Investigational small molecules in phase II clinical trials for the treatment of epilepsy

ABSTRACT

Introduction: Epilepsy is a neurological disorder that significantly impacts the quality of life of affected persons. Despite advances in research, nearly a third of patients have refractory or pharmacoresistant epilepsy. Even though numerous antiepileptic drugs (AEDs) have been approved over the past decade, there are no agents that halt the development of epilepsy. Thus, new and improved AEDs to prevent these conditions are necessary.

Areas covered: We highlight recent advances in new and innovative drugs for epilepsy disorders. We review three small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492 (Selurampanel) and Ganaloxone.

Expert opinion: The full potential of Cannabidivarin will be realized by testing in other types of treatment-resistant seizures; if they are beneficial, larger phase III clinical trials would probably be undertaken in the same patient population. About BGG492, the challenge will be to find ‘superselective’ AMPAR antagonists targeting only calcium-permeable receptors, with specific mechanisms, that may be attractive partners for drugs in polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a new submicron formulation that improves its absorption and pharmacokinetic profile, but new studies are necessary before progressing. Further clinical innovations will define the future for these small molecule-type drugs in epilepsy therapeutics.     

替尼泊苷-甲环亚硝脲联合治疗脑转移性肿瘤

目的 :研究、摸索治疗脑转移性肿瘤的有效方法。方法 :采用替尼泊苷 甲环亚硝脲 (VM2 6 MeCCNU)的组合化疗 ,结合传统的中医辩证论治 ,部分病例同时进行g刀或直线加速器照射等治疗。结果 :症状改善及消失率为84 .2 1 % ;影像学 (CT或MRI)复查 :CR 4例 ( 1 2 .5% ) ,PR 9例 ( 2 8.1 3 % ) ,NR 1 4例 ( 43 .75% ) ,PD 5例 ( 1 5.63 % ) ,有效率 4 0 .63 % ;存活时间少于 6个月者 7例 ( 2 3 .3 % ) ,超过 6个月者 2 3例 ( 76.67% ) ,其中超过 1年者 1 5例 ,超过 1 .5年者 1 1例 ,超过二年者 8例 ,平均存活时限 1 8.6月。结论 :以替尼泊苷 甲环亚硝脲联合化疗为主 ,辅以中药及放疗是治疗脑转移性瘤的有效治疗组合 ,其治疗效果优于文献报告。     

美托洛尔酒石酸盐胃内滞留漂浮型控释片的制备及药代动力学研究

本文根据水动力学平衡药物控释系统的设计原理制备了美托洛尔胃内滞留漂浮型控释片剂(简称M-HBS)。实验表明,本品的体外溶出符合一级动力学过程(K′r=0.1651 h^-1);贮存期为两年;人体胃内γ-闪烁照相结果表明,本品在胃内滞留时间(5～6 h)明显比普通片剂(1.0～1.5 h)长;体内动力学过程符合表观一级吸收与一级消除的单室模型;ⅳ美托洛尔体内为双室模型;体内数据经NONLIN计算机程序处理,求得各项参数:Ka=0.1944 h^-1,K=0.1867 h^-1,Vd=2.813,t_max=5.247 h,C_max=125.1 ng/ml。本品的体内外数据具有显著的相关性(P<0.01)。     

Methotrexate and liver function: a study of 13 psoriasis cases treated with different cumulative dosages

Background The need and frequency of hepatic biopsies during methotrexate (MTX) therapy are still controversial. Objectives The purpose of this investigation is to assess MTX liver toxicity in patients with psoriasis through percutaneous liver biopsy, and compare liver morphology changes with increasing cumulative dosages (1, 2, 3 and 4 g) of MTX. Results Cumulative dosages of 1 to 2 g MTX did not cause significant liver toxicity. From a cumulative dosage of 3 to 4 g, there is fibrosis formation, inflammation enhancement in the portal area and fibrous septa, configuring regenerative nodes. Conclusion In patients with no risk factors for liver disease, with normal physical examination and liver tests, biopsy can be done after a cumulative MTX dosage of approximately 1 to 1.5 g and repeated for each gram. In patients with risk factors, liver biopsy should be done before use of MTX, or within the first 2 months of treatment at the most, and repeated for each gram of cumulative dosage.     

New insights suggesting a possible role of a heat shock protein 70-kD family-related protein in antigen processing/presentation phenomenon in humans

A possible role of the peptide binding protein (PBP) 72/74 in antigen processing and presentation has been recently suggested in mice. In order to evaluate a possible analogous role of a PBP72/74-related protein in humans, immunoelectron microscope investigations, functional studies, and immunofluorescence analyses were performed on normal human peripheral antigen-presenting cells. We demonstrated that the determinant recognized by antiheat shock protein (HSP) 72/73 monoclonal antibody (MoAb) is constitutively expressed on the cell surface of monocytes as well as of B cells. Moreover, the capability of monocytes to present a recall antigen to T cells was significantly decreased when preincubated with an anti-HSP72/73 MoAb. These data add further strength to a potential role of a protein related to human PBP72/74 homologue in antigen processing and/or presentation. Finally, the capability of anti-HSP72/73 MoAb to impair the ability of fixed monocytes to present a synthetic peptide demonstrates that cell surface- localized PBP72/74-related protein could play a role in antigen presentation.     

Influence of Rh phenotype on the antigen density of C, c, and D: flow cytometric study using a frozen standard red cell

BACKGROUND: Flow cytometry is increasingly being used for the comparison of antigen density. Indirect immune fluorescence is more sensitive than direct immune fluorescence and thus allows the study of red cells (RBCs) with a weak D antigen. STUDY DESIGN AND METHODS: In indirect immune fluorescence, when the fluorescence is standardized by the use of aliquoted frozen standard RBCs, the coefficient of variation in fluorescence intensity was less than 5 percent, which allows accurate determination of minor variations of Rh antigen density. RESULTS: For D antigen, the well-known suppressive effect of C, and the low antigen density of the weak D phenotype, was demonstrated. Use of epitope-specific monoclonal antibodies yielded similar results and allowed the identification of a D category IV heterozygote; the relative antigen density measured with a monoclonal antibody that reacted with D(IV) was twice that measured with a monoclonal antibody that did not react with D(IV). RBCs from C and c homozygotes had significantly more antigen than those from heterozygotes. There was significant variation in antigen density, depending on Rh phenotype: for example, D+ RBCs had less C antigen than D- RBCs, and Rh:1,2,-3,4,5 (CcDee) RBCs had more c antigen than Rh:1,2,3,4,5 (CcDEe) RBCs. There was no difference in D, C, and c antigen density in neonatal and adult RBCs. CONCLUSION: Flow cytometry is an excellent tool for the demonstration of minor differences in antigen density.     

Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue

Introduction  

Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients.     

Psoriasis vulgaris and human leukocyte antigens

BACKGROUND: Psoriasis vulgaris is a skin disease with a complex immunological and genetic background, triggered by environmental factors. The association of human leukocyte antigens (HLA) and psoriasis has long been reported on population and familial studies. OBJECTIVES: To review and discuss studies on psoriasis vulgaris and HLA, in Caucasian and non-Caucasian populations. METHODS: The major population studies on psoriasis vulgaris and the associated HLA antigens and alleles are described and discussed based on a review of the current literature. RESULTS: Population studies demonstrate the presence of different HLA specificities as well as extended haplotypes in patients with psoriasis, when compared to controls. Some alleles occur in a lower frequency in patients with psoriasis, indicating they could be protection alleles. In all studies which HLA class I was typed, Cw6 or Cw*0602 was present in a significant frequency in patients with psoriasis, mainly when early onset and positive family history were considered. HLA-DRB1*0701 was also present in a higher frequency in patients in different populations. CONCLUSIONS: Different antigens and alleles from both HLA classes I and II were seen in a significantly higher frequency in patients with psoriasis vulgaris. HLA Cw*0602 and DRB1*0701 were represented in different reports, and the former was related mainly to psoriasis type I.     

垂体催乳素瘤的诊断和治疗指南

2005年6月,在San Diego举行了第九届国际垂体研究大会.大会邀请在催乳素瘤治疗领域被认可的国际知名专家,包括内分泌专家和神经外科专家,特定召开专业委员会,对催乳素瘤的诊断和治疗进行探讨,并形成该指南.指南发表在2006年8月的临床内分泌学杂志上(Clinical Endocrinology, 2006, 65: 265-273).