**5. Conclusion**

Chemotherapy-induced nausea and vomiting is a particularly distressing side-effect of chemotherapeutics for oncology patients both physically and psychologically. The use of 5-HT<sup>3</sup> R antagonists combined with NK<sup>1</sup> R antagonists, has enhanced physician's ability to further suppress nausea, the rates of acute- and delayed-vomiting in cancer patients receiving chemotherapy. In addition to the commonly reported adverse effects of these agents (including headache, diarrhea, constipation, hiccups, and fatigue), many patients still experience nausea and delayed vomiting [181–183]. Furthermore, the use of second generation 5-HT<sup>3</sup> R and NK1 R antagonists for the prevention of chemotherapy-induced nausea and vomiting is currently cost-prohibitive for most patients in the world. Mechanisms that cause nausea are only partially understood and probably in part overlap with those of vomiting. There are still unmet needs for newer and less expensive therapeutic options to improve the treatment across the entire spectrum of chemotherapy-induced nausea and vomiting. Additional studies should involve combinations of agents that inhibit other neurotransmitter systems involved in nausea and vomiting.

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As concluded in **Figure 2**, this systematic review shows clear evidence that Ca2+ modulation is an important contributor to antiemetic and probably anti-nausea signaling pathways. LTCC blockers, antagonists of intracellular IP<sup>3</sup> Rs and RyRs Ca2+ release channels as well as CysLT1R antagonists have the potential to provide less expensive (e.g., nifedipine, amlodipine, dantrolene, and pranlukast) broad-spectrum antiemetic agents for the clinic against diverse causes of nausea and vomiting. The discussed findings from the least shrew should help to open new avenues of research in other established animal models of emesis as well as in patients, targeting not only the already discussed Ca2+ channels, but also other Ca2+ channels that exist on both the plasma membrane and the membranes of intracellular organs such as the sarco/endoplasmic reticulum and mitochondria.
