Methotrexate - Safe Backbone for the Treatment of Rheumatoid Arthritis.

Methotrexate (MTX) is the primarily used disease-modifying antirheumatic drug (DMARD) for the treatment of Rheumatoid Arthritis (RA). MTX is a safe agent, even when used for years - provided that treatment is regularly monitored and prescribers follow some simple rules, such as prescribing tablets of a single strength only. Proper patient education contributes greatly to safe treatment. The knowledge of important pharmacologic facts, possible interactions, and clinical warning signs also helps to prevent or recognize intoxications early. Therefore, this review addresses key aspects regarding the safety of MTX. In this respect, it includes adverse events, possible interactions with frequently used drugs and details on the rare but life-threatening intoxication, e.g., due to erroneous daily intake.

The Study of the Effectiveness of Ethylmethylhydroxypyridine Succinate in Acute Alcohol Intoxication.

The effectiveness of ethylmethylhydroxypyridine succinate (EMHPS) in acute alcohol intoxication was tested in a study on SPF male outbred ICR mice. Ethanol (concentration 40%) was administered to animals once intraperitoneally at a dose of 4 g/kg. Control animals were injected with saline in an equivalent volume. In 15 min after the administration of alcohol, the animals were injected intravenously or intramuscularly with EMHPS at a dose of 50 or 100 mg/kg or with saline via the same route in an equivalent volume. Animal behavior was tested 3 and 24 h later after administration of the substances. After 3 and 24 h, mice in the pathological control groups developed semiptosis, the gait and the turning over reflex were impaired, the strength of the hind limbs decreased and the distance between the hind limbs increased when landing; in the open-field test, the latency of the first movement increased, and the number of rearing postures decreased. Intravenous and intramuscular administration of EMHPS in doses of 50 and 100 mg/kg had a pronounced antitoxic and neuroprotective effect in acute alcohol intoxication: all studied parameters did not differ significantly from the control.

The synthetic cathinones MDPHP and MDPV: comparison of the acute effects in mice, in silico ADMET profiles and clinical reports.

The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common synthetic cathinones present in the "bath salts". MDPHP has recently gained attention due to increasing seizures and involvement in human intoxications which occurred in Europe and Italy in the last years, but currently there is a lack of information about its pharmaco-toxicological effects. With the aim at filling this gap, the present study is endeavoured to (i) evaluate the effects of acute administration of MDPHP (0.01-20mg/kg; i.p.) on behaviour, cardiorespiratory and cardiovascular parameters in CD-1 male mice, comparing them to those observed after administration of MDPV; (ii) predict the ADMET profile of the two analogues using the Plus ADMET Predictor®; (iii) present clinical data related to MDPHP and MDPV-induced intoxications recorded between 2011 and 2023 by the Pavia Poison Control Centre (PCC) - National Toxicology Information Centre (Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Italy). Our results substantiated that MDPHP and MDPV similarly affect sensorimotor and behavioural responses in mice, importantly increased locomotion and induced aggressive behaviour, and, at higher dosage, increased heart rate and blood pressure. These findings are in line with those observed in humans, revealing severe toxidromes typically characterized by Central Nervous System (CNS) alterations (behavioural/neuropsychiatric symptoms), including psychomotor agitation and aggressiveness, cardiovascular and respiratory disorders (e.g. tachycardia, hypertension, dyspnoea), and other peripheral symptoms (e.g. hyperthermia, acidosis, rhabdomyolysis).

Development and validation of a rapid and simple HILIC-MS/MS method for the determination of biogenic amines in tuna fish.

The production of biogenic amines (BAs), which are markers of both quality and safety in fish and fishery products, is influenced by the harvesting technique, handling, and other operations including those carried out on board the vessel. Scombroid dark-meat fish (e.g. tuna) are the fish species most frequently linked to histamine poisoning. The most commonly found BAs in fish are histamine, tyramine, putrescine, and cadaverine, which are produced when microbes decarboxylate the corresponding free amino acids. In this study, a rapid and cost-effective HILIC-MS/MS method was developed and validated for the determination of putrescine, cadaverine, histamine and tyramine in tuna samples. A simple sample preparation procedure was followed using the solvent mixture MeOH/H2O (50/50, v/v), 0.1 % acetic acid for protein precipitation and analyte extraction. Intra- and inter-day accuracy, expressed as %Recovery (%R), ranged from 88.0 % (Cad) to 102.7 % (Tyr) and from 85.0 % (Cad) to 99.8 % (Tyr), respectively. Intra- and inter-day precision, expressed as %Relative Standard Deviation (%RSD), ranged from 0.4 % (Tyr, Put) to 3.3 % (His) and from 0.7 % (Tyr) to 5.0 % (Cad), respectively. Limits of detection (LOD) and quantification (LOQ) varied from 0.0009 to 0.0940 mg/kg and from 0.0030 mg/kg to 0.3100 mg/kg, respectively, depending on the analyte. Regarding the potential toxic effects linked to biogenic amines in foods, samples examined in this study showed no risk. The proposed method is an important analytical tool for routine analysis of BAs in fish products.

Significant increase in the number of occupational exposures reported to the Dutch Poisons Information Centre (2016-2022): the importance of poison centre data in health surveillance.

INTRODUCTION: Exposure to hazardous substances in the workplace can result in injuries and fatalities. This study aimed to investigate the characteristics and trend of occupational exposures reported to the Dutch Poisons Information Centre and to investigate whether the COVID-19 pandemic had an impact on the trend. METHODS: A retrospective analysis of all acute occupational exposures reported to the Dutch Poisons Information Centre between 1 January 2016 and 31 December 2022 was performed. Data on patient and exposure characteristics, symptoms and treatment recommendations were analyzed. RESULTS: Between 2016 and 2022, the Dutch Poisons Information Centre received 5,508 calls regarding acute occupational exposures. The annual number of calls on acute occupational exposures almost doubled over the years studied (from 475 in 2016 to 936 in 2022). During and after the COVID-19 pandemic (March 2020-December 2022), the number of calls stabilized, but the upward trend was not significantly affected. There were an estimated 0.20 calls per 1,000 human exposure calls per month (95 per cent confidence interval: -0.14; 0.53). Victims were often exposed through multiple routes, with inhalation being the most common route (44 per cent), followed by ocular (32 per cent) and dermal contact (30 per cent). Acids (1,138 exposures) and alkalis (912 exposures) were often involved. The Dutch Poisons Information Centre had information on 6,334 patients, although the total number of exposed patients was not known as some victims did not seek medical assistance, or were treated by healthcare professionals who did not consult our Centre. At the time of contact, 13 per cent (n = 795) of the patients reported no symptoms, 76 per cent (n = 4,805) reported mild to moderate symptoms and 3 per cent (n = 183) reported potentially severe symptoms. Information on symptoms was missing for 9 per cent (n = 551) of the patients. Hospital observation and treatment were recommended for 5 per cent (n = 325) of the patients. DISCUSSION: This study highlights the necessity for poisoning prevention strategies to reduce the number of work-related incidents involving hazardous substances. CONCLUSION: The continuing increase in the number of workplace incidents involving hazardous substances is of concern. A comprehensive and multidisciplinary approach should be taken to gain a full understanding of occupational exposure to hazardous substances and to identify risk factors.

A case of multiorgan failure due to carbamazepine intoxication successfully treated with multimodal blood purification therapy.

Carbamazepine (CBZ) intoxication can occur due to various factors, including drug interactions and over-ingestion. Extracorporeal elimination, particularly through hemodialysis and hemoperfusion, is effective in treating severe carbamazepine intoxication. However, as the effectiveness of various modalities can differ, method selection may be based on a specific clinical situation. A 47-year-old woman who took CBZ for schizophrenia presented to our hospital with episodes of vomiting and consciousness disorder. As the CBZ concentration was > 20 µg/mL, she was admitted to the intensive care unit with a diagnosis of acute CBZ poisoning. She underwent one session of hemoperfusion for 2 h, and her CBZ level decreased from > 20 µg/mL to 6.4 µg/mL. However, she developed acute kidney and liver injuries 2 days after admission and underwent intermittent hemodialysis, plasma exchange, continuous hemodiafiltration (CHDF), and online HDF, depending on her condition. Her general condition improved, and she was transferred to the psychiatric department. To our knowledge, no case reports have described severe acute CBZ poisoning in a patient who developed multiorgan failure to date, which was successfully treated with multimodal blood purification therapy. When treating severe CBZ intoxication, blood purification therapy should be tailored to the changing pathophysiology of the condition.

A Fatal Case Report of Chenopodium ambrosioides L. (M'khinza) Intoxication.

Chenopodium ambrosioides L. is a plant belonging to the Chenopodiaceae family, known for its use in traditional medicine as a remedy for its antiseptic, analgesic, antipyretic, antispasmodic, and anti-inflammatory properties. It is used for its therapeutic properties internally as an infusion or externally as a vermifuge. Its use can be responsible for serious, even fatal, side effects and intoxications, particularly in infants and children. These may include neurological, digestive, hepatic, or renal complications. We present a case of Chenopodium ambrosioides L. intoxication in a four-year-old girl, resulting from repeated high-dose infusions of this plant for antipyretic purposes. She was admitted to the pediatric emergency department for management of a disorder of consciousness four hours after ingesting Chenopodium ambrosioides L. to treat acute fever.

The undetected murder? Evaluation and validation of a practicable and rapid inductively coupled plasma-mass spectrometry method for the detection of arsenic, lead, and thallium intoxications in postmortem blood.

Homicide, suicide, or accident - elemental intoxication may be a cause in each of these types of deaths. Inductively coupled plasma mass spectrometry (ICP-MS) has emerged as the gold standard analytical method for toxic metal analysis in both clinical and forensic settings. An ICP-MS method was developed using a modified acidic workup for the quantitative determination of arsenic, lead, and thallium. Method validation focused on the assessment of linearity, between- and within-day precisions, limits of detection (LoD) and lower limits of quantification (LLoQ), and carryover. The method was applied to analysis of postmortem peripheral blood samples from 279 forensic cases for which orders for chemical-toxicological examination had been received from the public prosecutor's office. Using six-point and one-point calibrations (latter for rapid screening purposes), precisions and accuracies ranged from -4.8 to 5.8% and -6.4 to 7.5%. Analytical sensitivities for As, Pb, and Tl were 0.08, 0.18, and 0.01 µg/l (LoD) and 0.23, 0.66, and 0.03 µg/l (LLoQ), respectively. Observed postmortem peripheral blood concentrations were As, 1.31 ± 3.42 µg/L; Pb, 17.4 ± 13.1 µg/L; and Tl, 0.11 ± 0.07 µg/L (mean ± standard deviation [SD]). Elemental concentrations, determined in additional quality control samples, were in good agreement to those obtained with an external ICP-MS method based on alkaline sample processing. The current method is practicable and compatible with an ICP-MS system used for trace element analysis in an accredited medical laboratory. It allows for implementation of low-threshold investigations when metal intoxications are suspected in forensic routine.

Polymorphic Loci of Xenobiotic Biotransformation Genes in Accumulated Mercury Pollution Liquidators and in Workers with Chronic Mercury Vapors Exposure.

The allele and genotype frequencies of the polymorphic loci CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), GSTM1, and GSTT1 genes were studied in 517 men: in 389 accumulated mercury pollution liquidators (207 firefighters of the Ministry of the Russian Federation for Civil Defence, Emergencies and Elimination of Consequences of Natural Disasters and 182 employees of the Federal Environmental Operator) and 128 former workers (82 patients in the delayed period of chronic mercury intoxication and 46 individuals contacted with mercury and had no chronic mercury intoxication). We found differences in the frequencies of AA and AG genotypes in groups of former workers (χ2=6.96, p=0.008) for the polymorphic locus rs1048943, while the AG-CYP1A1 genotype was characterized by a 5.5-fold decrease in the odds ratio for the development of chronic mercury intoxication (OR=0.18, p=0.0041). An unfavorable combination of genotypes of the studied polymorphic loci increases the risk of undesirable health effects.

Reduced Pharmacological Intervention of Prehospital Services for Acute Alcohol Intoxication during the COVID-19 Pandemic in A Large District of Southern Italy.

Background Stress during a pandemic increases the risk of alcohol consumption, which may require pharmacological management. Methods An observational single-center retrospective study was conducted from 1 January 2018 to 31 December 2021, and divided into 2-year periods (2018-2019 and 2020-2021). This study focused on calls to one of the emergency departments (EDs) of seven hospitals in the Bari (Italy) metropolitan area for patients requiring emergency services (ESs) who were either admitted or not admitted, due to their refusal. Results A 30% reduction in emergency calls for alcohol-related issues and a 41.17% reduction in calls for patients who refused to be admitted to the ED were observed during the pandemic. During the pandemic, an inverse association was found between pharmacological treatment and number of calls coded green (non-critical) and yellow (fairly critical) in patients admitted to EDs. An inverse association was also found for calls coded green in patients not admitted to EDs and pharmacological treatment. Metadoxine was administered in almost all alcohol-related emergencies, primarily in conjunction with drugs acting on the gastrointestinal tract, irrespective of age, the period considered, and whether patients were admitted or not admitted to the ED. Conclusions ES is the first and only out-of-hospital service encountered by numerous patients with alcohol-use disorders who refuse to be admitted to the ED. These patients should be directed by ES personnel to a multidisciplinary program to receive treatment for drinking, improve their quality of life, and reduce sanitation costs.

Uncovering young people's situational construction of sexual consent.

Aim: To investigate how young Danes construct sexual consent generally, but also specifically in relation to heavy alcohol intoxication. Methods: Drawing on 30 qualitative in-depth interviews with young people, aged 19-25 years, and adopting a critical discursive psychological framework, we explored the interpretative repertoires that the participants made use of to construct sexual consent and the subject positions those repertoires enabled. Results: The participants made use of three interpretative repertoires that we named as follows: (1) sexual consent as an agreement between rational individuals; (2) sexual consent as a heteronormative practice; and (3) intoxicated sexual consent. Discussion: Young people draw on different repertoires when discussing sexual consent in general, sexual consent in relation to gendered practices and expectations, and sexual consent in relation to heavy alcohol intoxication. Conclusion: It is vital to keep the situational nature of young people's constructions of sexual consent in mind if we wish to understand and eventually reduce the number of non-consensual sexual experiences.

Is ethyl chloride the new nitrous oxide? A case report.

BACKGROUND: Over the last decade, there has been an emerging trend of recreational misuse of several drugs and inhaled solvent including ethyl chloride. This case report follows CARE guidelines and highlights, with supporting video, the neurological features of ethyl chloride intoxication. CASE PRESENTATION: A 48-year-old man was seen for the sudden occurrence of an unsteady gait with dizziness. His only medical history was a chronic and treated HIV infection without any complications. Clinical examination revealed a cerebellar syndrome associated with impairment of short-term memory. Biological and radiological workups were normal. After several days, the patient recalled ethyl chloride inhalation. He fully recovered after being discharged from hospital. CONCLUSION: Clinicians should recognise the clinical features and neurological manifestations of ethyl chloride intoxication due to the potential fatal cardiovascular complications of this intoxication.

[A case of chronic bromide intoxication due to continuous use of a commercially available analgesic in a patient diagnosed with pseudohyperchloremia].

An 87-year-old woman was admitted to our hospital with general fatigue, anorexia, nausea, and chest pain, and was diagnosed with Takotsubo cardiomyopathy and a stomal ulcer. Pseudohyperchloremia and a negative anion gap were detected in laboratory tests. She was continuously taking commercially available analgesics, including bromvalerylurea. On the 11th day of hospitalization, her bromide concentration was high (331.2 mg/L). She was readmitted with fatigue and anorexia one and a half years after her last hospitalization. On admission, her serum chloride and bromide levels were also high. Despite being instructed to stop taking analgesics after the first hospitalization, she was unable to stop taking the medication. It took more than two years for her blood bromide concentration to decrease and the withdrawal of the medication to be confirmed. Clinicians should consider bromide intoxication in patients with unclear neuropsychiatric symptoms and high chloride levels.

[A fish-intoxication as a rare cause of chest pain]. / Eine Fischintoxikation als seltene Ätiologie des Thoraxschmerzes.

INTRODUCTION: We describe the case of a 58-year-old patient who developed chest pain and an anaphylaktoide reaction after ingestion of contamined fish containing histamin. Histamin intoxication from food poisoning (also known as scombroid intoxication) can be mistaken for an anaphylactic reaction and occasionaly lead to cardiac symptoms, even in patients without atherosclerotic changes. This condition is called Kounis syndrom and has to be recognized as a separate syndrom with specific clinical features.

Testing for protonitazene in human hair using LC-MS/MS.

Protonitazene is a synthetic benzoimidazole opioid of the nitazenes class, developed in the 1950s as an effective analgesic, but never released on the market due to severe side effects and possible dependence. Despite its increasing use as a new psychoactive substance starting in 2019, its detection in human hair of intoxicated and deceased consumers has never been reported. We present the development and validation of a specific procedure to identify protonitazene in hair by LC-MS-MS. Drugs were incubated overnight at 40°C in 1 mL borate buffer, pH 9.5 with 20 mg pulverized hair and 1 ng/mg fentanyl-d5 used as internal standard. Drugs were then extracted with a mixture of organic solvents. The chromatographic separation was performed using a HSS C18 column with a 15 min gradient elution. Linearity was verified from 1 to 100 pg/mg. The limit of detection was estimated at 0.1 pg/mg. No interference was noted from a large panel of natural and synthetic opioids, fentanyl derivatives or other new synthetic opioids. Protonitazene was identified at 70 and at > 7600 pg/mg in the whole head hair specimens of two male subjects deceased from acute drug overdose in jail. Protonitazene was also identified at 14 and 54 pg/mg in two living co-prisoners. As nitazenes represent a growing threat to public health in various parts of the world, this method was developed in response to the challenges posed by the identification of this class of substances.

Use of contraception during first sexual intercourse among Norwegian adolescents: a national cross-sectional study.

BACKGROUND: Most Norwegian adolescents experience their first sexual intercourse during late adolescence. Use of contraception is important to avoid unwanted pregnancy, while condoms can also protect against sexually transmitted diseases. There are few studies on the use of contraception at first sexual intercourse, most with varying results, and some studies have only examined the use of contraception among girls. In our study, we aimed to determine the use of contraception at first sexual intercourse, and to investigate associations between use of contraceptives at first sexual intercourse, sociodemographic factors, and alcohol and other substance use. METHODS: The study was based on data from the national electronic youth survey Ungdata, conducted in 2020-2022 among 113 049 upper secondary pupils (15-19 years) in Norway, which was around 65% of pupils attending upper secondary school during the study period. Descriptive analysis was used to estimate the prevalence of contraceptive use at first sexual intercourse, and multivariate logistic regression analyses to investigate the association between contraceptive use, sociodemographic factors, and alcohol intoxication and substance use. RESULT: 32% of Norwegian adolescents did not use contraception at first sexual intercourse. More girls (57.4%) than boys (42.6%) reported use of contraception. Factors associated with non-use of contraception during first sexual intercourse among boys were having parents with no college /university education (OR = 1.22: CI 1.13-1.32), perceived poor family finances (OR = 1.22: CI 1.06-1.40), alcohol intoxication, and use of cannabis or other narcotic substances during the past 12 months. The same factors were associated with non-use of contraception among girls. Additionally, being older than 16 years (OR = 1.13: CI 1.06-1.19) was also associated with non-use of contraception at first sexual intercourse. CONCLUSION: Many adolescents did not use contraception at first sexual intercourse. Alcohol intoxication and use of cannabis or other narcotic substances were associated with a lower likelihood of using contraceptives. This highlights the importance of preventive efforts including earlier prevention education that focuses more on the consequences of not using contraception in order to prevent unwanted pregnancies and sexually transmitted infections.

[Stimulants : Current insights into the principles, diagnostics and treatment]. / Stimulanzien : Aktuelle Erkenntnisse zu Grundlagen, Diagnostik und Therapie.

BACKGROUND: Consumption of stimulant drugs, a heterogeneous group of addictive substances, has significantly increased in recent years with rising numbers of stimulant-associated intoxication and deaths. OBJECTIVE: To provide an overview of recent scientific evidence of the diagnosis and treatment of stimulant use disorders. MATERIAL AND METHODS: A literature review of the neuropathology, clinical presentation, diagnostic criteria and evidence-based treatment for stimulant use disorders. RESULTS: The chronic use of stimulant drugs is associated with significant physical (e.g., hypertension, tachycardia and dyspnoea) and psychological harm (e.g., dependence, psychotic disorders and affective disorders). Despite major advances in the research of the neuropathology of stimulant use disorder and the refinement of diagnostic criteria, the disorder still presents a challenge, not least because of the lack of effective treatments. There are currently no approved pharmacotherapeutic interventions for stimulant use disorder and meta-analyses show that the efficacy of behavioural interventions is low to moderate, similar to cognitive behavioural treatment. CONCLUSION: Despite growing insights into the neuropathology associated with stimulant use disorder, treatment remains a challenge. The lack of effective interventions makes it difficult to give clear recommendations for the clinical practice. Further scientific research is thus warranted.

A Case of Severe Organ Dysfunction and Skin Lesions Due to Methotrexate Toxicity.

Methotrexate is an anti-inflammatory and immunomodulatory drug, widely used for moderate to severe psoriasis and other rheumatological conditions such as rheumatoid arthritis, besides some types of malignancies. Side effects are more prevalent in high acute doses but can also be seen in low-dose chronic use, especially in cases of drug-dosing errors. Possible symptoms of toxicity include gastrointestinal, hepatic, hematologic and renal dysfunctions, but may also include mucositis and worsening of the psoriatic lesions. Here, we describe a case involving methotrexate toxicity in an elderly patient with psoriasis, detailing the management.

In vitro characterization of protonitazene metabolites, using human liver microsomes, and first application to two urines collected from death cases.

Protonitazene, or N,N-diethyl-5-nitro-2-[(4-propoxyphenyl)methyl]-1H-benzimidazole-1-ethanamine, is a novel synthetic opioid, which belongs to the nitazene family. Over the last four years, nitazenes have re-emerged on the new psychoactive substances market and have been reported in several fatal intoxication cases. The metabolism of several nitazene analogues have already been studied, but to date, no data exists regarding protonitazene. The aim of the study was the detection of protonitazene and its metabolites in authentic human urine collected in two fatal intoxication cases, comparing the data after in vitro incubation with human liver microsomes, and subsequent analysis by ultra-performance liquid chromatography-tandem mass spectrometry and ultra-performance liquid chromatography-high-resolution mass spectrometry. Protonitazene metabolites, including N-desethyl-protonitazene, 5-amino-protonitazene and 4-hydroxy-nitazene, were characterized in vitro and were identified in the urine of both cases. The ratios between metabolites and parent protonitazene, higher than 1, were calculated to estimate the proportionality of metabolites. The results suggest that testing protonitazene metabolites should increase the window detection of exposure to protonitazene.