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The potential of different commercially used starter cultures to form volatile organic compounds were determined. Special interest was laid on the so-called minor constituents compounds that are present in the low μg/kg-range in the end-product aroma of the investigated starter cultures. The variability of the tested single strain cultures was very wide within the investigated species. It was not possible to group the strains according to the species by applying statistical procedures such as principal component analysis or cluster analysis on the GC-MS-data of the samples. Applying the concept of odour unit values to all cultures tested, it was possible to estimate the impact of each volatile organic compound investigated on the resulting aroma of the end product. Of 32 quantified compounds only 2,3-butanedione (odour unit values between 6 and 362), 2,3-pentanedione (between 0 and 363), and to a lesser extent demethyl sulfide (between 6 and 12), and benzaldehyde (between 0 and 3) are supposed to have such an impact. Mixed cultures were formed, using three strains of Lb. delbruckii ssp. bulgaricus and S. salivarius ssp. thermophilus , respectively, to produce yogurt. The most interesting finding was that 2,3-pentanedione is produced by all mixed strain cultures in three to five times the amount of the sum produced by the respective single strains.

The potential of different commercial dairy starter cultures to form volatile organic compounds was assessed. Special interest was taken in the so-called minor constituents that are present in the low μg/kg range in the aroma of the end products of the investigated starter cultures. Volatile organic compounds produced by the starter bacteria are formed during production or within the first 24 h of storage. Quantitative changes that occurred after 2 and 4 wk proved to be less significant. Many of the aldehydes (pentanal and homologues up to undecanal) as well as some alcohols (1-propanol, 1-butanol, 1-pentanol) present in fermented dairy products were not produced by starter bacteria but originated from the milk. Only five of the compounds (dimethyl sulfide, 2,3-butanedione, 2,2-pentanedione, limonene and undecanal) together with ethanol are considered to have an impact on the resulting aroma, providing odour unit values >1.5. Using multiple stepwise regression analysis it was possible to differentiate between the five different culture types, and to discern the age of an unknown sample independent of its culture type.

The aim of this study was to apply a standard addition method to quantify volatile organic compounds in pasteurized milk and fermented dairy products. Thirty-three volatile organic compounds detected in the headspace of milk or fermented dairy products were added in various concentrations to pasteurized milk as a reference and chromatographically analysed by a combination of dynamic headspace analysis and GC-MS. The original concentrations in milk of the added compounds and their respective 95% confidence intervals were calculated by means of linear regression analysis. With the exception of ethanal all tested compounds resulted in usable linear regressions and the calculated concentrations in milk generally agree with data found in literature. Ethanal excepted, the applied dynamic headspace GC-MS method provides accurate results for the quantification of volatile organic compounds in milk. Response factors calculated from data of the linear regression analysis in milk also allow quantitative determination of volatile compounds in fermented milks, since their matrix effect appears to be the same as for milk.

Salmonella serovar Stanley is rare in Europe. In Switzerland, the number of reported isolates has increased from 2 in 2000 to 25 in 2005. A nationwide outbreak of gastrointestinal illness due to S. Stanley occurred from September 2006 through February 2007. Eighty-two cases were documented. Males were 56%; mean age of the cases was 45.7 years (range 0-92). Forty-seven cases (57%) occurred in three western cantons: Vaud, Bern, and Geneva. Twenty-three cases (28%) were hospitalised. In the case-control study conducted to find the source of the outbreak, cases were more likely than controls to have eaten local soft cheese (OR 11.4, p=0.008). One clone of S. Stanley strain was isolated from soft cheese and from 77 cases (94%) who reported no history of having travelled abroad. The outbreak ended after the withdrawal of the cheese from the market. This is the first S. Stanley outbreak in Switzerland and the first in Europe unrelated to imported products, suggesting an increased local circulation of this previously rare serotype.

The transdermal administration of nicotine by means of a transdermal nicotine system (TNS) affords a novel way of nicotine replacement to alleviate smoking cessation. The plasma levels of nicotine maintained with the TNS are in the range of the footpoint concentrations observed in smokers. The efficacy of the TNS was investigated in two placebo-controlled double-blind smoking cessation programs with minimal contact and minimal psychological support. A total of 311 smokers were treated for 3 months or 9 weeks. The abstinence rates at the end of the treatment and weaning periods were almost doubled in the TNS groups (36% and 39%) as compared to the placebo groups (23% and 20%) with a significant difference for both studies (p less than 0.05). These data suggest that the TNS can also improve the smoking cessation rates under the conditions of general medical advice, making it suitable for use outside of specialized smoking cessation centers.

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.

The novel reversible and selective inhibitor of monoamine oxidase-A (MAO-A) Ro 41-1049 [N-(2-aminoethyl)-5-(m-fluorophenyl)-4-thiazole carboxamide HCl] shows inhibition characteristics similar to those of the structurally related reversible MAO-B inhibitors Ro 16-6491 and Ro 19-6327. In the present study, tritiated Ro 41-1049 was used as a high affinity ligand to study the binding characteristics of this inhibitor to MAO-A and its interactions with the enzyme. An homogeneous population of high affinity binding sites for [3H]Ro 41-1049 was found in membrane preparations from human frontal cortex and placenta (Kd = 16.5 +/- 1.4 and 64.4 +/- 19.2 nM, respectively). In frontal cortex the Bmax value for [3H]Ro 41-1049 (2.6 +/- 0.4 pmol/mg of protein) was about one third of the Bmax calculated for the MAO-B-selective ligand [3H]Ro 16-6491. The density of [3H]Ro 41-1049 binding sites in human placenta varied greatly in the different tissue samples investigated, showing an average Bmax of 101.7 +/- 36.5 pmol/mg of protein. Apparent binding equilibrium was reached after 1 hr of incubation at 37 degrees. At this temperature the binding was reversible, with a dissociation t 1/2 of about 35 min. At lower temperatures the radioactivity dissociation was much slower. Among the various drugs tested, only inhibitors of MAO-A were able to effectively prevent [3H]Ro 41-1049 specific binding. As previously reported for the MAO-B ligands [3H]Ro 16-6491 and [3H]Ro 19-6327, the analysis of the membrane-bound radioactivity showed that [3H]Ro 41-1049 was entirely recovered in the form of its aldehyde derivative, indicating that Ro 41-1049 was deaminated by MAO-A. The existence of a Ro 41-1049 adduct reversibly bound to the enzyme active site might explain the inhibition mechanism of this compound. The exposure of the radioligand-enzyme complex to NaBH3CN at pH 4.5 caused the irreversible covalent incorporation of about 70% of the specifically bound radioactivity into a 60-kDa polypeptide. This incorporation was dependent on the pH and on the amount of NaBH3CN added. The presence of MAO-A- but not MAO-B-selective inhibitors prevented the covalent incorporation of [3H]Ro 41-1049. The present results indicate that [3H]Ro 41-1049 is incorporated into a subunit of MAO-A, in the presence of NaBH3CN, and modifies a protein domain that is essential for the enzyme activity.(ABSTRACT TRUNCATED AT 400 WORDS)

The selective, reversible inhibitors of monoamine oxidase (MAO) moclobemide and Ro 41-1049 (selective for MAO-A), as well as of Ro 16-6491 and Ro 19-6327 (selective for MAO-B) inhibited the enzyme with an initial competitive phase, followed by a time-dependent inhibition of MAO. Ro 41-1049, Ro 16-6491 and Ro 19-6327, being activated by MAO into reversible adducts, fit into the classification as mechanism-based inhibitors. Conversely, since no product formation was observed after incubation of tissue homogenates with moclobemide, this drug probably belongs to the class of the "slow-binding" MAO inhibitors.

Glassy carbon (GC) electrodes were activated by electrochemical constant potential anodization in order to generate high‐surface area, high‐capacitance electrodes. After anodic oxidation in sulfuric acid the electrodes exhibited increased capacitance. After subsequent electrochemical reduction of the activated layer, a further significant increase in capacitance was observed. Growth, structure, and surface properties of the activated electrodes were monitored by cyclic voltammetry, differential electrochemical mass spectrometry, spectroscopic ellipsometry, X‐ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). Two different types of glassy carbon obtained by pyrolysis at 1000°C and at 2200°C were compared. Differential electrochemical mass spectrometry reveals that is the main reaction product during oxidation, while and are detected during reduction. The values of surface layer capacitance and thickness determined by spectroscopic ellipsometry increase as linear functions of oxidation time. The resulting volumetric capacitance was at least . After oxidation, the presence of functional surface groups was demonstrated by XPS. The relative contributions of the different surface functionalities depend on the pyrolysis temperature of the GC. Reduction lowered the concentration of oxygen‐containing functional surface groups. The XPS results were qualitatively confirmed by Fourier transform infrared measurements carried out at the same samples. AFM measurements on glassy carbon showed that the film growth both into and out of the substrate, resulted in a raised surface after activation. A qualitative model for film growth is presented. © 2000 The Electrochemical Society. All rights reserved.

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.

The effects of single oral doses of oxprenolol (20 and 80 mg), phentolamine (20 and 40 mg), and combinations of oxprenolol and phentolamine (80:20 and 20:40 mg, respectively) on blood pressure, heart rate and the systolic time intervals (Q—S2c, PEPc, LVETc and PEP/LVET) have been studied under double-blind conditions in seven healthy volunteers during recumbency and passive tilting. Heart rate was slowed by oxprenolol and slightly increased by phentolamine, but was not affected by either of the combinations. There were only minimal non-significant changes in blood pressure in the subjects, all of whom were normotensive. Of the systolic time intervals, PEPc was most affected: it was prolonged by oxprenolol because of reduction in myocardial contractility, and shortened by phentolamine as a result of the cardiostimulant effect of this compound. When the two drugs were administered in combination, the negative inotropic effects of the β-blocker always predominated. The changes induced by the drugs were more pronounced during upright titling than in the recumbent position. Measurement of PEPc provides a suitable means of assessing the influence of cardiovascular drugs on left ventricular function in pharmacological studies in man.

As a first step toward total synthesis of histrionicotoxin and its congeners, the preparation of (±)-cis-Azaspiro[5.5]undecan-8-ol (11) is described.

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.

The effects of single oral doses of 5, 10, and 20 mg. of a new cardioselective β-stimulant, preparation C 50,005A-Ba, were tested and compared with the response to placebo in eight healthy volunteers (four aged 23 to 26 years and four aged 49 to 55 years). The compound induced a doserelated increase in myocardial contractility (reduction of 17 to 24 msec. in PEP c ) and in heart rate, which was accelerated by 8 to 20 beats/minute by comparison with the placebo values. The rise in systolic pressure observed in response to C 50,005A-Ba was both dose-related and dependent on the age of the subjects; in the younger group there was an increase of 16 to 31 mm. Hg and in the older group an increase of 7 to 21 mm. Hg. A slight decrease in diastolic pressure was noted, which was likewise more prominent in the younger subjects. These changes were ascribed to a decrease due to aging in the responsiveness of the adrenergic β-receptors to stimulation. The effects of the compound set in quickly, reached their maximum within 30 to 60 minutes, and persisted for about 4 hours. The only side effects observed were slight palpitations. Depression of the ST segment was noted in one 55-year-old subject and was interpreted as a manifestation of latent coronary disease. In view of this finding, it seems possible that the preparation could be used as a diagnostic agent for a simple test of coronary function. Continuous E.C.G. recordings over a period of 534hours, including three ergometer tests at submaximum effort, showed that by comparison with placebo, C 50,005A-Ba caused a slight increase in the frequency of isolated ventricular and supraventricular premature contractions, and also in the incidence and intensity of sinus arrhythmias not due to respiration. Essentially the same changes in cardiac rhythm were observed in four young volunteers during continuous E.C.G. recordings over a period of 9 hours in response to the repeated administration of C 50,005A-Ba in a dosage of 15 mg. three times a day on two consecutive days. The differences from the corresponding placebo values were, however, not statistically significant. C 50,005A-Ba is thus an orally active cardiostimulant agent with a high degree of β 1 -receptor selectivity and with only a very slight arrhythmogenic potential. It is well tolerated and could afford beneficial effects in the treatment of heart failure or as a countermeasure in therapy with β-blockers.

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.

The preparation of the title compounds 11, 37, and 39 is described. 37 will serve as starting material for a partial synthesis of the steroidal alkaloid batrachotoxinin A (1).

A novel method for the reductive epoxide opening in a 14β, 15β-epoxy-20-oxo-Δ16-pregnene 4 affords an almost quantitative yield of the 14β-hydroxy-20-oxo-Δ16-pregnene 5. This leads to a considerable improvement of the formerly published synthesis of 3-O-methyl 17 α, 20ξ-tetrahydrobatrachotoxinin A (2) [3].

A novel synthesis leading to the C(20) epimeric 7,8-dihydroderivatives 16 [1] and 34 of batrachotoxinin A (1) [5] is described.

In addition to the preliminary communication [1] a detailed description of the first partial synthesis of steroidal alkaloid batrochotoxinin A (1) is presented.

In a single-blind trial the antihypertensive effects of Nepresol, Nepresol and Trasicor and Trasicor alone were tested in 18 patients with mild to moderate hypertension. After a control period of 2 weeks during which a placebo was administered, each active compound was given for 3 weeks. Two patients failed to complete the trial and three of the remaining 16 did not respond satisfactorily to any of the treatments. The other 13 patients showed statistically significant reductions in systolic and diastolic blood pressures (systolic 8.6–13.2%; diastolic 7.4–8.2%) in response to each of the three treatments. Trasicor counteracted the increase in heart rate caused by Nepresol without impairing its hypotensive effect; the reduction in blood pressure was slightly greater, although not by a statistically significant amount. — The side-effects observed during treatment with Nepresol appeared to be less marked when the two drugs were given in combination. Doses of 75 mg Nepresol and 120 mg Trasicor, either alone or in combination, only produced an adequate response in two patients with mild hypertension. In all other patients the dose had to be doubled. — This study confirms the therapeutic usefulness of a combination of vasodilators and β-receptor blockers in the treatment of hypertension.

Im Rahmen der vorliegenden Mitteilung wird uber den erstmaligen partialsynthetischen Aufbau des Steroidalkaloids Batrachotoxinin A (23) [4] berichtet. Als Ausgangsmaterial der Synthese diente das 20-Oxo-pregnan-Derivat 2, das von uns bereits fruher [3] aus dem 18,20-Lacton 1 [2] dargestellt worden ist.

The influence of maprotiline or clomipramine on plasma tryptophan-binding and brain tryptophan was studied in rats. Neither compound altered tryptophan-binding nor brain tryptophan levels after acute of chronic treatment. In a comparative study maprotiline and clomipramine were administered to healthy volunteers for 4 days and the concentrations of total and free tryptophan in plasma were determined. Serotonin uptake was also measured in the platelets from these subjects. Maprotiline treatment did not inhibit serotonin uptake nor did it have any influence on plasma tryptophan binding. Clomipramine also had no influence on plasma tryptophan-binding but strongly inhibited serotonin uptake into platelets. These results confirm the earlier observation that maprotiline has no influence on serotonin uptake and can be clearly distinguished from clomipramine.

Investigations in six healthy volunteers given single oral doses of sulphinpyrazone (Anturan) showed that the drug had a potent uricosuric effect, even if the concentration of uric acid in the plasma was normal. In the dose range tested of 50 to 800 mg the increase in uric acid excretion was dose-related. It reached a maximum within 2 h and was still detectable 6--8 h after the drug was taken. There was a corresponding dose-related reduction in the plasma concentration of uric acid, which reached its lowest level after 8--10 h. The administration of 300 mg twice daily for four days to a further five healthy volunteers reduced plasma uric acid from 5.06 to 1.8 mg%. The findings indicate that, even if plasma uric acid levels are unknown, it would be advisable to avoid the risk of formation of urinary calculi by administering sulphinpyrazone in gradually increasing doses, ensuring adequate fluid intake and alkalinizing the urine during the first few days of treatment.

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).

The growing importance of epicutaneously applicable nitrates in the treatment of angina pectoris and heart failure prompted us to carry out a study in healthy volunteers in whom we monitored the plasma concentrations and hemodynamic effects and assured the tolerability of nitroglycerin (NTG) and isosorbide dinitrate (ISDN) administered in the form of ointments.

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.

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.

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.

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.

Die Frage ist durchaus berechtigt, ob die Medizin mit der „Pflastertherapie“ von einem Modetrend heimgesucht oder eventuell sogar bereichert worden ist. Charakteristisch fur eine Modestromung ist die Neuartigkeit und Attraktivitat, aber auch die rasche und oft sogar sturmische Ausbreitung der zugrundeliegenden Idee. Fur die Nitroglycerinpflaster, d. h. die transdermalen therapeutischen Systeme (TTS) zur perkutanen Verabreichung von Nitroglycerin (NTG) treffen diese drei Charakteristika in hohem Mase zu. Mode bedeutet aber auch Verganglichkeit, Kurzlebigkeit. Seit der Einfuhrung der ersten Nitroglycerinpflaster vor mehr als 3 Jahren lassen sich jedoch noch keinerlei Anzeichen einer Ermudung der „Pflastertrager“ und ihrer behandelnden Arzte erkennen. Dennoch ist nicht anzunehmen, das das arztliche Handeln in Zukunft ganz von Transdermalsystemen oder von anderen “advanced drug delivery systems” gekennzeichnet oder gar beherrscht sein wird. Allerdings hat bereits jetzt eine rasche Ausbreitung und Weiterentwicklung des transdermalen Konzepts mit verschiedenen Technologien und diversen anderen Wirksubstanzen wie Isosorbiddinitrat, Scopolamin, Clonidin und Ostrogen eingesetzt und es steht auf Grund der bisherigen Erfahrungen auser Zweifel, das — ob Modetrend oder nicht — die Transdermalsysteme nach dem Einpendeln zwischen enthusiastischer Befurwortung und volliger Ablehnung einen festen und wichtigen Platz auf der Palette der Therapeutika einnehmen werden.

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.

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)

In healthy persons the changes in heart rate and myocardial contractility induced by oxprenolol and phentolamine are more marked in the erect position and during physical exertion then in recumbency. Similarly, a dose-effect relation with regarded to the negatively inotropic activity of oxprenolol is more readily detectable in the upright position.

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.

Oxprenolol, 40, 80 and 160 mg, was administered orally to seven healthy volunteers. Over the following eight hours repeated measurements were made of the plasma concentrations and effects on heart rate, myocardial contractility (PEPC) and systolic and diastolic blood pressure in recumbency, in the upright position and during physical effort at a work load of 120 watts on a bicycle ergometer. The maximum plasma levels and the area beneath the plasma concentration curves increased roughly in proportion to the dosage increment. No evidence of first-pass inactivation in the liver was found. The half-life of the drug in plasma was approximately 80 minutes, irrespective of the dose administered. Oxprenolol slowed heart rate, prolonged PEPC and lowered systolic blood pressure, by comparison with values recorded after a placebo. The effects were generally least marked in the recumbent position and most marked during effort, when a clear-cut dose-response relation was found. The pharmacodynamic effects of oxprenolol were compared with its concentration in plasma. Marked beta-receptor blockade still persisted eight hours after dosing, although at this time, after doses of 40 and 80 mg, the drug could not be detected in plasma.

Prenalterol was studied in six healthy volunteers given single oral doses of 2.5, 5 and 10 mg and placebo. It displayed a distinct positive inotropic action, manifested as a dose-related reduction of 16.5–27.2 msec in the pre-ejection period (PEPc; systolic time-intervals), and an increase of 4.2–5.9 Ω/sec2 in the Heather index (impedance cardiography). There was also a dose-related increase of 17.6–34.0 mmHg in systolic blood pressure, whereas diastolic pressure showed a slight, transient decrease, not related to the dose given. Heart rate rose by 5–12 beats/min. Stroke volume, as determined by impedance cardiography, increased by 24.2–28.5 ml at all three dose-levels. The effects of the drug developed rapidly, reaching their maximum within 30–60 min and lasting for about 4 h. The time-course of the effects corresponded to the plasma concentrations of the drug. The increases in systolic pressure and contractility were linearly correlated with the plasma concentrations (r=0.8−0.9,p