The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8 T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Case series Patients: Male, 29-year-old • Male, 37-year-old Final Diagnosis: Noncardiogenic pulmonary edema Symptoms: Dyspnea Medication: — Clinical Procedure: — Specialty: Critical Care Medicine • Pulmonology Objective: Challenging differential diagnosis Background: Naloxone remains the mainstay for the treatment of opioids overdose both in the clinical and public settings. Naloxone has been showing relative safety, leading to trivial adverdse effects which are mostly due to acute withdrawal effects, but when used in patients with known long-term addiction, it usually requires additional dosing or rapid infusion to achieve detoxification effects in a timely manner or to sustain the effects after they fade away. In some patients this has resulted in fatal adverse effects, including non-cardiogenic pulmonary edema (NCPE), which may require intensive care for those patients. Whether the higher dose is the cause has been debatable and not enough studies have looked into this subject. Case Reports: Here, we report a series of 2 cases where 2 young patients were given naloxone following opioid overdose. Both our patients required frequent dosing due to insufficient response or owing to the washout of the naloxone effect shortly after, given its short half-life. Although the administered doses were different, both patients developed the adverse effect of NCPE and required ventilator support. Conclusions: Evidence suggests that such a catastrophic adverse effect following the administration of such a critical medication, which is known to be relatively safe and is being publicized for saving lives, might limit its use and would require more attention and further studies to standardize a safe dose, limiting these life-threatening events and decreasing the need for unnecessary invasive respiratory support as well as admissions to intensive care units, which might create an additional burden on the health care system.
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