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 (0.01-20 mg/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).

A case of severe benzalkonium chloride intoxication in a cat.

BACKGROUND: Benzalkonium chloride (BAC) is a quaternary ammonium compound (QAC), that can be found in a wide variety of household products-from disinfectants to medicaments and home fragrances-but also professional products. In pets, cats have long been reported as more sensitive than dogs to QACs; in fact, signs of irritation such as oral ulcerations, stomatitis and pharyngitis can be observed after contact with concentrations of 2% or lower. In a review of 245 cases of BAC exposure in cats, reported by the Veterinary Poisons Information Service (United Kingdom) only 1.2% of the cases died or were euthanized. Nevertheless, BAC toxidromes in cats can result in transitory CNS and respiratory distress, as well as severe mucosal and cutaneous lesions. Currently, only a few reports are available concerning BAC poisoning in this species. CASE PRESENTATION: A 4 month-old kitten presented with severe glossitis, lameness in the hindlimbs and episodes of vomiting and diarrhoea. The cause was unknown until the owners reported use of a BAC-containing mould remover (5%) 4 days later. The patient developed severe oral burns requiring a pharyngeal tube for feeding and severe cutaneous chemical burns. The kitten was managed with supportive therapy and required hospitalization for 10 days. The symptoms disappeared completely 3 weeks after exposure. CONCLUSIONS: BAC is a very common compound contained in several household and professional products but, to the best of our knowledge, no previous case had been reported in Italy. We hope that this report will help raise awareness on the hazards of BAC products for cats in both domestic and work contexts.

Pharmaco-toxicological effects of the novel tryptamine hallucinogen 5-MeO-MiPT on motor, sensorimotor, physiological, and cardiorespiratory parameters in mice-from a human poisoning case to the preclinical evidence.

RATIONALE: The 5-methoxy-N-methyl-N-isopropyltryptamine (5-MeO-MiPT, known online as "Moxy") is a new psychedelic tryptamine first identified on Italian national territory in 2014. Its hallucinogen effects are broadly well-known; however, only few information is available regarding its pharmaco-toxicological effects. OBJECTIVES: Following the seizure of this new psychoactive substances by the Arm of Carabinieri and the occurrence of a human intoxication case, in the current study we had the aim to characterize the in vivo acute effects of systemic administration of 5-MeO-MiPT (0.01-30 mg/kg i.p.) on sensorimotor (visual, acoustic, and overall tactile) responses, thermoregulation, and stimulated motor activity (drag and accelerod test) in CD-1 male mice. We also evaluated variation on sensory gating (PPI, prepulse inhibition; 0.01-10 mg/kg i.p.) and on cardiorespiratory parameters (MouseOx and BP-2000; 30 mg/kg i.p.). Lastly, we investigated the in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) profile of 5-MeO-MiPT compared to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) and N,N-dimethyltryptamine (DMT). RESULTS: This study demonstrates that 5-MeO-MiPT dose-dependently inhibits sensorimotor and PPI responses and, at high doses, induces impairment of the stimulated motor activity and cardiorespiratory changes in mice. In silico prediction shows that the 5-MeO-MiPT toxicokinetic profile shares similarities with 5-MeO-DIPT and DMT and highlights a cytochrome risk associated with this compound. CONCLUSIONS: Consumption of 5-MeO-MiPT can affect the ability to perform activities and pose a risk to human health status, as the correspondence between the effects induced in mice and the symptoms occurred in the intoxication case suggests. However, our findings suggest that 5-MeO-MiPT should not be excluded from research in the psychiatric therapy field.

Sex-specific behavioural, metabolic, and immunohistochemical changes after repeated administration of the synthetic cannabinoid AKB48 in mice.

BACKGROUND AND PURPOSE: AKB48 is a synthetic cannabinoid illegally sold for its psychoactive cannabis-like effects that have been associated with acute intoxication and whose effects are poorly known. EXPERIMENTAL APPROACH: Using a behavioural, neurochemical, and immunohistochemical approach, we investigated the pharmaco-toxicological effects, pharmacokinetics, and neuroplasticity at cannabinoid CB1 receptors in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. KEY RESULTS: The effects of AKB48 varied significantly depending on sex and treatment duration. The first injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate to a greater extent in females than in males; the second injection induced stronger effects in males while the third injection of AKB48 induced weaker responses in both sexes, suggesting emergence of tolerance. The CB1 receptor antagonist NESS-0327 prevented the effects induced by repeated AKB48, confirming a CB1 receptor-mediated action. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 levels in both sexes, suggesting an inhibitory effect on cytochrome activity. Finally, immunohistochemical analysis revealed higher expression of CB1 receptors in the cerebellum and cortex of females, and a rapid CB1 receptor down-regulation in cerebellar and cortical areas following repeated AKB48 injections, with neuroadaptation occurring generally more rapidly in females than in males. CONCLUSION AND IMPLICATIONS: We have shown for the first time that AKB48 effects significantly vary with prolonged use and that sex affects the pharmacodynamic/pharmacokinetic responses to repeated administration, suggesting a sex-tailored approach in managing AKB48-induced intoxication.

The Designer Drug αPHP Affected Cell Proliferation and Triggered Deathly Mechanisms in Murine Neural Stem/Progenitor Cells.

Increasing reports of neurological and psychiatric outcomes due to psychostimulant synthetic cathinones (SCs) have recently raised public concern. However, the understanding of neurotoxic mechanisms is still lacking, particularly for the under-investigated αPHP, one of the major MDPV derivatives. In particular, its effects on neural stem/progenitor cell cultures (NSPCs) are still unexplored. Therefore, in the current in vitro study, the effects of increasing αPHP concentrations (25-2000 µM), on cell viability/proliferation, morphology/ultrastructure, genotoxicity and cell death pathways, have been evaluated after exposure in murine NSPCs, using a battery of complementary techniques, i.e., MTT and clonogenic assay, flow cytometry, immunocytochemistry, TEM, and patch clamp. We revealed that αPHP was able to induce a dose-dependent significant decrease of the viability, proliferation and clonal capability of the NSPCs, paralleled by the resting membrane potential depolarization and apoptotic/autophagic/necroptotic pathway activation. Moreover, ultrastructural alterations were clearly observed. Overall, our current findings demonstrate that αPHP, damaging NSPCs and the morpho-functional fundamental units of adult neurogenic niches may affect neurogenesis, possibly triggering long-lasting, irreversible CNS damage. The present investigation could pave the way for a broadened understanding of SCs toxicology, needed to establish an appropriate treatment for NPS and the potential consequences for public health.

Methylglyoxal-induced neurotoxic effects in primary neuronal-like cells transdifferentiated from human mesenchymal stem cells: Impact of low concentrations.

In the last decades, advanced glycation end-products (AGEs) have aroused the interest of the scientific community due to the increasing evidence of their involvement in many pathophysiological processes including various neurological disorders and cognitive decline age related. Methylglyoxal (MG) is one of the reactive dicarbonyl precursors of AGEs, mainly generated as a by-product of glycolysis, whose accumulation induces neurotoxicity. In our study, MG cytotoxicity was evaluated employing a human stem cell-derived model, namely, neuron-like cells (hNLCs) transdifferentiated from mesenchymal stem/stromal cells, which served as a source of human based species-specific "healthy" cells. MG increased ROS production and induced the first characteristic apoptotic hallmarks already at low concentrations (≥10 µM), decreased the cell growth (≥5-10 µM) and viability (≥25 µM), altered Glo-1 and Glo-2 enzymes (≥25 µM), and markedly affected the neuronal markers MAP-2 and NSE causing their loss at low MG concentrations (≥10 µM). Morphological alterations started at 100 µM, followed by even more marked effects and cell death after few hours (5 h) from 200 µM MG addition. Substantially, most effects occurred as low as 10 µM, concentration much lower than that reported from previous observations using different in vitro cell-based models (e.g., human neuroblastoma cell lines, primary animal cells, and human iPSCs). Remarkably, this low effective concentration approaches the level range measured in biological samples of pathological subjects. The use of a suitable cellular model, that is, human primary neurons, can provide an additional valuable tool, mimicking better the physiological and biochemical properties of brain cells, in order to evaluate the mechanistic basis of molecular and cellular alterations in CNS.

MAM-2201 acute administration impairs motor, sensorimotor, prepulse inhibition, and memory functions in mice: a comparison with its analogue AM-2201.

RATIONALE: 1-[(5-fluoropentyl)-1H-indol-3-yl](4-methyl-1-naphthalenyl) methanone (MAM-2201) is a potent synthetic cannabinoid receptor agonist illegally marketed in "spice" products and as "synthacaine" for its psychoactive effects. It is a naphthoyl-indole derivative which differs from its analogue 1-[(5-Fluoropentyl)-1H-indol-3-yl](1-naphthylenyl) methanone (AM-2201) by the presence of a methyl substituent on carbon 4 (C-4) of the naphthoyl moiety. Multiple cases of intoxication and impaired driving have been linked to AM-2201 and MAM-2201 consumption. OBJECTIVES: This study aims to investigate the in vitro (murine and human cannabinoid receptors) and in vivo (CD-1 male mice) pharmacodynamic activity of MAM-2201 and compare its effects with those induced by its desmethylated analogue, AM-2201. RESULTS: In vitro competition binding studies confirmed that MAM-2201 and AM-2201 possess nanomolar affinity for both CD-1 murine and human CB1 and CB2 receptors, with preference for the CB1 receptor. In agreement with the in vitro binding data, in vivo studies showed that MAM-2201 induces visual, acoustic, and tactile impairments that were fully prevented by pretreatment with CB1 receptor antagonist/partial agonist AM-251, indicating a CB1 receptor mediated mechanism of action. Administration of MAM-2201 also altered locomotor activity and PPI responses of mice, pointing out its detrimental effect on motor and sensory gating functions and confirming its potential use liability. MAM-2201 and AM-2201 also caused deficits in short- and long-term working memory. CONCLUSION: These findings point to the potential public health burden that these synthetic cannabinoids may pose, with particular emphasis on impaired driving and workplace performance.

Acute Cardiovascular and Cardiorespiratory Effects of JWH-018 in Awake and Freely Moving Mice: Mechanism of Action and Possible Antidotal Interventions?

JWH-018 is the most known compound among synthetic cannabinoids (SCs) used for their psychoactive effects. SCs-based products are responsible for several intoxications in humans. Cardiac toxicity is among the main side effects observed in emergency departments: SCs intake induces harmful effects such as hypertension, tachycardia, chest pain, arrhythmias, myocardial infarction, breathing impairment, and dyspnea. This study aims to investigate how cardio-respiratory and vascular JWH-018 (6 mg/kg) responses can be modulated by antidotes already in clinical use. The tested antidotes are amiodarone (5 mg/kg), atropine (5 mg/kg), nifedipine (1 mg/kg), and propranolol (2 mg/kg). The detection of heart rate, breath rate, arterial oxygen saturation (SpO2), and pulse distention are provided by a non-invasive apparatus (Mouse Ox Plus) in awake and freely moving CD-1 male mice. Tachyarrhythmia events are also evaluated. Results show that while all tested antidotes reduce tachycardia and tachyarrhythmic events and improve breathing functions, only atropine completely reverts the heart rate and pulse distension. These data may suggest that cardiorespiratory mechanisms of JWH-018-induced tachyarrhythmia involve sympathetic, cholinergic, and ion channel modulation. Current findings also provide valuable impetus to identify potential antidotal intervention to support physicians in the treatment of intoxicated patients in emergency clinical settings.

The Old and the New: Cardiovascular and Respiratory Alterations Induced by Acute JWH-018 Administration Compared to Δ9-THC-A Preclinical Study in Mice.

Several new psychoactive substances (NPS) are responsible for intoxication involving the cardiovascular and respiratory systems. Among NPS, synthetic cannabinoids (SCs) provoked side effects in humans characterized by tachycardia, arrhythmias, hypertension, breathing difficulty, apnoea, myocardial infarction, and cardiac arrest. Therefore, the present study investigated the cardio-respiratory (MouseOx Plus; EMKA electrocardiogram (ECG) and plethysmography TUNNEL systems) and vascular (BP-2000 systems) effects induced by 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018; 0.3-3-6 mg/kg) and Δ9-tetrahydrocannabinol (Δ9-THC; 0.3-3-6 mg/kg), administered in awake CD-1 male mice. The results showed that higher doses of JWH-018 (3-6 mg/kg) induced deep and long-lasting bradycardia, alternated with bradyarrhythmia, spaced out by sudden episodes of tachyarrhythmias (6 mg/kg), and characterized by ECG electrical parameters changes, sustained bradypnea, and systolic and transient diastolic hypertension. Otherwise, Δ9-THC provoked delayed bradycardia (minor intensity tachyarrhythmias episodes) and bradypnea, also causing a transient and mild hypertensive effect at the tested dose range. These effects were prevented by both treatment with selective CB1 (AM 251, 6 mg/kg) and CB2 (AM 630, 6 mg/kg) receptor antagonists and with the mixture of the antagonists AM 251 and AM 630, even if in a different manner. Cardio-respiratory and vascular symptoms could be induced by peripheral and central CB1 and CB2 receptors stimulation, which could lead to both sympathetic and parasympathetic systems activation. These findings may represent a starting point for necessary future studies aimed at exploring the proper antidotal therapy to be used in SCs-intoxicated patient management.

Humoral immunogenicity of COVID-19 vaccines in patients with coeliac disease and other noncoeliac enteropathies compared to healthy controls.

OBJECTIVES: Data are lacking on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients affected by coeliac disease, Whipple's disease and other noncoeliac enteropathies (NCE), characterised by primary or drug-related immunosuppression. We aimed to assess humoral response to SARS-CoV-2 vaccination in these patients compared to controls. METHODS: Between December 2021 and January 2022, IgG anti-SARS-CoV-2 spike protein antibodies were measured in serum samples of coeliac disease, Whipple's disease and NCE patients attending our gastroenterology outpatient clinic for follow-up, who had received their first SARS-CoV-2 vaccination dose 3-6-9 (±1) months prior. Humoral response was compared with healthy controls (vaccinated healthcare workers undergoing serological screening), matched for gender, age, and time from first vaccine dose at sample collection. RESULTS: A total of 120 patients [107 coeliac disease; 10 Whipple's disease; 2 common-variable immunodeficiency (CVID); 1 idiopathic villous atrophy; 77 F, 42 ± 16 years] and 240 matched controls (154 F, 43 ± 14 years) were enrolled. At 3, 6 and 9 months, humoral response in coeliac patients was not impaired compared to controls. Inadequate humoral response to vaccination was significantly more common among Whipple's disease patients than controls ( P < 0.001). Patients on immunosuppressive therapy had markedly lower IgG anti-SARS-CoV-2 antibody titres (median 14 vs. 520 BAU/mL, P < 0.001). As expected, patients with CVID showed no humoral response to vaccination. CONCLUSIONS: Humoral immunogenicity of SARS-CoV-2 vaccines was not reduced in coeliac disease patients compared to controls, although it was in Whipple's disease and CVID patients. Post-vaccination humoral response should be monitored in patients with Whipple's disease and chronic enteropathies on immunosuppressive therapy in order to schedule vaccine booster doses.

Searching for a Longevity Food, We Bump into Hericium erinaceus Primordium Rich in Ergothioneine: The "Longevity Vitamin" Improves Locomotor Performances during Aging.

Phenotypic frailty is characterized by a progressive decline in physical functioning. During ageing, morphological and functional alterations involve the brain, and chief theories involve oxidative stress, free radical accumulation, and reduced antioxidant defenses as the most implicated mechanisms. From boosting the immune system to fighting senescence, medicinal mushrooms have been found to have a number of health and longevity benefits. Among them, Hericium erinaceus (He) has been demonstrated to display a variety of physiological effects, including anti-aging properties. Thus, He represents an attractive natural source for developing novel medicines and functional foods, based on the identification of its active ingredients and metabolites. Particularly, H. erinaceus primordium (He2) extract contains a high amount of Ergothioneine (ERGO), the longevity vitamin. Herein, we revealed the preventive effect of ERGO-rich He2 extract in a preclinical model, focusing on locomotor decline during ageing monitored through spontaneous behavioral test. This effect was accompanied by a significant decrease in some oxidative stress markers (NOS2, COX2) paralleled by an increase in P53, showed in cerebellar cortex cells and fibres by immunohistochemistry. In summary, we demonstrated the neuro-protective and preventive effects of He2 extract during aging, probably due to its peculiarly high ERGO content.

Significant variations of dangerous exposures during COVID-19 pandemic in Italy: a possible association with the containment measures implemented to reduce the virus transmission.

BACKGROUND: In response to the COVID-19 health emergency, mass media widely spread guidelines to stop the virus transmission, leading to an excessive and unaware use of detergents and disinfectants. In Italy and in other countries this tendency caused a significant increase of exposures to these products in 2020. Evaluating data collected by the Italian Pavia Poison Centre (PPC), this study intends to examine the relationship between the COVID-19 lockdown and the variations of exposures to specific product categories possibly associated to the containment measures implemented. Simultaneously, this work shows the effectiveness of the European Product Categorisation System (EuPCS) in surveillance activities of dangerous chemicals. METHODS: Exposure cases managed by the PPC during March-May 2020 (lockdown) and during the same months of 2017-2018-2019 were compared. Differences in categorical variables were tested with the Chi-square test. The level of significance was set at Alpha = .05. The study included all EuPCS groups but specifically focused on cleaners, detergents, biocides and cosmetics. RESULTS: During the lockdown, calls from private citizens showed a highly significant increase (+ 11.5%, p < .001) and occupational exposures decreased (- 11.7%, p = .011). Among Cleaners, exposures to Bleaches slightly increased while Drain cleaning products went through a significant reduction (- 13.9%, p = .035). A highly significant increase of exposures to Disinfectants was observed (+ 7.7%, p = .007), particularly to those for surfaces (+ 6.8%, p = .039). Regarding Cosmetics, both handwashing soaps and gel products significantly increased (respectively: + 25.0, p = .016 and + 9.7%, p = .028). Among children 1-5 years, the statistical significance is reached with exposures to Dishwashing detergents (+ 13.1%, p = .032), handwashing soaps (+ 28.6%, p = .014) and handwashing gel products (+ 16.8%, p = .010). Contrarily, Liquid Laundry Detergent Capsules decreased in a highly significant manner (- 25%; p = .001). The general severity of exposures showed a highly significant decrease (Moderate: - 10.1%, p = .0002). CONCLUSIONS: This study investigated the relationship between the COVID-19 lockdown and the variations of exposures to some product categories related to the containment measures. The results obtained support any action to be taken by Competent Authorities to implement measures for a safer use of cleaners/disinfectants. This paper shows the benefit in applying the EuPCS to categorize products according to their intended use, though an extension of this system to products not covered by CLP Regulation may be a further advantage.

Infant Botulism: Checklist for Timely Clinical Diagnosis and New Possible Risk Factors Originated from a Case Report and Literature Review.

Infant botulism is a rare and underdiagnosed disease caused by BoNT-producing clostridia that can temporarily colonize the intestinal lumen of infants less than one year of age. The diagnosis may be challenging because of its rareness, especially in patients showing atypical presentations or concomitant coinfections. In this paper, we report the first infant botulism case associated with Cytomegalovirus coinfection and transient hypogammaglobulinemia and discuss the meaning of these associations in terms of risk factors. Intending to help physicians perform the diagnosis, we also propose a practical clinical and diagnostic criteria checklist based on the revision of the literature.

Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

The complex and constantly evolving public health threat of new psychoactive substances in Italy: addressing the main functions of a national observatory of drugs.

At the end of the 90s in Europe, the new psychoactive substances (NPS) phenomenon was limited to a small number of molecules created to mimic the actions and psychoactive effects of licensed medicines and existing drugs that are controlled by the United Nations drug conventions and therefore traded as their "legal" replacements. NPS were mostly circulating in rave parties and electronic music festivals. The globalization, the evolution of e-commerce and the growing popularity of NPS, facilitated the development of a wide illegal market in constant expansion. The dynamic nature of this phenomenon has led to an evolution in the prevention and monitoring of NPS trafficking within the European Union. The European legislative system has been amended with the aim of creating a faster and more effective regulatory system to tackle NPS diffusion and ban their sale and circulation. At the end of 2008, in compliance with the European Council Decision 2005/387/JHA, the Anti-Drug Policies Department of the Presidency of the Council of Ministers activated the National Early Warning System to promote a rapid exchange of information on NPS between Italy and the EU.

A New Platinum-Based Prodrug Candidate for Chemotherapy and Its Synergistic Effect With Hadrontherapy: Novel Strategy to Treat Glioblastoma.

Glioblastoma (GBM) is the most common tumor of the central nervous system. Current therapies, often associated with severe side effects, are inefficacious to contrast the GBM relapsing forms. In trying to overcome these drawbacks, (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(IV), also called Pt(IV)Ac-POA, has been recently synthesized. This new prodrug bearing as axial ligand (2-propynyl)octanoic acid (POA), a histone deacetylase inhibitor, has a higher activity due to (i) its high cellular accumulation by virtue of its high lipophilicity and (ii) the inhibition of histone deacetylase, which leads to the increased exposure of nuclear DNA, permitting higher platination and promoting cancer cell death. In the present study, we investigated the effects induced by Pt(IV)Ac-POA and its potential antitumor activity in human U251 glioblastoma cell line using a battery of complementary techniques, i.e., flow cytometry, immunocytochemistry, TEM, and Western blotting analyses. In addition, the synergistic effect of Pt(IV)Ac-POA associated with the innovative oncological hadrontherapy with carbon ions was investigated, with the aim to identify the most efficient anticancer treatment combination. Our in vitro data demonstrated that Pt(IV)Ac-POA is able to induce cell death, through different pathways, at concentrations lower than those tested for other platinum analogs. In particular, an enduring Pt(IV)Ac-POA antitumor effect, persisting in long-term treatment, was demonstrated. Interestingly, this effect was further amplified by the combined exposure to carbon ion radiation. In conclusion, Pt(IV)Ac-POA represents a promising prodrug to be incorporated into the treatment regimen for GBM. Moreover, the synergistic efficacy of the combined protocol using chemotherapeutic Pt(IV)Ac-POA followed by carbon ion radiation may represent a promising approach, which may overcome some typical limitations of conventional therapeutic protocols for GBM treatment.

Prevalence of Stimulant, Hallucinogen, and Dissociative Substances Detected in Biological Samples of NPS-Intoxicated Patients in Italy.

A number of new psychoactive substances (NPS) have been released in the last decade, and the list of NPS continues to grow. This paper reports a retrospective evaluation of the toxicological analyses in 1,445 suspected intoxication cases by psychostimulant, hallucinogen, and dissociative NPS occurring in hospitals across Italy from 2011 to 2019. The objectives of the study were to contribute to the monitoring of the NPS diffusion based on analytically confirmed intoxications, and to evaluate the importance of the clinical toxicological laboratory in the diagnosis of NPS intoxication. For at least one NPS of the considered classes, 246 patients (17.0%) tested positive. Forty-four different NPS were detected and a consistent turnover was observed during the nine-year period, especially regarding cathinones. Among the positive cases, 47.2% tested positive for dissociative NPS, with particular regard to ketamine. Hallucinogens (30.9%) was the second most frequent NPS involved. Stimulants were found in 20% of the positive cases with a considerable presence of cathinones. Findings confirm the dynamism of the NPS phenomenon, underline the importance of awareness of this new public health threat among health care professionals, and highlight the need for analytical confirmation for the identification of the drugs in forensic contexts.

Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?

In the last decades, increasing evidence has revealed that a large number of channel protein and ion pumps exhibit impaired expression in cancers. This dysregulation is responsible for high proliferative rates as well as migration and invasiveness, reflected in the recently coined term oncochannelopathies. In glioblastoma (GBM), the most invasive and aggressive primary brain tumor, GBM cells modify their ionic equilibrium in order to change their volume as a necessary step prior to migration. This mechanism involves increased expression of BK channels and downregulation of the normally widespread Kir4.1 channels, as noted in GBM biopsies from patients. Despite a large body of work implicating BK channels in migration in response to an artificial intracellular calcium rise, little is known about how this channel acts in GBM cells at resting membrane potential (RMP), as compared to other channels that are constitutively open, such as Kir4.1. In this review we propose that a residual fraction of functionally active Kir4.1 channels mediates a small, but continuous, efflux of potassium at the more depolarized RMP of GBM cells. In addition, coinciding with transient membrane deformation and the intracellular rise in calcium concentration, brief activity of BK channels can induce massive and rapid cytosolic water loss that reduces cell volume (cell shrinkage), a necessary step for migration within the brain parenchyma.