Nucleoside transporter inhibitors

Nimodipine, but not other DHPs, is also a potent inhibitor of nucleoside transport with actions similar to known nucleoside transport inhibitors such as dipyr-idamol. It is likely that this mechanism also contributes to the potent vasodilating properties of this DHP. 

Anticonvulsant action of the nucleoside transport inhibitor, soluflazine, on synaptic and non-synaptic epileptogenesis in the guinea-pig hippocampus. Epilepsy Res. 2 (2), 65-71. 

Hoppenbrouwers, M. L. Van den Busche, G. (1987). Mioflazine, a nucleoside transport inhibitor effective as sleep promotor in humans . Abstract, International Symposium Current Trends in Slow Wave Sleep Research, Beerse, Belgium, p. 38. 

Wauquier, A., Van Belle, H., Van den Broeck, W. A. Janssen, P. A. (1987). Sleep improvement in dogs after oral administration of mioflazine, a nucleoside transport inhibitor. Psychopharmacology 91 (4), 434-9. 

The DNA-mediated effects of fluropyrimidines can be modulated by a number of agents, such as leucovorin (LV), levamisole, and interferon-alpha (IFN-alpha). LV prolongs TS inhibition by increasing the availability of the reduced folate cofactor necessary for formation of the inactive TS-FdUMP complex (21) (Fig. 4). Studies show alpha-interferon can potentiate 5-FU-mediated cyotoxicity, but the mechanisms are not yet defined (22,23). Another approach to modulate the activity of fluoropyrimidines is the use of the nucleoside transport inhibitor dipyridamole. Dipyridamole probably permits... 

There is evidence that in cerebral ischaemia adenosine may have protective effects, since it inhibits the release of many excitatory neurotransmitters, such as glutamate, and it also stabilises the membrane potential. Unfortunately, adenosine has an extremely short half-life, but recently nucleoside (adenosine) transport inhibitors, e.g. draflazine, have been developed that prevent the endothelial uptake and breakdown of adenosine and prolong its beneficial effects. Nucleoside transport inhibitors also have myocardial protective properties and may have a role in organ preservation prior to transplantation. Adenosine also has an antinociceptive function and various adenosine analogues have antinociceptive activity, which correlates with their affinity for the A1 receptors (Lipkowski and co-workers 1996). 

Some adenosine nucleoside transport inhibitors have been reported to be useful against pain, especially neuropathic pain (animal models) (Meert and van Belle (Janssen Pharm), 1998 Deleo and Schubert, 2000). 

Nucleoside transport inhibitors, active in neuropathic pain ... 

The pharmacokinetics of fluorouracil have been studied with escalating doses as a 72-hour intravenous infusion alone or in combination with a fixed dose of dipyridamole, a nucleoside transport inhibitor, and an enhancer of fluorouracil cytotoxicity (143). Stomatitis was dose-limiting at a fluorouracil dose of 2300 mg/m /day. For courses... 

BLOCKER and coronary vasodilator activity. It is also a nucleoside transport inhibitor with cardioprotective activity, mioflazine hydrochloride mioflazine. 

An alternative mechanism may involve an inhibition of nucleoside transport. It has been shown that S-acetylamidobenzamide inhibits adenosine transport, and we have shown that SAB inhibits thymidine transport (unpublished results). This would explain the differential effect of SAB on purine base and nucleoside cytotoxicity. Grem and Fischer (17) observed that nucleoside transport inhibitors enhanced the cytotoxicity of 5 fluorouracil by preventing efflux of 5 -fluorodeoxyuridine. Since purine base analogues can be interconverted to the nucleoside derivatives, a similar mechanism could apply for the potentiation of 6TG by SAB. However in this case, we might expect to see an enhancement of 6TG cytotoxicity by dipyridamole, which is not seen. 

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