Use of acetylcysteine as the life-saving antidote in Amanita phalloides (death cap) poisoning. Case report on 11 patients

alpha-Amanitin is an amatoxin known to produce deleterious effects on the liver and the kidneys, when circulating in the blood. It is produced by a particular kind of mushroom called amanita phalloides. Therapeutic options employed to treat mushroom intoxication, such as haemodiaperfusion on activated charcoal, high dosages of penicillin G, oral charcoal, etc., very often failed to act properly and liver transplantation (when a graft is available) appeared to be the only solution. In recent years, as suggest by some authors, it has been postulated that the oxidant effects of alpha-amanitin could be counteracted by the use of antioxidants such as silibinin. High dosages of N-acetyl-cysteine (CAS 616-91-1, NAC), already used as antioxidant in paracetamol poisoning, were successfully used in our Intensive Care Unit (ICU) in the treatment of Amanita phalloides poisoning. In the last two years, 11 patients (mean age of 5-72 = 38.5) were treated for Amanita phalloides poisoning of various degrees, with a protocol (haemodiaperfusion on activated charcoal, high dosages of penicillin G, etc.) further comprehending NAC (fluimucil). All the patients recovered successfully but one (bearing precedent liver disease) needed liver transplantation. Daily monitoring of liver enzymes, creatinine, coagulation, LDH, blood and urinary alpha-amanitin were used to screen the progresses of the patients.     

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.

A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.     

Tau-targeted treatment strategies in Alzheimer's disease

With populations ageing worldwide, the need for treating and preventing diseases associated with high age is pertinent. Alzheimer's disease (AD) is reaching epidemic proportions, yet the currently available therapies are limited to a symptomatic relief, without halting the degenerative process that characterizes the AD brain. As in AD cholinergic neurons are lost at high numbers, the initial strategies were limited to the development of acetylcholinesterase inhibitors, and more recently the NMDA receptor antagonist memantine, in counteracting excitotoxicity. With the identification of the protein tau in intracellular neurofibrillary tangles and of the peptide amyloid-β (Aβ) in extracellular amyloid plaques in the AD brain, and a better understanding of their role in disease, newer strategies are emerging, which aim at either preventing their formation and deposition or at accelerating their clearance. Interestingly, what is well established to combat viral diseases in peripheral organs - vaccination - seems to work for the brain as well. Accordingly, immunization strategies targeting Aβ show efficacy in mice and to some degree also in humans. Even more surprising is the finding in mice that immunization strategies targeting tau, a protein that forms aggregates in nerve cells, ameliorates the tau-associated pathology. We are reviewing the literature and discuss what can be expected regarding the translation into clinical practice and how the findings can be extended to other neurodegenerative diseases with protein aggregation in brain.     

PULMONARY RESPONSE TO TONER,TiO2 AND CRYSTALLINE SILICA UPON CHRONIC INHALATION EXPOSURE IN SYRIAN GOLDEN HAMSTERS

A chronic inhalation study of a test toner, TiO2, and crystalline silica was conducted by exposure of groups of Syrian golden hamsters (strain: Han:AURA) for 6 h/day, 5 days/ wk for 18 mo. Subsequently, the animals inhaled clean air only for an additional period of 5 mo. The target test aerosol exposure concentrations were 1.5, 6, and 24 mg/3m for the test toner, 40 mg/m3 for TiO2, and 3 mg/m3 for SiO2. The latter two materials were used as negative and positive controls for fibrogenicity. The aerosol concentrations were changed to 4, 16, and 64 mg/m3 for toner (referred to as toner low, toner medium, and toner high) and 30 mg/m3 for TiO2 after 5 mo, in order to achieve the desired lung burdens. Inhalation of the test toner or the control materials showed no signs of overt toxicity. Body weight, hematology and clinical chemistry values, food consumption, and organ weights were normal in the toner-, TiO2-, and SiO2-exposed groups, except for relative lung weights with elevations of up to 56%, 98%, and 98% for the toner high, the TiO2, and the SiO2 group at the end of the study. Small increases in the number of segmented neutrophils and decreases in the mean percentage of lymphocytes were observed in the same groups, indicating a mild inflammatory reaction in the lung. All of the changes in the toner-exposed groups were restricted to the lungs or associated lymph nodes. A chronic inflammatory response was evident from the bronchoalveolar lavage parameters for the toner high-, the TiO2-, and the SiO2-exposed groups. Primary lung tumors were not found in the control or toner-exposed groups. One small-sized bronchioloalveolar adenoma was observed in a female of the TiO2exposed group and one in a female of the SiO2-exposed group. A very slight to slight degree of interstitial fibrosis was observed after exposure to toner medium (in 49% of hamsters), to toner high (83%), to TiO2(82%), and SiO2(91%). Two squamous-cell carcinomas of the forestomach were observed in the male toner high group as well as in the female SiO2 group. Upon closer examination, an increased incidence of fore stomach papillomas was detected in all particle-exposed groups, but there was no doseresponse relationship among the three toner-exposed groups. Several of the observed lesions randomly distributed in most of the exposure groups, such as the neuroendocrine tumors (larynx and trachea), heart thrombosis, and forestomach papilloma(s), are not considered to be relevant for human risk assessment. The maximum tolerated dose (MTD) criterion was exceeded at the toner high and the TiO exposure concentra2 tions. The results of the present investigation coupled with the previously documented chronic inhalation studies in rats lead to the firm conclusion that inhalation of toner does not represent a carcinogenic hazard.     

Validation of the PHQ-9 as a screening instrument for depression in diabetes patients in specialized outpatient clinics

Background  

For the treatment of depression in diabetes patients, it is important that depression is recognized at an early stage. A screening method for depression is the patient health questionnaire (PHQ-9). The aim of this study is to validate the 9-item Patient Health Questionnaire (PHQ-9) as a screening instrument for depression in diabetes patients in outpatient clinics.