The Necessary Evil: Balancing the risks and benefits of fluvoxamine in a patient with treatment refractory depression on warfarin:A Case Report

Warfarin, a commonly prescribed anticoagulant, has a narrow therapeutic index; and is metabolised by a number of cytochrome P-450 isoenzymes. Fluvoxamine is an effective antidepressant. It is a potent SSRI, with proven efficacy on obsessive-compulsive symptoms, anxiety, and psychotic depression. It is also a potent inhibitor of a number of cytochrome P-450 isoenzymes and has the potential to cause pharmacokinetic interactions with warfarin, resulting in elevated International Normalised Ratio (INR). We report a case of an elderly man, who was on warfarin for atrial fibrillation. He also suffered from severe and complex depressive episodes, with marked anxiety, and obsessive-compulsive symptoms which at times were impervious to reassurance and rational explanations. The depression responded inadequately to a number of trial of antidepressants, including a combination of antidepressants. Hence a decision was taken to commence Fluvoxamine. Co-administration resulted in the marked and rapid elevation of INR, necessitating adjustment in the dose of Warfarin. Although Fluvoxamine, by dint of its pharmacokinetic profile as a Selective Serotonin Reuptake Inhibitor (SSRI) has a high likelihood of interaction with Warfarin, there are very clinical few case-reports of such an interaction. Over the years, the use of Fluvoxamine in clinical practice has declined following the availability of other SSRIs that have less effect on the cytochrome enzyme system. However, in certain clinical situations where the use of Fluvoxamine is warranted, careful consideration of the drug interactions is highly recommended The case demonstrates the necessity of close monitoring when Fluvoxamine is co-administered with Warfarin, as the INR is elevated and the risk of haemorrhage increases even at small doses of Fluvoxamine. This close monitoring becomes even more relevant in the elderly because of prolonged half-life of Fluvoxamine in this population

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

Abstract Background Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. Methods The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Results Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors. Conclusions The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer