All-trans retinoic acid plus low doses of cytarabine for the treatment of “poor-risk” acute myeloid leukemias

Summary Thirteen refractory/resistant AML patients no suitable for additional aggressive chemotherapy, were treated with a combination including all -trans retinoic acid (45 mg/m² sine die) and low doses of Ara-C (20 mg/m² subcutaneously, twice in a day, days 1–10, every 28 days). Ten patients were évaluable; 8 of them achieved a complete remission, two patients with an important tumor burden, failed to achieve a response. One complete remission patient relapsed after 7 months but is still receiving the same therapy and is now in partial remission. We believe this combination effective as inducer of complete remission in those AML patients which cannot tolerate additional heavy treatments. The role of tumor burden in affecting response to therapy remains to be still evaluated.     

Cell kinetics after high dose cytosine arabinoside in patients with acute myelocytic leukemia

Summary In this study 10 patients with acute myelocytic leukemia (AML) each received a rapid intravenous injection of high dose cytosine arabinoside (HD Ara-C; 1 g/m²). Bone marrow aspirates were obtained before and after Ara-C administration to determine the percentage of cells in S-phase measured by flow cytometry. In 5 out of 10 cases synchronization of the leukemic cells in S-phase of the cell cycle was observed. However, the time of maximum synchronization turned out to be difficult to predict. Therefore, the strong correlation between percentage of cells in S-phase at diagnosis and the time of maximal accumulation of S-phase cells after Ara-C administration, as observed by others in childhood AML, could not be confirmed for adult AML patients. Although synchronization of AML cells after in vivo Ara-C administration could be demonstrated in at least half of the patients, the practical consequences are such that clinical application was hampered.     

Pharmacotherapy for tonic–clonic seizures

Introduction: Occurrence of generalized tonic–clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies.

Areas covered: It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used.

Expert opinion: Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate.     

Antidermatophytic activity of pyrazolo[3,4-c]isothiazoles: a preliminary approach on 4-chlorophenyl derivative for evaluation of mutagenic and clastogenic effects on bacteria and human chromosomes in vitro

The antifungal activity of eight pyrazolo[3,4-c]isothiazole derivatives was evaluated on five dermatophytes: three were of an anthropophilic species (i.e., Epidermophyton floccosum, Trichophyton rubrum, and Trichophyton tonsurans) and two were of a geophilic species (i.e., Microsporum gypseum and Nannizzia cajetani). The new compounds proved to be unlikely effective in inhibiting the growth of the different strains. In general, the fungi parasitic on man were more sensitive than the geophilic species. This fact can be positive for a possible practical-therapeutic utilization of this class of compounds. To verify their possible use against fungi of medical interest, the most interesting substance at low doses, 6-(4-chlorophenyl)-4-methyl-6H-pyrazolo[3,4-c]isothiazol-3-amine, was chosen to perform in vitro genotoxicity tests using the following: Salmonella/microsome test (SAL), sister chromatid excange test (SCE), cytokinesis-blocked micronucleus test (CBMN), and its improvement (Ara-C/CBMN). The compound showed no mutagenic activity at low doses, whereas at the highest dose (100 µg/mL), it caused a generalized cytotoxic effect. The high growth inhibition exerted on fungi at the lowest dose and the concomitant lack of genotoxicity, at least until the dose of 50 µg/mL, might suggest the compound as a safe candidate as an antidermatophytic substance.     

阿糖胞苷及阿克拉霉素联合G-CSF治疗复发急性髓系白血病的临床研究

目的研究阿糖胞苷（Ara-C）,阿克拉霉素（Acla）联合粒细胞集落刺激因子（G-CSF）治疗复发急性髓系白血病的临床疗效。方法将我院2008年1月至2009年3月收治的47例复发急性髓系白血病患者随机分为A组24例和B组23例,A组采用Ara-C、Acla联合G-CSF（CAG方案）治疗,B组采用Acla,足叶乙甙（VP16）和Ara-C（AEA方案）治疗。结果A、B两组的疗效无显著性差异,但A组的不良反应发生率低于B组。结论Ara-C、Acla联合G-CSF治疗复发急性髓系白血病获得较佳疗效,且不良反应少,值得临床关注。     

肿节风总黄酮对阿糖胞苷诱发小鼠S180血小板减少模型的影响

目的：观察肿节风总黄酮对阿糖胞苷诱发小鼠肉瘤S180血小板减少模型的影响。方法：通过腹腔注射阿糖胞苷100 mg/kg,1次/d,连续2 d,第3天改用50 mg/kg作为维持剂量继续腹腔注射,1次/d,连续3 d。每天灌胃给予肿节风总黄酮,连续10 d,于实验第3、5、7、10天测定白细胞及血小板。结果：腹腔注射阿糖胞苷可在第7天成功造成血小板减少模型,肿节风总黄酮可显著升高白细胞和血小板（P〈0.01）。结论：阿糖胞苷可成功造成荷瘤鼠血小板减少模型,肿节风总黄酮可显著升高血小板。     

阿糖胞苷对急性白血病细胞中cFLIP表达的影响

目的:研究在不同类型初治急性白血病细胞中cFLIP基因的表达以及阿糖胞苷（Ara-C）对其表达的影响。方法:选取36例初治的急性白血病患者骨髓,分离单个核细胞在体外培养,分成两组:未处理组、Ara-C处理组,同时选取10例非恶性血液病患者的骨髓并分离单个核细胞作为对照组,培养48小时后,采用逆转录PCR（RT-PCR）法检测cFLIP基因的表达水平。结果:cFLIP在正常人骨髓细胞中不表达或低表达,急性白血病患者骨髓细胞的cFLIP表达水平增高（P＜0.05）;cFLIP在不同类型急性白血病之间的表达无显著统计学差异(P＞0.05);Ara-C可使初治急性白血病患者骨髓细胞的cFLIP表达水平明显下降(P＜0.05)。结论:cFLIP表达水平增高可能与急性白血病的发生相关;Ara-C治疗白血病的机制之一可能是通过抑制cFLIP的表达而促进白血病细胞的凋亡。     

Pattern of Liver Disease Following High-Dose Cytosine Arabinoside (HDARAC) Therapy in Children with Acute Myeloid Leukemia

The occurrence of liver disease and its relation to HBV markers were investigated in ten children with AML who were given HDARAC as late consolidation therapy. None of them developed jaundice or biochemical evidence of cholestasis. During therapy, SGPT values were normal in 5/10 patients, while in the other 5 a sharp increase was noted. These enzyme elevations followed an unusual timing, peaking just before each infusion of HDARAC. Evidence of long-lasting hepatocellular necrosis after therapy withdrawal was found in 8/8 cases. One child died of fulminant type B hepatitis and HBsAg positivity was found in 2/10 patients during therapy and 3/8 after withdrawal of the drug. Three children developed HBV antibodies during the observation period. We conclude that the use of HDARAC in childhood leukemia is not associated with major evidence of direct drug hepatotoxicity while it clearly affects the natural outcome of viral hepatitis     

Synergistic and antagonistic interactions of methotrexate and 1-β-D-arabinofuranosylcytosine in hepatoma cells: The modulating effect of purines

A 4-hr pretreatment with methotrexate antagonized the cytotoxic effect of subsequent arabinosylcytosine treatment in rat hepatoma cells of lines N₁S₁ and 3924A, but in the hepatoma line 8999R and the fibroblast line BF5, MTX pretreatment was synergistic with the arabinosylcytosine treatment. Measurement of cellular deoxyribonucleoside triphosphate concentrations showed that in those lines in which antagonism was found the dCTP increased, whereas in the lines where the drugs were synergistic the dCTP pool was decreased. Conversely, dATP levels were high when the drugs were synergistic and low when antagonism was obtained. Although methotrexate pretreatment antagonized arabinosylcytosine in N₁S₁ and 3924A cells, pretreatment of these cells with the combination of methotrexate plus a purine (either hypoxanthine or 2′-deoxyadenosine) resulted in synergism with arabinosylcytosine. Deoxynucleotide pool measurements showed that methotrexate in combination with either hypoxanthine or 2′-deoxyadenosine increased dATP and decreased dCTP in the N₁S₁ and 3924A hepatoma cells. In N₁S₁ cells, pretreatment with 2′-deoxyadenosine alone for 4 hr was synergistic with arabinosylcytosine. It was concluded that elevated dATP pools enhanced arabinosylcytosine cytotoxicity by depleting the dCTP pool, through feedback inhibition of ribonucleotide reductase, thus causing greater inhibition of DNA biosynthesis and greater incorporation of AraCTP into nucleic acid. Methotrexate was synergistic in those cell lines where dATP accumulated and dCTP was decreased, but when methotrexate had a potent antipurine effect dCTP pools increased and arabinosylcytosine was antagonized. The synergistic interaction was more marked at cytocidal drug concentrations than it was at growth-inhibitory doses.