Bioreductive prodrugs as cancer therapeutics: targeting tumor hypoxia / 癌症

Hypoxia, a state of low oxygen, is a common feature of solid tumors and is associated with disease progression as well as resistance to radiotherapy and certain chemotherapeutic drugs. Hypoxic regions in tumors, therefore, represent attractive targets for cancer therapy. To date, five distinct classes of bioreactive prodrugs have been developed to target hypoxic cells in solid tumors. These hypoxia-activated prodrugs, including nitro compounds, N-oxides, quinones, and metal complexes, generally share a common mechanism of activation whereby they are reduced by intracellular oxidoreductases in an oxygen-sensitive manner to form cytotoxins. Several examples including PR-104, TH-302, and EO9 are currently undergoing phase II and phase III clinical evaluation. In this review, we discuss the nature of tumor hypoxia as a therapeutic target, focusing on the development of bioreductive prodrugs. We also describe the current knowledge of how each prodrug class is activated and detail the clinical progress of leading examples.

Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Acute gout is an intensely painful, inflammatory arthritis. Although the non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for this condition, the efficacy is based on only a few studies, particularly in China. We tried to assess the safety and efficacy of etoricoxib in the treatment of acute gouty arthritis in China.</p><p><b>METHODS</b>A randomized, double-blind, active comparator study was conducted at 10 sites in China. Patients (n = 178; ≥ 18 years of age) with acute gouty attack (< 48 hours) were treated for 5 days with etoricoxib (120 mg/d; n = 89) or indometacin (75 mg twice daily; n = 89). The primary efficacy end point was self-assessed pain in the affected joint (0-4 point Likert scale) from days 2 - 5. Secondary end points included investigator assessments of tenderness and swelling, patient/ investigator global assessments of response to therapy, and patients discontinuing treatment. Safety was assessed by adverse events (AEs).</p><p><b>RESULTS</b>Etoricoxib and indometacin had comparable primary and secondary end points. Mean change difference from baseline from days 2 - 5 was 0.03 (95% confidence interval (CI) -0.19 to 0.25; P = 0.6364), which fell within the prespecified comparative bounds of -0.5 to 0.5. No severe AEs were associated with etoricoxib use. Non-severe AEs were mainly digestive and general, and most (73.7%) were mild, although they caused withdrawal of two subjects in the etoricoxib group, due to bilateral renal calculi and uronephrosis of the left kidney (unrelated to etoricoxib) and fever and chills (potentially etoricoxib-related). Overall, AEs were similar, although the absolute number of AEs in the etoricoxib group (n = 31) was less than the indometacin group (n = 34).</p><p><b>CONCLUSIONS</b>Etoricoxib (120 mg once daily) is effective in treating acute gout, is generally safe and well-tolerated, and is comparable in efficacy to indometacin (75 mg twice daily).</p>

Evaluation of efficacy and safety of diacerein in knee osteoarthritis in Chinese patients / 中国医学科学杂志(英文版)

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of diacerein in patients with knee osteoarthritis (OA).</p><p><b>METHODS</b>A total of 223 patients satisfying the American College of Rheumatology criteria for knee OA were chosen for this 17-week, randomized, double-dummy, diclofenac sodium-controlled trial, with diacerein dosage of 100 mg/d and diclofenac sodium of 75mg/d. Efficacy and safety of both drugs were evaluated.</p><p><b>RESULTS</b>Totally 106 patients in the diacerein group and 107 patients in the diclofenac group were considered qualified for the evaluation. After 12 weeks of treatment, the total effective rates of patients/physicians' overall assessment in diacerein and diclofenac groups were 65.4%/61.6% and 61.2%/61.2%, respectively (P > 0.05). The primary efficacy parameter [visual analog scale (VAS) assessment of pain on 20 metres walking] and the secondary efficacy parameters [tenderness on palpation, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and 36-item Short-Form (SF-36) Health Survey] significantly improved compared with baseline in both groups (P < 0.05). In the follow-up period, there were no obvious changes in above parameters in diacerein group. However, in diclofenac group, pain on 20 metres walking, tenderness on palpation, and WOMAC became aggravated after withdrawing the drug for 4 weeks (P < 0.05). Moreover, the consumption of paracetamol was significantly lower in diacerein group than in diclofenac group during follow-up (P < 0. 001). The incidences of related adverse events were 35.7% in diacerein and 45.1% in diclofenac group, respectively. Mild-to-moderate gastrointestinal disorders were the most frequent adverse events.</p><p><b>CONCLUSIONS</b>Diacerein is as effective as diclofenac sodium in treating patients with knee OA. Furthermore, it has better extended effect and a good safety profile. It is generally well tolerated and has no severe adverse effect.</p>

Adult-onset Still's disease and acute severe hepatic lesion / 中华风湿病学杂志

1000 IU/L,TBil 40～250 mg/L,and mild liver dysfunction at beginning of the disease,but acute severe hepatic lesion occurred due to the use of antibiotics,immunodepressant or NSAIDs.Three patients developed liver function failure and died,7 patients' liver function recovered to nor- mal by increasing dosage of glucocorticoid.Conclusion AOSD with mild liver dysfunction is frequently en- countered.During the treatment,acute severe hepatic lesion may occur due to certain drugs.Therefore,any drug used in AOSD with mild liver dysfunction should be cautious.Once acute severe hepatic lesion happens, increases the dosage of glucocorticoid promptly can improve prognosis.