Cisplatin also pharmacology

Parallel with the developments in the benzamide area, progress was also made in several nonbenzamide series of compounds. MDL 72222 (26) [20], atropine ester of 3,5-dichlorobenzoic acid, was the first selective 5-HT3 receptor antagonist and a potent antagonist of cisplatin-induced emesis in the ferret [21]. ICS 205-930 (27) [22,23 ], the tropine ester of 3-indolecarboxylic acid, exhibited similar pharmacological and antiemetic profiles. 

Sulfites, including potassium metabisulfite, can react with various pharmaceutical compounds including sympathomi-metics such as epinephrine (adrenaline), chloramphenicol, cisplatin, and amino acids, which can result in their pharmacological inactivation. Sulfites are also reported to react with phenylmercuric nitrate, and may adsorb onto rubber closures. 

A striking feature of the cellular effects of bismuth compounds in animals (and one shared only by lead) is the production of intranuclear inclusion bodies of up to 5 ixm in diameter (87), for example, in the tubular epithelial cells of the kidney. Electron probe microanalysis shows that these contain both Bi and S, and so could be a complex with a Cys-rich protein such as metallothionein. Bismuth is known to be a potent inducer of renal metallothionein synthesis, and pretreatment of animals with bismuth salts can prevent some of the toxic side effects induced by cisplatin (88). The role of metallothionein in the pharmacology of bismuth remains to be established, but the strong involvement of zinc, also an inducer of metallothionein synthesis, in the metabolism of skin cells, for example, may be related. Like several other elements of Group V, the development of the biological chemistiy of Bi is hampered by the lack of good physical properties, in particular of a well-behaved NMR isotope. 

These observations were further supported by the pharmacological studies. For example, in the ovarian cell line panel the acetate was equally active against a cisplatin-resistant cell line, CH1R, as against its cisplatin-sensitive counterpart, CHI. The mechanism of resistance to cisplatin in this cell line is repair of cisplatin-induced DNA damage. Also, [Au(OAc)2(damp)] had little activity against the ADJ/PC6 murine tumour, which is known to be particularly sensitive to compounds which cross-link DNA, such as cisplatin69. 

Pharmacology. Spiroplatin is more rapidly protein-bound than cisplatin and also has 10-times the biliary excretion of the latter drug over a 6 h interval in rats [115]. Rapid protein binding appears to be a direct result of the fact that in solution the compound possesses excellent leaving ligands. Pharmaco-... 

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