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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Cisplatin has a number of dose-limiting side effects, which include myelotoxicity (bone marrow suppression) and nephrotoxicity (kidney damage). Therefore, intensive intravenous hydration and diuresis are essential during treatment to prevent renal damage. Nausea and vomiting can also be problematic as cisplatin is one of the most emetogenic of chemotherapy agents, although this can be ameliorated with prophylactic antiemetics such as ondansetron or granisetron in combination with corticosteroids. The Neurokinin-1 (NK1) receptor antagonist aprepitant (EmendTM) or its prodrug form fosaprepitant, which blocks substance P from attaching to NK1 receptors, in combination with ondansetron and dexamethasone, has been shown to be more effective than just ondansetron and dexamethasone. Peripheral neurotoxicity, ototoxicity, and electrolyte disturbances such as hypomagnesaemia, hypokalemia, and hypocalcaemia are also known side effects. Finally, hemolytic anemia can develop after several courses of cisplatin. Despite all of these potential clinical problems, after many years of clinical experience cisplatin is increasingly given in a day-care setting.
Drug Development with Radiopharmaceuticals
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
In the early discovery phase, the evaluation of target expression and function related to a particular disease leads to important target identification, the key to the downstream discovery of a target-modulating drug. Target validation involves positively linking the target expression to the particular disease as well as demonstrating that modulation of the target has a positive impact on the disease phenotype (28,29). Receptor-based agents or radiotracers that target cell surface proteins are examples of probes that may be used to establish a disease-associated target. Central nervous system imaging agents targeting neurotransmitter systems, specifically receptor subtypes and transporters, are among the earliest examples of proof of target studies. Measuring receptor occupancy by a therapeutic agent provides proof that one is hitting the desired target. For these studies, PET scans are obtained following administration of varying concentrations of test drug. A curve of receptor occupancy as measured by PET versus concentration administered or plasma concentration measured is generated to determine the effective dose. Farde and colleagues (30) followed the loss of [11C]raclopride, a dopamine D2 receptor-imaging agent, to assess D2 occupancy by classic and atypical antipsychotics given to schizophrenic patients. They found that the receptor occupancy ranged from 65% to 85%. Receptor occupancy alone does not constitute a suitable validation of the target. One may also wish to correlate the occupancy with a measure of PD information. In a recent example, a fluorine-18-labeled NK1 receptor agent [18F]SPA-RQ demonstrated the 80% to 90% receptor occupancy of NK1 receptors by the aprepiant, a NK1 receptor antagonist. In spite of the high receptor occupancy, aprepiant was not found to be an effective treatment of depression; however, at these receptor occupancy levels, aprepiant did prevent chemotherapy-induced nausea and vomiting (31). This information provided valuable feedback for halting the continuation of the development of aprepiant as an antidepressant.
Pharmacological management of cannabinoid hyperemesis syndrome: an update of the clinical literature
Published in Expert Opinion on Pharmacotherapy, 2022
Guillermo Burillo-Putze, John R. Richards, Consuelo Rodríguez-Jiménez, Alejandro Sanchez-Agüera
Aprepitant, an NK1 receptor antagonist, has been used in prevention of post-chemotherapy nausea and vomiting. Aprepitant has been studied in children with CVS. By blocking NK1 receptors from substance P, aprepitant mitigates nausea and vomiting. There is one case report in which aprepitant successfully resolved CHS symptoms in a patient who failed to improve after conventional antiemetics and haloperidol [130]. A 2019 guideline recommended all patients with CVS, regardless of concomitant cannabis use, be offered standard therapy for both prophylaxis and treatment of acute episodes, specifically tricyclic antidepressants such as amitriptyline, aprepitant, and topiramate as alternatives [131]. The use of these medications for acute treatment of CHS is uncommon, but these may represent therapeutic alternatives in the future.
Current understanding of the etiology of cyclic vomiting syndrome and therapeutic strategies in its management
Published in Expert Review of Clinical Pharmacology, 2022
Rosita Frazier, Thangam Venkatesan
Amitriptyline is recommended as a first-line therapy for the prophylaxis of CVS. Abortion medications such as triptans, anti-emetics like ondansetron and other medications such as diphenhydramine are recommended. Aprepitant, an NK1 receptor antagonist, is used as both prophylactic and abortive treatment in CVS. However, there is a lack of randomized controlled trials (RCT) and many of these medications have side effects that limit their use. It is unlikely that RCTs of TCAs and other medications used off-label will be completed due to logistics, such as recruitment and funding.
A pharmacological overview of aprepitant for the prevention of postoperative nausea and vomiting
Published in Expert Review of Clinical Pharmacology, 2023
Andrew Padilla, Ashraf S Habib
Aprepitant is currently the only NK1 receptor antagonist available for the management of PONV. The data support the superior anti-vomiting efficacy of NK1 antagonists compared to other antiemetics. Along with a long duration of action and a favorable side effect profile, aprepitant provides clear benefits for the prophylaxis against PONV and post-discharge nausea and vomiting. However, aprepitant’s anti-nausea efficacy is comparable to that of 5HT3 receptor antagonists.