Further development of HDAC inhibitors...Novel approaches to the treatment of depression

Todays Headlines from across the DailyUpdates network (access DailyUpdates 15th June, 2006 here)

• Breaking News (from DailyUpdates-Oncology): CuraGen and TopoTarget to test the promising combination of HDAC inhibition and retinoic acid receptor activation in patients with solid tumors The histone deacetylase inhibitor class of therapeutics represents a highly exciting approach to cancer. Merck's ZOLINZA (SAHA; vorinostat) and Gloucester Pharmaceuticals' Depsipeptide (FK228) lead this class however . Both candidates are evaluated in our feature Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies. The lead indication for both of these agents is cutaneous T-cell lymphoma. Despite the efficacy of these agents in lymphoma the full potential of the HDAC inhibitors will not become clear until efficacy has been demonstrated in a wider range of cancers including the most common solid tumors. This issue is starting to be addressed by Merck who are evaluating ZOLINZA in lung cancer and by Gloucester Pharmaceuticals who have ongoing studies in prostate and renal cancer. One of the most exciting aspects of the HDAC inhibitors is their ability to synergize with other therapeutic approaches and clinical trials evaluating different combinatorial strategies are eagerly awaited. Preclinical studies have suggested that ZOLINZA can synergize with Velcade (bortezomib), Gleevec and retinoic acid. With respect to the latter HDAC inhibitors have been reported to increase the expression of the retinoic acid receptors RAR and RXR in cancer cells. In our report Retinoids : An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development we favor strategies able to reintroduce the expression of RAR in cancer cells that otherwise show reduced expression as these may confer such cells sensitive to the antineoplastic effects of retinoid agonists. Today we headline the exciting news that CuraGen and TopoTarget are initiating a phase I study of their HDAC inhibitor, PXD101alongside cis-retinoic acid in patients with various solid cancers [press release].

Featured Journal Article (from DailyUpdates-Psychiatric Disorders): Wyeth publish new data suggesting an improved approach to depression: Major Depressive Disorder (MDD) is estimated to affect over 34 million individuals yearly across the seven major markets. Only a fraction of this patient population is treated adequately, resulting in lost productivity, unnecessary patient suffering and unfulfilled revenue potential for manufacturers (see our feature Major Depressive Disorder). Despite this total world revenues for branded antidepressant drugs was worth over $13bn in 2004. The serotonergic class dominates the market, accounting for 58% of market share in 2002. This class includes the serotonin reuptake inhibitors (SSRIs) such as fluoxetine which is the third most commonly prescribed antidepressant in the US . Over 23 million scripts were dispensed for fluoxetine in the US in 2006 but despite this, revenue is quite low due to generic competition. Prior to genericization, Fluoxetine marketed as Prozac by Lilly brought in approximately $2.7 billion in annual sales and was the fourth largest-selling medication in the US . However within weeks of the first generic fluoxetine being released by Barr Laboratories the majority of patients had switched from Prozac. Both serotonin and noradrenaline are involved in depression and early tricyclic antidepressants modified both pathways. In an attempt to improve side effect profiles industry developed SSRIs. Such selectivity may however limit efficacy and thus venlafaxine was developed as a dual serotonin, noradrenaline reuptake inhibitor offering a broader mechanism of action and improved efficacy. While blocking reuptake represents one way of increasing extraneuronal noradrenaline, alpha adrenergic receptor antagonists represents an alternative. This class of agent blocks central presynaptic alpha 2 adrenergic inhibitory autoreceptors resulting in an increase in noradrenaline release. Mirtazapine represents one example of this class. These receptors are present on both adrenergic and serotonergic neurons creating the possibility that their blockade could enhance the efficacy of reuptake inhibitors. Today’s featured journal article, published by Wyeth researchers, suggests that this is indeed the case demonstrating that alpha2A-adrenoceptor antagonism enhanced the extracellullar levels of serotonin and noradrenaline in the rat frontal cortex in the presence of fluoxetine. No such effect was observed when fluoxetine was administered alongside alpha2B- or alpha2C-adrenoceptor antagonists. A number of companies are investigating the development of mixed alpha2 antagonists/SSRIs; the current study suggests that such mixed agents would benefit from selectively targeting the alpha2A-adrenoceptor subtype [Eur J Pharmacol. 2006 Apr 19; [Epub ahead of print]].