Dexamethasone does not diminish sugammadex reversal of neuromuscular block - clinical study in surgical patients undergoing general anesthesia.

BACKGROUND: Sugammadex reverses neuromuscular block (NMB) through binding aminosteroid neuromuscular blocking agents. Although sugammadex appears to be highly selective, it can interact with other drugs, like corticosteroids. A prospective single-blinded randomized clinical trial was designed to explore the significance of interactions between dexamethasone and sugammadex. METHODS: Sixty-five patients who were anesthetized for elective abdominal or urological surgery were included. NMB was assessed using train-of-four stimulation (TOF), with rocuronium used to maintain the desired NMB depth. NMB reversal at the end of anaesthesia was achieved using sugammadex. According to their received antiemetics, the patients were randomized to either the granisetron or dexamethasone group. Blood samples were taken before and after NMB reversal, for plasma dexamethasone and rocuronium determination. Primary endpoint was time from sugammadex administration to NMB reversal. Secondary endpoints included the ratios of the dexamethasone and rocuronium concentrations after NMB reversal versus before sugammadex administration. RESULTS: There were no differences for time to NMB reversal between the control (mean 121 ± 61 s) and the dexamethasone group (mean 125 ± 57 s; P = 0.760). Time to NMB reversal to a TOF ratio ≥0.9 was significantly longer in patients with lower TOF prior to sugammadex administration (Beta = -0.268; P = 0.038). The ratio between the rocuronium concentrations after NMB reversal versus before sugammadex administration was significantly affected by sugammadex dose (Beta = -0.375; P = 0.004), as was rocuronium dose per hour of operation (Beta = -0.366; p = 0.007), while it was not affected by NMB depth before administration of sugammadex (Beta = -0.089; p = 0.483) and dexamethasone (Beta = -0.186; p = 0.131). There was significant drop in plasma dexamethasone after sugammadex administration and NMB reversal (p < 0.001). CONCLUSIONS: Administration of dexamethasone to anesthetized patients did not delay NMB reversal by sugammadex. TRIAL REGISTRATION: The trial was retrospectively registered with The Australian New Zealand Clinical Trials Registry (ANZCTR) on February 28th 2012 (enrollment of the first patient on February 2nd 2012) and was given a trial ID number ACTRN12612000245897 and universal trial number U1111-1128-5104.

Thermal (In)stability of Atropine and Scopolamine in the GC-MS Inlet.

The intoxication due to unintentional or intentional ingestion of plant material containing tropane alkaloids is quite frequent. GC-MS method is still widely used for the identification of these toxicologically important substances in human specimen. During general unknown analysis, high temperature of inlet, at least 270 °C, is commonly used for less volatile substances. Unfortunately, both tropanes are thermally unstable and could be overlooked due to their degradation. The temperature-related degradation of tropanes atropine and scopolamine was systematically studied in the inlet of a GC-MS instrument in the range 110-250 °C by increments of 20 °C, additionally also at 275 °C, and in different solvents. At inlet temperatures not higher than 250 °C, the degradation products were formed by elimination of water and cleavage of atropine's ester bond. At higher temperatures, elimination of formaldehyde became predominant. These phenomena were less pronounced when ethyl acetate was used instead of methanol, while n-hexane proved unsuitable for several reasons. At an inlet temperature of 275 °C, tropanes were barely detectable. During systematic toxicological analysis, any tropanes' degradation products should indicate the possible presence of atropine and/or scopolamine in the sample. It is not necessary to prepare thermally stable derivatives for confirmation. Instead, the inlet temperature can be decreased to 250 °C, which diminishes their degradation to a level where their detection and identification are possible. This was demonstrated in several case studies.

Accidental poisoning with autumn crocus (Colchicum autumnale): a case series.

INTRODUCTION: Colchicum autumnale (autumn crocus) is a plant that contains highly toxic alkaloid colchicine. The aim was to evaluate accidental C autumnale poisoning and assess serum troponin as a prognostic parameter. METHODS: In this study, we retrospectively included all adult patients with a history of accidental C autumnale ingestion and serum colchicine confirmation during the study period from 2000 to 2019. The medical files of enrolled patients were reviewed. Literature search of accidental ingestions of C autumnale was done. RESULTS: Over the study period of 20 years, 16 adult patients were admitted to the University Medical Centre Ljubljana due to acute colchicine poisoning after ingestion of C autumnale. They all mistakenly ingested C autumnale's leaves instead of Allium ursinum in the spring and had confirmed colchicine in serum by GC-MS or LC-MS/MS (15.5 µg/L (0.5-80 µg/L)). They developed vomiting and diarrhoea within 1-9 h after the meal. Vomiting within 2 h was associated with lethality (p=.04). Bone marrow suppression developed in 15 patients (94%). Acute myocardial injury with positive troponin I (>0.10 µg/L) developed in five patients; lethal cardiogenic shock with decreased cardiac output and hypotension occurred in four of these patients despite supportive therapy. Positive troponin I ultra (>0.10 µg/L) was associated with need for intensive support therapy (p=.01), decreased cardiac output (p=.01) and death (p=.01). The mortality was 4/16 (25%). On review, we found 58 cases; 95% cases accidently ingested leaves of C autumnale instead of A ursinum. Troponin I was reported in 3% cases. The lethality of this and reviewed cases was 35% (26/74). CONCLUSIONS: In unexplained gastroenterocolitis after ingestion of wild plants as a salad or spice in the spring, especially when wild garlic is mentioned, we should always consider C autumnale poisoning. Cardiogenic shock can be predicted by a positive serum troponin I measurement.

The Influence of a Single Intra-Articular Lidocaine Injection on the Viability of Articular Cartilage in the Knee.

OBJECTIVE: To evaluate the in vivo effect of a single intra-articular injection of local anesthetic (LA) lidocaine on the viability of articular cartilage in the intact or osteoarthritic (OA) human knees, and to measure the synovial postinjection concentration of lidocaine in the knee. DESIGN: This study includes 3 interconnected experiments: (A) Synovial LA concentration measurement after a 2% lidocaine injection before knee arthroscopy in 10 patients by liquid chromatography-tandem mass spectrometry (LC-MS/MS). (B) Human osteochondral explants (N = 27) from intact knees procured at autopsies were incubated for different time intervals (30 minutes, 2 hours, 24 hours) with 2% lidocaine, 0.04% lidocaine (measured), or culture medium (control), and later evaluated for cell viability by LIVE/DEAD staining. (C) Ten out of 19 matched patients scheduled for knee replacement received a single intra-articular injection of 2% lidocaine approximately 30 minutes prior to the procedure; 9 patients served as control. Osteochondral samples with OA changes were harvested during surgery and analyzed for chondrocyte viability by LIVE/DEAD staining. RESULTS: (A) The synovial LA concentration was significantly lower than the primary concentration injected: average 0.23 mg/mL (0.02%), highest measured 0.37 mg/mL (0.04%). (B) In vitro exposure to a reduced LA concentration had no significant influence on chondrocyte viability in intact cartilage explants (24-hour averages: control, 93%; 0.04% lidocaine, 92%; 2% lidocaine, 79%). (C) Viability of chondrocytes in OA knees was similar between 2% lidocaine injection (85%) and control (80%). CONCLUSIONS: A single intra-articular knee injection of 2% lidocaine did not influence the chondrocyte viability neither in healthy nor in OA cartilage. A fast postinjection reduction of synovial LA concentration (more than 40 times) is the most likely protective mechanism.

Ibogaine Has Sex-Specific Plasma Bioavailability, Histopathological and Redox/Antioxidant Effects in Rat Liver and Kidneys: A Study on Females.

Ibogaine induces rapid changes in cellular energetics followed by the elevation of antioxidant activities. As shown earlier in male rats, ibogaine treatment with both 1 and 20 mg/kg b.w. per os led to significant glycogenolytic activity in the liver. In this work, female rats treated with the same doses of ibogaine per os displayed lower liver glycogenolytic activity relative to males, dilatation of the central vein and branches of the portal vein, and increased concentration of thiols 6 h after treatment. These changes were followed by increased catalase activity and lipid peroxidation, and decreased xanthine oxidase activity after 24 h. In kidneys, mild histopathological changes were found in all treated animals, accompanied by a decrease of glutathione reductase (after 6 and 24 h at both doses) and an increase of catalase (6 h) and xanthine oxidase activity (6 and 24 h). Ibogaine did not affect antioxidant enzymes activity in erythrocytes. Bioavailability of ibogaine was two to three times higher in females than males, with similar kinetic profiles. Compared to previous results in males, ibogaine showed sex specific effect at the level of antioxidant cellular system. Effects of ibogaine in rats are sex- and tissue-specific, and also dose- and time-dependent.

A study of midazolam plasma concentrations in patients undergoing conscious sedation.

We studied midazolam plasma concentrations in patients undergoing middle ear surgery (MES) in local anesthesia and sedation. This study was based on the clinical measurement of the level of sedation and determination of the sedation dose of midazolam. For optimal level of sedation for this type of surgery we suggest the midazolam plasma concentrations with median of 0.03 mg L-1 and range from 0.01-0.10 mg L-1. This can be contrasted to the other studies where considerably higher plasma concentrations of midazolam (0.2 mg L-1) were proposed (S. Michalk et al., Intens. Care Med. 1988, 15, 37-41). Despite low midazolam concentrations the level of sedation was adequate.

Metabolic acidosis in prometryn (triazine herbicide) self-poisoning.

INTRODUCTION: Prometryn is a triazine herbicide, which is one of the most extensively used groups of herbicides. The mechanism of acute triazine herbicide toxicity in humans is not known. We report a first case of acute prometryn poisoning. CASE REPORT: A 62-year-old male ingested 50 g of prometryn and ethanol in a suicide attempt. On arrival two hours after ingestion, he was somnolent and vomited. Seven hours after ingestion laboratory tests showed metabolic acidosis with a calculated anion gap of 47.5 mmol/L and lactate of 23.4 mmol/L. Gas chromatography/mass spectrometry revealed serum prometryn concentrations of 48.1 mg/L. Hemodialysis corrected metabolic acidosis, but the serum prometryn concentration increased to 67.7 mg/L. The lactate level after hemodialysis was 11.7 mmol/L and returned within normal limits 47 hours after ingestion. The patient was discharged without any sequelae after psychiatric evaluation. CONCLUSION: In high anion gap metabolic acidosis we should consider poisoning with prometryn and other triazine herbicides. Hemodialysis corrects metabolic derangements, but it does not lower serum prometryn concentration.

Pharmacokinetics of levobupivacaine 0.5% after superficial or combined (deep and superficial) cervical plexus block in patients undergoing minimally invasive parathyroidectomy.

STUDY OBJECTIVE: To evaluate the pharmacokinetic profile of 0.35 mL/kg of 0.5% levobupivacaine during superficial and combined (deep and superficial) cervical plexus block (CPB) in patients undergoing minimally invasive parathyroidectomy. DESIGN: Prospective randomized study. SETTING: Operating theater of a university hospital. PATIENTS: 12 ASA physical status II and III patients (11 women and 1 man), scheduled for minimally invasive parathyroidectomy. INTERVENTIONS: Seven and 5 patients were randomly assigned to receive either superficial or combined CPB, respectively. The superficial CPB was performed with an injection of 0.35 mL/kg of 0.5% levobupivacaine subcutaneously along the posterior border of the sternocleidomastoid muscle and deeper on its medial surface. The combined CPB was initiated by the deep block at the C3 level vertebra by injecting 0.2 mL/kg of 0.5% levobupivacaine, followed by the superficial block with an injection of the remaining 0.15 mL/kg. After completion of the block, venous blood was sampled at the intervals of 5, 10, 15, 20, 30, 45, and 60 minutes. MEASUREMENTS AND MAIN RESULTS: Venous plasma concentrations were measured using gas chromatography-mass spectroscopy. Mean +/- SD of maximal concentrations of levobupivacaine was 0.58 +/- 0.41 mg/L in group superficial and 0.52 +/- 0.28 mg/L in group combined (P = 0.71). The median (range) time required to reach the maximal concentrations was 30 minutes (20-30 min) in group superficial and 20 minutes (15-30 min) in group combined (P = 0.45). The areas under the drug concentration/time curve (AUC(10-60)) were also similar in both groups. No signs of central nervous system or cardiovascular toxicity or other untoward events were observed in any patient. CONCLUSION: With the given dose regimen, levobupivacaine plasma concentrations were within safe ranges.

Urinary serotonin level is associated with serotonin syndrome after moclobemide, sertraline, and citalopram overdose.

INTRODUCTION: Altered mental status, autonomic dysfunction, and neuromuscular abnormalities are a characteristic triad of serotonin syndrome. No laboratory tests confirm the diagnosis of serotonin syndrome. CASE REPORT: A 35-year-old woman took moclobemide, sertraline, and citalopram in a suicide attempt. She was conscious with mild tachycardia, hypertension, and tachypnea one hour after ingestion. In the second hour after ingestion diaphoresis, mydriasis, horizontal nystagmus, trismus, hyperreflexia, clonus, and tremor appeared. She became agitated and unresponsive. In the third hour after ingestion she became comatose and hyperthermic. She was anesthetized, paralyzed, intubated, and ventilated for 24 hours. Serum moclobemide, sertraline, and citalopram levels were above therapeutic levels. The serum serotonin level was within normal limits and the urinary 5-hydroxyindoleacetic acid:creatinine ratio was below the average daily value. The urinary serotonin:creatinine ratio was increased on arrival (1 mg/g). DISCUSSION AND CONCLUSION: The urinary serotonin level is increased in serotonin syndrome due to a monoamine oxidase inhibitor and selective serotonin-reuptake inhibitors overdose. It is possible that urinary serotonin concentration could be used as a biochemical marker of serotonin syndrome.

Occupational transdermal poisoning with synthetic cannabinoid cumyl-PINACA.

CONTEXT: Synthetic cannabinoids are getting more popular among young people and illicit manufacturers. We report a case series of occupational transdermal poisoning with synthetic cannabinoids. CASE DETAILS: Three customs inspectors got in contact with a sticky substance with their fingertips because they were not wearing protection gloves and the delivered package was damaged. Despite washing their hands with water, signs of synthetic cannabinoids intoxication started occurring half an hour after exposure. On arrival at the Emergency Department six hours later, they were somnolent, lethargic and confused. They showed signs of mydriasis, blurred vision, ataxia, weakness, numbness, tachycardia and one of them had orthostatic hypotension. Two days later, they were feeling much better and reported amnesia and slowed perception of time after exposure. Toxicology analysis by LC-MS/MS revealed synthetic cannabinoid cumyl-PINACA (SGT-24) in their blood samples taken on admission. cumyl-PINACA was also confirmed with NMR method in liquid samples seized at the airport. It was 98% pure substance with the purpose of being diluted and sold further in the drug market by drug dealer. DISCUSSION: This case series highlights the possible transdermal exposure to synthetic cannabinoids oil resulting in prolonged cannabinoid syndrome.

Rare tradition of the folk medicinal use of Aconitum spp. is kept alive in Solcavsko, Slovenia.

BACKGROUND: Aconitum species are poisonous plants that have been used in Western medicine for centuries. In the nineteenth century, these plants were part of official and folk medicine in the Slovenian territory. According to current ethnobotanical studies, folk use of Aconitum species is rarely reported in Europe. The purpose of this study was to research the folk medicinal use of Aconitum species in Solcavsko, Slovenia; to collect recipes for the preparation of Aconitum spp., indications for use, and dosing; and to investigate whether the folk use of aconite was connected to poisoning incidents. METHODS: In Solcavsko, a remote alpine area in northern Slovenia, we performed semi-structured interviews with 19 informants in Solcavsko, 3 informants in Luce, and two retired physicians who worked in that area. Three samples of homemade ethanolic extracts were obtained from informants, and the concentration of aconitine was measured. In addition, four extracts were prepared according to reported recipes. RESULTS: All 22 informants knew of Aconitum spp. and their therapeutic use, and 5 of them provided a detailed description of the preparation and use of "voukuc", an ethanolic extract made from aconite roots. Seven informants were unable to describe the preparation in detail, since they knew of the extract only from the narration of others or they remembered it from childhood. Most likely, the roots of Aconitum tauricum and Aconitum napellus were used for the preparation of the extract, and the solvent was homemade spirits. Four informants kept the extract at home; two extracts were prepared recently (1998 and 2015). Three extracts were analyzed, and 2 contained aconitine. Informants reported many indications for the use of the extract; it was used internally and, in some cases, externally as well. The extract was also used in animals. The extract was measured in drops, but the number of drops differed among the informants. The informants reported nine poisonings with Aconitum spp., but none of them occurred as a result of medicinal use of the extract. CONCLUSIONS: In this study, we determined that folk knowledge of the medicinal use of Aconitum spp. is still present in Solcavsko, but Aconitum preparations are used only infrequently.

The syndrome of inappropriate antidiuretic hormone secretion after giant leaf frog (Phyllomedusa bicolor) venom exposure.

INTRODUCTION: In Europe body purification and natural balance restoring rituals are becoming increasingly popular, but an introduction of Amazonian shamanic rituals in urban Europe can result in unexpected adverse events. CASE REPORT: A 44-year-old woman attended a Kambô or Sapo ritual in Slovenia where dried skin secretion from a giant leaf frog (Phyllomedusa bicolor) was applied to five freshly burned wounds at her shoulder. Afterwards, she drank 6 litres of water and gradually developed nausea and vomiting, confusion, lethargy, muscle weakness, spasms and cramps, seizure, decreased consciousness level and short-term memory loss. The initial laboratory tests showed profound plasma hypoosmolality (251 mOsm/kg) proportional to hyponatremia (116 mmol/L) combined with inappropriately elevated urine osmolality (523 mOsm/kg) and high urine sodium concentration (87 mmol/L) indicating a syndrome of inappropriate antidiuretic hormone secretion. The patient was treated with 0.9% sodium chloride and a restriction of water intake. Plasma osmolality and hyponatremia improved one day after venom exposure, but the symptoms disappeared as late as the third day. CONCLUSION: In patients presenting with neurological symptoms and a line of small body burns Phyllomedusa bicolor venom exposure should be suspected. Acute symptomatic hyponatremia after Phyllomedusa bicolor venom exposure is the result of inappropriate antidiuretic hormone secretion that can be exacerbated by excessive water intake.

Case report: fatal poisoning with Colchicum autumnale.

INTRODUCTION: Colchicum autumnale, commonly known as the autumn crocus, contains alkaloid colchicine with antimitotic properties. CASE REPORT: A 76-year-old man with a history of alcoholic liver disease and renal insufficiency, who mistakenly ingested Colchicum autumnale instead of wild garlic (Aliium ursinum), presented with nausea, vomiting and diarrhea 12 hours after ingestion. On admission the patient had laboratory signs of dehydration. On the second day the patient became somnolent and developed respiratory insufficiency. The echocardiogram showed heart dilatation with diffuse hypokinesia with positive troponin I. The respiratory insufficiency was further deteriorated by pneumonia, confirmed by chest X-ray and later on by autopsy. Laboratory tests also revealed rhabdomyolysis, coagulopathy and deterioration of renal function and hepatic function. The toxicological analysis disclosed colchicine in the patient's urine (6 microgram/l) and serum (9 microgram/l) on the second day. Therapy was supportive with hydration, vasopressors, mechanical ventilation and antibiotics. On the third day the patient died due to asystolic cardiac arrest. DISCUSSION AND CONCLUSION: Colchicine poisoning should be considered in patients with gastroenterocolitis after a meal of wild plants. Management includes only intensive support therapy. A more severe clinical presentation should be expected in patients with pre-existing liver and renal diseases. The main reasons for death are cardiovascular collapse, respiratory failure and leukopenia with infection.

Polydipsia as another mechanism of hyponatremia after 'ecstasy' (3,4 methyldioxymethamphetamine) ingestion.

Acute symptomatic hyponatremia after ecstasy (3,4 methyldioxymethamphetamine; MDMA) ingestion is well documented and has been attributed to the syndrome of inappropriate antidiuretic hormone (SIADH). We report the case of an 18-year-old woman who took five tablets of ecstasy in a suicide attempt and drank 1700 ml water at the Emergency Department (ED). The laboratory findings obtained 5 h after ingestion showed a serum sodium concentration of 130 mmol/l, plasma osmolality of 264 mOsm/kg, urinary osmolality of 335 mOsm/kg and natriuresis of 101 mmol/l. The plasma arginine vasopressin level by radioimmunoassay was 33.7 pmol/l 5 h after ingestion. A gas chromatography-mass spectrometry assay confirmed MDMA in blood samples, with serum concentrations of 0.87 mg/l on arrival. This case report strongly suggests that MDMA reduces serum sodium levels through the dual pathways of SIADH and polydipsia. Accordingly, we believe that hyponatremia may be prevented in ED patients after MDMA ingestion by the early restriction of water intake.

Acute poisoning with autumn crocus (Colchicum autumnale L.).

INTRODUCTION: Colchicum autumnale, commonly known as the autumn crocus or meadow saffron, contains the antimitotic colchicine, which binds to tubulin and prevents it forming microtubules that are part of the cytoskeleton in all cells. CASE REPORT: A 71-year-old woman ate a plant she thought to be wild garlic (Allium ursinum). Ten hours later she arrived at the emergency department complaining of nausea, vomiting and watery diarrhea. Ingestion of a poisonous plant was suspected and she was treated with gastric lavage, oral activated charcoal and an infusion of normal saline. Toxicology analysis with gas chromatography and mass spectrometry revealed colchicine in the patient's gastric lavage, blood (5 microg/l) and urine (30 microg/l). She developed arrhythmias, liver failure, pancreatitis, ileus, and bone marrow suppression with pancytopenia. Alopecia began in the third week. Treatment was supportive only. Five months later she had no clinical or laboratory signs of poisoning. DISCUSSION: The patient mistakenly ingested autumn crocus instead of wild garlic because of their great similarity. Colchicine primarily blocks mitosis in tissues with rapid cell turnover; this results in gastroenterocolitis in the first phase of colchicine poisoning, bone marrow hypoplasia with pancytopenia in the second and alopecia in the third, all of which were present in our patient. Colchicine toxicity in tissues without rapid cell turnover caused arrhythmias, acute liver failure and pancreatitis. CONCLUSION: Colchicine poisoning can result in gastroenterocolitis followed by multi-organ dysfunction syndrome. In unexplained gastroenterocolitis after ingestion of wild plants as a salad or spice, especially when wild garlic is mentioned, we should always consider autumn crocus. Diagnosis could be confirmed only by toxicology analyses. Management of colchicine poisoning is restricted to supportive therapy.

Simple validated LC-MS/MS method for the determination of atropine and scopolamine in plasma for clinical and forensic toxicological purposes.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of atropine and scopolamine in 100µL human plasma was developed and validated. Sample pretreatment consisted of protein precipitation with acetonitrile followed by a concentration step. Analytes and levobupivacaine (internal standard) were separated on a Zorbax XDB-CN column (75mm×4.6mm i.d., 3.5µm) with gradient elution (purified water, acetonitrile, formic acid). The triple quadrupole MS was operated in ESI positive mode. Matrix effect was estimated for deproteinised plasma samples. Selected reaction monitoring (SRM) was used for quantification in the range of 0.10-50.00ng/mL. Interday precision for both tropanes and intraday precision for atropine was <10%, intraday precision for scopolamine was <14% and <18% at lower limit of quantification (LLOQ). Mean interday and intraday accuracies for atropine were within ±7% and for scopolamine within ±11%. The method can be used for determination of therapeutic and toxic levels of both compounds and has been successfully applied to a study of pharmacodynamic and pharmacokinetic properties of tropanes, where plasma samples of volunteers were collected at fixed time intervals after ingestion of a buckwheat meal, spiked with five low doses of tropanes.

Risk assessment of buckwheat flour contaminated by thorn-apple (Datura stramonium L.) alkaloids: a case study from Slovenia.

In Slovenia, a mass poisoning incident involving 73 consumers with symptoms such as dry mouth, hot red skin, blurred vision, tachycardia, urinary retention, ataxia, speech disturbance, disorientation and visual hallucinations occurred in 2003. In all cases, consumers had eaten buckwheat flour food products within the last few hours. Investigations by responsible authorities identified the contamination of a range of buckwheat food products with thorn-apple (Datura stramonium L.) seeds containing toxic alkaloids, atropine and scopolamine. To ensure the safe consumption of buckwheat food products, we carried out risk characterisation and proposed provisional maximum residue levels (MRLs) of atropine and scopolamine mixture in buckwheat flour. In the absence of critical "no observed adverse effect levels" for atropine and scopolamine, we based our estimation of the acute reference doses on the lowest recommended therapeutic doses. Taking into account the additive effect of the two alkaloids, we calculated acute reference doses of the mixture, that is 0.05 µg/kg of body mass for atropine and 0.03 µg/kg of body mass for scopolamine. MRLs for atropine and scopolamine mixture in buckwheat flour were estimated in a worst-case scenario, that is consumption of 100 g of flour by a child weighing 10 kg and taking into account a range of atropine/scopolamine ratio in implicated food products, that is 0.85-3.3. We proposed the national MRLs for atropine/scopolamine mixture in buckwheat food products: 4.0 µg/kg (atropine) and 2.0 µg/kg(scopolamine). However, in view of the large variability in the alkaloid content, depending on the origin of the Datura, we propose that risk assessment should be carried out on a case-by-case basis, taking into account the ratio between atropine and scopolamine content in a particular sample.

Metabolic plasticity and the energy economizing effect of ibogaine, the principal alkaloid of Tabernanthe iboga.

ETHNOPHARMACOLOGICAL RELEVANCE: The root bark of iboga plant-Tabernanthe iboga has been used traditionally in Central Africa as a psychoactive substance in religious rituals, while in smaller doses it is appreciated due to its stimulant properties. The iboga root bark, iboga extract or pure ibogaine are being recognized in the West as an anti-addiction remedy and their use is increasing. AIM OF THE STUDY: Our previous studies have demonstrated a transient ATP pool reduction under ibogaine accompanied by the induction of energy metabolism related enzymes. The present study aimed to find the cause of this energy deprivation and to foresee its immediate and long-term impact on metabolism. The overall project is designed to disclose the common mechanism of action at these seemingly diverse indications for iboga use, to predict eventual adverse effects and to build the grounds for its safe and beneficial utilization. MATERIALS AND METHODS: The rate of carbon dioxide (CO(2)) as a marker of energy metabolism in stationary yeast model under aerobic conditions in the presence of ibogaine at concentration of 1, 4 and 20mg/l was measured for 5h by gas chromatography. The overall oxidative load was determined fluorimetrically by 2',7'-dichlorofluorescein diacetate (H(2)DCFDA) and in vitro antioxidant properties of ibogaine were defined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) test. RESULTS: The CO(2) production under ibogaine was temporarily increased in a dose dependent manner. The increased energy consumption as an early effect of ibogaine was proven by the fact that in spite of energy mobilization, the ATP pool has been simultaneously decreased. Although increased cellular respiration co-produces reactive oxygen species (ROS), the overall oxidative load was significantly lowered by ibogaine. Since ibogaine does not show any significant in vitro antioxidant properties, the results indicate its stimulating influence on physiological oxidative stress defence system. CONCLUSION: Ibogaine triggers remodeling of the housekeeping metabolism. Under the initial energy cost it results in increased efficacy of physiological antioxidative systems, which reduce oxidative damage and lowers basal metabolic needs. Together with induced catabolic enzymes they set a new metabolic equilibrium that saves energy and makes it easily available in case of extra needs. While healthy organism profits from improved fitness and mental performance and can withstand higher stress without risking a disease, due to the same principle ibogaine provides beneficial support at the recovery after diseases including addiction syndrome.

Haemodialysis clearance of baclofen.

BACKGROUND: Baclofen is a centrally acting gamma-aminobutyric acid agonist used for spasticity of spinal origin and mainly excreted unchanged by the kidneys. We report haemodialysis clearance and the haemodialysis removal rate constant of baclofen in a comatose patient with baclofen overdose due to acute renal failure. CASE REPORT: A 60-year-old man with spastic tetraplegia on chronic baclofen therapy was admitted due to pneumonia and acute renal failure. The patient became comatose and, as a result of the baclofen dosage being left unchanged despite a deterioration leading to renal failure due to hypotension, the concentration of baclofen was determined to be in the toxic range (0.70 mg/L). During a 4-hour-long bicarbonate haemodialysis the patient woke up and became completely orientated and cooperative. Baclofen therapy was subsequently stopped, and the patient remained conscious. The pharmacokinetics calculations revealed a baclofen haemodialysis removal rate constant of 0.152 h(-1) and a haemodialysis clearance of 2.14 mL/s. CONCLUSIONS: Patients on a stable baclofen regime can develop baclofen toxicity due to acute renal failure. Haemodialysis removes baclofen as effectively as normal kidneys, and it would appear that haemodialysis is a reasonable treatment modality in patients with accidental baclofen overdose due to acute renal failure.