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.

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.

[Smoking and low socio-economic status]. / Rauchen und unterer Sozialstatus.

People of lower socio-economic strata increasingly use legal as well as illegal drugs. Tobacco and alcohol are legal drugs that cause particular concern. Both drugs are widely abused in Germany by people attempting to escape their everyday problems. For decades it has been known that tobacco and alcohol use are more prevalent in lower socio-economic strata of society (those with low educational achievement, compared to people with further or higher education qualifications). Tobacco and alcohol abuse is particularly high among the unemployed, either temporarily or longterm, as well as among persons living alone. Children and women are more concerned about smoking than men. Male loneliness, often accompanied by the appearance of depressive reactions or of depression, increases the likelihood of cigarette smoking. Poor people spend up to 20 % of their income on tobacco. In many industrialised countries, the age of onset of smoking is becoming younger and younger, increasing the risk of development of avoidable tobacco-related illnesses at an earlier age. This means that young smokers who develop chronic tobacco-related illnesses require medical care for many years, increasing the cost of treating tobacco-related disease. Within the next few years, effective prevention programmes against smoking must be developed, particularly for the lower socio-economic populations, to prevent the cost of health care systems spiralling during the next few decades.

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.

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.

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.

Effects of cigarette smoking or nicotine replacement on cardiovascular risk factors and parameters of haemorheology.

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 haemorheology parameters. DESIGN: Open, parallel-group trial (intervention group and control smokers). SETTING: Clinic within university department of pharmacology. SUBJECTS: One hundred and ninety-seven males, aged 25-45 years, smoking >20 cigarettes per day. INTERVENTIONS: One hundred and sixty-four 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. At the end of the study, the NRT group was divided into abstainers (self-reported, verified by exhaled carbon monoxide <10 ppm) and relapsers, who were unable to remain abstinent. MAIN OUTCOME MEASURES: Plasma viscosity, fibrinogen, erythrocyte deformability, reactive capillary blood flow, transcutaneous partial oxygen tension (tcpO2) and haematocrit, assessed at 4, 8, 12, and 26 weeks. Results. After 6 months, plasma fibrinogen (9.95 vs. 8.24 micromol x L(-1) at baseline; P < 0.003), reactive capillary flow (t-pmax: 9.3 vs. 11.2 s at baseline; P < 0.005), and tcpO2 (50.4 vs. 34.9 mmHg at baseline; P < 0.0001) were significantly improved in abstainers, but changes in plasma viscosity and erythrocyte deformability were inconclusive. Other CV risk factors, such as haematocrit and white blood cell count, decreased to a greater extent in abstainers than in relapsers. Expired carbon monoxide concentrations reflected the changes in smoking and decreased in abstainers from 30.4 ppm at baseline to 4.2 ppm; P < 0.0001). Conclusions. Smoking cessation improved CV parameters, and use of nicotine medications did not negate these improvements.

[Health consequences of passive smoking]. / Gesundheitliche Folgen des Passivrauchens.

Environmental tobacco smoking (ETS) represents a main risk factor for the generation of diseases of the respiratory tract and of the cardiovascular system in spite of statements to the contrary. ETS enhances the risk of lung cancer by a factor of 2-3. Newborn and small children (< 2 years of life) are at high risk if they live within this period of time in a household exposed to maternal more than fraternal smoking. Endothelial cells of the blood vessels are damaged as early as during the first month of life of passive smoking children, and these defects can be detected during the first decade of life. ETS over a period of more than ten years changes the intima/media ratio by enhancing the thickness of the vessel wall. Additionally, poor health behaviour is seen in households of smokers because the behaviour of the parents is transferred to that of their children, and this behaviour is the starting point of further health risks and damages. The presented data should cause a call for primary smoking prevention preferably among children and young persons on the one hand, and the organisation of programs against ETS at the workplace and in public buildings, as well as in the private house on the other hand. Non-smokers must be informed about the risks and dangers of ETS more than it is the case up to now.

[Health consequences of passive smoking]. / Gesundheitliche Folgen des Passivrauchens.

Environmental tobacco smoking (ETS) represents a main risk factor for the generation of diseases of the respiratory tract and of the cardiovascular system in spite of opposite assertions. ETS enhances the risk of lung cancer by a factor of 2-3. New born and small children (< 2 years of life) are at high risk if they live within this period of time in a household together with a maternal more than fraternal smoking. Endothelial cells of the blood vessels were already damaged during the first month of life of passive smoking children, and these defects can be measured during the first decade of life. ETS over a period of more than ten years changes the intima/media ratio by enhancing the thickness of the vessel wall. In addition, poor health behaviour is seen in households of smokers because the behaviour of the parents is transferred to that of their children, and this behaviour is the starting point of further health risks and damages. The represented data should firstly lead to enhancing primary smoking prevention among children and young people, and secondly to organizing programs against ETS at the workplace and in public buildings and at last also in the private home. More than up to date, the non-smoker must be informed about the risks and damages of ETS.

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.

[Antidepressive drug against nicotine. A method for smoking cessation]. / Antidepressivum kontra Nikotin. Neue Methoden der Raucherentwöhnung.

Currently, two drugs are considered useful for those wishing to quit smoking in Germany--nicotine and bupropion. The mechanism of action appears to involve reuptake inhibition of the transmitters noradrenaline and/or dopamine by the brain. Treatment with a daily dose of 300 mg delayed release buproplon for 7 to 9 weeks resulted in smoking cessation in 30.3% (buproplon) and 35.5% (bupropion plus nicotine patch) of the smokers at 12 months (placebo: 15.6%, nicotine patch: 16.4%). A large number of the participants had had negative experience with nicotine preparations in previous attempts to stop smoking. Most side effects of bupropion involve the nervous system (disturbed sleep, trembling, loss of concentration, headache, dizziness, depression, restlessness, anxiety) and the gastrointestinal tract (dry mouth, nausea, vomiting, abdominal pain, constipation) and elevated temperature (> 1% of the treated subjects). It is suggested that, at present, bupropion should be used for this indication only in those smokers in whom treatment with nicotine has failed.

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.

[Smoking: health care and politics in flux]. / Rauchen: Gesundheitswesen und Politik im Wechselspiel.

The cigarette is the only legally sold product with carcinogenic, cardiovascular damaging and addictive effects. With a yearly profit of several billions, the tobacco industry supports politicians to solve their tasks, whereas these polticians, do not promote projects against smoking and the protection of nonsmokers, despite of some less compulsory statements. Up to now, the tobacco industry denies the health hazard effects occurring to cigarette smokers after two or three decades. On the other hand, the public health insurance do not provide any financial support for smoking prophylaxis and smoking cessation. Instead of this, they have to cover costs for subsequent health injuries, early disability included, which are more than 100-1000 times higher. The solidary community has to finance the pensions for relatives of those numerous smokers, who died early, and whose lives were shortended by provable 5 to 6 years. Politicians refuse to represent the will of a population majority for measures to prevent nonsmokers.

Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon.

Anticoagulants of the cumarin-type (warfarin, phenprocoumon, and acenocoumarol) are drugs for the long-term treatment and prevention of thromboembolic disorders. Because of their narrow therapeutic range, many patients have bleedings of variable severity or have recurrent thrombotic events. For this reason, the study of the pharmacokinetic parameters of phenprocoumon (PPC), considering its influence on blood clotting factors, is of high interest. The elimination kinetics of PPC, its interaction with phytomenadion (vitamin K), and the pharmacokinetic behavior of the anticoagulant under steady-state conditions have been investigated in studies with healthy volunteers and patients taking anticoagulants. The maintenance dose and the plasma levels of PPC were correlated with prothrombin time (PT) in 89 patients treated with PPC. Varying parameters in each patient (e.g., elimination kinetics of PPC, activity of the cumarin-dependent blood-clotting factors, endogenous phytomenadion stores), render it impossible to use a different means of monitoring than that of PT determination.

[Smoking, cardiovascular diseases and possibilities for treating nicotine dependence]. / Zigarettenrauchen, Herz-Kreislauf-Erkrankungen und Möglichkeiten der Behandlung der Nikotinabhängigkeit.

Diseases of the cardiovascular system such as coronary heart disease, hypertesion, peripheral occlusive arterial disease, and their final or lethal states (acute myocardial infarction, apoplectic stroke, congestive heart failure) occur 3 to 4 times more frequently than lung cancer in heavy smokers. Cigarette smoking impairs the courses of the microcirculation by an elevated viscosity of the blood or plasma, by a diminished deformability of the red blood cells, by elevated white cell counts, by activation of several blood clotting factors such as factor XIII and von Willebrand factor, by an elevated aggregability of the blood platelets, and by an increased uptake of fibrinogen into the endothelium of the blood vessels. After cessation of smoking these effects are widely normalized even though nicotine is still administered. Proposals for the cessation of smoking and for the use of nicotine replacement (patch, chewing gum, etc.) were offered because the inhaled tobacco smoke mainly damages health while the smokers are addicted only by nicotine. A less restrictive distribution of nicotine preparations for replacement therapy should enable the heavy smoker in his first phase of smoking cessation to combine the nicotine administration with reduced cigarette smoking. Each decrease in the carbon monoxide content of the expired air with subsequent decrease in the carboxyhemoglobin content of the blood possibly diminishes the risk of cardiovascular events. This way of treatment gives new opportunities for the treatment of the smoking patient for every physician.

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.