John joins Amgen from Bristol-Myers Squibb (BMS), where he served as the global head of Clinical Development for marketed products as well as global clinical operations. Earlier roles at BMS included head of worldwide Medical and as a full development team lead in oncology. In these roles, John led a number of innovative changes to the company’s development and medical organizations and practices. He also served as chief medical officer, Europe, head of . Medical and vice president of Cardiovascular Medical. Prior to joining BMS, he was cardiovascular group leader at Pfizer, and was a member of the faculty staff at Kaiser Hospital in San Francisco.
Figure 11-1. Arousal spectrum of sleep and wakefulness . One’s state of arousal is more complicated than simply being “awake” or “asleep.” Rather, arousal exists as if on a dimmer switch, with many phases along the spectrum. Where on the spectrum one lies is influenced in large part by five key neurotransmitters: histamine (HA), dopamine (DA), norepinephrine (NE), serotonin (5HT), and acetylcholine (ACh). When there is good balance between too much and too little arousal (depicted by the gray [baseline] color of the brain), one is awake, alert, and able to function well. As the dial shifts to the right there is too much arousal, which may cause hypervigilance and consequently insomnia at night. As arousal further increases this can cause cognitive dysfunction, panic, and in extreme cases perhaps even hallucinations. On the other hand, as arousal diminishes, individuals may experience inattentiveness, cognitive dysfunction, sleepiness, and ultimately sleep.
However, studies that examine the potential pleiotropic and nonglycemic effects of DPP-4 inhibitors on various cells and tissues may help to understand and interpret the difference in the observed cardiovascular side effects in some of the clinical trials. Recently, many reviews have tried to clarify the effects caused by DPP-4 inhibitors. They interact strongly with the heart, vascular system, kidney, liver, neuroendocrine system, immune system, and hematopoietic system affecting hormones or second messengers like brain natriuretic peptide (BNP), substance P, activation of chemokine and cytokine pathways, intracellular calcium concentrations, and the release of nitric oxide (NO) shown in different animal models in vivo and ex vivo [ 28 – 32 ]. Interactions of DPP-4 inhibitors with the cardiovascular system and cardiomyocytes were successfully revealed, yet a direct link between DPP-4 inhibitors and its effects on cardiac contractility and/or electrophysiological function is still unknown, and the corresponding downstream mechanisms have yet to be determined. Therefore, studies that explored effects of DPP-4 inhibitors on cardiovascular system are of particular interest.