Leflunomide-associated pancytopenia with or without methotrexate

OBJECTIVE: To report 18 cases of pancytopenia associated with leflunomide use in Australia, 5 of which were treated at Princess Alexandra Hospital, Brisbane. case summaries: Leflunomide was used in the treatment of rheumatoid arthritis in 17 of 18 patients; the other patient was diagnosed with systemic lupus erythematosus. Median age was 65.5 years (range 18-79), and 15 of the patients were female. Fourteen patients were on combined treatment with methotrexate. Pancytopenia was typically severe, requiring hospital admission, withdrawal of the immunosuppressant(s), intensive supportive therapy, and treatment of neutropenic sepsis. Five patients died, 4 of whom were receiving concomitant methotrexate. Time to onset of pancytopenia ranged from 11 days to 4 years (median 4 mo). In one case in which the patient had been stable while receiving leflunomide, methotrexate, and hydroxychloroquine for 4 years, fatal pancytopenia was triggered by acute renal failure secondary to dehydration and use of nonsteroidal antiinflammatory drugs. The Naranjo probability scale suggested a probable causal association in 5 cases and possible association in the remainder. DISCUSSION: Leflunomide, indicated for treatment of active rheumatoid arthritis, inhibits pyrimidine synthesis in lymphocytes and other rapidly dividing cells and may rarely be associated with life-threatening pancytopenia. Combination therapy with methotrexate may increase the risk. Time to onset is variable, and clinicians should remain vigilant, particularly when there is a change in the patient's baseline health status. CONCLUSIONS: The risk of pancytopenia during leflunomide therapy appears to be increased when the drug is combined with methotrexate and in older patients. Onset may be delayed, and ongoing monitoring of blood counts is essential.     

Stable paclitaxel formulations in oily contrast medium.

Stable paclitaxel/Lipiodol solutions as well as emulsions were developed for the treatment of solid tumors including hepatocellular carcinoma. Paclitaxel could be dissolved in Lipiodol, an oily contrast medium, but precipitated out and formed aggregates with time. Paclitaxel precipitation was due to the inter- and intra-molecular hydrogen bonding of paclitaxel molecules. Time-dependent paclitaxel aggregation was completely prevented by adding small amounts of additional solvents, which are miscible with Lipiodol. It was also notable that paclitaxel helped in stabilizing the water-in-oil (w/o) type emulsion of Lipiodol and Iopamiro. The stability, physical properties and in vitro drug release profiles of the stable paclitaxel solutions and emulsions were characterized. When the stable oily paclitaxel solution was used for the treatment of B16F10 melanoma in C57BL/6 mice, the malignant cells were eradicated completely in 2 weeks, whereas the solid tumor grew rapidly and metastasized to the thigh and to other organs in the control group. Also, the mice survived for more than 1 year after the paclitaxel treatment, whereas all of those in the control group died in 40 days.     

Brassiere wearing and breast cancer risk: A systematic review and meta-analysis

AIM: To evaluate existing evidence for the association between different type of brassiere exposures and the risk of breast cancer. METHODS: Ovid Medline, CINAHL, Cochrane Data Base of Systematic Reviews, Pubmed, Scopus, Proquest, Sciencedirect, Wiley Online Library, WanFang Data, Hong Kong Index to Chinese Periodicals, China Journal Net, Chinese Medical Current Contents, Chinese Biomedical Literature Database, China Academic Journals Full-Text database, Taiwan Electronic Periodical Services and HyRead; reference lists of published studies; original research studies published in English or Chinese examining the association between type and duration of brassiere-wearing and breast cancer risk. Data were abstracted by a first reviewer and verified by a second. Study quality was rated according to predefined criteria. “Fair” or “good” quality studies were included. Results were summarised by meta-analysis whenever adequate material was available. RESULTS: Twelve case-control studies were included in the review. Meta-analysis showed brassiere wearing during sleep was associated with a two times of increased odds. CONCLUSION: The present review demonstrates insufficient evidence to establish a positive association between the duration and type of brassiere wearing and breast cancer. Further research is essential; specifically, a large-scale epidemiological study of a better design is needed to examine the association between various forms of brassiere exposure in detail and breast cancer risk, with adequate control of confounding variables.     

Hypocaloric total parenteral nutrition: effectiveness in prevention of hyperglycemia and infectious complications--a randomized clinical trial

OBJECTIVE: To determine whether the frequency rate of hyperglycemia and infectious complications can be reduced by an underfeeding strategy in patients requiring total parenteral nutrition (TPN), without deleterious effects on nitrogen balance. DESIGN: Prospective, randomized, controlled nonblinded trial. SETTING: A university-affiliated teaching hospital with a dedicated TPN service. PATIENTS: TPN was initiated in 40 adult patients and continued for > or =5 days. INTERVENTION: Two different TPN feeding strategies were compared: hypocaloric feeding (1 L containing 70 g protein and 1000 kcal) and standard weight-based regimen, begun in similar amounts initially, but advanced in increments toward 25 kcal and 1.5 g protein/kg dry (or adjusted ideal) weight. MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency rate of hyperglycemia, average blood glucose, numbers and types of infections while receiving nutritional support and nitrogen balance after 5 days of TPN. There were significant differences between the quantities of calories, dextrose, fat, and protein provided to the two groups. However, average blood glucose, frequency rate of hyperglycemia, and infection rates (from intravenous catheter, pneumonia, and wound/abdominal collection) were similar in each group. The control group showed a trend toward a higher insulin requirement. Nitrogen balance, only available as a subset, was significantly more negative in the hypocaloric group. CONCLUSIONS: Provision of TPN to a goal of 25 kcal/kg was not associated with more hyperglycemia or infections than a deliberate underfeeding strategy. A regimen of 1.5 g/kg protein in conjunction with 25 kcal/kg did, however, provide significant nutritional benefit in terms of nitrogen balance in comparison with hypocaloric TPN.     

Should we screen for globin gene mutations in blood samples with mean corpuscular volume (MCV) greater than 80 fL in areas with a high prevalence of thalassaemia?

AIMS: To investigate whether it is worthwhile, in areas where thalassaemia is common, to screen for globin gene mutations in subjects with a mean corpuscular volume (MCV) above 80 fL, especially in partners of known thalassaemia carriers. METHODS: Blood samples from 95 subjects with MCV between 80 and 85 fL were screened for the presence of alpha globin gene mutations and the haemoglobin (Hb) E mutation. RESULTS: Thirty four subjects harboured globin gene mutations. Of these, 31 had deletions of one alpha globin gene, one had Hb Constant Spring, and three had Hb E mutations. CONCLUSION: Based on the above figures and known prevalence rates of thalassaemia carriers, it would seem worthwhile to screen for globin gene mutations in partners of known thalassaemia carriers, regardless of MCV, to identify pregnancies at risk of Hb H disease or Hb E/beta thalassaemia.     

Chisomicines A-C, limonoids from Chisocheton ceramicus

Three new limonoids, chisomicines A-C (1-3), have been isolated from the bark of Chisocheton ceramicus. Their structures were determined by 2D NMR, CD spectroscopic methods, and X-ray analysis. Chisomicine A (1) exhibited NO production inhibitory activity in J774.1 cells stimulated by LPS dose-dependently at high cell viability.     

粉防己碱的抗氧化能力与心肌保护作用的相关性研揪

目的:探讨粉防己碱(tetrandrine,TET)的体内外抗氧化作用及该作用与其心肌保护药理功能的关系.方法:测定TET的体外清除DPPH自由基能力以及对过氧化氢(H2O2)损伤的H9c2大鼠心肌细胞活力的影响.并利用皮下注射异丙肾上腺素(ISO),在大鼠体内造成心肌损伤模型,从死亡率和心电图两方面观察TET的心肌保护作用.再初步检测TET对大鼠左心室超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽(GSH)以及丙二醛(MDA)4个体内抗氧化能力指标的影响.结果:TET能够显著性地、呈剂量依赖性地清除体外DPPH自由基、降低H2O2对H9c2细胞的生长抑制率.并且,预先腹腔注射TET能够降低ISO引起的大鼠死亡率和心电图sT段电压上抬的幅度,初步检测后发现.TET亦能够升高大鼠左心室SOD、CAT和GSH水平,降低MDA含量.结论:TET具有良好的心肌保护功能,其作用可能与它抗氧化的能力有关.     

A comparative study on the hepatic toxicity and metabolism of Crotalaria assamica and Eupatorium species

The oral LD50 of Crotalaria assamica, which contains mainly monocrotaline, was found to be 154 mg/kg in mice. Neither liver necrosis nor morbidity was demonstrated with Eupatorium extract at a dose level of 144 mg/kg, which was equivalent to the LD20 of Crotalaria. Pretreatment with phenobarbitone enhanced the toxicity of both plant extracts in mice. In in vitro studies, "metabolic pyrrole" was formed by incubating Eupatorium japonicum extracts with liver microsomes. The rate of "pyrrole" formation was similar to that of Crotalaria extract and pure monocrotaline alkaloid, but was much slower than retrorsine. The rate of N-oxide formation was, in descending order, retrorsine, Eupatorium japonicum and Crotalaria/monocrotaline. It is concluded that the alkaloid in Eupatorium species is metabolized to "pyrrole" and an N-oxide metabolite in the liver, but hepatotoxicity is much lower when compared with that caused by Crotalaria.