Corrigendum: Impact of climate change on non-communicable diseases due to increased ambient air pollution.

[This corrects the article on p. 103-121 in vol. 8, PMID: 37799533.].

[Adaptation to climate change-associated health risks as a task of environmental health protection. Analysis of a nationwide investigation by the Federal Environment Agency]. / Anpassung an die gesundheitlichen Risiken des Klimawandels als Aufgabe des umweltbezogenen Gesundheitsschutzes. Analyse einer bundesweiten Recherche und Erhebung des Umweltbundesamtes.

The German Strategy for Adaptation to Climate Change (DAS, 2008) identified 'human health' as an important sector with a need for adaptation. In line with the DAS, the Federal Environment Agency (UBA) and the Robert Koch Institute jointly elaborated guidelines for decision makers and stakeholders. Building on these, in 2013/2014, UBA has conducted a nationwide survey, collecting data on completed, ongoing and planned adaptation measures. UBA also analysed 32 adaptation strategies of the Federal States. Selected best practice examples of potential health-related prevention and adaptation measures concerning heat stress, UV radiation exposure and the spread of Ambrosia artemisiifolia are presented in this article. The data collection with more than 330 activities can be found on the website of the German National Environment and Health Action Plan (APUG; www.apug.de , in German only). In the course of this project, the APUG website was also significantly extended with comprehensive information and overviews on health risks of climate change, hence creating a central platform for this particular topic.

The role of imatinib in the treatment of pulmonary hypertension.

Imatinib mesylate, a receptor tyrosine kinase inhibitor that has been approved for several oncology conditions, is currently under investigation for pulmonary arterial hypertension. The therapeutic rationale is that its targets, platelet-derived growth factor receptor beta (PDGFR-ß) and proto-oncogene c-Kit, are pivotal for the proliferation, migration and apoptosis resistance of peripheral artery smooth muscle cells which reduces the lumen of the pulmonary artery, leading to diminished blood oxygenation and pressure overload in the right heart ventricle. Interfering with this process could slow disease progression, which is incompletely addressed by current therapies which focus on vasorelaxation. Results from two efficacy studies have been reported; while the first missed its primary endpoint (but provided valuable insights on efficacy in subgroups), the phase III IMPRES study and its ongoing extension revealed an impressive degree of added benefit for imatinib against a background of conventional combination therapy. The side effect profile of imatinib in this condition requires more investigation.

Iguratimod: a new disease-modifying antirheumatic drug.

Iguratimod, a methanesulfonanilide, is a novel disease-modifying antirheumatic drug that has been developed exclusively in Japan and China. It inhibits the production of immunoglobulins and various inflammatory cytokines (interleukin-1, -6 and -8 and TNF), and exerts anabolic effects on bone metabolism by stimulating osteoblastic differentiation and inhibiting osteoclastogenesis. On the molecular level, it inhibits the nuclear transcription factor NF-κB but not its inhibitor, IκBα. In addition to these immunomodulatory and other long-lasting effects, iguratimod inhibits cyclooxygenase-2, which provides a synergistic short-term action against pain and inflammation. Efficacy and tolerability are comparable to salazosulfapyridine, and probably also to methotrexate. Combination with methotrexate is synergistic in patients with insufficient response to methotrexate and does not significantly increase adverse events. Liver enzyme elevations and thrombocytopenia are the most significant side effects to watch for. In summary, iguratimod is a welcome addition to the small-molecule drug therapy of rheumatoid arthritis.

Memantine in moderate to severe Alzheimer's disease: an observational post-marketing study.

Memantine is an N-methyl-D: -aspartate (NMDA) receptor antagonist, approved for the treatment of moderate to severe Alzheimer's disease (AD). We conducted a 4-month observational, post-marketing, Austrian study of memantine in 377 outpatients with moderate to severe AD. In this 'real-life' setting, memantine was well-tolerated, and produced benefits in cognition (Mini-Mental State Examination), activities of daily living (Activities of Daily Living score), and global function (Clinical Global Impression scale). Treatment effects were apparent in both pre-treated and treatment-naïve patient subgroups.

Randomized, crossover, single-blind, placebo-controlled, human pharmacology clinical trial with desoxypeganine, a new cholinesterase and selective MAO-A inhibitor: multiple-dose pharmacokinetics.

UNLABELLED: Desoxypeganine, a naturally occurring alkaloid, is being developed for its potential utility in the pharmacological treatment of alcohol abuse to reduce craving and depression in alcohol abusers, and might also be useful as a smoking cessation aid. During the preclinical development it was characterized as a cholinesterase inhibitor, acting preferentially on butyrylcholinesterase, and as a selective inhibitor of monoamine oxidase A but not monoamine oxidase B. OBJECTIVE: The aim of the present human pharmacology clinical trial was to assess the oral bioavailability, pharmacokinetic profile and tolerability of desoxypeganine, administered in a multiple-dose regimen to healthy volunteers. SUBJECTS AND METHODS: Eighteen healthy adult volunteers of both sexes received placebo, 50 mg and 100 mg desoxypeganine (b.i.d. for 3 days) in a single-blind, crossover, randomized manner. Main pharmacokinetic parameters after single and multiple doses were estimated. Clinical tolerability and clinical laboratory safety, including effect on QTc interval, were assessed. RESULTS: Non-compartmental estimations of Cmax, AUC, tmax, t1/2 and MRT at 12-h intervals are given. No significant dose effect was observed in tmax, t1/2 and MRT. Cmax and AUC are approximately double with the dose of 100 mg comparing with the dose of 50 mg. A significant increase (p < 0.05) on Cmax and AUC was also obtained with the highest dose administered in comparison with the lowest one, revealing a slight but clinically insignificant accumulation. Steady state of drug concentration was reached in both genders during the study period. Plasma protein binding of desoxypeganine amounted to approximately 18%. No severe adverse events were recorded and none of the subjects suffered from any adverse event that led to withdrawal from the study. Most frequently recorded adverse event was dizziness. No significant effects of desoxypeganine on vital signs, laboratory parameters or QTc interval were observed. CONCLUSIONS: The present clinical trial describes the pharmacokinetic profile of two doses of desoxypeganine, administered orally in multiple dose to healthy volunteers. The drug was well tolerated without any severe clinical, clinical laboratory, or ECG adverse events being recorded.

Phase I clinical trial with desoxypeganine, a new cholinesterase and selective MAO-A inhibitor: tolerance and pharmacokinetics study of escalating single oral doses.

Desoxypeganine (DOP) is a natural alkaloid that has been characterized as a cholinesterase inhibitor and a selective inhibitor of monoamine oxidase A. DOP has been investigated for its potential utility in the pharmacological treatment of alcohol abuse and as a smoking cessation aid. The aim of this clinical trial was to evaluate the tolerance and single-dose pharmacokinetic profile of DOP in healthy human volunteers. The study was an open-label, dose-escalation, phase I clinical trial involving the administration of increasing single oral doses of DOP (50, 100, 150 and 200 mg). The study was conducted according to the Declaration of Helsinki and Good Clinical Practice. Eighteen healthy adult volunteers (8 males and 10 females, age ranging 20-30 years) were recruited. DOP was administered sequentially, escalating in single doses of 50, 100, 150 and 200 mg in four experimental sessions with a washout period of at least 1 week between them. Progress to the next dose was allowed only if the previous dose was tolerated. Pharmacokinetic parameters were determined using noncompartmental methods. Clinical and analytical safety was assessed throughout the study, and QTc intervals were measured at regular intervals. The main pharmacokinetic parameters and renal excretion are described. No serious adverse events were registered, and none of the subjects discontinued the study because of lack of tolerance. All the adverse events recorded were mild to moderate and increased with the dose. The ECG measurements revealed that even at a higher dose, the QTc interval remained below the safety threshold. In summary, this first phase I study indicates that DOP has linear and dose-proportional pharmacokinetics, satisfactory oral bioavailability and plasma half-life and renal excretion. Also, DOP has shown an adequate safety profile that allows the continuation of clinical development.

Data from the VITA Study do not support the concept of vascular depression.

OBJECTIVE: Cerebrovascular lesions that are apparent in magnetic resonance scans and regioselective atrophy of the brain have been proposed as a causative or exacerbating factor in depression with late-life onset. The objective of this study was to investigate whether deep white matter or periventricular hyperintensities, small ischemic lesions, and brain atrophy contribute to late-onset depression in the nondemented elderly. METHOD: Based on a group of 606 individuals of identical age (75.8 years, standard deviation: 0.45 years) residing in two districts of Vienna, the authors built a case-control cohort (ratio: 1:4) consisting of 51 individuals with late-onset major or minor depression matched with 204 subjects of identical gender and education status without depression, resulting in two groups that were homogenous with respect to age, place of residence, gender, and education. Scores for focal brain lesions, mediotemporal lobe atrophy, and ventricular enlargement as well as risk factors for vascular disease were compared with cognition and depression status. RESULTS: Depressed individuals had significantly lower scores than nondepressed subjects in all measures of cognitive and executive function. No significant relation was found between a diagnosis of depression and any type of discrete brain lesions, but measures of brain atrophy (Cella Media indices, mediotemporal atrophy) showed a clear statistical relation to depression. No relationship was found between depression and lipid parameters. CONCLUSION: The authors found no indication that white matter hyperintensities or minor ischemic lesions played a role in our depressed cohort, casting doubt on the vascular hypothesis of late-onset depression.

Apheis: public health impact of PM10 in 19 European cities.

STUDY OBJECTIVE: Apheis is a public health surveillance system that aims to provide European, national, regional, and local decision makers, environmental health professionals, and the general public with up to date and easy to use information on air pollution and public health. This study presents the health impact assessment done in 19 cities of Western and Eastern European countries. DESIGN: Apheis developed guidelines for gathering and analysing data on air pollution and the impact on public health. Apheis has analysed the acute and chronic effects of fine particles on premature mortality using the estimates developed by Aphea2 study and two American cohort studies. This health impact assessment was performed for different scenarios on the health benefits of reducing levels of particles less than 10 microm in size (PM(10)). MAIN RESULTS: PM(10) concentrations were measured in 19 cities (range: 14-73 microg/m(3)). The population covered in this health impact assessment includes nearly 32 million inhabitants. The age standardised mortality rates (per 100 000 people) range from 456 in Toulouse to 1127 in Bucharest. Reducing long term exposure to PM(10) concentrations by 5 microg/m(3) would have "prevented" between 3300 and 7700 early deaths annually, 500 to 1000 of which are associated with short term exposure. CONCLUSIONS: Apheis shows that current levels of air pollution in urban Europe have a non-negligible impact on public health, and that preventive measures could reduce this impact, even in cities with low levels of air pollution.

Genomics and dementia--new drug targets ahead?

Pharmacogenomics--the application of genomic technologies such as gene sequencing and gene expression analysis to drugs--is beginning to make its impact on central nervous system drug development. The mapping of genes (including their polymorphisms) and their expression in normal and disease states to discover new drug targets will also change the scenery of dementia therapeutics' development completely because it uses a "bottom-up" strategy, identifying genes whose expression is changed in dementia or by drug therapy. Drugs identified this way should be mechanistically novel, more potent and specific, and probably quicker to develop. Pharmacogenomics can however also greatly contribute to the improvement of drugs targeting currently known receptors and enzymes.

MT-500 (POZEN).

MT-500 (formerly RS-127445) is a 5-HT2B antagonist being developed for the prophylactic treatment of migraine. POZEN acquired MT-500 from Roche in November 1999, and assumed full responsibility for its development for migraine propylaxis. Roche may elect to reacquire the compound at certain stages. The company expected to commence phase II trials during the first half of 2000 [348204]. POZEN has three other compounds, MT-400, MT-300 and MT-100, in phases I, II and III, respectively, for the treatment of acute migraine. Before outlicensing the compound, Roche Bioscience had completed phase I trials with MT-500 which indicate that it has a favorable side effect and safety profile [348204]. In January 2001, US Bancorp Piper Jaffray predicted phase II development beginning in 2001, with a launch in 2006 [396247].

TAK-147 (Takeda).

TAK-147 is a CNS-specific acetylcholinesterase inhibitor under development by Takeda as a potential treatment for Alzheimer's disease. By November 1999, it had entered phase III trials in Japan [348496]. In August 1999, Lehman Brothers predicted product launch in 2002, with potential peak sales of $250 million in 2012 [349228].

Cognitive relapse after discontinuation of drug therapy in Alzheimer's disease: cholinesterase inhibitors versus nootropics.

In a cross-sectional study of outpatients diagnosed with dementia of the Alzheimer type who had been treated with a broad variety of drugs supposed to improve cognition or to delay cognitive decline, we have investigated the effects of abruptly discontinuing therapy on cognition. Termination of therapy with any cholinesterase inhibitor was associated with a cognitive decline during the following 6-7 weeks which was significantly more pronounced than that experienced by patients who had received nootropic drugs or calcium channel blockers (3.41 vs. 1.17 points on the ADAS-Cog scale; -1.14 vs. -0.06 points on the MMSE scale). This effect was not modified by gender, apolipoprotein E genotype, or the extent of ventricular enlargement on CT scans. Its magnitude was comparable to the cognitive response observed in published clinical trials when cholinesterase therapy commenced, and also with the data obtained during a 6-week placebo washout phase.

Ambient air quality programmes for health impact assessment in the WHO European region.

An important aim of air quality assessment is to provide information about population exposure and health impact assessment. Numerous epidemiological studies have already shown that exposure to excessive levels of ambient air pollutants are associated with either acute or chronic health effects. Until recently, the adequacy of monitoring population exposure in relation to quantitative assessment of health effects of air pollution was rarely considered in ambient air monitoring strategies. This made the formulation of health-related recommendations to risk management difficult and weakens preventive and other measures to reduce adverse health effects of air pollution. To improve local and national capacities for health impact assessment, the European Centre for Environment and Health of the World Health Organization has prepared methodology guidelines concerning selected aspects of air monitoring. The WHO Collaborating Centre for Air Quality Management and Air Pollution Control support efforts in line with international programmes on quality assurance and control for Europe.

Alosetron.

Alosetron, a 5-HT(3)-receptor antagonist that is very closely related to ondansetron in terms of both chemistry and pharmacology, is the first compound of this type to be developed for irritable bowel syndrome. Clinical data for up to 3 months of treatment indicate that alosetron is orally bioavailable in tablet form, is well tolerated and is significantly superior to both placebo and the smooth muscle relaxant, mebeverine, in improving perception of visceral pain, spasms and diarrhea in female diarrhea-predominant irritable bowel syndrome. In males, symptoms were not alleviated to a statistically significant extent.