Rebirth Of Terodiline

Terodiline (Figure 11.1) was first marketed in 1965 as an antianginal agent ("Bicor") in Scandinavia (Wibell, 1968), a relatively small market. This period of original marketing of terodiline is worthy of note for three reasons: (a) it antedates any serious regulatory or clinical interest in drug-induced prolongation of the QT interval, (b) it antedates the first description of torsade de pointes, a unique proarrhythmia associated with prolonged QT interval (Dessertenne, 1966) and (c) the drug probably co-existed with prenylamine, also an antianginal agent. Because of its potent antic-holinergic properties, urinary retention proved to be a frequent and troublesome side-effect during its use as an antianginal agent and terodiline was therefore re-developed in early 1980s for clinical use in urinary incontinence due to detrusor instability.

In the period intervening between these two indications, it was also being investigated by some workers for use in chronic obstructive airways disease (Castenfors et al., 1975), presumably in an attempt to harness the same, otherwise unwanted, pharmacological property. In isolated airways preparations from rats, terodiline had been shown to block the bronchoconstrictor effect of acetyl-choline but was ineffective against that caused by serotonin and bradykinin. The shift in the dose-response curves of acetylcholine by terodiline indicated that this property may explain the cilio-

Figure 11.1. (+)-(R)-terodiline.

stimulatory effect of this drug (Iravani and Melville, 1975).

It was first introduced in the United Kingdom as "Terolin" (later changed to "Micturin") in July 1986 for use in urinary frequency, urgency and incontinence in patients with detrusor instability and neuogenic bladder disorders. In the EU, it was approved at that time in Denmark, Ireland, Luxembourg, Belgium, the Netherlands, Spain and West Germany, but not in France, Greece, Italy or Portugal. Overall, the drug was approved in 20 countries worldwide and marketed in a number of these but the major markets were the United Kingdom, Sweden and Japan. The recommended dose of the drug was 12.5-25 mg twice daily in young adults and otherwise healthy elderly but 12.5 mg twice daily in frail elderly patients. In general, the doses used in Sweden were lower than those used in the United Kingdom while the dose approved in Japan was half the UK recommended dose.

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