Acute pancreatitis in a patient treated with imatinib and gefitinib

Introduction Use of oral antineoplastic agents (OAAs) has increased significantly in recent years. OAAs currently represent 30-50% of all cancer treatments. Drug interactions are the most frequent drug-related problem affecting OAAs. We describe the case of a patient who presented acute pancreatitis, possibly induced by the concomitant use of imatinib and gefitinib. Case report A female patient received imatinib and gefitinib for the treatment of chronic myeloid leukemia and lung adenocarcinoma, respectively. Liver function and pancreatic enzyme values gradually worsened after initiation of imatinib, and the patient was diagnosed with acute pancreatitis. Management and outcomes Imatinib was discontinued owing to pancreatic toxicity. Gefitinib was subsequently discontinued owing to tumor progression. The patient received supportive measures for pancreatitis, although she eventually died 3 months after the onset of symptoms. Discussion To our knowledge, this is the first case in the medical literature of acute pancreatitis possibly induced by an interaction between imatinib and gefitinib. The interaction most likely arose because imatinib is a CYP2D6 inhibitor and could therefore impair the metabolism of gefitinib (a CYP2D6 substrate) and increase its serum concentration. This interaction is extremely rare. However, due to its severity, hepatic and pancreatic function should be carefully monitored in patients treated with imatinib and/or gefitinib and other inhibitors or inducers of CYP2D6 and CYP3A4.

Targeting the kinase insert loop of PERK selectively modulates PERK signaling without systemic toxicity in mice

Chronic activation of the unfolded protein response (UPR), notably the branch comprising the kinase PERK and the translation initiation factor eIF2α, is a pathological feature of many neurodegenerative diseases caused by protein misfolding. Partial reduction of UPR signaling at the level of phosphorylated eIF2α is neuroprotective and avoids the pancreatic toxicity caused by full inhibition of PERK kinase activity. However, other stress pathways besides the UPR converge on phosphorylated eIF2α in the integrated stress response (ISR), which is critical to normal cellular function. We explored whether partial inhibition of PERK signaling may be a better therapeutic option. PERK-mediated phosphorylation of eIF2α requires its binding to the insert loop within PERK’s kinase domain, which is, itself, phosphorylated at multiple sites. We found that, as expected, Akt mediates the phosphorylation of Thr799 in PERK. This phosphorylation event reduced eIF2α binding to PERK and selectively attenuated downstream signaling independently of PERK activity and the broader ISR. Induction of Thr799 phosphorylation with a small-molecule activator of Akt similarly reduced PERK signaling and increased both neuronal and animal survival without measurable pancreatic toxicity in a mouse model of prion disease. Thus, promoting PERK phosphorylation at Thr799 to partially down-regulate PERK-eIF2α signaling while avoiding widespread ISR inhibition may be a safe therapeutic approach in neurodegenerative disease.

Characterisation and Anti-diabetic Activity of Phenylquinoline, and Narceine Isolated from Ficus polita Leaf

The present study was conducted to evaluate anti-diabetic potentials of column chromatography fractions (F1-F6) of chloroform leaf extract of Ficus polita and to detect the probable bioactive compounds present in the most active fraction using spectroscopic techniques. Antidiabetic potential of the fractions (F1-F6) were tested at a dose of 50 mg/kg on wistar rats. Fraction 3 and metformin treated diabetic groups showed significant decreases in fasting blood glucose (FBS) level, ameliorate hepatic and renal damages by decreasing the levels of serum total bilirubin, direct bilirubin AST, ALT, creatinine, urea, potassium and chloride, but increasing the levels of serum total protein, albumin, sodium, and bicarbonate compared to untreated diabetic rats. Fraction 3 also stimulates insulin secretion by β cells. After alloxan administration, the levels of hepatic and renal tissues antioxidant markers such as GSH, SOD and catalase were decreased whereas the level of hepatic and renal tissues MDA was elevated. The levels of these antioxidant markers were brought to normalcy by fraction 3 (F3). Histological studies of the pancreas supported the biochemical findings, and treatment with fraction 3 (F3) was found to be effective in restoring alloxan-induced pancreatic toxicity in rats. FTIR and GCMS and analyses were conducted for the detection of bioactive compound(s) in fraction 3 (F3) and the result revealed the presence of "8-methoxy-4-phenylquinoline and narceine The study concludes that; the anti-diabetic property of the leaf of Ficus polita is mediated by the bioactive compounds " 8-methoxy-4-phenylquinoline, and narceine." through their antioxidant properties and stimulation of damaged pancreas to produce more insulin.

Improving the Reliability and Utility of Streptozotocin-Induced Rat Diabetic Model

The Streptozotocin- (STZ-) induced diabetic model is widely used; however, unexplained acute toxicity has given the model an unreliable reputation. To improve the reliability and utility of this model, we characterize the age dependence of STZ toxicity and introduce novel endpoints to assess diabetic complications and reveal possible mechanisms for diabetic development. Diabetes was induced by STZ injection into male, 6 to 23 weeks old, Sprague-Dawley rats. Their metabolic (glucose, lipids, and hormones), inflammatory (cytokines), histologic and behavioral endpoints were observed for 1.2 years. Analgesic compounds were assessed for efficacy treating neuropathy. Acute mortality, within a week of STZ injection (50–65 mg/kg i.v.), was inversely correlated to animal age. Only 3% of rats, age 6–11 weeks, died in the week following STZ injection, whereas 83% of rats 12 to 17 weeks old and 91% of rats 18 weeks or older died in the same week. Partial model recovery (normalized insulin, glucose and food/water intake) was observed starting at week 36; however, pain scores, kidney enlargement, and cataract formation continued to show progression consistent with the diabetic state. Unique noninvasive observational measurements, such as haircoat quality and diarrhea scores, served as useful endpoints for this model. The increased plasma cytokines (such as TNF-α, IL-4, and IL-6) and inflammatory cell infiltration into the pancreatic islets are strong evidence of inflammation in the STZ-induced diabetic model. Pancreatic tissue staining revealed total islet area reduction and confirmed STZ-specific pancreatic toxicity; however, the β-cell density per area in pancreatic islets and insulin levels statistically increased over time in the diabetic rats, suggesting a mechanism for partial recovery of diabetic symptoms. Voltage-gated sodium channel (NaV1.7 specific, peripherally restricted) blocker, CC4148, inhibited neuropathy without side effects as compared to a nonspecific sodium channel inhibitor, Mexiletine, or GABA analog, Pregabalin, which inhibited neuropathy with side effects.

ANALYSIS OF HEMATOLOGIC, HEPATIC AND PANCREATIC TOXICITY DURING NEOADJUVANT CHEMORADIOTHERAPY IN PATIENTS WITH LOCALLY ADVANCED GASTRIC CANCER

Purpose.We analyzed the frequency and severity of hematologic, hepatic and pancreatic toxicity during and after completion of neoadjuvant chemoradiotherapy in patients with gastric cancer.Material and methods. Phase II clinical trial was conducted to evaluate the efficacy of the combined modality treatment including neoadjuvant chemoradiotherapy followed by D2 gastrectomy for patients with locally advanced gastric cancer. The main inclusion criteria were: histologically verified gastric cancer, cT3-4N0, cT2-4N1-3; M0. Before starting neoadjuvant therapy, all patients underwent thoracic and abdominal CT and laparoscopy to exclude peritoneal carcinomatosis. A total dose of radiation therapy was 45 Gy (1 + 1.5 Gy/fraction/day with a 4–5 hour interval) concurrently with the modified CAPOX chemotherapy regimen. Gastrectomy or subtotal resection of the stomach was planned 4-6 weeks after the completion of chemoradiotherapy. The toxicity assessment of neoadjuvant chemoradiotherapy was performed using the NCI CTC scale, version 3.0. The assessment of hematological, hepatic and pancreatic toxicities was done.Results.Among the toxicity during and after completion of neoadjuvant chemoradiotherapy, thrombocytopenia, neutropenia and leukopenia (grade 1–2) were the most common, requiring no additional symptomatic therapy. Radiation therapy was completed in 45 (98 %) patients. Chemotherapy was completed in 42 (91 %) patients. The median time between the completion of chemoradiotherapy and surgery was 44 days. Surgery following chemoradiotherapy was performed in 100 % of patients, including R0 resection in 93 % of patients.Conclusion.Preoperative chemoradiotherapy was well tolerated by patients, could be completed in most cases and did not prevent subsequent surgical treatment.