A clinically relevant combination treatment with doxorubicin and cyclophosphamide does not induce hepatotoxicity in C57BL/6J mice.

BACKGROUND AND AIM: Chronic exposure to chemotherapeutics can lead to severe adverse events including hepatotoxicity. A combination chemotherapy regimen of doxorubicin (DOX) and cyclophosphamide (CPS) is employed in treatment of several cancers such as leukemia, lymphoma, and breast cancer. It is not well understood whether a combination therapy of DOX and CPS can induce hepatotoxicity. We therefore sought to determine whether co-administration of DOX and CPS at their clinically relevant doses and frequency results in hepatotoxicity. METHODS: Male C57BL/6J mice received one intraperitoneal injection of saline or DOX-2mg /kg and CPS-50mg/kg once a week for 4 weeks. After the treatment period, liver histology and various serum biomarkers of hepatotoxicity were assessed. RESULTS: Co-treatment of DOX and CPS did not alter the serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, globulin, or total protein. Similarly, co-administration of DOX and CPS did not result in a noticeable change in liver histology. However, it was notable that the concomitant treatment with DOX and CPS resulted in a significant increase in serum levels of aspartate aminotransferase (AST). Elevated serum AST levels were also associated with increased serum creatinine kinase (CK) levels, suggesting that the elevated serum AST levels are likely due to muscle injury following the co-administration of DOX and CPS. CONCLUSION: Taken together, our results, for the first time, suggest that co-administration of DOX and CPS, at their clinically relevant doses and frequency does not induce a significant hepatotoxicity in the mice.

Oroxylum indicum extract, at a physiologically relevant dosage, does not induce hepatotoxicity in C57BL/6J mice.

BACKGROUND: Botanical supplements have been proven to provide beneficial health effects. However, they can induce unintended adverse events such as hepatotoxicity. Oroxylum indicum extract (OIE, Sabroxy®) has several health benefits including anti-inflammatory, anti-arthritic, antifungal, antibacterial, and neuroprotective effects. It is currently unknown whether OIE has the potential to induce hepatotoxicity. PURPOSE: In the current study, we sought to determine whether OIE can induce hepatotoxicity in C57BL/6J mouse model. METHODS: The male mice were fed powdered rodent food (control group) or powdered rodent food mixed with OIE (Sabroxy®, 500mg/kg) daily for 4 weeks. Following the treatment, we assessed liver histology and serum levels of biomarkers commonly associated with liver damage, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). RESULTS: No significant alterations were observed in liver histology, and serum levels of ALT, AST, ALP, bilirubin, albumin, globulin and total protein in the OIE fed mice compared to the control mice. CONCLUSION: Taken together, our results suggest that OIE, when fed at its physiologically relevant dosage, does not induce hepatotoxicity in C57BL/6J mice.

Predictable hematological markers associated with cognitive decline in valid rodent models of cognitive impairment.

Endogenous (hyperglycemia) and exogenous (therapeutic, prophylactic, street drugs) factors can considerably contribute to cognitive impairment (CI). Currently, there are few invasive and/or noninvasive markers that correlate with CI and those that do exist require expensive or invasive techniques to predict and accurately measure the cognitive decline. Therefore, we sought to determine hematological markers as predictors of CI in two different chemically induced valid rodent models of CI (streptozotocin induced hyperglycemic model and chemotherapy [doxorubicin/cyclophosphamide] treated rodent model). Hematological markers were analyzed in the above rodent models of CI CI and compared to their respective control groups. There was a significant increase in creatinine kinase, lactate dehydrogenase and aspartate aminotransferase (AST) in the chemotherapy group. Blood urea nitrogen (BUN), alkaline phosphatase (ALP), bilirubin, creatinine and glucose levels were significantly increased in the streptozotocin group. Interestingly, triglycerides were significantly elevated in both the streptozotocin and chemotherapy groups. Previous studies with human subjects have shown a potential link between the increase in triglyceride levels and CI. Likewise, our data indicate a notable correlation with an increase in triglycerides to cognitive impairment in the rodent models. This suggests elevated levels of triglycerides could prove to be a potential noninvasive hematological marker for the increased risk of CI. Further studies are warranted to determine the causal relationship between elevated triglyceride levels and CI.

A randomized phase II trial of first-line treatment with gemcitabine, erlotinib, or gemcitabine and erlotinib in elderly patients (age ≥70 years) with stage IIIB/IV non-small cell lung cancer.

INTRODUCTION: Single-agent gemcitabine is a standard of care for elderly patients with advanced non-small cell lung cancer, but novel therapies are needed for this patient population. METHODS: We performed a noncomparative randomized phase II trial of gemcitabine, erlotinib, or the combination in elderly patients (age ≥70 years) with stage IIIB or IV non-small cell lung cancer. Patients were randomized to arms: A (gemcitabine 1200 mg/m on days 1 and 8 every 21 days), B (erlotinib 150 mg daily), or C (gemcitabine 1000 mg/m on days 1 and 8 every 21 days and erlotinib 100 mg daily). Arms B and C were considered investigational; the primary objective was 6-month progression-free survival. RESULTS: Between March 2006 and May 2010, 146 eligible patients received protocol therapy. The majority of the patients (82%) had stage IV disease, 64% reported adenocarcinoma histology, 90% reported current or previous tobacco use, and 28% had a performance status of 2. The 6-month progression-free survival rate observed in arms A, B, and C was 22% (95% confidence interval [CI] 11-35), 24% (95% CI 13-36), and 25% (95% CI 15-38), respectively; the median overall survival observed was 6.8 months (95% CI 4.8-8.5), 5.8 months (95% CI 3.0-8.3), and 5.6 months (95% CI 3.5-8.4), respectively. The rate of grade ≥3 hematological and nonhematological toxicity observed was similar in all three arms. The best overall health-related quality of life response did not differ between treatment arms. CONCLUSIONS: Erlotinib or erlotinib and gemcitabine do not warrant further investigation in an unselected elderly patient population.

Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis.

This study examined the prognostic value of circulating peripheral blood plasma cells (PBPCs) in patients with primary systemic amyloidosis (AL). A sensitive slide-based immunofluorescence technique was used to assess 147 patients for circulating PBPCs. Circulating monoclonal plasma cells were quantified as a percentage of circulating cytoplasmic immunoglobulin-positive cells (PBPC%). The absolute circulating plasma cell count was also determined. When analyzed retrospectively, 24 (16%) of 147 patients were found to have detectable circulating PBPCs. Overall survival for patients with high PBPC%'s (> 1%) was poorer (median survival, 10 vs 29 months; P =.002). Similarly, overall survival for patients with high PBPC counts (> 0.5 x 10(6)/L) was significantly poorer (median, 13 vs 31 months; P =.003). Increased percentages of bone marrow plasma cells (BMPC%; P =.0004), increased levels of serum beta(2)-microglobulin (P =.04), and dominant cardiac amyloid involvement (P =.03) also predicted poorer survival. The combined consideration of circulating PBPCs and BMPC% identified low-, intermediate-, and high-risk groups with median survivals of 37.5, 15.5, and 10 months, respectively (P =.0003). Multivariate analysis revealed circulating PBPCs and BMPC% to be independent prognostic factors for survival. Patients with PBPC%'s of 2% or higher were significantly more likely to have a coexisting clinical diagnosis of multiple myeloma (50% vs 12%, P =.008). The prognostic value of circulating PBPCs may help select treatment for patients with AL.