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Switzerland1 Caffeine (10mM)-induced relaxation of guinea-pig isolated trachealis was attenuated and converted to a small spasmogenic response on cooling to 220C. The relaxant response was restored on rewarming to 370C and was abolished by indomethacin (2.8 pM). Cooling to 220C in the presence of indomethacin revealed spasmogenic responses to caffeine which were abolished on rewarming to 370C.2 Trachealis treated with indomethacin (2.8upM) was repeatedly dosed with acetylcholine (ACh, 10pM). Caffeine (1 or 10mm), added as each ACh-induced spasm reached equilibrium, transiently augmented but then suppressed the spasm. On cooling from 370C to 12'C, the increment in spasm evoked by caffeine increased relative to the spasm evoked by ACh.3 Trachealis treated with indomethacin (2.8pM) was repeatedly dosed with caffeine (10mM). At 370C caffeine had little effect but it caused spasm when the tissue was cooled to 32°C. Spasm amplitude increased as cooling progressed to 12°C. Similar results were obtained with caffeine (1 mM).4 At 370C, caffeine, enprofylline, 1,3,7,9-tetramethylxanthinium (TMX), theobromine, theophylline, xanthine and forskolin each caused concentration-dependent suppression of tracheal tone. Among the xanthine derivatives the rank order of potency was enprofylline > theophylline > caffeine > theobromine > xanthine > TMX. 5 In trachealis treated with indomethacin (2.8pM) and maintained at 120C, the xanthines each caused concentration-dependent spasm. The rank order of potency was theobromine > theophylline > caffeine > enprofylline > xanthine > TMX. Forskolin was devoid of spasmogenic activity. 6 Trachealis treated with indomethacin (2.8 pM) and maintained at 120C was repeatedly dosed with either caffeine (10 mM) or potassium chloride (KCl, 40mM). Caffeine-induced spasm was attenuated in a Ca2"-free medium containing EGTA (2mM), modestly at first but subsequently more profoundly. KCl did not evoke spasm at 12°C but at 37°C the KCl-induced spasm was virtually abolished at its first trial in the Ca2 -free, EGTA-containing medium. 7 It is concluded that caffeine, other alkylated xanthines and xanthine itself share a spasmogenic action in guinea-pig isolated trachealis which is best observed when the tissue is treated with indomethacin (2.8 M) and maintained at 12°C. The spasmogenic action represents the release of Ca2+ from intracellular sites of sequestration and may not depend on the intracellular accumulation of cyclic AMP. The rank order of spasmogenic potency of the xanthine derivatives differs markedly from their rank order of potency in suppressing the spontaneous tone of the trachealis observed at 370C. Since, at 12°C, TMX is spasmogenic at concentrations identical to those causing relaxation at 37°C, it is likely that TMX penetrates the cell. The relaxant effects of TMX do not, therefore, indicate that methylxanthine-induced relaxation is mediated by a receptor located on the external surface of the cell.

The Chinese tree Ginkgo biloba or "maiden hair tree" is extensively cultivated for the exploitation of the medicinal properties of its leaves. From these, a well-defined extract designated "EGb 761" has been developed, which was commercialized initially as Tanakan, Tebonin and Rokin; a similar product, Kaveri (LI 3170), also exists. The major therapeutic applications for these products are "cerebral insufficiency", other cerebral disorders, neurosensory problems and peripheral circulatory disturbances. Four primary concepts of action have been proposed to explain the pharmacotherapeutic benefits of EGb761; these are: vasoregulatory, cognition-enhancing, stress-alleviating, and gene-regulatory. These actions are believed to be realized through the principal active ingredients, flavonoids and the terpenoids ginkgolides and bilobalide acting simultaneously in concert, combination and synergy, so-called polyvalent action. It has been proposed that EGb761 may improve the memory of healthy volunteers, and in an assessment of [corrected] forty clinical studies, it was reported that Ginkgo was able to improve the twelve different symptoms comprising 'cerebral insufficiency', all of which are manifest in the elderly. These were supported in a second major study, using LI1370. However, in both instances, the evidence was largely based upon the results of self-assessment questionnaires. Latterly, in a large double blind study of men and women with the diagnosis of uncomplicated dementia who were administered Ginkgo for a year, a further positive outcome was claimed. In this study, patients were tested using ADAS-cog, GERRI and CGIC. It is suggested that whilst these different outcomes are compatible with (but do not affirm) a clinical benefit resulting from the use of Ginkgo, the application of a more objective system of assessment would be able to provide firm proof. It is proposed, therefore, that an objective, computer-based testing system for assessment of clinical improvement in volunteers and patients administered Ginkgo (such as CANTAB) would provide the convincing evidence currently being sought by patients, carers, physicians, legislators and the pharmaceutical industry.

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