[Weaning of young smokers using a transdermal nicotine patch]. / Entwöhnung junger Raucher mit Hilfe eines transdermalen Nikotinpflasters.

To assess efficacy and tolerance of a transdermal nicotine system (TNS) as adjuvant to tobacco withdrawal, 112 young, nicotine-dependent cigarette smokers were treated for nine weeks with TNS (n = 56) or placebo (n = 56). Initial doses of nicotine (21 or 14 mg/24 h) were based on previous smoking habits and stepwise reduced to 7 mg/24 h if abstinence was achieved during medication. After treatment, 39.3% of the TNS users were abstinent versus 19.6% on placebo (p less than 0.05). The craving for cigarettes diminished steadily, but not more significantly on TNS medication. Tenseness, difficulty in concentration and feelings of hunger were consistently and in part significantly lessened in the TNS group. The other withdrawal symptoms were not influenced by TNS treatment. Nine-month follow-up cotinine-verified abstinence rates were 12.5% in the TNS and 3.6% in the placebo group (n. s.). Transient mild or moderate erythema at the application site appeared in 20% of the TNS and 6.3% of the placebo group, and 7.1% of the TNS users dropped out because of severe localized erythema. Other mild, transient, systemic side effects reported by 33.9% of the TNS and 26.8% of the placebo users (n. s.) did not lead to drop-outs.

Circulatory counter-regulations induced by continuous administration of nitroglycerin.

In a placebo-controlled, double-blind, cross-over study in seven healthy volunteers, continuous transdermal administration of nitroglycerin over 48 h by means of Nitroderm TTS 10 evoked counter-regulations that interfered with the nitrate effects. These counter-regulations comprised an increase in sympathico-adrenal activity, manifested in elevated plasma levels of adrenaline and noradrenaline, and an internal hemodilution, readily perceptible from the decrease in the hematocrit readings. As a result, several of the circulatory effects of nitroglycerin were no longer in evidence, or much weaker on the second day of the study. The effects concerned were the reduction of systolic and diastolic blood pressure, the increase in heart rate, the prolongation of PEPc, and shortening of LVETc, and the change in digital-pulse morphology (increase in the a/b quotient). On the other hand, the increase in venous distensibility and the decrease in hematocrit were unaltered throughout the observation period. The attenuation of the action of nitroglycerin noticeable 24 h after application of the patches is, therefore, not indicative of any loss of effect of the substance per se, but due to the circulatory counter-regulations, which were largely confined to the arterial side of the circulation and scarcely affected the venous system. One or two hours after removal of the patches, counter-regulations had practically ceased.

Pharmacokinetics and bioavailability of nicotine in healthy volunteers following single and repeated administration of different doses of transdermal nicotine systems.

Healthy nicotine-dependent smokers were applied different doses of transdermal nicotine systems (TNS) during single and repeated administrations. Plasma and urine nicotine and cotinine concentrations were determined by high performance liquid chromatography (HPLC). After single application of TNS, the maximal concentration (Cmax) and area under curve (AUC) of nicotine in plasma as well as the amount of nicotine excreted in urine were linearly related to the dose. The stable urinary cotinine excretion was not influenced by the amount of nicotine delivered by the TNS. The relevant 24 h plasma nicotine concentration reached after TNS application compares well with the plasma nicotine footpoints--not the peaks--observed in moderate to heavy cigarette smokers. A comparison between different nicotine doses from different TNS allowed to conclude to the functionality of the systems as regards pharmacokinetics and bioavailability. One or two hours after removal of the systems, there was a very slow decline of the nicotine concentrations. After repeated application of TNS, there was evidence for only a very limited nicotine accumulation in plasma (+14%) or in urine (+9%) over 10 days. The steady-state of nicotine was reached within 4 days. The continuous delivery of nicotine over 24 h resulted in an early morning plasma concentration which probably decreases or prevents the craving for the first cigarette.

Human pharmacological investigations of a transdermal nicotine system.

To define the pharmacological properties of a newly developed transdermal nicotine system (TNS) designed to facilitate abstention from smoking, three human pharmacology studies were performed in healthy, nicotine-dependent smokers. The first study, in which cigarette smoking served as the standard mode of nicotine intake, was carried out to evaluate the most suitable non-invasive methods for detecting the pharmacodynamic effects of nicotine and to provide a baseline for comparisons with the results of the subsequent studies to assess the effects of single and repeated applications of the TNS. The pharmacodynamic changes induced by smoking were generally most pronounced after the first cigarette following 10 hours' abstinence. The most sensitive parameters were heart rate, which increased, stroke volume measured by impedance cardiography, which decreased, cutaneous blood flow measured by Laser Doppler flowmetry and skin temperature, which diminished to a statistically significant extent after each cigarette. Increases in blood pressure were not very pronounced. Plasma catecholamines were consistently elevated after each cigarette, but the changes were not statistically significant. Compared with those induced by cigarette smoking, the cardiovascular effect seen after either a single application of the TNS (10, 20 and 40 mg/24 h) or repeated application of a TNS delivering 14 mg nicotine/24 h were minor. A slight increase in blood pressure was detectable only on the first day of application and had disappeared after 10 days' repetitive application, suggesting the development of partial tolerance. Heart rate was slightly increased by 3-7% and stroke volume decreased by 5-12% on the tenth day of TNS application.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of a transdermal nicotine system in smoking cessation studies.

To investigate the effectiveness and tolerability of a transdermal nicotine system (TNS) as an aid towards easing smoking cessation, two double-blind placebo-controlled randomized field studies were performed. The TNS was available in sizes of 10, 20 and 30 cm2, delivering 7, 14 and 21 mg of nicotine per 24 h. A first study was undertaken in general medical practice by a group of 21 doctors (Practitioner Study). This study involved 199 nicotine-dependent cigarette smokers of whom 100 were allocated to the nicotine group and 99 to the placebo group. The second trial was performed in 112 young people, 56 in each treatment group, at the Universities of Basle and Zurich (University Study). The placebo and the nicotine groups were comparable in both studies. Participants smoking more than 20 cigarettes a day were treated with the 30-cm2 system and the others with the 20-cm2 system. When abstinence, as verified by CO measurements, was achieved, the next smaller system was applied. In the Practitioner Study, the double-blind treatment phase lasted for 12 weeks with consultations every month and in the University Study the consultations during the 9-weeks' treatment period took place every 3 weeks. Abstainers in both studies will be followed up until 12 months after treatment was begun. After 1, 2 and 3 months of treatment 41%, 36% and 36% of the participants in the nicotine group of the Practitioner Study were abstinent. The corresponding figures in the placebo group were 19.4%, 20.4% and 22.5%. The differences were statistically significant for all three months (p = 0.001; p = 0.018 and p = 0.043). Body weight did not increase in the TNS group, but did in the placebo group (+ 4.4 kg). The craving for cigarettes and withdrawal symptoms decreased more under nicotine substitution. Abstinence rates in the University Study were initially higher with 51.8% in the nicotine group and 28.6% in the placebo group after 3 weeks of treatment, but then declined to 42.9% after 6 weeks and 39.3% after 9 weeks in the nicotine group and to 25% and 19.6%, respectively, in the placebo group. The differences between the groups were statistically significant on all 3 occasions, with p = 0.012, p = 0.046 and p = 0.023.(ABSTRACT TRUNCATED AT 250 WORDS)

Controlled trial of transdermal nicotine patch in tobacco withdrawal.

A transdermal nicotine patch, which delivers 0.7 mg/cm2 per 24 h and is available in sizes of 10, 20, and 30 cm2 was tested in subjects from 21 general medical practices in a 3-month, placebo-controlled randomised double-blind study. The nicotine group (n = 100) and the placebo group (n = 99) were similar at entry. Participants who smoked more than 20 cigarettes a day were treated with the 30 cm2 patch and the others with the 20 cm2 patch. When abstinence, defined as smoking 0-3 cigarettes per week and verified by CO measurement, was achieved, the next smallest patch was applied. After 1, 2, and 3 months of treatment 41, 36, and 36%, respectively, in the nicotine group were abstinent. The corresponding figures in the placebo group were 19, 20, and 23%. The differences were significant for all 3 months. Body weight did not increase in the nicotine group, but in the placebo group the mean increase was 4.4 kg. Craving and withdrawal symptoms decreased more with nicotine substitution for cigarettes. The patches were generally well tolerated, although 25% of subjects in the nicotine group and 13% in the placebo group had transient local erythema after application of the patch; 5 members of the nicotine group withdrew because of poor cutaneous tolerance.

Pharmacological profiling of cardiovascular agents in healthy volunteers by means of non-invasive methods.

In a placebo-controlled study the hemodynamic effects of single doses of oxprenolol, metoprolol, prenalterol, phentolamine, nifedipine, nitroglycerin, angiotensin II and frusemide have been investigated in 9 healthy volunteers by means of the combined measurement of heart rate, blood pressure, pre-ejection period (systolic time intervals) and stroke volume (impedance cardiography) in the supine and tilted positions (70 degrees). Each cardiovascular agent exhibited its characteristic pharmacodynamic profile, which allowed a clear-cut discrimination. The effects of oxprenolol and metoprolol, however, could not be distinguished by this procedure. The pre-ejection period, although not a very specific parameter, proved to be most sensitive to the pharmacological interventions, whereas stroke volume was less often influenced. It is concluded that the proposed selection of non-invasive parameters is a very suitable and simple means for early cardiovascular drug testing in man.

Human pharmacokinetics of cadralazine: a new vasodilator.

The pharmacokinetic profiles in plasma and the renal elimination of 2-(3-[6-(2-hydroxypropyl)ethylamino]pyridazinyl)ethylcarbazate+ ++ were investigated in six healthy volunteers following single oral doses of 5, 10 and 20 mg of cadralazine. The study was run in a randomized change-over design experiment. Concentrations of cadralazine in plasma and urine were determined by a high-performance liquid chromatography method. Maximum plasma levels (Cmax) were reached between 0.25 and 1.0 h (tmax) after administration and ranged from 69.8 to 210.0 ng/g after the 5 mg dose, 148.9 to 333.3 ng/g after the 10 mg dose and 292.9 to 474.5 ng/g after the 20 mg dose. The corresponding area under the plasma concentration-time curve (AUC24hO) are 330, 621 and 1168 (ng/g). h. Mean renal elimination of the unchanged-drug ranged from 69 to 73% of the dose. Mean Cmax, AUC24hO and mean total renal elimination were linearly dose-related. An elimination half-life from plasma of about 2.5 h was observed for cadralazine. Estimations for the mean renal and total clearance range from 185 to 216 ml/min and 251 to 295 ml/min, respectively.

Studies of the bioavailability of nitroglycerin from a transdermal therapeutic system (Nitroderm TTS).

In 6 healthy volunteers, intravenous infusions of nitroglycerin 4.8 and 10.6 micrograms/min yielded mean steady-state plasma concentrations of 0.5 +/- 0.02 and 0.82 +/- 0.04 ng/ml as determined by a gas chromatographic/mass spectrometric method. The plasma concentrations reached in the same subjects 17 h after application of Nitroderm TTS 5 and 10 with in vivo release rates of 3.7 and 5.7 micrograms/min were 0.28 +/- 0.01 and 0.37 +/- 0.01 ng/ml, respectively. Thus, 75% of the quantity of nitroglycerin released by the systems passed into the circulation. The inter-individual and intra-individual variations in plasma concentrations were similar for both modes of administration. The nitroglycerin-induced morphological changes in the fingerpulse wave were clearly dose-dependent, but it seems that this pharmacodynamic parameter is determined less by the plasma concentration than by the nitroglycerin content of the vascular wall.

Human pharmacological studies of a new transdermal system containing nitroglycerin.

A new transdermal therapeutic system (TTS) for the administration of nitroglycerin (NTG) was tested in human pharmacological studies in 26 healthy volunteers. Plasma concentrations and haemodynamic responses were determined after the application of the system in different dosages. The concentrations of NTG reached in the plasma were uniform and dose-related, i.e. dependent on the drug-release area, and showed only minor inter-individual variation. They remained almost constant as long as the system was in contact with the skin. Renewal of the system caused no appreciable change in the plasma concentration. The haemodynamic effects, like those of all nitrates, were not clearly related to the dose administered, and were not always dependent on the plasma concentration. Upon repeated application, NTG-TTS was well tolerated locally and systemically and led to no alteration in blood chemistry or haematological parameters. The typical nitrate headaches disappeared after a few days. The presence of the system on the skin caused no discomfort or inconvenience.

Plasma concentrations and haemodynamic effects of nitroglycerin during and after intravenous infusion in healthy volunteers.

The effects of nitroglycerin, infused intravenously at 3.4 and 7.5 micrograms/min over 30 min, on haemodynamic parameters were determined in the morning and the afternoon in a randomized, placebo-controlled study in 5 healthy volunteers. The mean steady-state concentrations of nitroglycerin reached in the plasma during the infusions of 3.4 and 7.5 micrograms/min were 0.35 +/- 0.06 ng/ml and 0.64 +/- 0.22 ng/ml, respectively. Wide inter-individual variation was noted. The nitroglycerin-induced increase in the orthostatic rise in heart rate and the change in digital-pulse-wave morphology roughly paralleled the plasma concentration, whereas the reduction in systolic blood pressure in the upright position was still evident 15 mins after the infusion, i.e. when nitroglycerin was no longer measurable in plasma. No significant diurnal variation in vascular sensitivity to the vasodilative action of nitroglycerin was demonstrable. The change in pulse-wave morphology resulting from the reduction in peripheral resistance (shift of the dicrotic wave in the descending limb towards the base-line) proved to be the most sensitive haemodynamic parameter.

Difference in nitroglycerin dose-response in the venous and arterial beds.

In twelve healthy volunteers given nitroglycerin sublingually (1.6 mg) or epicutaneously (12 mg), venous distensibility was found to be maximal, even at low plasma concentrations (less than 0.2 ng/ml); there was no further change with increasing concentrations. Peripheral arterial resistance, on the other hand, decreased progressively with rising plasma concentrations and no distinct plateau was demonstrable, even at the highest plasma concentration measured (greater than 2.0 ng/ml).

Validity of the Wu-Hoak method for the quantitative determination of platelet aggregation in vivo.

Quantitative determinations of platelet aggregation were made by a modified version of the Wu-Hoak-method in venous blood samples from ten healthy volunteers. It was demonstrated that the extent to which aggregates are formed depends on the rate of flow in the needle and on other methodical influences as well as on the platelet count. Accordingly, no definite conclusions concerning aggregation conditions in vivo can be drawn from the results obtained with venous blood samples.

Quantitative changes in platelet aggregation due to physiological and pathological factors and medication.

Quantitative measurements of platelet aggregation in samples of venous blood were made in altogether 66 healthy volunteers by a modified version of the method of Wu and Hoak. The formation of aggregates was found to be unaffected or at the most barely affected by such factors as sex, age, smoking, fatty food, physical exertion and medication with isoprenaline or ovulation inhibitors. No difference in the number of aggregates formed was noted between 12 control patients and 16 patients with myocardial infarcts or 14 with other conditions predisposing to arterial thrombosis. Anticoagulant therapy had no effect on aggregation. It is suspected that aggregation in vitro due to methodological factors may obscure any quantitative alterations in the formation of aggregation present in vivo.

The influence of acetysalicylic acid on changes in platelet function due to physical exertion.

The influence of acetylsalicylic acid (ASA) on alterations of the platelets resulting from physical exertion was studied in 10 healthy volunteers. Before and 2 h after the administration of placebo or 1 g ASA, venous blood samples were taken for platelet counts, thrombelastography (TEG) and tests of ADP- and epinephrine-induced platelet aggregation. The blood in which the 2-h values were determined was sampled at the highest work-load during sub-maximum exercise on a bicycle ergometer (5 min each at 50, 100 and 150 watts). ASA had no effect on the alterations of the platelets due to physical effort: the increase in the first phase of epinephrine-induced aggregation, the elevation of the platelet count and the hypercoagulability demonstrable by TEG still persisted after the administration of ASA. Some effects were noted, however, that are also observed after the administration of ASA at rest: the second phase of epinephrine-induced aggregation was suppressed and disaggregation after induction with ADP was accelerated.

Inhibition of adrenaline-induced platelet aggregation by the orally administered alpha-adrenergic receptor blocker phentolamine (Regitine).

In eight healthy volunteers pretreatment with phentolamine 40 mg p o inhibited platelet aggregation (1st and 2nd phases) induced by low concentrations of adrenaline (2, 1 and 0.5 muM) in plasma from blood sampled 30 min after administration of the compound. The lower the concentration of adrenaline use, the greater was the degree of inhibition elicited. These results are indicative of competitive inhibition of the action of adrenaline on the platelet membrane by phentolamine. Four to six hours after administration of the compound, the aggregation characteristics had reverted to normal. It is concluded that the increased tendency toward platelet aggregation associated with elevated blood levels of catecholamines can be prevented by therapeutic doses of phentolamine.