Increased Demand for Pharmaceutical Drugs Containing Potassium Iodide In Connection with the Russia-Ukraine Conflict.

The current conflict between Russia and Ukraine increased concerns in the German population of a release of radioactive substances, e.g.radioactive iodine. A high dose of potassium iodide (PI) may prevent accumulation of radioactive iodine in the thyroid gland. Therefore, the German government keeps a sufficient quantity of PI in stock for public supply in case of an emergency. We investigated ambulatory drug dispensing rates of PI and found that the total dispensing of PI (statutory health insurance (SHI), private health insurance (PHI), and overthe-counter (OTC)) increased by 106% from February to March 2022. Changes in PI dispensing were mainly due to an increase in OTC sales, where PI as an antidote showed a sevenfold increase from around 930 packages (February 2022) to 6,500 packages (March 2022), while SHI and PHI dispensing remained relatively low. Furthermore, we investigated whether these changes in dispensing raised the number of suspected adverse drug reactions (ADR). We found no increase of ADR reports related to the use of PI-containing medicinal products between February and September 2022, neither in our national pharmacovigilance nor in the European EudraVigilance database. The data suggest that the mere possibility of a nuclear disaster in Ukraine raised the demand of PI in Germany. Thus, timely and proactive information and reassurance of the public of supply reliability by the Government in a case of a nuclear emergency could be helpful in preventing potential drug shortages and unfounded concern.

Elucidation of removal processes in sequential biofiltration (SBF) and soil aquifer treatment (SAT) by analysis of a broad range of trace organic chemicals (TOrCs) and their transformation products (TPs).

Many chemicals with different physico-chemical properties are present in municipal wastewater. In this study, the removal of a broad range of trace organic chemicals (TOrCs) was determined in two biological treatment processes differing in hydraulic retention time: sequential biofiltration (SBF) and soil-aquifer treatment (SAT), operated in Germany and Spain. Occurrence and the degree of removal of more than 150 TOrCs with different physico-chemical properties were analysed, including precursors as well as human metabolites and environmental transformation products (TPs). Ninety TOrCs were detected in the feed water of the SBF system, 40% of these showed removal efficiencies of higher than 30% during biological treatment. In SAT, 70 TOrCs were detected in the feed water, 60% of these could be reduced by more than 30% after approximately 3 days of subsurface treatment. For uncharged and negatively charged TOrCs biological degradation was mainly responsible for the removal, while positively charged TOrCs were most likely also removed by ionic interactions. The detections of TPs confirmed that biodegradation was a major removal process in both systems. The analysis of positively and negatively charged, neutral and zwitterionic TOrCs and the simultaneous analysis of precursors and their biologically formed TPs enabled a detailed understanding of underlying mechanisms of their removal in the two systems. On this basis, criteria for site-specific indicator selection were proposed.

[Lipoid Pneumonia Associated with Lipid-Containing Nasal Sprays and Nose Drops]. / Lipidpneumonie durch Lipid-haltige Nasensprays und -tropfen.

BACKGROUND: Regularly updating the German pharmacopoeia on contemporary preparations DAC/NRF, chapter "Nasal Applications" and the recommendations on "Nasal Oils" as well as "Nasal Ointments and Emulsions", the issue of the risk of lipoid pneumonia associated with the use of plant oils and when compared to mineral oils arose. MATERIAL AND METHODS: We searched different databases: the "Grosse Deutsche Arzneimittelspezialitäten-Taxe" containing all products available in German pharmacies, the Cochrane Library, the pharmacovigilance-database of the BfArM, and Medline to evaluate the benefit/risk-ratio of plant oils in nasal drops and sprays. RESULTS: In German pharmacies, a number of both, mineral oil-containing drugs for nasal application and plant oil-containing medical devices are available. The risk of lipoid pneumonia described for mineral oil-containing nasal products can not entirely be transferred to plant oil-containing products. However, evidence from the literature suggests a risk for lipoid pneumonia, which needs to be considered given the non-proven efficacy of such medical devices in the majority of proposed indications. To minimize risks, recommendations are made for patient groups that should not use lipid-containing nasal products. CONCLUSIONS: Acknowledging the potential lethal outcome of lipoid pneumonia, a demanding diagnosis, and absence of a specific therapy, lipid-containing nasal products should be used only with great caution. Based on the current knowledge, the statements regarding the risk of lipoid pneumonia for lipid-containing nasal products in the DAC/NRF should not be modified.

Detection of pyrrolizidine alkaloids in German licensed herbal medicinal teas.

BACKGROUND: Because of the hepatotoxic, mutagenic, and cancerogenic effects of pyrrolizidine alkaloids (PAs) the German Federal Institute for Risk Assessment (BfR) recommends not to exceed a daily PA intake of 0.007 µg/kg body weight (0.42 µg/60 kg adult). In a recent study conducted by the BfR, up to 5647 µg PA/kg dried herbal material were detected in tea products marketed as food. PURPOSE: The present study aimed at elucidating whether medicinal teas licensed or registered as medicinal products contain PAs as well. STUDY DESIGN: One hundred sixty-nine different commercially available medicinal teas, i.e. 19 nettle (Urtica dioica L.), 12 fennel (Foeniculum vulgare Mill.), 14 chamomile (Matricaria recutita L.), 11 melissa (Melissa officinalis L.) and 4 peppermint (Mentha piperita L.) teas as well as 109 tea mixtures were analyzed for the presence of 23 commercially available PAs. METHOD: LC/MS was used for the determination of the PAs RESULTS: In general, the total PA contents ranging 0-5668 µg/kg. Thirty percent of the tested single-ingredient tea products and 56.9% of the tested medicinal tea mixtures were found to contain PA concentrations above the limit of quantification (LOQ) of 10 µg/kg. In 11 medicinal teas PA contents >300 µg/kg dry herb were determined thus exceeding the recommended limit for PA intake by BfR. In addition three products of the investigated tea mixtures revealed extremely high PA contents of 4227, 5137, and 5668 µg/kg. Generally, single-ingredient tea products contained much less or even no detectable amounts of PAs when compared to the tea mixtures. PAs in the range between 13 and 1080 µg/kg were also detected in five analyzed aqueous herbal infusions of the medicinal tea mixture products with the highest PA content. Two out of the five investigated herbal infusions exceeded the recommended BfR limit for PA intake. CONCLUSION: This study demonstrates clearly that also medicinal teas licensed as medicinal products may partly contain high amounts of PAs exceeding current recommendations. For that reason manufacturers are advised to carry out more rigorous quality control tests devoted to the detection of PAs. This is very important to minimize PAs in medicinal teas accounting for possible additional exposure of the consumer to PAs from other food sources (e.g. honey).

Spots, blots, peaks and chips: proteomic approaches in autoimmune diseases.

During the past five years, investigations employing a variety of proteomic technologies have yielded a wealth of information on a number of autoimmune disorders. Animal models of autoimmune disease have been examined and have provided clues that can be useful in elucidating molecular pathways and mechanisms that play a role in autoimmune disorders. Human sera and body fluids have been analyzed and have resulted in the identification of autoantibodies that can be used as diagnostic markers in specific autoimmune diseases, and proteomic fingerprints of tissues and body fluids have resulted in the identification of individual proteins or patterns of protein expression that are deregulated in autoimmune diseases. The information provided by these proteomic studies are of diagnostic and therapeutic potential. This review provides an overview of the approaches used in the proteomic analyses of autoimmune disease.

Effects of transforming growth factor beta1 on bonelike tissue formation in three-dimensional cell culture. II: Osteoblastic differentiation.

We supplemented rat marrow stromal cells (rMSCs) seeded on poly(L-lactic-co-glycolic acid) fiber meshes with transforming growth factor beta1 (TGF-beta1) to improve bone tissue formation for tissue engineering. Whereas our first study (Lieb, E., et al. Tissue Eng. 10, 1399-1413, 2004) investigated the effects of TGF-beta1 on matrix formation and mineralization, this second study focused on the differentiation of rMSCs to the osteoblastic phenotype in dynamic cell culture (orbital shaker). We assessed a series of bone markers to determine a dosing regimen for TGF-beta1 that enhances collagenous matrix formation and preserves or increases osteoblastic differentiation. Bone sialoprotein and osteonectin formation were investigated immunohistochemically and by RT-PCR. For alkaline phosphatase activity (ALP), we employed an enzyme assay. Osteocalcin was examined by RT-PCR as well as by an immunoassay. Whereas bone sialoprotein appeared to be dose-dependently increased in the immunochemistical stainings after supplementation with TGF-beta1, osteonectin remained unchanged. Both ALP activity and osteocalcin were suppressed by high doses of TGF-beta1, such as single doses of 10 ng/mL or four doses of 1 ng/mL added once a week. Considering the effects of TGF-beta1 both on differentiation and on matrix formation and mineralization, TGF-beta1 at 1 ng/mL, added once a week in the first 1 to 2 weeks, was selected as an effective dose to improve bonelike tissue formation in vitro.

Effects of transforming growth factor beta1 on bonelike tissue formation in three-dimensional cell culture. I. Culture conditions and tissue formation.

Bone tissue engineering based on growing bone marrow stromal cells on poly(L-lactic-co-glycolic acid) fiber meshes suffers from limited matrix production and mineralization when the cells are cultured with the standard differentiation supplements (dexamethasone, beta-glycerophosphate, and ascorbic acid). To overcome this problem we included transforming growth factor beta1 (TGF-beta1), which is described as playing a key role in collagen type I formation, although its effect on mineralization is controversially discussed. The investigations focused on establishing culture conditions for the application of TGF-beta1 in three-dimensional cell culture and on the effects of different doses of TGF-beta1 (1-20 ng/mL) on bonelike extracellular matrix formation. Immunohistochemical staining showed that TGF-beta1 enhanced the formation of procollagen type I, collagen type I, and collagen type V, especially under dynamic culture conditions (orbital shaker). A long-term study confirmed positive effects on the formation of extracellular matrix, which penetrated the scaffold to a depth of 250 to 300 microm. Mineralization, qualified by scanning electron microscopy in combination with energy-dispersive X-ray analysis and evaluated by determination of the Ca2+ content per scaffold, was up to 1.7-fold increased by TGF-beta1 compared with the control. In conclusion, the growth factor TGF-beta1 seems to be effective in improving extracellular bonelike matrix formation in vitro.

Timbre-specific enhancement of auditory cortical representations in musicians.

Neural imaging studies have shown that the brains of skilled musicians respond differently to musical stimuli than do the brains of non-musicians, particularly for musicians who commenced practice at an early age. Whether brain attributes related to musical skill are attributable to musical practice or are hereditary traits that influence the decision to train musically is a subject of controversy, owing to its pedagogic implications. Here we report that auditory cortical representations measured neuromagnetically for tones of different timbre (violin and trumpet) are enhanced compared to sine tones in violinists and trumpeters, preferentially for timbres of the instrument of training. Timbre specificity is predicted by a principle of use-dependent plasticity and imposes new requirements on nativistic accounts of brain attributes associated with musical skill.

A combined functional in vivo measure for primary and secondary auditory cortices.

Auditory evoked magnetic fields are reliable physiological in vivo markers of activity generated in auditory cortices. In recent years, several components of auditory evoked fields have been demonstrated with specific topographies within the auditory cortex in man. Their differential elicitation and analyses has rendered the discrimination of neural activities in primary vs. secondary auditory cortical fields possible. This in vivo measure may be of interest in a number of (neuro)psychiatric and neuropsychological disorders with central auditory deficits, in which in vivo anatomical measures do not allow a clear distinction of primary vs. secondary auditory cortex involvement. To help better understand the pathophysiology of such disorders, we developed and introduce a combined measure of steady-state field (SSR) and the N1 component of the transient evoked field. The acoustic stimulus for this paradigm consists of a 500-ms tone burst with 39-Hz amplitude modulation of the carrier frequency. This combined stimulation allows assessment of both auditory cortex components in one brief examination to be well tolerated by patients. We examined the source locations of SSR and N1 component with separate classical stimulation and combined stimulation within-session in healthy volunteer subjects. We demonstrate here that the distinct sources of steady-state (primary auditory cortex) and N1 (secondary auditory cortex) responses can be reliably measured without significant spatial distortion with this combined stimulation paradigm.

Cost-effectiveness of vitamin E therapy in the treatment of patients with angiographically proven coronary narrowing (CHAOS trial). Cambridge Heart Antioxidant Study.

Epidemiologic studies have suggested that vitamin E (alpha-tocopherol) may play a preventive role in reducing the incidence of atherosclerosis. The aim of this paper was to conduct a cost-effectiveness analysis of vitamin E supplementation in patients with coronary artery disease using data from the Cambridge Heart Antioxidant Study (CHAOS). The study compared cost-effectiveness in the context of Australian and United States (US) health care utilization. The main clinical outcome used in the economic evaluation was the incidence of acute myocardial infarction (AMI) which was nonfatal. Utilization of health care resources was estimated by conducting a survey of Australian clinicians and published Australian and US cost data. Cost savings of $127 (A$181) and $578/patient randomized to vitamin E therapy compared with patients receiving placebo were found for Australian and US settings, respectively. Savings in the vitamin E group were due primarily to reduction in hospital admissions for AMI. This occurred because the vitamin E group had a 4.4% lower absolute risk of AMI than did the placebo group. Less than 10% of health care costs in the Australian evaluation was due to vitamin E ($150 [A$214/patient]). Our economic evaluation indicates that vitamin E therapy in patients with angiographically proven atherosclerosis is cost-effective in the Australian and US settings.

Microsomal membrane proteins and vanadate-sensitive ATPase from Vicia faba root tips after clinostat treatment.

Microsomal and soluble protein fractions from Vicia faba root tips were used for SDS-PAGE and Western-immunoblot analysis with anti-ubiquitin antibodies after 9 h clinostat treatment of the plants. In contrast to soluble proteins omnilateral gravistimulation (9 h) resulted in an enhanced proteolytic capacity for microsomal proteins. The increase of vanadate-sensitive ATPase activity was 83% after 9 h clinostat treatment, when the enzyme activity was measured directly after membrane preparation. Enhanced ATPase activity was correlated with the appearance of a polypeptide of about 100 kDa and its fragments (93 and 80 kDa). ATPases are not the only membrane bound proteins, which are changed during clinostat treatment, as several ubiquitinated polypeptides were also affected. A 1 h storage of microsomal fractions led to a shift of band intensities on ubiquitin-specific Western-blots. The demonstrated effect could not be observed, when fractions were isolated in the presence of protease inhibitors. In accordance with the polypeptide analysis omnilateral gravistimulation resulted in an enhanced capacity to degrade specific microsomal ubiquitin-conjugates, whereas the soluble ubiquitin-pool was not visibly affected.

The effect of fetal neocortical transplants on lesion-induced cerebral cortex plasticity.

Sensorimotor cortical lesions in newborn rats lead to the formation of abnormal projections from the opposite intact sensorimotor cortex. In the present study the influence of fetal neocortical transplants on this lesion-induced plasticity was examined. Newborn rats received unilateral frontal neocortical lesions. One experimental group received grafts of fetal neocortical tissue (E14-E16) into the lesion cavities. Another group served as lesion-only animals, while a third group was left unlesioned and without grafts as normal controls. At 3 mo of age, the animals received injections of the anterograde tracer biotinylated dextran amine (BDA) into the sensorimotor cortex contralateral to the lesion/transplantation area. After sacrifice 2 wk later, the brains were processed histochemically for detection of BDA-labeled cells and fibers. As a measure of the lesion-induced axonal sprouting response, corticothalamic and corticopontine fibers crossing the midline were counted. Significantly fewer cortical efferent fibers crossed the thalamic midline in the transplanted rats compared to the lesion-only controls. In contrast, the presence of transplants did not reduce the corticopontine sprouting response. These results therefore indicate that fetal neocortical grafts have a modulatory, yet variable effect on the lesion-induced axonal sprouting of contralateral sensorimotor cortical neurons.

Effects of fast clinostat treatment and microgravity on Vicia faba L. mesophyll cell protoplast ubiquitin pools and actin isoforms.

With parabolic rocket flights and fast clinostat treatments, the effect of microgravity on ubiquitin, ubiquitin-protein conjugates, and actin isoforms of Vicia faba mesophyll protoplasts was studied. Western immunoblotting with ubiquitin antibodies revealed that simulated and particularly, real microgravity influenced the amount of free ubiquitin and of 18, 19, and 40 kD ubiquitin conjugates by inducing strong oscillations in the proteins concentrations over time. Simulated microgravity and microgravity-phase during parabolic rocket flights resulted in a decrease of actin isoforms. Results obtained support the assumption, that microgravity and fast clinostat treatment have a direct effect on Vicia faba mesophyll protoplast metabolic activities.

[A compilation of therapeutic and toxic plasma drug concentrations]. / Zusammenstellung therapeutischer und toxischer Plasmakonzentrationsbereiche von Arzneistoffen.

In order to assess the significance of drug levels measured in clinical and forensic toxicology as well as for therapeutic drug monitoring (TDM), it is essential that good collections of data are readily available. For more than 400 frequently used drugs therapeutic and, if data were available, toxic and fatal plasma concentrations as well as elimination half-lives were compiled in a table including, e.g., hypnotics like barbiturates and benzodiazepines, neuroleptics, antidepressants, sedatives, analgesics, anti-inflammatory agents, antihistamines, anti-epileptics, beta-adrenergic antagonists, antibiotics (penicillins, cephalosporins, aminoglycosides, gyrase inhibitors), diuretics, calcium-channel blockers, cardiac glycosides, anti-arrhythmics, anti-asthmatics, angiotensin converting enzyme inhibitors, opioid agonists, and local anaesthetics. Data have been abstracted from published information, both compilations and primary sources, and supplemented with data collected in our own forensic and clinical toxicology laboratories. Wherever possible, ranges for therapeutic plasma concentrations are expressed as trough concentration at steady-state. The range of (or single) half-life values given for each drug are chosen to represent the terminal log-linear phase at most. In addition to the assessment of significance of drug levels for the therapeutic monitoring of patients, this list can assist the diagnostic assessment in cases of intoxication.

Chronic borrelia encephalomyeloradiculitis with severe mental disturbance: immunosuppressive versus antibiotic therapy.

A 57-year-old male was repeatedly admitted to hospital because of complex neurological symptoms, including radicular pain, disturbance of micturition, seizures, and severely impaired mental state. The diagnosis was encephalomyeloradiculitis possibly of viral origin, and treatment with immunosuppressants was initiated. An alternating course with a tendency towards improvement ensued. Two and a half years after the occurrence of the initial symptoms, identification of specific antibodies in the blood and CSF led to the diagnosis of borreliosis with CNS involvement. High-dose therapy with penicillin rapidly reduced the symptoms, beginning with those of radicular pain and followed by an improvement of the mental state. Attention is directed to the wide spectrum of clinical symptoms of chronic borreliosis with CNS involvement. Previous reports that immunosuppression may result in some improvement but with a tendency towards relapse are confirmed. Our encouraging treatment results support those of other reports that penicillin therapy may lead to improvement even at late chronic stages in patients with severe CNS deficits.

[Tryptophan metabolism research in oligophrenic children. 4.: Activity and possibility of activating hepatic kynureninase after vitamin B6 treatment]. / Tryptophanstoffwechseluntersuchungen bei oligophrenen Kindern. 4. Mitteilung: Aktivität und Aktivierbarkeit der hepatischen Kynureninase nach Vitamin B6-Behandlung

In 8 selected test persons of the 3rd series of experiments who were showing signs of pathological kynureninase activity, hepatic kynureninase was again established after 3 week's treatment with large doses of vitamin B6. The enormous in-vivo activation of the kynureninasis established goes to prove that apoenzyme synthesis may be stimulated by pyridoxine. On the basis of these results and the relative frequency of disorders dependent on B6, the question arises whether children from endangered families should not be given prophylactic vitamin B6 treatment from birth.