A strategy for development of NSAIDs with lower risk for side effects

Tohru Mizushima

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.

Original languageEnglish
Pages (from-to)255-261
Number of pages7
JournalYakugaku Zasshi
Volume128
Issue number2
DOIs
Publication statusPublished - 2008 Feb
Externally publishedYes

Fingerprint

Anti-Inflammatory Agents
Pharmaceutical Preparations
Gastrointestinal Agents
Stomach Ulcer
Gastrointestinal Tract
Membranes
Cardiovascular System
Cell Death
Cardiovascular Diseases

Keywords

  • Gastrointestinal complication
  • Membrane
  • Nonsteroidal antiinflammatory drugs

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

A strategy for development of NSAIDs with lower risk for side effects. / Mizushima, Tohru.

In: Yakugaku Zasshi, Vol. 128, No. 2, 02.2008, p. 255-261.

Research output: Contribution to journalArticle

Mizushima, Tohru. / A strategy for development of NSAIDs with lower risk for side effects. In: Yakugaku Zasshi. 2008 ; Vol. 128, No. 2. pp. 255-261.
@article{1c575533baa8494cb00adaba37ff7f1c,
title = "A strategy for development of NSAIDs with lower risk for side effects",
abstract = "Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.",
keywords = "Gastrointestinal complication, Membrane, Nonsteroidal antiinflammatory drugs",
author = "Tohru Mizushima",
year = "2008",
month = "2",
doi = "10.1248/yakushi.128.255",
language = "English",
volume = "128",
pages = "255--261",
journal = "Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan",
issn = "0031-6903",
publisher = "Pharmaceutical Society of Japan",
number = "2",

}

TY - JOUR

T1 - A strategy for development of NSAIDs with lower risk for side effects

AU - Mizushima, Tohru

PY - 2008/2

Y1 - 2008/2

N2 - Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.

AB - Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.

KW - Gastrointestinal complication

KW - Membrane

KW - Nonsteroidal antiinflammatory drugs

UR - http://www.scopus.com/inward/record.url?scp=39049139245&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39049139245&partnerID=8YFLogxK

U2 - 10.1248/yakushi.128.255

DO - 10.1248/yakushi.128.255

M3 - Article

C2 - 18239373

AN - SCOPUS:39049139245

VL - 128

SP - 255

EP - 261

JO - Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

JF - Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan

SN - 0031-6903

IS - 2

ER -