MAM-2201, One of the Most Potent-Naphthoyl Indole Derivative-Synthetic Cannabinoids, Exerts Toxic Effects on Human Cell-Based Models of Neurons and Astrocytes.

Considering the consequences on human health, in general population and workplace, associated with the use of new psychoactive substances and their continuous placing on the market, novel in vitro models for neurotoxicology research, applying human-derived CNS cells, may provide a means to understand the mechanistic basis of molecular and cellular alterations in brain. Cytotoxic effects of MAM-2201, a potent-naphthoyl indole derivative-synthetic cannabinoid, have been evaluated applying a panel of human cell-based models of neurons and astrocytes, testing different concentrations (1-30 µM) and exposure times (3-24-48 h). MAM-2201 induced toxicity in primary neuron-like cells (hNLCs), obtained from transdifferentiation of mesenchymal stem cells derived from human umbilical cord. Effects occurred in a concentration- and time-dependent manner. The lowest concentration affecting cell viability, metabolic function, apoptosis, morphology, and neuronal markers (MAP-2, NSE) was 5 µM, and even 1 µM induced apoptosis. Effects appeared early (3 h) and persisted after 24 and 48 h. Similar behavior was evidenced for human D384-astrocytes treated with MAM-2201. Differently, human SH-SY5Y-neurons, both differentiated and undifferentiated, were not sensitive to MAM-2201. On D384, the different altered endpoints were reversed, attenuated, or not antagonized by AM251 indicating that CB1 receptors may partially mediate MAM-2201-induced cytotoxicity. While in hNLCs, all toxic effects caused by MAM-2201 were apparently unrelated to CB-receptors since they were not evidenced by immunofluorescence. The present in vitro findings demonstrate the cytotoxicity of MAM-2201 on human primary neurons (hNLCs) and astrocytes cell line (D384), and support the use of these cellular models as species-specific in vitro tools suitable to clarify the neurotoxicity mechanisms of synthetic cannabinoids.

Bowel perforation due to methotrexate therapeutic error: an insidious adverse reaction.

OBJECTIVE: Methotrexate (MTX) is widely used in the treatment of rheumatic and non-rheumatic disorders. Severe adverse effects are often associated with therapeutic errors, such as daily intake rather than weekly intake. Among them, the risk of bowel perforation is extremely rare (0.1%). We describe a case of bowel perforation, occurred following daily intake of MTX. CASE REPORT: A 68-year-old man was prescribed to take MTX 7,5 mg orally once a week, while waiting for switch to abatacept for a recent reactivation of rheumatoid arthritis. After 10 days he started having pharyngodynia, hematochezia and general malaise. At medical examination he presented oral and nasal mucositis; moreover, blood exams showed thrombocytopenia. The anamnesis revealed that he had been taken the prescribed dosage of MTX daily, instead of weekly. Therapy with Lederfolin 1000 mg (mg/m²/die) and urine alkalinization started. After 7 days of hospitalization, there was an abrupt worsening of clinical conditions and an emergency CT scan revealed millimetric gas bubbles indicating bowel perforation. The patient underwent an emergency exploratory laparotomy that resulted in peritoneal toilette and sigma resections. Anatomopathological findings were suggestive of MTX poisoning. CONCLUSIONS: The patient was discharged on the 17th day in good clinical condition.