Unusual case of intra-arterial doxorubicin chemoembolization-associated posterior reversible encephalopathy syndrome.

A 63-year-old white female with a history of metastatic breast cancer to the liver developed acute-onset nausea, vomiting, mental status change, and generalized seizures following transarterial chemoembolization using doxorubicin. The patient was hospitalized with the above symptoms immediately following transarterial chemoembolization using drug eluting bead doxorubicin into the right hepatic artery. The patient developed intractable nausea, vomiting, and abdominal pain and had a generalized tonic-clonic seizure lasting for 40 seconds, approximately 24 hours after the procedure. The patient was confused and lethargic for 2 days with progressive improvement in her mental status. Her neurological examination showed encephalopathy with disorientation to time, place or person, and she also had a glassy look. Cranial nerves were normal other than lack of response to threat stimulus bilaterally; motor and sensory examination was unremarkable. Initial blood pressure was 130/90 mm Hg and routine chemistry and complete blood count on admission were within normal limits. The cerebrospinal fluid analysis showed clear and colorless fluid with glucose of 56 mg/dL, protein of 42 mg/dL, white blood cells of 2/µL, and red blood cells of 10/µL and did not show any evidence of infectious or toxic etiology on encephalopathy. Continuous electro encephalography showed diffuse slowing but no epileptiform discharges. The magnetic resonance imaging (MRI) revealed increased signal intensity in the bilateral parieto-occipital area, right more than the left, on fluid-attenuated inversion recovery, apparent diffusion coefficient, and T2-weighted imaging, with no increased signal on diffusion weighted image consistent with vasogenic edema. The patient's symptoms and MRI findings were consistent with diagnosis of posterior reversible encephalopathy syndrome. Resolution of the MRI changes is noted on the follow-up imaging 8 weeks later. Posterior reversible encephalopathy syndrome in this case is most likely related to intra-arterial doxorubicin infusion because of the temporal association between administration, symptom onset, and MRI changes.

Extrapyramidal symptoms with concomitant use of amitriptyline and amiodarone in an elderly patient.

BACKGROUND: Amitriptyline is a tricyclic antidepressant useful for the treatment of depression. Amiodarone is a class III antiarrhythmic agent used for the treatment of cardiac dysrhythmias. OBJECTIVE: The objective of the current report is to describe the case of a previously asymptomatic patient receiving amitriptyline who developed extrapyramidal symptoms within 1 month of initiating concomitant treatment with amiodarone for atrial fibrillation. CASE SUMMARY: An 82-year-old, right-handed, white woman was brought to the medical center's emergency department with speech difficulty suggesting stroke. She was noted to have continuous orobuccal dyskinesias, upper and lower extremity shaking, and dry mouth. Once it was determined that no other focal neurologic findings indicated stroke, her medications were reviewed. The patient had been taking amitriptyline 50 mg/d for the past year for insomnia without any adverse events. However, 1 month before presentation, she also initiated treatment with amiodarone 200 mg/d for atrial fibrillation and had developed the symptoms of concern shortly thereafter. The patient's amitriptyline treatment was discontinued and she received benzotropine for extrapyramidal symptoms from amitriptyline toxicity. She experienced complete resolution of dysarthric speech and limb shaking within 2 days. A total score of 7 was achieved using Naranjo's adverse drug reaction causality algorithm, suggesting amitriptyline was a probable cause of these adverse events. CONCLUSION: This was a probable case of extrapyramidal symptoms in an elderly woman who began using amiodarone while also taking amitriptyline.

Calmodulin binding to cellular FLICE-like inhibitory protein modulates Fas-induced signalling.

We and others have demonstrated that Fas-mediated apoptosis is a potential therapeutic target for cholangiocarcinoma. Previously, we reported that CaM (calmodulin) antagonists induced apoptosis in cholangiocarcinoma cells through Fas-related mechanisms. Further, we identified a direct interaction between CaM and Fas with recruitment of CaM into the Fas-mediated DISC (death-inducing signalling complex), suggesting a novel role for CaM in Fas signalling. Therefore we characterized the interaction of CaM with proteins recruited into the Fas-mediated DISC, including FADD (Fas-associated death domain)-containing protein, caspase 8 and c-FLIP {cellular FLICE [FADD (Fas-associated death domain)-like interleukin 1beta-converting enzyme]-like inhibitory protein}. A Ca(2+)-dependent direct interaction between CaM and FLIP(L), but not FADD or caspase 8, was demonstrated. Furthermore, a 37.3+/-5.7% increase (n=6, P=0.001) in CaM-FLIP binding was observed at 30 min after Fas stimulation, which returned to the baseline after 60 min and correlated with a Fas-induced increase in intracellular Ca(2+) that reached a peak at 30 min and decreased gradually over 60 min in cholangiocarcinoma cells. A CaM antagonist, TFP (trifluoperazine), inhibited the Fas-induced increase in CaM-FLIP binding concurrent with inhibition of ERK (extracellular-signal-regulated kinase) phosphorylation, a downstream signal of FLIP. Direct binding between CaM and FLIP(L) was demonstrated using recombinant proteins, and a CaM-binding region was identified in amino acids 197-213 of FLIP(L). Compared with overexpression of wild-type FLIP(L) that resulted in decreased spontaneous as well as Fas-induced apoptosis, mutant FLIP(L) with deletion of the CaM-binding region resulted in increased spontaneous and Fas-induced apoptosis in cholangiocarcinoma cells. Understanding the biology of CaM-FLIP binding may provide new therapeutic targets for cholangiocarcinoma and possibly other cancers.