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Therapeutic Advances: 10th January 2003

Posted on: 15 Jan 03


The current edition of TherapeuticAdvances features data on anti-migraine drugs; emerging approaches to the blockade of transcription, angiogenesis and metastasis; and two therapeutic strategies for t
November 14th


An overview of TherapeuticAdvances

10th January 2003

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As usual TherapeuticAdvances highlights 14 publications selected from recent updates of DailyUpdates, LeadDiscovery’s daily feed of scientific publications with drug development importance.

The current edition of TherapeuticAdvances features data on anti-migraine drugs; emerging approaches to the blockade of transcription, angiogenesis and metastasis; and two therapeutic strategies for the treatment of Alzheimer's disease. Major industrial advances are also highlighted including a novel caspase inhibitor for the treatment of cardiovasular disease; a p-glycoprotein inhibitor for use in cancer & CNS disorders; and a treatment of bone disorders.

In this weeks edition:

  • Migraine - a re-emerging aspect of chronic pain [more]
  • Blocking tumor progression  [more]
  • Advances in Alzheimer's disease [more]
  • Advances from industry [more]

Migraine - a reemerging aspect of chronic pain

Estimates of the number of Americans suffering chronic pain range from 40-70 million and it is therefore not surprising that the development of analgesics has represented a major pharmaceutical objective. (click here for "Pain 2002" an analysis of future directions in analgesic therapeutics). Migraine is a specific example of painful conditions affecting 4-16% of the global population. Advances in the mid-1990’s have led to a 60% increase in diagnosis, an expansion of therapeutic options and a 5-fold increase in the migraine market over the past decade. This market is no longer therefore a low growth, low value market, dominated by sales of aspirin/paracetamol, and should now be considered as a target by companies involved in pain. Much of the advances in migraine management can be attributed to the development of 5HT1D receptor agonists and in this edition of TherapeuticAdvances we highlight research investigating the mechanism of action of this class. Of further interest, in a recent dossier (click here to access) we analyze the migraine market and focus on the emergence of the 5-HT7 receptor as a possible therapeutic target [for further details of this and other projects log on to TherapeuticAdvances]

Blocking tumor progression 

The drive to develop improved treatments of cancer has resulted in the development of a number of strategies designed to regulate transcription. The retinoic acids represent one early target for the regulation of transcription (see our recent report), as do the histone deacetylase (HDAC) inhibitors (click here for a second report). HDAC inhibitors regulate histone plasticity and can control gene transcription is a selective manner. A second modification that is responsible for chromatin plasticity is DNA methylation and in TherapeuticAdvances we highlight research emerging from Canada showing that the combination of 5-aza-2'-deoxycytidine (an inhibitor of DNA-methylation) and depsipeptide (an HDAC inhibitor) produce a synergistic antineoplastic effect. In breast cancer cells this was found to be related to the reactivation of maspin and gelsolin expression, two genes whose function is to suppress tumor metastasis.

A second strategy for preventing tumor progression and metastasis is the inhibition of angiogenesis. The development of angiogenesis inhibitors is attractive for the treatment of not only cancer but also rheumatoid arthritis (click here for access to our recent DiscoveryDossier "Inhibitors of angiogenesis for the treatment of rheumatoid arthritis"). The increase in interest in angiogenesis has been mirrored by a constantly expanding repertoire of molecular targets. Most recently, researchers at Thomas Jefferson University have identified endorepellin, an inhibitor of angiogenesis derived from the carboxyl terminus of perlecan. This exciting molecule, which is highlighted in TherapeuticAdvances, displays potent anti-angiogenic activity and almost completely blocks the angiogenic activity of highly tumorogenic colon cancer cells. This was proposed to be due to the high affinity binding of endorepellin to endothelial cells as well as a block of the adhesion of tumor cells to the extracellular matrix. Perlecan is highly expressed in cartilage suggesting that endorepellin may play a role in the pathophysiology of rheumatoid arthritis as well as tumor progression [for further details of this and other projects log on to TherapeuticAdvances]

Advances in Alzheimer's disease

Four million Americans currently suffer from Alzheimer's disease and experts estimate that by 2025 22 million people around the world will be afflicted. Alzheimer's disease patients suffer both affective and memory disorders and current treatments generally focus on the use of antidepressants and memory enhancers to treat these symptoms. As an alternative to treating disease symptoms recent therapeutic developments include the targeting the accumulation of beta amyloid (see, for example, our recent dossier highlighting the therapeutic potential of glycogen synthase kinase), or the toxic response to this accumulation. TherapeuticAdvances focuses on two recent articles that will hopefully lead to advances in the treatment of Alzheimer's disease. The first article reports that sigma(1) agonists igmesine and PRE-084 showed antidepressant efficacy in beta(25-35) amyloid peptide treated animals, a finding that may be related to both altered progesterone levels and sigma binding site numbers in the hippocampus of patients. The second publication focuses on data emerging from a collaboration of researchers at the University of Toronto and the University of Konstanz, Germany advancing the development of beta amyloid vaccine. This group has developed a strategy that may offer therapeutic benefit without the detrimental CNS inflammation seen with earlier vaccines [for further details of these and other projects log on to TherapeuticAdvances]

Advances from industry

This edition of TherapeuticAdvances features a number of industrial advances including:

  • Caspase 3/7 inhibitors from Pfizer: The development of apoptosis agonists has gained much interest in the treatment of cancer (click here for example). On the other hand apoptosis antagonist are being developed for the treatment of cardiovascular diseases associated with ischemic cell death. Pfizer researchers have recently published data concerning the efficacy of a lead caspase 3/7-selective inhibitor that may serve to limit ischemic death.
  • ONT-093, a p-glycoprotein inhibitor for the reversal of multi-drug resistance and the enhancement of CNS penetration of centrally acting drugs: A variety of chemotherapies are available to oncologists and these generally reduce the rate of tumor progression. However intrinsic or acquired tumor-mediated drug resistance is a major clinical obstacle that can result in the lack of tumor responsiveness in patients undergoing treatment. Drug resistance is in part due to active efflux transporters such as p-glycoprotein. More recently data has suggested that p-glycoprotein is also involved in the passage of molecules across the blood brain barrier, and in inducing apoptosis in peripheral blood mononuclear cells. Ontogenx are developing ONT-093, an inhibitor of p-glycoprotein which reverses multi-drug resistance in various cancer cell lines, and enhances the antinociceptive effect of analgesics.
  • T-614, a treatment for rheumatoid arthritis: Two of the most predominant skeletal diseases are osteoporosis and arthritis (go to the bottom of this page for various dossiers produced by LeadDiscovery analyzing pharmaceutical opportunities in this area). These two markets are large and on the increase. The treatment of both conditions can involve the reduction of bone destruction. T-614, a clinical phase candidate for rheumatoid arthritis, is one example of this approach. The potential of this molecule has however been further boosted by recent reports that it also possesses anabolic effects on bone metabolism

[for further details of these and other projects log on to TherapeuticAdvances]

Please remember that you can learn more about the publications mentioned above by logging on to TherapeuticAdvances. This is completely free and without obligation, so why not click the link and pay us a visit. In addition please note that we are currently featuring 6 new reports:

The retinoids : Therapeutic & pharmaceutical opportunities [More]
Targeting endogenous inhibitors of apoptosis: Therapeutic Opportunities [More]
Dual prevention of osteoporosis and atherosclerosis [More]
Inhibitors of angiogenesis as treatments of rheumatoid arthritis [More]
5-HT7: Pharmaceutical opportunities in the fields of CNS and cardiovascular disorders [More]
Pharmaceutical development opportunities surrounding osteoporosis [More]

In order that we may serve you better, we are now offering you the opportunity to vote for future dossiers. Please click here to see our list of possible future dossiers or to suggest titles that may be of use to you.


Dr Jon Goldhill

Last updated on: 27/08/2010 11:40:18

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