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Objective: We examined whether nitroglycerin (glyceryl trinitrate, GTN) patch treatment for 24 h could induce local cutaneous changes that impaired drug delivery and clinical efficacy., Methods: Twenty angina patients were exercise-tested after 2 and 24 h of treatment and then 2 h after patch renewal. The patch was either renewed on a new skin location or on the previous application site in a randomised, double-blind, cross-over protocol. GTN plasma concentrations and finger plethysmography were obtained before and after each exercise test., Results and Conclusions: The clinical efficacy, the effect seen on plethysmography and the GTN plasma concentrations tended to increase after patch renewal, regardless of the application site of the renewed patch. Hence, cutaneous changes of clinical importance could not be demonstrated.

Objective: In a double-blind, parallel study, the effects of 25 mg carvedilol and 50 mg atenolol on peripheral finger circulation and arterial pulse curve configuration were compared., Methods: Healthy volunteers (n = 17) were examined at baseline and for 15 min after 60 s of hand cooling in ice-water. Finger temperature and digital plethysmography were recorded each minute from the cooled and the control hands. Measurements were also made before and 2 h after drug administration., Results: Blood pressure declined from 120/86 to 108/74 mm Hg after atenolol (n = 9), and from 122/88 to 108/73 mm Hg after carvedilol (n = 8). In both groups, baseline finger temperature increased slightly after drug, and a more rapid rise in finger temperature was observed after cooling. There was no group difference in the drug effect on finger temperature, except in the first few minutes after cooling, when temperature recovery was greater after carvedilol. Carvedilol reduced the vasoconstrictor response to local cooling (digital plethysmography), compared both to the value before drug and after atenolol. At rest, carvedilol changed the pulse curves (control hand) towards vasodilatation and high compliance, expressed as a mean change in the relative height of the dicrotic notch of -10.3% versus 0.0% after atenolol., Conclusion: Future studies should clarify whether the vasoactive profile of carvedilol may translate into reduced occurrence of cold hands and feet amongst patients treated for hypertension.

Objective: We examined the relationship between tolerance development, counterregulatory responses and arterial vasodilating effects evaluated by digital pulse plethysmography., Methods: Twenty patients with stable angina pectoris were exercise tested before, after 2 and after 24 h of open nitrate patch treatment., Results: The effects observed after 2 h of treatment on exercise duration, ST-segment depression, blood pressure and heart rate were lost in most individuals after 24 h. In contrast, the effects on the arterial pulse curves persisted after 24 h, with a mean change from baseline of 29%, compared to 33% at 2 h. After 24 h, a significant decrease in haematocrit and an increase in body weight were observed. The haematocrit changes correlated with the loss of clinical efficacy (r = 0.57 for ST-segment depression, and r = 0.54 for exercise duration)., Conclusion: Clinical nitrate tolerance may be observed despite maintenance of the arterial vasodilating effects, and tolerance is more related to plasma volume expansion as a counterregulatory mechanism.

Twenty non-smoking middle-aged men with mild untreated essential hypertension were compared to age-matched controls (n = 22) in a double-blind placebo controlled study. Plasma and urinary concentrations of the platelet-specific protein beta-thromboglobulin (beta-TG), platelet count and mean platelet volume were measured before and after chewing 2 mg nicotine gum. The mean plasma nicotine concentration increased to 4.3 ng/ml in the hypertensive group and to 3.9 ng/ml in the normotensive group after 30 minutes of chewing the nicotine gum. Blood pressure and heart rate increased significantly, but there was no difference between the groups. Venous plasma catecholamine concentrations were unchanged. beta-TG concentrations in plasma and urine were similar in the two groups, and plasma beta-TG levels did not change after nicotine gum in either group. Urinary high molecular weight beta-TG decreased after nicotine compared to placebo. Platelet count and volume increased significantly in the hypertensive group, but not in the normotensive group. The response in platelet count was significantly higher in the hypertensive group. Thus, small amounts of nicotine increase platelet counts more in hypertensive than in normotensive non-smoking men, without inducing the platelet release reaction.

In a double-blind, cross-over study the acute clinical efficacy and pharmacokinetic profile of a newly developed isosorbide dinitrate extended-release (ISDN-ER) formulation (10 mg immediate release and 60 mg slow release) were examined in eight angina patients. Exercise tests were done 1 h before and 1, 6 and 10 h after acute ISDN or placebo; similar testing was repeated after 14 days of open-labelled treatment. At 1, 6 and 10 h after administration, ISDN-ER significantly reduced the mean ST depression at highest comparable workload (HCWL) by 0.8, 0.6, and 0.6 mm, respectively. Total exercise duration increased significantly by 46, 42 and 72 s. The rate-pressure product at HCWL was not reduced significantly at any time, while digital plethysmography demonstrated a significant effect on arterial pulse curves throughout the 10 h. After 14 days of once-daily treatment, similar or somewhat attenuated clinical effects were observed. Pharmacokinetic measurements showed a first peak of ISDN at 1-2 h and a second peak at 4-5 h. The 5-isosorbide mononitrate (5-ISMN) metabolite peaked at 5-8 h and remained high at 10 h. After 14 days of treatment, the mean plasma concentrations of ISDN and 5-ISMN before drug were 0 and 69 ng.ml-1, respectively. Thus, satisfactory acute clinical efficacy and low nitrate levels during the night were observed. However, long-term clinical efficacy needs to be established in larger, placebo-controlled trials.