Clinical Potential of a New Class of Antiemetic for the Prevention of Chemotherapy-Evoked Acute- and Delayed Vomiting: Supportive Evidence from the Least Shrew (Cryptotis Parva) Model of Emesis

Mini Review

Austin Pharmacol Pharm. 2017; 2(1): 1006.

Clinical Potential of a New Class of Antiemetic for the Prevention of Chemotherapy-Evoked Acute- and Delayed Vomiting: Supportive Evidence from the Least Shrew (Cryptotis Parva) Model of Emesis

Darmani NA*, Chebolu S and Zhong W

Department of Basic Medical Sciences, Western University of Health Sciences, USA

*Corresponding author: Darmani NA, Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, USA

Received: July 22, 2017; Accepted: August 09, 2017; Published: August 16, 2017

Abstract

This mini-review summarizes our recent published findings on the: i) emetic potential of cysteinyl leukotrienes LTC4, LTD4 and LTE4 in the least shrew (Cryptotis parva) model of emesis, ii) mechanism of action of their corresponding cysteinyl leukotrienes receptor 1 (CysLT1R) antagonist, pranlukast, against LTC4- induced vomiting, and iii) potential of pranlukast as a new class of antiemetic for the suppression of the acute- and delayed phases of vomiting caused by the cytotoxic cancer chemotherapeutic agent, cisplatin. Pranlukastis currently used in patients for the treatment of various respiratory disorders including asthma. Our findings demonstrate that unlike other leukotrienes (e.g. LTA4, LTB4 and LTF4), the above discussed leukotrienes are effective emetogens with the following potency order: LTC4=LTD4>LTE4. Prior treatment with pranlukast was shown to completely suppress LTC4-evoked emesis suggesting that CysLT1Rs are involved in vomiting. These and other findings indicate an important role for the emetic leukotrienes in the mediation of chemotherapy-induced nausea and vomiting (CINV). In fact we have demonstrated that blockade of the CysLT1R by pranlukast, not only can reduce cisplatin-evoked vomiting, but also intracellular markers of cisplatin-induced emetic signals. Moreover, pranlukast potentiated the antiemetic efficacy of serotonin 5-HT3 receptor antagonists, tropisetron and palonosetron, against CINV. If analogs of pranlukast such as montelukast and zafirlukast can also provide similar antiemetic potential, then clinical trials should be initiated since this class of drugs are relatively inexpensive than available effective antiemetic regimens against CINV.

Keywords: Cisplatin; Pranlukast; Least shrew; Palonosetron; Tropisetron; Emesis

Abbreviations

CINV: Chemotherapy-Induced Nausea and Vomiting; GIT: Gastrointestinal Tract; 5-HT3R: Serotonergic 5-HT3 Receptors; DVC: Dorsal Vagal Complex; NK1R: Neurokinin NK1 Receptors; SP: Substance P; NTS: Nucleus of the Solitary Tract; CysLT1: Cysteinyl Leukotriene 1; IP: Intraperitoneal; ERK1/2: Extracellular Signal- Regulated Protein Kinases 1 and 2; PKA: Protein Kinase A; PKCa/β II: Protein Kinase C Alpha/Beta II

Introduction

In this short review we briefly discuss: i) the progression of neurotransmitter hypothesis of chemotherapy-induced nausea and vomiting (CINV) and the current Status of clinically-relevant antiemetics for the prevention of CINV, ii) cost-effectiveness of antiemetics, and iii) introduction of pranlukast as an inexpensive new class of antiemetic for the prevention of CINV.

The neurotransmitter basis for chemotherapy-induced nausea and vomiting (CINV) and the current status of clinically-relevant antiemetics for the prevention of CINV

It is well recognized that cisplatin-like cytotoxic cancer chemotherapeutics evoke nausea and vomiting in cancer patients. The initial bout of vomiting occurs within a few hours of completion of intravenous administration of such chemotherapeutics to cancer patients and is referred to as the early- or acute-phase CINV [1]. This phase often subsides one day after the start of chemotherapy. Thereafter, a quiescent phase is observed where there can be little or no emesis as exemplified in the case of the least shrew animal model of emesis in the middle of Figure 1A and Figure 1B. Cancer patients will then experience additional bouts emesis, called the delayed-phase vomiting, which frequently starts from day three and can persist up to seven days post-treatment. Depending on the dose and route of administration, vomit-competent animals also exhibit both phases of CINV which can last from 2 (least shrews, see Figure 1) to 3 days (ferrets) post-cisplatin treatment [2-3]. Based upon the information obtained from animal models, the neurotransmitter basis of acuteand delayed-phases of CINV began in the late 1970s. Thus, initially it was proposed that the acute emesis is due to serotonin release from the enterochromaffin cells in the gastrointestinal tract (GIT), which will then stimulate the serotonergic 5-HT3 receptors (5-HT3R) located on the GIT vagal afferent neurons leading to afferent signaling to the brainstem [4]. Subsequently, the brainstem emetic nuclei in the dorsal vagal complex (DVC) are activated which evoke vomiting via vagal efferents. The delayed phase was thought to be due to activation of central neurokinin NK1 receptors (NK1R) subsequent to release of substance P (SP) in the medial nucleus of the solitary tract (NTS) in the DVC [4].

Citation:Darmani NA, Chebolu S and Zhong W. Clinical Potential of a New Class of Antiemetic for the Prevention of Chemotherapy-Evoked Acute- and Delayed Vomiting: Supportive Evidence from the Least Shrew (Cryptotis Parva) Model of Emesis. Austin Pharmacol Pharm. 2017; 2(1): 1006.