Antiemetic agent

A highly fluorinated androgen agonist, LGD-2941, is in early clinical development for the treatment of several indications related to the beneficial effects of the androgen receptor activation (e.g., hypogonadism). 

Dutasteride inhibits both type 1 and type 2 5a-reductase, which is the enzyme responsible for converting testosterone to dihydrotestosterone in the prostate. It has 

Elocalcitol (BXL-628) is the fluoro analogue of the D3 metabolite that inhibits the growth factors involved in benign prostatic hyperplasia (BPH) it is without direct androgenic effects and does not cause hypercalcemia. It is in Phase 11 development for the treatment of BPH and overactive bladder (cf. Chapter 4).  

Finrozole is a nonsteroidal competitive aromatase inhibitor that is being evaluated in Phase II trials for the treatment of lower urinary tract symptoms associated with a reduced androgen/estrogen ratio in aging males associated with BPH. 

Several fluorine-containing drugs are currently in development for the treatment of diabetes. These are peroxisome proliferator-activated nuclear receptor (PPAR) agonists, aldose reductase, and dipeptidylpeptidase IV (DPP-IV) inhibitors. 

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Trans-2-chloro-9-(aj-dimethylamino-propylidene)-thioxanthene [MP 98°C, MP of the hydrochloride 225°C (corr.)], is a valuable medicinal agent, being used as a tranquilizer and antiemetic agent, whereas the corresponding cis isomer (MP 44°C, MP of the hydrochloride 209°C) is not useful for these indications, as described in U.S. Patent 3,115,502, which describes procedures for conversion of the cis to the trans form. 

TABLE 17-2. Antiemetic Agents Adult Doses and Adverse Effects... 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

This discussion will be limited to the neural serotonin 5-HT3 receptors which came to the forefront with the advent of antiemetic agents exhibiting 5-HT3 antagonist properties. At the present time, there is no evidence that 5-HT, and 5-HT2 receptors play an important role in vomiting [64],... 

It can be concluded that direct evidence linking endogenous 5-HT to emesis is not convincing. On the other hand, selective effectiveness of 5-HT3 antagonists as antiemetic agents and presence of 5-HT3 receptors in the area postrema and vagus nerve do implicate 5-HT mechanisms. 

Pharmacokinetics Dimenhydrinate has a depressant action on hyperstimulated labyrinthine function. The precise mode of action is not known. The antiemetic effects are believed to be caused by the diphenhydramine, an antihistamine also used as an antiemetic agent. 

Antiemetic Aprepitant, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. 

Frisch, C., R. U. Hasenohri, C. M. Mattern, R. Hacker, and J. P. Huston. Blockade of lithium chloride-induced conditioned place aversion as a test for antiemetic agents comparison of metoclopramide with combined extracts of Zingiber officinale and Ginkgo biloba. Pharmacol Biochem Behav 1995 52(2) 321-327. 

Mechanism of Action A general anesthetic and antiemetic agent that antagonizes dopamine neurotransmission at synapses by blocking postsynaptic dopamine receptor sites partially blocks adrenergic receptor binding sites. Therapeutic Effect Produces tranquilization, antiemetic effect. 

Effective antiemetic agent for the treatment of postoperative nausea and vomiting, nausea and vomiting secondary to mildly emetic chemotherapeutic agents, and vomiting secondary to radiation therapy and toxins... 

The answer is d. (Hardman, p 414.) Antipsychotic agents, particularly prochlorperazine, are also useful as antiemetic agents, thought to be due to dopamine blockade at the stomach and at the chemoreceptor trigger zone of the medulla. 

Action on CTZ Chlorpromazine depresses the chemoreceptor trigger zone (CTZ) and acts as a powerful antiemetic agent. 

A subcategory of dopamine receptor antagonists has found some use as antiemetic agents administered in conjunction with antimmor chemotherapy. The preparation of one of these agents based on a benzotriazole nucleus begins with nitration of the amino salicylate ester (67-1). Catalytic hydrogenation of the product (67-2) leads to the orf/zo-diamine (67-3). Treatment of this last product with nitrous acid... 

Identification of the different neurotransmitters involved with emesis has allowed development of a diverse group of antiemetic agents that have affinity for various receptors. Combinations of antiemetic agents with different mechanisms of action are often used, especially in patients with vomiting due to chemotherapeutic agents. 

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