Percutaneous endovascular treatment of infrainguinal PAOD: Results of the PSI register study in 74 German vascular centers.

BACKGROUND: The percutaneous infrainguinal stent (PSI) register study aimed to collate all percutaneous endovascular procedures for infrainguinal peripheral arterial occlusive disease (PAOD) conducted in 74 German vascular centers between September and November 2015 (3 months). In order to obtain representative results all consecutive treatment procedures had to be submitted by the participating trial centers. MATERIAL AND METHODS: This was a prospective, nonrandomized multicenter study design. All patients suffering from intermittent claudication (IC, Fontaine stage II) or critical limb ischemia (CLI, Fontaine stages III and IV) were included. Trial centers with less than 5 cases reported within the 3­month trial period or centers that could not ensure the submission of all treated patients were excluded. RESULTS: In the final assessment 2798 treated cases from 74 trial centers were reported of which 65 (87.8 %) centers were under the leadership of a vascular surgeon. Approximately 33 % of the interventions in centers under the leadership of vascular surgeons were conducted by radiologists. Risk factors, especially chronic renal disease, diabetes and cardiac risk factors were significantly different between patients with IC and CLI. Of the patients with Fontaine stage II PAOD 41.3 % had 3 patent crural vessels compared to only 10.8 % of patients with Fontaine stage IV. With respect to peri-interventional complications, percutaneous endovascular treatment of IC was a safe procedure with severe complications in less than 1 % and no fatalities. Only 4.5 % of the procedures were conducted under ambulatory conditions. In the supragenual region self-expanding bare metal stents, standard percutaneous transluminal angioplasty (PTA) and drug-coated balloons were the most frequently used procedures. For interventions below the knee, standard PTA was the most commonly employed treatment. CONCLUSION: The main aim of the PSI study was to obtain a realistic picture of percutaneous endovascular techniques used to treat suprapopliteal and infrapopliteal PAOD lesions and to describe the treatment procedures used by vascular specialists in Germany. To investigate the change in trends for treatment over time, this study has to be repeated in the future in order to test how quickly the results of randomized studies can be implemented in practice.

A real-time Global Warming Index.

We propose a simple real-time index of global human-induced warming and assess its robustness to uncertainties in climate forcing and short-term climate fluctuations. This index provides improved scientific context for temperature stabilisation targets and has the potential to decrease the volatility of climate policy. We quantify uncertainties arising from temperature observations, climate radiative forcings, internal variability and the model response. Our index and the associated rate of human-induced warming is compatible with a range of other more sophisticated methods to estimate the human contribution to observed global temperature change.

Pharmacotherapy of nicotine dependence.

Withdrawal treatment of cigarette smokers is a task of the utmost urgency in view of the consequences for national health programs and legislative policies of the high morbidity and mortality rates caused by smoking. Smokers need medical consultation in addition to drug-based treatment, but this results in self-willed quitting of the smoking habit in a limited number of smokers only. From the point of view of the criteria of "evidence-based medicine", non-drug methods such as hypnosis therapy and acupuncture are not effective (odds ratio = 1.22). Among the drug-based methods, treatment with nicotine substitution preparations has shown confirmed efficacy in numerous studies (odds ratio 1.63 to 2.67, depending on the application form used) and results in successful withdrawal from the smoking habit in 30-40% of cases. A decisive problem in the initial therapeutic phase appears to be the amount of the applied nicotine dose, but beyond that can be mastered above all by combining 2 or 3 application forms (patchs, chewing gum, nasal spray). Treatment is then continued for 4-12 weeks, depending on the degree of dependence, with successively reduced nicotine dosage. Two controlled studies with disparate designs have been done on bupropion (odds ratio 2.3/3.0). However, further studies are desirable due to concern about undesirable effects of bupropion described recently. Other substances subjected to trials in years past, such as clonidine, lobeline, mecamylamine and antidepressants including buspirone cannot be recommended on the basis of current data for treatment of smokers seeking a withdrawal cure.

State of the art--treatment of peripheral occlusive arterial disease (POAD) with drugs vs. vascular reconstruction or amputation.

Peripheral occlusive arterial disease (POAD) is a disease with a progressive course in about half of the patients affected. The Fontaine stage II and III have been treated not always successfully in the last decades with physical exercise, vasoactive substances (pentoxifyllin, naftidrofuryl, buflomedil) and with alprostadil. Recently methods of vascular surgery such as PTA, stent implantation and bypass operations are introduced in the treatment of Fontaine POAD stages III and IV, but these procedures are not recommended in patients younger than 50 years in order to delay amputation of a limb. The vasoactive substances are seen in a new light, because they improve processes of the microcirculation such as decreasing plasma viscosity, the raised plasma fibrinogen level and increasing the deformability of red blood cells and inhibiting platelet aggregation. According to a number of studies pentoxifylline and naftidrofuryl may delay the progression of arteriosclerosis. Therefore, a new concept of the treatment of POAD must be evaluated (1) resulting in a combination of vascular surgery and intermittent drug therapy with vasoactive agents, (2) leading to a decrease in the risk of amputation frequency and (3) reducing the treatment costs in spite of a higher frequency of the disease and a longer average life expectancy.

Bupropion: pharmacological and clinical profile in smoking cessation.

Chemistry, pharmacokinetics, pharmacology, clinical efficacy, adverse effects and dosage of bupropion hydrochloride (BP), an aminoketone antidepressant used in smoking cessation, are reviewed. The nicotinergic acetylcholine receptors are inhibited at clinically relevant concentrations of BP. BP does not inhibit monoamine oxidase, and it has minimal inhibitory effects on presynaptic noradrenaline and dopamine uptake. BP is rapidly absorbed after oral administration and demonstrates biphasic elimination with an elimination half-life of 11 - 14 hours. BP is extensively metabolized by oxidation and reduction to at least 6 metabolites, 2 of which may be active. The plasma levels of the erythro-amino alcohol of BP correlate with several side effects such as insomnia and dry mouth. Efficacy of BP(SR) in smoking cessation has been examined in several double-blind, randomized trials in which daily doses of 150 or 300 mg have been administered for 7 or 9 weeks. In addition, 1 study examined the combination of BP(SR) plus nicotine patch. The point prevalences of stopping smoking reached values between 21.2 and 38%, but they did not exceed those after nicotine replacement therapy alone. Long-term administration (52 weeks) of BP did not improve abstinence compared with placebo after a 2-year follow-up period. Thus, the efficacy of BP in smoking cessation is comparable to that of nicotine replacement therapy. However, BP possesses a broad spectrum of infrequent adverse effects and interferes with the degradation of several drugs such as tricyclic antidepressants, beta-recpetor blocking agents, class Ic-antiarrhythmics etc. As the risk-benefit ratio of BP is smaller than that of nicotine replacement, BP should be considered as a second-line treatment in smoking cessation.

Cigarette smoking, nicotine and pregnancy.

Smoking cigarettes during pregnancy and nursing causes considerable health damage to the fetus and to the infant during the initial growth phase. A smoking mother puts her child at considerable risk, not only of higher incidence of spontaneous abortion, premature ablatio placentae and reduced weight at birth, but also of deformities (cheilognathopalatoschisis, deformed extremities, polycystic kidneys, aortopulmonary septum defects, gastroschisis, skull deformation, etc.). Development of the Down syndrome is the subject of some controversy. These types of damage are caused by the hypoxia followed by carboxyhemoglobinemia occurring during smoking and are also observed in CO poisonings that also result in deformities. Numerous infants die during the first months of life of the so-called sudden infant death syndrome (SIDS), which can also be caused by maternal smoking and passive smoking. The contribution of nicotine to such health damage is still unclear, especially because only animal trial data are available, the applicability of which to human beings is questionable. It can be said that studies to date have revealed no deformities confirmed as having been caused by nicotine. Cardiopulmonary disturbances resulting from changes in the regulation of dopaminergic receptors are under discussion, but have not yet reached the status of a pathogenic principle. On the whole, all child health complications arising during pregnancy can be attributed almost exclusively to tobacco combustion products including the CO formed. Passage of nicotine into human milk has been confirmed in nursing smokers; passive smoking by mother and child also raises nicotine and cotinine levels in the milk and in the infant. These findings could lead to a reconsideration of smoking withdrawal therapy for pregnant women.

Pharmacokinetics of phenprocoumon.

The pharmacokinetics of phenprocoumon was studied in 24 healthy volunteers between the ages of 23 and 28 years and a mean body weight of 72 kg by intraindividual comparison of the plasma level after i.v. and oral administration of 9 mg phenprocoumon (PPC) or by the evaluation of the total plasma clearance of PPC by simultaneous measurement of the urinary excretion and of the plasma concentration after the administration of 9 mg PPC. The following mean data were obtained after i.v. injection:t1/2 alpha 0.432h, t1/2 beta 128 h, co 0.651 microgram/ml, Vd 14.41,AUCo-omega 121 micrograms x h/ml. After intake of 9 mg PPC the following mean values were measured: tmax 2.25 h, Cmax 1.01 micrograms/ml, tabs 0.553 h, co 0.865 micrograms/ml, t1/2 beta 132 h, AUC0-infinity 164 micrograms x h/ml. By comparison of the PPC plasma level with the corresponding urinary excretion, a total mean PPC clearance of 20.0 (i.v.) and 15.1 (per os) ml/h was calculated within the first 8 h post dose, while the values measured did not differ between 8 and 48 h post dose (14.8 vs 15.3 ml/h). The steep decline in plasma level after i.v. injection of PPC might be caused by an enhanced renal and hepatic elimination of the free drug to a higher degree than after oral intake, while no differences existed between both modes of administration during the phase of elimination. A nearly total absorption of PPC from the tablet formulation is suggested.

The effects of 2 beta-receptor blocking agents on the microcirculation of healthy subjects and of hypertensive patients.

The effects on parameters of the capillary system of the beta 1-blocker bisoprolol and of the alpha 1/beta-blocker carvedilol were investigated in 12 healthy female and 12 male non-smokers and smokers and in 20 hypertensive patients (state WHO I-II). Besides the antihypertensive and heart rate-reducing effect, carvedilol but not bisoprolol provoked a short-term increase in the capillary red blood cell velocity by 20% and an increase in the oxygen tension (tcpO2) in healthy smokers by 27% (p < 0.05). In hypertensive patients the single intake of carvedilol enhanced the capillary velocity by 16% after the first dose, the effect decreased by 5.4% after the intake for 4 weeks. The simultaneously observed increase in tcpO2 lasted only 30 min post dose, while bisoprolol was without significant effects. Carvedilol did not change the venous capacity after the first dose but increased it by 35% after intake for 4 weeks, while bisoprolol with its slight peripheral resistance-enhancing effect decreased the venous capacity after intake for 2 and 4 weeks. The venous outflow increased 1.5 and 2 h after carvedilol administration, but this was not seen 2 and 4 weeks later. The deformability of red blood cells was not changed by both beta-blockers. The data in volunteers and hypertensives indicate a weak vasodilating effect of carvedilol in contrast to bisoprolol in the arterial and venous capillary bed. These effects must be confirmed by additional studies.

Extraordinary efficacy of 16 alpha-gitoxin, an ultra-short acting semi-synthetic digitalis glycoside.

The positive inotropic effect of 16 alpha-gitoxin was studied in 52 female and male healthy volunteers between the ages of 21 and 27 years and a body weight between 55 and 76 kg after the single i.v. injection or oral administration in doses between 2.5 and 15 mg. The inotropic effect was evaluated by the use of the systolic time intervals (left ventricular ejection time, LVET, and electromechanic systole, QS2) and by the QT-Interval of the ECG. The glycoside plasma level was measured simultaneously to the pharmacodynamic parameters by a radioimmunoassay, 16 alpha-gitoxin abbreviated dose-dependently the STI (LVET and QS2) for 30 (i.v.) or 15 ms (per os) and the QT interval for 35 ms. A mean plasma concentration of 401 ng/ml was measured 15 minutes after the i.v. injection of 5 mg and a mean plasma level of 402 ng/ml was measured 1 hour after the oral intake of 10 mg 16 alpha-gitoxin as an aqueous-ethanolic solution. The shortening of the STI-values and of the QT-interval correlated with the administered glycoside dose and with the AUC0-6-value. The AUC-values increased linearly with the administered dose. The ratio of the AUC0-6-values after i.v. or oral administration of 7.5 mg 16 alpha-gitoxin amounted to 0.673. Doses of 16 alpha-gitoxin which induce a maximum abbreviation of STI or QT did neither provoke a distinct decrease in heart rate nor cardiac disturbances. Sixteen-alpha-gitoxin develops a positive inotropic effect within a few minutes after i.v. injection and also after oral intake.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pentaerithrityl-tetranitrate on parameters of the microcirculation.

AIM OF THE STUDY: The effect of organic nitrates on microcirculation was first studied in 1964 and with regard to glyceroltrinitrate (GTN) an "internal hemodilution" (i.e. a fluid shift from the extravascular fluid to the intravascular compartment) was observed. Therefore, we found it of interest to study the effects of the long-acting PETN on parameters of hemorrheology. METHODS: The effects of single doses of 25, 50, and 80 mg PETN, 0.4 mg GTN, and of placebo were investigated on the capillary erythrocyte velocity (CEV; Capiflow), the tissue oxygen tension (tcpO2), the deformability of red blood cells, the plasma viscosity and of the fibrin content of the plasma in a single-blind, randomized study over 12 h in 12 healthy female and male volunteers. The CEV and the tcpO2 were measured in the nailfold of the fourth finger and on the skin of its end phalanx, respectively. Statistical analysis was performed by analysis of variance, the calculation of epsilon (Greenhouse-Geisser), and the multiple t test. RESULTS: After administration of 50 or 80 mg PETN the CEV decreased by 30% over a period of 2 or 4 h (p = 0.02 or 0.002). A decrease by 11% was measured 1 and 2 h after administration of GTN (p = 0.034). Under the same PETN doses tcpO2 increased from 1.41 to 1.78 mm mercury (p = 0.002). The deformability of red blood cells was slightly increased after 50 and 80 mg PETN under share rates of 60 Pa from 55.5 to 58.0% 8 and 12 h after intake. The plasma viscosity was decreased after intake of 50 mg PETN 4 to 8 h (1.36 vs. 1.34 Pa x s, p = 0.023) and after intake of 80 mg 2 to 12 h post dose (1.36 vs. 1.33 Pa x s, p = 0.015). The systolic or diastolic blood pressure decreased, but was not significant. CONCLUSIONS: The PETN-induced decrease in CEV can be explained with the pre- and afterload decreasing properties of the nitrates. The increase in tcpO2 and erythrocyte deformability and the decrease in viscosity are additional advantageous effects on the microcirculation. If the results are transferred from the nailfold of the finger to the myocardium, the benefit of nitrates could not only be seen in the decrease in preload due to their vasodilating properties, but also in improving the parameters of microcirculation. The internal hemodilution and the slightly enhanced deformability might provide an additional supply of myocardial capillaries in case of myocardial ischemia.

Cost-benefit analysis--a prerequisite of a rational pharmacotherapy in cardiovascular diseases. Timely thrombolysis in the acute myocardial infarction.

The worldwide increase in the expenses of the National Health Services compels the legislation of some countries to take economizing regulatory measures. In Germany the existent and planned activities are an essential part of the German Structural Health Act of 1993. In the last years methods have been developed to estimate the cost-benefit relationship of special therapeutic interventions giving the physician an aid to avoid the application of those of low cost-efficiency. The cost-effectiveness and the cost-utility analyses are the recently most usual ones. The timely thrombolysis of the acute myocardial infarction is presented under the viewpoint of the economical drug use in cardiovascular disease. Investigations to evaluate the cost-effectiveness of streptokinase and the newer thrombolytics anistreplase and alteplase are carried out in some European countries and in the USA. Parameters of efficacy are the amelioration of cardiac functions, the shortening of the rehospitalization duration, and the extension of the survival time. The use of a thrombolytic within 4 to 6 hours after the onset of the first signs is recommended and economically justified especially in anterior myocardial infarction and also in patients aged 75 years and above. Streptokinase is designated by a low cost-effectiveness ratio. The successful thrombolysis does not result in a continous deterioration of the quality of life in the patients. In this review no attempt was made to extrapolate the findings to the recent situation because of possible national pecularities with regard to the morbidity of and the therapeutic procedures in the acute myocardial infarction and because of the changes in the cost structure and currency parity which occurred in the meantime.

A review of the pharmacological and psychopharmacological aspects of smoking and smoking cessation in psychiatric patients.

The data reviewed confirm that mentally ill patients smoke twice as many cigarettes as patients without mental illness. The secretion of neurotransmitters such as noradrenaline, serotonin, dopamine, acetylcholine, gamma-amino-butyric acid and glutamate is increased by the binding of nicotine to central nicotine receptors. There are also data showing that serotonin formation and secretion in patients with mental illness are influenced by chronic smoking. Cigarette smoke inhibits the activity of monoamine oxidase B, which is responsible for the catabolism of several brain neurotransmitters. Patients suffering from major depression show a comorbidity between heavy smoking and the disease. In patients with schizophrenia treated with neuroleptics, increased cigarette smoking reduces adverse reactions to the drug therapy presumably because of an increase in metabolism of the neuroleptics. There is also evidence suggesting that quitting smoking is more difficult for mentally ill patients than patients without psychiatric disease. Several studies have been carried out on smoking cessation in psychiatric patients. The alternative method of harm reduction, e.g. reducing the number of cigarettes smoked using nicotine patches or chewing gum, is necessary in patients not able to quit. The data indicate that strategies such as the coupling of smoking prohibition with administration of nicotine preparations are useful in smoking cessation. A no-smoking policy in psychiatric clinics, even when this leads to withdrawal symptoms in the patients affected, has no negative effect on mental illness. Because patients with mental diseases are particularly vulnerable to the marketing strategies of the tobacco industry, this chronically ill section of the population requires special protection by the law-makers.

Transport of various substances through human enamel and dentine.

The penetration of 14C-labelled alcohols (methanol, ethanol, n-butanol), 14C-labelled carbonic acids (formic, acidic, propionic, valerianic, octanoic, malonic, succinic and lactic acid), 14C-drugs (procain, barbital), and 14C-sugars (saccharose, xylose) into about 800 human deciduous or permanent teeth, both healthy and carious, was investigated. Dental enamel up to the cemento-enamel junction was incubated at a pH-value of 5.0 or 6.8 for 1 or 24 hours. For measurement of radioactivity, the dentine of the root was obtained by trepanation. Between intact and carious permanent teeth only slight differences were observed in case of the diffusion of methanol and ethanol (2% of the incubation medium), while n-butanol penetrated the dentine to an extent of 4.2% at a pH of 5.0. The monocarbonic acids penetrated the enamel of healthy teeth within 24 hours to an extent of 6.6-19.2% of the content of the incubation medium, while the dicarbonic (succinic and malonic) acids reached amounts of 3.6 and 9.2%, and the percentage of lactid acid which penetrated the enamel reached 2.9%, respectively. Under all conditions tested, saccharose penetration was higher in carious than in healthy teeth (3.8 vs 6.5%). The highest uptake was found in experiments with barbital; it was more pronounced in deciduous than permanent teeth (16.2 vs 12.4%). The data could be of interest in the therapy of inflammatory and other processes of the pulp.

Bioequivalence of allopurinol-containing tablet preparations.

AIM: The study was undertaken to prove the bioequivalence of two allopurinol tablet preparations. SUBJECTS, MATERIALS AND METHODS: The relative bioavailability of allopurinol from two tablet preparations (Uribenz vs. Zyloric 300) was estimated on 18 volunteers of both sexes in an open randomized study by administering one tablet of each preparation at an interval of 2 weeks. The plasma concentrations of allopurinol and its active metabolite oxypurinol were measured over a time-period of 72h by HPLC. RESULTS: While the mean AUC(0-72) values of allopurinol and oxypurinol after the test and reference preparations are entirely identical (5.33 vs. 5.21 and 137.95 vs. 137.96 microg h ml(-1), respectively), the C(max) values of oxypurinol unlike those of allopurinol show small differences (4.59 vs. 4.78 and 1.91 vs. 193 microg/ml, respectively). According to the parametric and non-parametric analysis, the quotients AUC(T)/AUC(R) and C(maxT)/C(maxR) lie within the confidence intervals 0.8 to 1.2 and 0.7 to 1.3 respectively With regard to the t(max) of allopurinol, the differences of test and reference preparations are between 0.10 to 0.05h and of oxypurinol between -0.10 to 0.87h (parametric analysis). Both, Uribenz 300 and Zyloric 300 caused a maximum decrease of the uric acid concentration in the volunteers by 18% after 10 and 24h, respectively. CONCLUSION: Thus the bioequivalence of the allopurinol tablet preparations is demonstrated.

Bioequivalence of tolbutamide-containing tablet preparations.

The present crossover study was undertaken to investigate in 22 volunteers (15 males, 7 females, aged 22-28 years) whether the 2 tolbutamide preparations (tolbutamide R.A.N. vs. rastinon Hoechst) are bioequivalent. After administering a single dose of one 1 g tablet of each preparation the plasma tolbutamide concentration was measured by HPLC over a time-period of 48 hours. The mean AUC0-48 values are nearly identical (998.42 vs. 997.73 micrograms x h x ml-1), while the Cmax values (51.1 vs. 58.8 micrograms/ml) and the tmax values (4.55 vs. 3.82 h) show slight differences. The Westlake intervals claimed to prove bioequivalence lies in the 95% confidence interval between the limits 0.972 and 1.046 (AUC), 0.896 and 0.978 (Cmax), and 0.056 and 1.346 (tmax). For example, this is the result of the parametric analysis considering the randomization. In the case of the parameters of the multiplicative model (AUC and Cmax) the probability of correctly concluding bioequivalence (power) between the 2 preparations reaches 2.0. Regarding maintenance therapy it is of minor importance that the maximum plasma tolbutamide concentrations is 0.7 h later observed with the test preparation than with the standard. The results of this study allow the conclusion that the 2 tablet preparations are bioequivalent.

Changes in hemorheological and biochemical parameters following short-term and long-term smoking cessation induced by nicotine replacement therapy (NRT).

OBJECTIVES: Cigarette smoking causes cardiovascular (CV) disease, but the relative roles of nicotine and other components of tobacco smoke remain unclear. We investigated the effect of stopping smoking by using nicotine replacement therapy (NRT) on hemorheology parameters, on the cotinine and thiocyanate plasma concentrations and the exhaled carbon monoxide (CO). DESIGN: Open, parallel-group trial (intervention group and control smokers). SUBJECTS: 197 males, aged 25-45 years, smoking > 20 cigarettes per day (cpd). INTERVENTIONS: 164 subjects were instructed to stop smoking and received NRT for 12 weeks and 33 acted as controls. After 12 weeks, NRT was discontinued and all subjects were followed-up at 26 weeks. Beginning with week 4, the treated subjects were divided into abstainers (self-reported, verified by exhaled CO < 10 ppm) and nonabstainers, not able to stay abstinent since baseline. The group of the nonabstainers was stratified in 2 subgroups, the reducers (smoked < 50% of baseline number of cpd) and relapsers (smoked 50-100% of baseline cpd). MAIN OUTCOME MEASURES: Plasma viscosity, erythrocyte deformability, fibrinogen, transcutaneous partial oxygen tension (tcpO2), hematocrit, white blood cells, cotinine and thiocyanate plasma concentrations and exhaled CO, all assessed at 4, 8, 12 and 26 weeks. RESULTS: After 6 months, plasma fibrinogen (228.2 vs. 275.4 mg/dl at baseline, p < 0.001), tcpO2 (50.4 vs. 34.9 mm mercury at baseline, p < 0.0001) were significantly improved in abstainers, but changes in plasma viscosity and erythrocyte deformability were inconclusive. Cotinine and thiocyanate (abstainers: 6.2 ng/ml at week 26 vs. 10.4 ng/ml at baseline, p < 0.0001) and expired CO (abstainers: 30.4 vs. 4.2 ppm, control vs. week 26, p < 0.0001) accurately followed the changes in smoking and/or NRT use in all of the groups. Other CV risk factors such as hematocrit and white blood cell count decreased to a greater extent in abstainers than in reducers and relapsers. Not only abstainers but also reducers did benefit of the temporarily stop smoking. CONCLUSIONS: Smoking cessation improved CV parameters despite the measured cotinine and thiocyanate plasma levels, and use of nicotine medications did not negate these improvements. A smoking cessation for a short time and smoking of reduced cpd also improved these parameters temporarily.

Absorption and bioavailability of pentaerithrityl-tetranitrate (PETN, Dilcoran 80).

The effects of 80 mg pentaerithrityl-tetranitrate (PETN) as suspension or formulated as tablets were compared to placebo in a single blind, randomized, crossover study in 18 healthy subjects (study A), and the bioequivalence of two tablet formulations (marketed Dilcoran 80 vs a new formulation) was studied in 24 healthy subjects after administration of single oral doses of 80 mg PETN according to a placebo controlled, randomized, double blind, two-way crossover study design (study B). The perfusion of the right middle finger was measured by rheography (altitude A of the changes of resistance and of the incisure D) before and 24 h post-dose, and blood pressure and heart rate were measured in supine position at the same time. The values of area under curve (AUC) of the ratio A/D were calculated by the trapezoidal rule. In study A the mean A/D-values were reduced from about 2.0 to about 1.3 after intake of PETN (solution or tablet) with a minimum 60 to 90 min postdose (solution) and 2 h postdose (tablet). A significant reduction in this ratio was seen up to 8 (solution) or 12 h (tablet) post dose. Changes in blood pressure were not observed while the heart rate decreased in the subjects of all three groups 1 to 2 h postdose followed by an increase by 6 to 10 beats per min. After subtraction of the AUC values of placebo from the PETN-derived AUC values, mean values of 6.61 (SD 1.52, solution) and 7.25 (SD 1.48, A/D*h, tablet) were calculated (p > 0.1, study A).(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent shortening of systolic time intervals after intake of pengitoxin.

The systolic time intervals (STI) corrected for changes in the heart rate, electromechanical systole (QS2c) and left ventricular ejection time (LVETc), and the ECG-derived PQ-time and QT-interval were measured in five female and four male healthy subjects. Each volunteer took 0.15, 0.30, 0.45, 0.60, 0.75 or 0.90 mg pengitoxin over six days, with a glycoside-free interval of two or three weeks between two doses. The glycoside plasma level was measured radioimmunologically. Linear correlations were found between the shortening of QS2, LVET, and QT (delta QS2c, delta LVETc, delta QTc) and the plasma level of 16-acetyl-gitoxin. The PQ-time showed a flat dose-dependent increase. The shortening of STI observed after therapeutic and subtoxic doses of pengitoxin was in accordance with that after intake of digitoxin and digoxin in corresponding doses. The efficacy of pengitoxin estimated by shortening of STI justifies the administration of daily maintenance doses between 0.30 and 0.45 mg.

[Bioavailability of etilefrine from Thomasin and Thomasin sustained-release tablets]. / Zur Bioverfügbarkeit von Etilefrin aus Thomasin- und Thomasin retard-Tabletten.

In 6 healthy volunteers absorption and elimination of etilefrine were studied in cross-over after intake of 20 mg each of a solution (A) and tablet (B) (Thomasin) or after intake of 25 mg as a sustained-release tablet (C; Thomasin retard). Etilefrine and its sulfoconjugate were measured by the GC technique in plasma and urine. From the data obtained the AUC-(plasma) and CUE-values (urine) were calculated. Peak plasma levels of 10 to 25 (A) and 6 to 13 ng . ml-1 were observed 30 min after intake. The concentrations decreased to the lower detection limit (less than 2 ng . ml-1) 2 h after intake. Plasma peak levels of 5 ng . ml-1 were measured 1-2 h after intake of the sustained-release form (C). The etilefrine plasma level decreased more slightly (C) than after intake of the other formulations (A, B). The etilefrine conjugate reached plasma peak concentrations of 600 ng . ml-1 1 h (A, B) or 2 h (C) after intake. A mean bioavailability of 70 and 58 per cent (Thomasin) or of 78 and 108 per cent (Thomasin retard) was calculated by comparison of the corresponding AUC- and CUE-values of the total etilefrine.

[Quantitative thin-layer chromatographic estimation of aminophenazone (I.N.N.), 4-methylaminophenazone and 4-aminophenazone in plasma (author's transl)]. / Quantitative dünnschichtchromatografische Bestimmung von Aminophenazon (I.N.N.), 4-Methylaminophenazon und 4-Aminophenazon im Plasma.

A TLC method for measurement of aminophenazone (1) and of its degradation products 4-methylaminophenazone (2) and 4-aminophenazone (3) in plasma was described. After chloroform extraction amd separation on Silufol plates the substances were stained by ferric chloride/potassium hexacyanotoferrate(III) and the area of the spots was measured. Concentrations from 1 to 25 micrograms 1, 2 and 3 per ml plasma could be estimated.