Clinical toxicity associated with tiazofurin

Summary Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23–36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity ( grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity.     

N-CAM promotes recovery in injured nerves

The neural cell adhesion molecule, N-CAM, makes critical contributions to the development of the nervous system. It mediates the stability of homophilic adhesion in embryonic neurons and participates in morphologic differentiation. The goal of these studies was to determine N-CAM contributions to nerve regeneration and recovery of function in two species with an excised segment of sciatic nerve. N-CAM was isolated from embryonic brains, affinity purified and admixed in collagen gel for administration. Recovery was compared 30 days after surgery for two types of N-CAM delivery: entubulization versus direct application. For control nerves, tubes contained gel only. In preliminary chicken studies, latency of nerve responses was measured to demonstrate N-CAM's ability to improve upon spontaneous recovery. In subsequent studies of rodent nerves, the direct application of N-CAM significantly improved recovery in evoked nerve response amplitude, number of regenerated axons and behavioral activity. Results demonstrate N-CAM's ability to augment nerve regeneration and suggest a potential for therapeutic use.     

Levels of messenger-RNA coding for DNA topoisomerase-ii isoforms do not correlate with in-vitro drug-sensitivity

The relationship between cellular levels of mRNA coding for DNA topoisomerase II, both the alpha and beta isoforms, and in vitro sensitivity to anticancer drugs were evaluated. Using a sensitive RNA-polymerase chain reaction technique, the levels of mRNA coding for the alpha and beta isoforms of topoisomerase II were estimated relative to beta-actin mRNA. A relatively narrow range of expression was observed across a broad range of approximately 60 human tumor cell lines representing eight major histological types which have been characterized in detail with respect to their in vitro sensitivity to standard anticancer drugs. No significant correlations were observed between mRNA level and cellular response to drugs thought to inhibit topoisomerase II or any of the other drugs studied. These results suggest that predictive tests for response to topoisomerase II-related drugs can not be based on estimation of levels of mRNA.     

Physiologic Monitoring of Circulatory Dysfunction in Patients with Severe Head Injuries

RID=" ID=" <E5>Correspondence to:</E5> G.C. Velmahos, M.D., Ph.D.     

Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea

OBJECTIVE: To evaluate the impact of zinc supplementation on the clinical course, stool weight, duration of diarrhoea, changes in serum zinc, and body weight gain of children with acute diarrhoea. DESIGN: Randomised double blind controlled trial. Children were assigned to receive zinc (20 mg elemental zinc per day) containing multivitamins or control group (zinc-free multivitamins) daily in three divided doses for two weeks. SETTING: A diarrhoeal disease hospital in Dhaka, Bangladesh. PATIENTS: 111 children, 3 to 24 months old, below 76% median weight for age of the National Center for Health Statistics standard with acute diarrhoea. Children with severe infection and/or oedema were excluded. MAIN OUTCOME MEASURES: Total diarrhoeal stool output, duration of diarrhoea, rate of weight gain, and changes in serum zinc levels after supplementation. RESULTS: Stool output was 28% less and duration 14% shorter in the zinc supplemented group than placebo (p = 0.06). There were reductions in median total diarrhoeal stool output among zinc supplemented subjects who were shorter (less than 95% height for age), 239 v 326 g/kg (p < 0.04), and who had a lower initial serum zinc (< 14 mmol/l), 279 v 329 g/kg (p < 0.05); a shortening of mean time to recovery occurred (4.7 v 6.2 days, p < 0.04) in those with lower serum zinc. There was an increase in mean serum zinc in the zinc supplemented group (+2.4 v -0.3 mumol/l, p < 0.001) during two weeks of supplementation, and better mean weight gain (120 v 30 g, p < 0.03) at the time of discharge from hospital. CONCLUSIONS: Zinc supplementation is a simple, acceptable, and affordable strategy which should be considered in the management of acute diarrhoea and in prevention of growth faltering in children specially those who are malnourished.     

Approach to the management of complex hepatic injuries

BACKGROUND: Complex hepatic injuries American Association for the Surgery of Trauma Organ Injury Scale grades IV and V incur high mortality rate ranging from 40 to 80%, respectively. The objective of this study is to assess the clinical experience with an aggressive approach to the management of these, the most complex of hepatic injuries. METHODS: This is a retrospective 6-year study (1992-1997) at an American College of Surgeons urban Level I trauma center of patients sustaining complex hepatic injuries whose interventions included surgery, angiographic embolization, endoscopic retrograde cholangiopancreatography plus biliary stenting and percutaneous computed tomographic-guided drainage. The main outcome measure was survival. RESULTS: A total of 22 patients sustaining complex hepatic injuries; mean age of 26 years (range, 10-52 years), mean Revised Trauma Scale score of 9.9, mean Injury Severity Score of 32 (range, 16-75), American Association for the Surgery of Trauma - Organ Injury Scale grade IV (13 cases); grade V (9 cases). Mean estimated blood loss was 4,600 mL; mean number of units of blood transfused was 15. The patients underwent the following interventions: surgery (n = 22), re-operated (n = 13), mean number of operations 1.6 (range, 1-4), extensive hepatotomy and hepatorrhaphy (n = 17), nonanatomic resection (n = 7), formal hepatectomy (n = 4), packing (n = 10), direct approach to hepatic veins (n = 3); angiographic embolization (n = 15); endoscopic retrograde cholangiopancreatography and stenting (n = 5); computed tomographic guided drainage (n = 6). Mean length of stay in the intensive care unit was 21 days (range, 2-134 days), mean hospital length of stay was 40 days (range, 2-147 days). Overall mortality rate was 14% (3 of 22 cases), hepatic mortality rate was 9% (2 of 22 cases), mortality rate by injury grade was 8% grade IV (1 of 13 cases) and 22% grade V (2 of 9 cases). CONCLUSION: In this select patient population, improvements in mortality rates can be achieved with an aggressive approach to the management of complex hepatic injuries, including surgery, early packing, angiographic embolization, endoscopic retrograde cholangiopancreatography and stenting of biliary leaks, and drainage of hepatic abscesses.     

催醒宁在大鼠离体灌流肝脏中的生物转化

用离体大鼠肝脏灌流方法,研究了胆碱酯酶抑制剂CXN的生物转化过程。径HPLC分离纯化及光谱分析,鉴定了CXN的六个脂溶性代谢产物的化学结构。产物Ⅰ为CXN原形,其余均为氧化产物。其中产物Ⅲ尚保留部分抑酶活力,而产物Ⅱ,Ⅴ及Ⅵ对小鼠全脑胆碱酯酶的抑酶活力明显下降。另外还观察到,代谢产物Ⅱ及Ⅴ对小鼠的急性毒性也明显减小。     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.