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Methods and compositions for studying, imaging, and treating pain

A technology of compounds and substances, applied in drug combination, compound screening/testing, preparations for in vivo experiments, etc., can solve problems such as inappropriate treatment of patients during surgery

Inactive Publication Date: 2012-05-16
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, despite such evidence to the contrary, the use of these anatomically based imaging findings is unfortunately still an important part of the treatment protocol for many diseases! As a result, a large number of patients suffer from unnecessary surgeries and inappropriate treatments

Method used

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  • Methods and compositions for studying, imaging, and treating pain
  • Methods and compositions for studying, imaging, and treating pain
  • Methods and compositions for studying, imaging, and treating pain

Examples

Experimental program
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Embodiment 1

[0270] Voltage-gated sodium channel (Na V ) Plays an indispensable role in the production of bioelectricity and is also necessary for all life processes. (See literature: for example, Hille, B. Ion Channels of Excitable Membranes, third edition, Sinauer: Sunderland, MA, 2001). It has been identified encoding 10 unique sodium channel isoforms (Na V 1.1-1.9, Na X ) Genes (see literature: (a) Catterall, W.A.; Yu, F.H. Genome Biology 2003, 4, 207. (b) Catterall, W.A.; Goldin, A.L.; Waxman, S.G. Pharm. Rev. 2005, 57, 397). The differences in biophysical properties between these protein subtypes, their membrane concentration and spatial distribution define the signal characteristics of neurons. (See literature: for example, (a) Novakovic, SD; Eglen, RM; Hunter, JCTrends in Neurosci. 2001, 24, 473. (b) Lai, HC; Jan, LY; Nat. Rev. Neurosci. 2006, 7 , 548; (c) Rush, AM; Cummins, TR; Waxman, SGJPhysiol. 2007, 579, 1.) usually considered abnormal Na V Function and / or expression are assoc...

Embodiment 2

[0329] This example provides the synthetic pathways of saxitoxin analogs and related molecules. Take the synthesis of genus goniotoxin 3 (GTX3) as an example, which is similar to other saxitoxin analogs (such as saxitoxin). , New saxitoxin and other genus algae toxins) structure of small molecule biguanide group paralytic shellfish toxin. The first synthesis route of any one of more than 20 known sulfated toxins-Gnometoxin 3 (GTX3) is described in the following documents ( Picture 9 ). (Refer to literature: (a) Shimizu, Y.; Buckley, LJ; Alam, M.; Oshima, Y.; Fallon, WE; Kasai, H.; Miura, I.; Gullo, VP; Nakanishi, KJAm. Chem Soc. 1976, 98, 5414-5416. (b) Boyer, GL; Schantz, EJ; Schnoes, HKJ Chem. Soc., Chem. Comm. 1978, 889-890.. (c) Onodera, H.; Satake , M.; Oshima, Y.; Yasumoto, T.; Carmichael, WWNatural Toxins 1997, 5, 146-151. The following documents describe incomplete synthesis of GTX2 and 3: Hannick, SM; Kishi, YJOrg. Chem .1983, 48, 3833-3835.)

[0330] We recently dis...

Embodiment 3

[0391] After obtaining many molecular probes derived from saxitoxin with linear long-chain branches using the foregoing oxazolidinone intermediates, we further used this chemical property to synthesize many branched-chain derivatives. These molecules have a large volume of space near the saxitoxin mother nucleus, which potentially makes the binding of the toxin unstable. We envision using these molecules in combination with mutant sodium channels to map out the three-dimensional environment around the side chains of STX when it binds to the channel. In addition, it is conceivable to introduce additional chemical structure parts ("bumps") to design saxitoxin derivatives so that they have low binding affinity for wild-type channels and have corresponding "holes" for mutants. High binding affinity. (See the document: Annual Review of Cell and Developmental Biology 2001, 17, 405-433, the content of which is incorporated herein by reference).

[0392] In the initial study, we design...

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Abstract

Saxitoxin analogue compounds, compositions, pharmaceutical compositions, methods of synthesis of saxitoxin analogues, methods of imaging, methods of treatment, including methods of treating pain, are provided. Saxitoxin (STX), gonyautoxin (GTX), and zetekitoxin, and variant STX compounds bind to sodium channels and are effective to reduce or block flow of sodium ions through such channels. Such channel block affects nerve and muscle action, and may be effective to reduce or block pain sensations, relax muscles, reduce muscle spasm, and reduce wrinkles. STX analogue binding to sodium channels may also be useful to locate, image, or mark sodium channels, and so be useful in studying sodium channels and sodium channel disorders, and in the diagnosis and treatment of patients suffering from sodium channel disorders. In embodiments, the variant STX compounds include conjugates having increased serum half-life as compared to STX when administered to a subject. In embodiments, the present disclosure provides a method for alleviating pain in a subject in need of treatment, the method comprising administering to the subject an effective amount of a saxitoxin analogue compound, or a pharmaceutically acceptable salt, isomer, tautomer or prodrug thereof, whereby pain in said subject is alleviated.

Description

[0001] Cross references to related applications [0002] According to 35U.SC§119(e), this application requires the name "METHODS AND COMPOSITIONS FOR STUDYING, IMAGING, AND TREATING PAIN" to be submitted on May 7, 2009 (Methods and compositions for research, imaging and treatment of pain The priority of US provisional patent application 61 / 176,172 of ), the entire content of which is incorporated into this application by reference. [0003] This application relates to the serial number XX / XXX,XXX, and the name "METHODS AND COMPOSITIONS FOR STUDYING, IMAGING, AND TREATING PAIN" submitted by Du Bois et al. on May 7, 2010 (methods for research, imaging and treatment of pain And composition), the entire content of which is incorporated into this application by reference. [0004] Statement on Federal Government Funding of Research [0005] The present invention was made under a government-supported contract / approval number 5R01NS045684-07 (issued by the National Institutes of Health). Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/12C07D487/14A61P29/00
CPCC07D487/14A61Q19/08A61K49/0032A61K49/0052A61K51/0459A61K8/4953C07D487/16A61P1/00A61P1/02A61P1/04A61P1/14A61P11/00A61P13/00A61P13/10A61P13/12A61P15/00A61P17/00A61P19/00A61P19/02A61P21/00A61P21/02A61P25/00A61P25/02A61P25/04A61P25/06A61P25/08A61P27/02A61P27/16A61P29/00A61P35/00A61P43/00A61P9/06A61P9/08A61P9/10A61K49/0002A61K49/0004A61Q19/02
Inventor 贾斯廷·杜波伊斯约翰·马尔卡希布赖恩·安德烈森戴维·C·约曼斯桑迪普·比斯沃
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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