Phenibutan-an Illegal Food Supplement With Psychotropic Effects and Health Risks.

BACKGROUND: Phenibut (ß-phenyl-γ-aminobutyric acid) is an analog of the neurotransmitter gamma-aminobutyric acid (GABA). Like abapentin and pregabalin, it inhibits α2-δ-subunits of voltagedependent presynaptic calcium channels. The potential harm resulting from the use of these gabapentinoids is currently a matter of debate. METHODS: This review is based on pertinent publications retrieved by a selective literature search and on cases reported to the Giftinformationszentrum-Nord (GIZ-Nord), a poison information center at the University of Göttingen, Germany. RESULTS: Phenibut is a prescription drug in Russia but its production, possession, use, trafficking, or administration is illegal in Germany. The phenibut toxicity syndrome resembles that of gabapentinoids and GABA mimetics: benzodiazepine-like with - drawal symptoms including epileptic seizures, delirium and paradoxical activation have been described, as have cases of abuse and dependence. A few cases of use in the setting of multidrug abuse, and of phenibut-related death, have been described to date in the USA. The GIZ-Nord received 17 inquiries about phenibut, 55 about gabapentin, and 126 about pregabalin over the period 2008-2022. Over the same period, the GIZ-Nord was informed of 1207 cases involving Z substances and 4324 involving benzodiazepines. In the majority of the registered intoxications, including those with phenibut, the symptoms were mild. Overdoses of phenibut (2-100 g) were reported in 15 of the 17 cases; 8 of the persons who had taken an overdose were somnolent. In such cases, observation in intensive care was recommended. Respiratory depression or coma was not encountered in any case, not even in the patient who had taken 100 g of phenibut. CONCLUSION: Phenibut causes symptoms resembling those of gabapentinoid and benzodiazepine use. There have been reports of phenibut use in combination with other psychotropic drugs; in particular, its use together with opiates could increase the risk of coma and respiratory depression. No deaths due to phenibut intoxication have been published in Germany or elsewhere in Western Europe, although such cases may have been overlooked, as this drug is still largely unknown to Western medicine.

[Intoxications in childhood and adolescence]. / Intoxikationen im Kindes- und Jugendalter.

Poisoning of children requires quick and rational action. It is crucial to recognize a poisoning, to interpret the symptoms correctly, and to assess the severity of the poisoning as precisely as possible. This is the best way to find the optimal therapy for each patient.Cases of suspected poisoning are common in childhood. The risk of a potential poisoning must be recognized and interpreted correctly. Based on this, symptomatic and specific therapy can be carried out. The poisons information centres have a great experience in the diagnosis and treatment of poisonings and can help the attending physicians to plan the further therapeutic steps.Both the hazard of a toxic substance and a realistic exposure assessment must be considered. This is especially crucial in cases of suspected poisoning of (still) mostly asymptomatic patients. This is the way to prevent overtreatment without overlooking dangerous poisonings.

[Commercial soda lime ingestion during a dive]. / Akzidentelle Atemkalkingestion im Rahmen eines Tauchganges.

Breathing lime is used in closed circuit and semi-closed circuit rebreathers (CCR/SCR) for technical diving. Similar to the use in anesthesia systems, the lime usually contains hydroxycarbamide, which can react to caustic soda under the influence of water. The ingestion of components of the soda lime can lead to burns of the esophageal mucosa with the formation of colliquation necrosis and the danger of esophageal perforation. Early endoscopy is essential in this case to assess the consequences of ingestion.

[Inhalation of Flue Gases - Carbon Monoxide Intoxication]. / Vergiftung durch Rauchgase ­ Kohlenmonoxidintoxikation.

Most intoxications caused by inhalation are due to carbon monoxide (CO). Usually the reasons are fires in buildings from which people cannot escape quickly enough, open fire places or carbon monoxide emissions from combustion plants. In Germany, there are more than 4000 intoxications and over 600 fatalities resulting from CO poisining every year. Although there is a general awareness of the risks associated with CO, the specific risks and especially methods of protection are not sufficiently known.

Mushroom Poisoning.

BACKGROUND: Poisonous mushrooms are eaten by mushroom hunters out of ignorance, after misidentification as edible mushrooms, or as a psychoactive drug. Mushroom poisoning commonly leads to consultation with a poison information center and to hospitalization. METHODS: This review is based on pertinent publications about the syndromes, toxins, and diagnostic modalities that are presented here, which were retrieved by a selective search in PubMed. It is additionally based on the authors' longstanding experience in the diagnosis and treatment of mushroom intoxication, expert consultation in suspected cases, macroscopic identification of wild mushrooms, and analytic techniques. RESULTS: A distinction is usually drawn between mushroom poisoning with a short latency of less than six hours, presenting with a gastrointestinal syndrome whose course is usually relatively harmless, and cases with a longer latency of six to 24 hours or more, whose course can be life-threatening (e.g., phalloides, gyromitra, orellanus, and rhabdomyolysis syndrome). The DRG diagnosis data for Germany over the period 2000-2018 include a total of 4412 hospitalizations and 22 deaths due to the toxic effects of mushroom consumption. 90% of the fatalities were due to the death cap mushroom (amatoxins). Gastrointestinal syndromes due to mushroom consumption can be caused not only by poisonous mushrooms, but also by the eating of microbially spoiled, raw, or inadequately cooked mushrooms, or by excessively copious or frequent mushroom consumption. CONCLUSION: There are few analytic techniques available other than the qualitative demonstration of amatoxins. Thus, the diagnosis is generally made on the basis of the clinical manifestations and their latency, along with meticulous history-taking, assisted by a mushroom expert, about the type(s) of mushroom that were consumed and the manner of their preparation.

[Poisoning by exotic pets]. / Vergiftungen durch exotische Haustiere.

Exotic poisonous animals such as snakes, marine animals, spiders, and scorpions are a rarity in Central Europe, but are kept as pets by some people. Poisoning caused by these animals is a particular challenge in medical care.Over a period of six years (2001-2006), a total of 202 cases of poisoning with exotic animals were registered and evaluated at four poison information centers in Germany and France. Of the accidents, 91% happened in the home environment; the rest in pet stores. The poisonings were caused by snakes (38%), marine animals (31%), arthropods (spiders and scorpions, 27%), and other poisonous animals (4%). Severe poisoning was involved in 8% of the cases, all caused by snake bites. The severe poisonings were in the form of coagulopathies, severe local symptoms, and a respiratory insufficiency requiring intubation. In six cases of severe poisoning, an immune serum (antivenom) was administered and in three cases a surgical procedure was needed. Deaths did not occur.After the bite of a poisonous animal, the affected limb should usually be immobilized and disinfected, but not tied, cut, or sucked. The exact biological name of the species should be identified. In addition to hospitalization, it is recommended to consult a poison information center.

Mushroom poisoning: A proposed new clinical classification.

Mushroom poisoning is a significant and increasing form of toxin-induced-disease. Existing classifications of mushroom poisoning do not include more recently described new syndromes of mushroom poisoning and this can impede the diagnostic process. We reviewed the literature on mushroom poisoning, concentrating on the period since the current major classification published in 1994, to identify all new syndromes of poisoning and organise them into a new integrated classification, supported by a new diagnostic algorithm. New syndromes were eligible for inclusion if there was sufficient detail about both causation and clinical descriptions. Criteria included: identity of mushrooms, clinical profile, epidemiology, and the distinctive features of poisoning in comparison with previously documented syndromes. We propose 6 major groups based on key clinical features relevant in distinguishing between poisoning syndromes. Some clinical features, notably gastrointestinal symptoms, are common to many mushroom poisoning syndromes. Group 1 - Cytotoxic mushroom poisoning. Syndromes with specific major internal organ pathology: (Subgroup 1.1; Primary hepatotoxicity); 1A, primary hepatotoxicity (amatoxins); (Subgroup 1.2; Primary nephrotoxicity); 1B, early primary nephrotoxicity (amino hexadienoic acid; AHDA); 1C, delayed primary nephrotoxicity (orellanines). Group 2 - Neurotoxic mushroom poisoning. Syndromes with primary neurotoxicity: 2A, hallucinogenic mushrooms (psilocybins and related toxins); 2B, autonomic-toxicity mushrooms (muscarines); 2C, CNS-toxicity mushrooms (ibotenic acid/muscimol); 2D, morel neurologic syndrome (Morchella spp.). Group 3 - Myotoxic mushroom poisoning. Syndromes with rhabdomyolysis as the primary feature: 3A, rapid onset (Russula spp.); 3B, delayed onset (Tricholoma spp.). Group 4 - Metabolic, endocrine and related toxicity mushroom poisoning. Syndromes with a variety of clinical presentations affecting metabolic and/or endocrine processes: 4A, GABA-blocking mushroom poisoning (gyromitrins); 4B, disulfiram-like (coprines); 4C, polyporic mushroom poisoning (polyporic acid); 4D, trichothecene mushroom poisoning (Podostroma spp.); 4E, hypoglycaemic mushroom poisoning (Trogia venenata); 4F, hyperprocalcitoninemia mushroom poisoning (Boletus satanas); 4G, pancytopenic mushroom poisoning (Ganoderma neojaponicum). Group 5 - Gastrointestinal irritant mushroom poisoning. This group includes a wide variety of mushrooms that cause gastrointestinal effects without causing other clinically significant effects. Group 6 - Miscellaneous adverse reactions to mushrooms. Syndromes which do not fit within the previous 5 groups: 6A, Shiitake mushroom dermatitis; 6B, erythromelagic mushrooms (Clitocybe acromelagia); 6C, Paxillus syndrome (Paxillus involutus); 6D, encephalopathy syndrome (Pleurocybella porrigens).

Transformation of Coiled α-Helices into Cross-ß-Sheets Superstructure.

The fibrous silk produced by bees, wasps, ants, or hornets is known to form a four-strand α-helical coiled coil superstructure. We have succeeded in showing the formation of this coiled coil structure not only in natural fibers, but also in artificial films made of regenerated silk of the hornet Vespa simillima xanthoptera using wide- and small-angle X-ray scatterings and polarized Fourier transform infrared spectroscopy. On the basis of time-resolved simultaneous synchrotron X-ray scattering observations for in situ monitoring of the structural changes in regenerated silk material during tensile deformation, we have shown that the application of tensile force under appropriate conditions induces a transition from the coiled α-helices to a cross-ß-sheet superstructure. The four-stranded tertiary superstructure remains unchanged during this process. It has also been shown that the amorphous protein chains in the regenerated silk material are transformed into conventional ß-sheet arrangements with varying orientation.

Intox, detox, antidotes - Evidence based diagnosis and treatment of acute intoxications.

BACKGROUND AND AIM: Aim of this review is to describe the role of clinical toxicology in the context of acute medicine. A special focus is put on antidotes and important aspects of diagnosis and therapy of acute intoxications. The data of the annual report of GIZ-Nord Poisons Centre is analyzed concerning the following aspects: what intoxications are relevant in acute medicine, are there special aspects in therapy, e.g. antidotes, and what antidotes are relevant? More over intoxication-related fatalities are analyzed. RESULTS AND CONCLUSION: In 2015 the poisons centre was consulted in 33,000 cases of acute intoxications. The most important groups are drugs (e.g. antidepressants, beta blockers and calcium channel blockers), chemical products (e.g. products containing surfactant, corrosive substances and toxic alcohols like methanol), plants and recreational drugs. Intoxications are relevant in acute medicine. Some substances can cause fatal intoxications. Important antidotes are naloxone for opiods, acetylcystein for paracetamol, fomepizole and ethanol for toxic alcohols and diazepam for intoxications caused by chloroquine.

Mitochondrial cytochrome c oxidase is inhibited by ATP only at very high ATP/ADP ratios.

In the past, divergent results have been reported based on different methods and conditions used for enzymatic activity measurements of cytochrome c oxidase (CytOx). Here, we analyze in detail and show comparable and reproducible polarographic activity measurements of ATP-dependent inhibition of CytOx kinetics in intact and non-intact rat heart mitochondria and mitoplasts. We found that this mechanism is always present in isolated rat heart mitochondria and mitoplasts; however, it is measurable only at high ATP/ADP ratios using optimal protein concentrations. In the kinetics assay, measurement of this mechanism is independent of presence or absence of Tween-20 and the composition of measuring buffer. Furthermore, the effect of atractyloside on intact rat heart mitochondria confirms that (i) ATP inhibition occurs under uncoupled conditions [in the presence of carbonly cyanide m-chlorophenyl hydrazone (CCCP)] when the classical respiratory control is absent and (ii) high ATP/ADP ratios in the matrix as well as in the cytosolic space are required for full ATP inhibition of CytOx. Additionally, ATP inhibition measured in intact mitochondria extends in the presence of oligomycin, thus indicating further that the problem to measure the inhibitory effect of ATP on CytOx is apparently due to the lack of very high ATP/ADP ratios in isolated mitochondria.

[Accidental ingestion of methadone by children and suggestions for better prevention]. / Akzidentelle Methadoneinnahme durch Kinder - Gedanken zur Verbesserung der Prävention.

Despite the medial attention attracted by the presented case in January 2012 and the determined measures taken to minimize the risk of accidental poisoning for children in the direct surroundings of substituted persons, we recently faced two more cases of methadone-intoxicated children in Hamburg. We believe that the most important step to increase awareness of the dangerous effects of methadone for children might be the storage of methadone in lockable boxes, which would make it safe from access by children and third parties. Moreover this way of storing reminds the patients of the risks resulting from their medication. Repeated and comprehensive instruction appears to be the best protection against cases like this to counteract careless handling of the substitution medication.

Polymer/Nanoparticle Hybrid Materials of Precise Dimensions by Size-Exclusive Fishing of Metal Nanoparticles.

Polymer cages prepared by etching of gold nanoparticles from polymer templates by the "grafting around" method are designed for selective separation of metal nanoparticles. The separation process is demonstrated as a fast biphasic ligand exchange reaction. The high separation efficiency and size selectivity of the polymer cage is verified by comparison with the linear block copolymer.

Storage stability of optimal liposome-polyethylenimine complexes (lipopolyplexes) for DNA or siRNA delivery.

The delivery of nucleic acids such as DNA or siRNA still represents a major hurdle, especially with regard to possible therapeutic applications in vivo. Much attention has been focused on the development of non-viral gene delivery vectors, including liposomes or cationic polymers. Among them, polyethylenimines (PEIs) have been widely explored for the delivery of nucleic acids and show promising results. The combination of cationic polymers and liposomes (lipopolyplexes) for gene delivery may further improve their efficacy and biocompatibility, by combining the favourable properties of lipid systems (high stability, efficient cellular uptake, low cytotoxicity) and PEIs (nucleic acid condensation, facilitated endosomal release). In this study, we systematically analyse various conditions for the preparation of liposome-polyethylenimine-based lipopolyplexes with regard to biological activity (DNA transfection efficacy, siRNA knockdown efficacy) and physicochemical properties (size, zeta potential, stability). This includes the exploration of lipopolyplex compositions containing different liposomes and different relevant branched or linear low-molecular-weight PEIs. We establish optimal parameters for lipopolyplex generation, based on various PEIs, N/P ratios, lipids, lipid/PEI ratios and preparation conditions. Importantly, we also demonstrate that certain lipopolyplexes retain their biological activity and physicochemical integrity upon prolonged storage, even at 37°C and/or in the presence of serum, thus providing formulations with considerably higher stability as compared to polyplexes. In conclusion, we establish optimal liposome-polyethylenimine lipopolyplexes that allow storage under ambient conditions. This is the basis and an essential prerequisite for novel, promising and easy-to-handle formulations for possible therapeutic applications.

Ultrasound-mediated synthesis of high-molecular weight polystyrene-grafted silver nanoparticles by facile ligand exchange reactions in suspension.

Ultrasound mediated facile ligand exchange method in suspension for the formation of polystyrene-grafted silver nanoparticles is reported. Amazingly, this method allows even grafting of very high molecular weight polystyrenes (up to 217 200 g mol(-1) ) having a single terminal thiol group at the chain end. Detailed studies are carried out to gain insights in the role of molecular weight of the ligands and the mechanism of the ligand exchange reactions. Key factors are determined to be the droplet formation by ultrasonification and low silver content, which enhances the availability of the terminal thiol end group significantly. The extraordinary compatibility of the ligand exchange method in particular regarding high molecular weights is attributed to hydrophilic orientation of the terminal thiol groups at the liquid-liquid interphase. This is proved conclusively by using an in situ method as a reference approach in which agglomeration occurs at considerably lower molecular weights due to the absence of preferred end group orientation within the polymer coil. In homogeneous phase only the chain length is found to be the crucial factor in stabilization of silver nanoparticles.

Evidence of α-helical coiled coils and ß-sheets in hornet silk.

α-Helical coiled coil and ß-sheet complexes are essential structural building elements of silk proteins produced by different species of the Hymenoptera. Beside X-ray scattering at wide and small angles we applied cryo-electron diffraction and microscopy to demonstrate the presence and the details of such structures in silk of the giant hornet Vespa mandarinia japonica. Our studies on the assembly of the fibrous silk proteins and their internal organization in relation to the primary chain structure suggest a 172 Å pitch supercoil consisting of four intertwined alanine-rich α-helical strands. The axial periodicity may adopt even multiples of the pitch value. Coiled coil motifs form the largest portion of the hornet silk structure and are aligned nearly parallel to the cocoon fiber axis in the same way as the membrane-like parts of the cocoon are molecularly orientated in the spinning direction. Supercoils were found to be associated with ß-crystals, predominantly localized in the l-serine-rich chain sequences terminating each of the four predominant silk proteins. Such ß-sheet blocks are considered resulting from transformation of random coil molecular sequences due to the action of elongational forces during the spinning process.

Antioxidant treatment and outcome of Cortinarius orellanus poisoning: a case series.

OBJECTIVES: To study the frequency, severity, and long-term outcome of renal injury in Cortinarius orellanus poisoning, to evaluate the association between the ingested amount of C. orellanus and outcome, and to evaluate the effect of N-acetylcysteine and corticosteroid treatment on outcome. METHODS: Case series of eight patients. Diagnosis and severity of acute kidney injury (AKI) and chronic kidney disease (CKD) were classified according to current AKI and CKD definitions. N-acetylcysteine and corticosteroids were administered to six patients, former according to the standard for paracetamol poisoning. MAIN FINDINGS: All patients developed AKI, six in the most severe stage and four required renal replacement therapy (RRT). After 12 months, seven patients presented with CKD, of whom three required chronic RRT and further two were in advanced CKD. AKI and CKD severity highly correlated with the consumed amounts of Cortinarius orellanus (r = 0.98, p < 0.001 and r = 0.78, p = 0.02, respectively) but not with N-acetylcysteine and corticosteroid treatment. CONCLUSIONS: AKI and CKD by current definitions and classifications are frequent and severe after Cortinarius orellanus poisoning. The ingested amount of Cortinarius orellanus correlates with the severity of both AKI and CKD. N-acetylcysteine and corticosteroid treatment do not seem to have a beneficial effect on either AKI or CKD.

Of pills, plants, and paraquat: the relevance of poison centers in emergency medicine.

The organization and work of a poisons center are demonstrated on the basis of GIZ-Nord Poisons Center Annual Report for 2011. In a short summary the basic principles of clinical toxicology are elucidated: the indications for gastric lavage and the application of activated charcoal. Moreover the means of enhanced elimination are presented: hemodialysis, hemoperfusion, multi-dose activated charcoal and molecular absorbent recirculating system (MARS). Gastric lavage is indicated within one hour after ingestion of a life-threatening dose of a poison. In intoxications with CNS penetrating substances gastric lavage should be performed only after endotracheal intubation due to the risk of aspiration. The basic management of the intoxicated patient by emergency medicine personnel out of hospital and on the way into the hospital is presented. The "Bremen List", a compilation of five antidotes (atropine, 4-DMAP, tolonium chloride, naloxone, activated charcoal) for the out of hospital treatment by emergency doctors is introduced.

Targeting the blind spot of polycationic nanocarrier-based siRNA delivery.

Polycationic nanocarriers attract increasing attention to the field of siRNA delivery. We investigated the self-assembly of siRNA vs pDNA with polycations, which are broadly used for nonviral gene and siRNA delivery. Although polyethyleneimine (PEI) was routinely adopted as siRNA carrier based on its efficacy in delivering pDNA, it has not been investigated yet why PEI efficiently delivers pDNA to cells but is controversially discussed in terms of efficacy for siRNA delivery. We are the first to investigate the self-assembly of PEI/siRNA vs PEI/pDNA and the steps of complexation and aggregation through different levels of hierarchy on the atomic and molecular scale with the novel synergistic use of molecular modeling, molecular dynamics simulation, isothermal titration calorimetry, and other characterization techniques. We are also the fist to elucidate atomic interactions, size, shape, stoichiometry, and association dynamics for polyplexes containing siRNA vs pDNA. Our investigation highlights differences in the hierarchical mechanism of formation of related polycation-siRNA and polycation-pDNA complexes. The results of fluorescence quenching assays indicated a biphasic behavior of siRNA binding with polycations where molecular reorganization of the siRNA within the polycations occurred at lower N/P ratios (nitrogen/phosphorus). Our results, for the first time, emphasize a biphasic behavior in siRNA complexation and the importance of low N/P ratios, which allow for excellent siRNA delivery efficiency. Our investigation highlights the formulation of siRNA complexes from a thermodynamic point of view and opens new perspectives to advance the rational design of new siRNA delivery systems.