Amphetamine, Past and Present – a Pharmacological and Clinical Perspective.

Amphetamine, past and present – a pharmacological and clinical perspective.

J Psychopharmacol. 2013 Mar 28;
Heal DJ, Smith SL, Gosden J, Nutt DJ

Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine’s diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine’s distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed. HubMed – drug

Cancer pharmacogenomics: early promise, but concerted effort needed.

Science. 2013 Mar 29; 339(6127): 1563-6
McLeod HL

The past decade has brought together substantial advances in human genome analysis and a maturation of understanding of tumor biology. Although there is much progress still to be made, there are now several prominent examples in which tumor-associated somatic mutations have been used to identify cellular signaling pathways in tumors. This in turn has led to the development of targeted therapies, with somatic mutations serving as genomic predictors of tumor response and providing new leads for drug development. There is also a realization that germline DNA variants can help optimize cancer drug dosing and predict the susceptibility of patients to the adverse side effects of these drugs-knowledge that ultimately can be used to improve the benefit:risk ratio of cancer treatment for individual patients. HubMed – drug

Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V.

Haematologica. 2013 Mar 28;
Gleixner KV, Peter B, Blatt K, Suppan V, Reiter A, Radia D, Hadzijusufovic E, Valent P

Patients with advanced systemic mastocytosis, including mast cell leukemia, have a poor prognosis. In these patients, neoplastic mast cells usually harbor the KIT mutant D816V that confers resistance against tyrosine kinase inhibitors. We examined the effects of the multi-kinase blocker ponatinib on neoplastic mast cells and asked whether ponatinib would synergize with other antineoplastic drugs. Ponatinib was found to inhibit the kinase activity of KIT G560V and KIT D816V in the human mast cell leukemia cell line HMC-1. In addition, ponatinib was found to block Lyn- and STAT5 activity in neoplastic mast cells. Ponatinib induced growth inhibition and apoptosis in HMC-1.1 cells (KIT G560V+) and HMC-1.2 cells (KIT G560V+/KIT D816V+) as well as in primary neoplastic mast cells. The effects of ponatinib were dose-dependent, but higher IC50-values were obtained in HMC-1 cells harboring KIT D816V compared to cells lacking KIT D816V. In drug combination experiments, ponatinib was found to synergize with midostaurin in producing growth inhibition and apoptosis in HMC-1 cells and primary neoplastic mast cells. The ponatinib+midostaurin combination induced substantial inhibition of KIT-, Lyn-, and STAT5 activity, but did not suppress Btk. We then applied a Btk siRNA and found that the Btk knock-down sensitizes HMC-1 cells against ponatinib. Finally, we were able to show that ponatinib synergizes with the Btk-targeting drug dasatinib to produce growth inhibition in HMC-1 cells. Ponatinib exerts major growth-inhibitory effects on neoplastic mast cells in advanced systemic mastocytosis and synergizes with midostaurin and dasatinib in inducing apoptosis in neoplastic mast cells. HubMed – drug

Pre-incubation of Pituitary Tumour Cells with the Epidrugs Zebularine and Trichostatin A are Permissive for Retinoic Acid Augmented Expression of the BMP-4 and D2R genes.

Endocrinology. 2013 Mar 28;
Yacqub-Usman K, Duong CV, Clayton RN, Farrell WE

Retinoic acid (RA) induced expression of bone morphogenetic protein (BMP-4) inhibits in vitro and in vivo cell proliferation and ACTH synthesis in corticotroph derived tumour cells. Reduced expression of BMP-4 in this adenoma subtype is associated with epigenomic silencing and similar silencing mechanisms are also associated with the RA responsive dopamine D2 receptor (D2R) in somatolactotroph cells. We now show that pre-incubation with the epidrugs, zebularine and TSA is obligate and permissive for RA induced expression of the BMP-4 and the D2R genes in pituitary tumour cells. Combined epidrug challenges are associated with marginal reduction in CpG island methylation. However, significant change to histone tail modifications toward those associated with expression-competent genes is apparent, whereas RA challenge alone or in combined incubations does not impact on these modifications. Epidrug mediated and RA augmented expression of endogenous BMP-4 increased or decreased cell proliferation and CFE in GH3 and AtT-20 pituitary tumour cells respectively, and recapitulating recent reports of challenges of these cells with exogenous ligand. The specificity of the BMP-4 mediated effects was further supported by knock-down experiments of the BMP-4 antagonist noggin (siRNA). Knock-down of noggin, in the absence and the presence of epidrugs, induced and augmented BMP-4 expression respectively. In cell proliferation assays, challenge with either epidrugs or siRNA led to significant increase in cell numbers at the 72hr time point, however, in siRNA treated cells co-incubated with epidrugs a significant increase was apparent at the 48hr time point. These studies show the potential of combined drug challenges as a treatment option, where epidrug renders silenced genes responsive to conventional therapeutic options. HubMed – drug