonstrated the importance of corticotropin-releasing factor (CRF) in the control of...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K31/505A61K31/70A61K31/7105A61K31/7115A61K31/712A61K31/7125A61K38/00A61P25/08A61P25/16A61P25/22A61P25/24A61P25/28A61P43/00C12N15/113
CPCC12N2310/346C12N2310/345C12N15/1136C12N2310/3231A61K38/00C12N2310/315A61K31/7125A61P25/08A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P35/00A61P43/00A61K31/7088
Inventor S·P·候
Owner BRISTOL MYERS SQUIBB PHARMA CO
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