Temporal effects of newly developed oximes (K027, K048) on malathion-induced acetylcholinesterase inhibition and lipid peroxidation in mouse prefrontal cortex

The potency of newly developed asymmetric bispyridinium oximes (K027, K048) in reactivating acetylcholinesterase and in eliminating oxidative stress induced by acute exposure to malathion was evaluated in mouse prefrontal cortex using in vivo methods. Malathion (1g/kg, dissolved in saline) was administered subcutaneously. The asymmetric bispyridinium oximes K027 or K048 (1/4 of LD(50), dissolved in saline, i.p.) were administered immediately after malathion and atropine sulfate (20mg/kg, dissolved in saline, i.p.). Control group received saline instead of malathion and antidotes. Acetylcholinesterase activity and biochemical parameters related to oxidative stress (glutathione levels, glutathione peroxidase and glutathione reductase activity and lipid peroxidation) were evaluated in mouse prefrontal cortex at two different time points (3 or 24 h after malathion poisoning). Malathion administration markedly inhibited cortical acetylcholinesterase activity (around 55%) at 3h after malathion challenge and such inhibition was maintained till 24 h after poisoning. Although neither atropine sulfate nor oximes were able to eliminate cortical acetylcholinesterase inhibition at 3h after malathion poisoning, K027 (in combination with atropine) completely eliminated the inhibitory effect of malathion exposure on cortical acetylcholinesterase activity at 24 h after malathion administration. K048 (in combination with atropine) significantly decreased acetylcholinesterase inhibition at 24 h after malathion poisoning. Even though glutathione levels and glutathione peroxidase and glutathione reductase activities were not affected, malathion administration markedly increased lipid peroxidation in the prefrontal cortex at 24 h after poisoning and the oxime K027 (in combination with atropine) was able to significantly decrease such phenomenon. Thus, our results clearly demonstrate that the newly developed asymmetric bispyridinium oximes K027 and K048 are able to reverse malathion-induced acetylcholinesterase inhibition in mouse prefrontal cortex. Moreover, the ameliorative effect of the oxime K027 on the increased lipid peroxidation observed at 24 h after malathion poisoning suggests a potential link between the hyperstimulation of cholinergic system and oxidative stress in the mouse prefrontal cortex after malathion exposure.     

Olanzapine orally disintegrating tablet: a review of efficacy and compliance

Medication nonadherence, especially in psychiatric disorders, has been associated with treatment failure and other negative outcomes. Orally disintegrating formulations have been developed as an alternative to improve medication adherence. This report reviews the properties, efficacy, and safety profile of olanzapine as an orally disintegrating tablet, and explores their association with medication compliance compared with standard oral formulation. Medical literature, published on orally disintegrating formulation of olanzapine identified using Pubmed and EMBASE, was used. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Studies evaluating the biostability, biodisposability, pharmacokinetics, efficacy, and safety of orally disintegrating olanzapine as treatment of patients with psychiatric disorders were reviewed. Measurement tools included the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale, and Nursing Assessment of Medication Acceptance (NAMA). Orally disintegrating olanzapine, an effective atypical antipsychotic with an acceptable safety profile, can facilitate the burden of treatment on patients and caregivers due to its ease of administration. This is especially important in diseases such as schizophrenia and bipolar disorder, which can be chronic and require long-term treatment.     

Comparison of antithrombotic efficacy between edoxaban, a direct factor Xa inhibitor, and fondaparinux, an indirect factor Xa inhibitor under low and high shear rates

Edoxaban is an oral, direct factor Xa (FXa) inhibitor under late-phase clinical development. This study compared the antithrombotic efficacy of edoxaban with that of an indirect FXa inhibitor, fondaparinux, in in vivo venous and arterial thrombosis models and in ex vivo perfusion chamber thrombosis model under low and high shear rates in rats. Venous and arterial thrombi were induced by platinum wire insertion into the inferior vena cava and by application of FeCl? to the carotid artery, respectively. The perfusion chamber thrombus was formed by blood perfusion into a collagen-coated capillary at 150 s?1 (low shear rate) and 1,600 s?1 (high shear rate). Effective doses of edoxaban that reduced thrombus formation by 50% (ED??) in venous and arterial thrombosis models were 0.076 and 0.093 mg/kg/h, respectively. In contrast, ED?? of fondaparinux in the arterial thrombosis model (>10 mg/kg/h) was markedly higher compared to ED?? in the venous thrombosis model (0.021 mg/kg/h). In the perfusion chamber thrombosis model, the ratio of ED?? under high shear rate (1.13 mg/kg/h) to that under low shear rate (0.63 mg/kg/h) for edoxaban was 1.9, whereas that for fondaparinux was more than 66. While the efficacy of fondaparinux markedly decreased in arterial thrombosis and in a high-shear state, edoxaban exerted consistent antithrombotic effects regardless of flow conditions. These results suggest that shear rate is a key factor in different antithrombotic effects between edoxaban and fondaparinux.     

Study on the efficacy and tolerability of amisulpride in medical/surgical inpatients with delirium admitted to a general hospital

PurposeTo evaluate the efficacy and safety of amisulpride in medical inpatients who present with delirium.MethodOpen label prospective study with 7-day follow-up. Forty hospital inpatients with delirium were recruited, seven of whom died and two of whom refused medication. The average dose of amisulpride for delirium treatment was 200–300 mg/day. Daily assessments were performed with Delirium Rating Scale (DRS), Positive Subscale of the Positive and Negative Syndrome Scale (PANSS-P), Mini Mental State Examination (MMSE), Neurological Subscale of the UKU side effect rating scale. Variance analysis was performed through repeated measurements, with the general linear model with paired comparisons and Bonferroni correction for each measured variable.ResultsPatients showed significant improvement on the DRS from the first day of treatment DRS = 17.55 until day 7 DRS = 7.26 (F = 92.485; p < 0.001), psychotic symptoms improved from first day PANSS-P = 18.26 to last day PANSS-P = 9.35 (F = 144.83; p < 0.001). Cognitive status showed a significant improvement from day 2 MMSE = 18.71 until day 7 MMSE = 24.06 (F = 96.56; p < 0.001), and the neurological subscale of the UKU side effect rating scale showed a significant improvement the last day with respect to baseline pretreatment level (F = 7.539; p = 0.01).ConclusionsThese results suggest a good response to amisulpride in the acute phase of delirium, although further randomized controlled studies must be performed.     

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor, in rat models of venous and arterial thrombosis.

The antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis. After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50, (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively. In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P < 0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively. The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times. These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.     

骨骼肌肌浆网Na+，K+-ATP酶和Ca2+-ATP酶活性在不同训练条件下的变化

背景：Na+,K+-ATP酶和Ca2+-ATP酶在物质运送、能量转换以及信息传递方面具有重要作用。肌浆网在肌肉兴奋-收缩耦联过程中起关键作用,与运动性骨骼肌疲劳的发生密切关。 目的：通过建立SD大鼠有氧和无氧训练模型,观察不同训练负荷条件对大鼠骨骼肌肌浆网Na+,K+-ATP酶和Ca2+-ATP酶活性的影响。 方法：参照Bedford TG标准,建立有氧和无氧运动大鼠跑台训练模型,有氧运动组采用递增负荷训练,无氧运动组采用高速间歇训练,正常对照组大鼠正常笼内生活,不运动。各组动物训练结束后用超速离心法提取大鼠骨骼肌肌浆网,紫外分光光度计检测大鼠骨骼肌肌浆网Na+,K+-ATP酶和Ca2+-ATP酶的活性。 结果与结论：训练4周后,两个运动组大鼠骨骼肌肌浆网Na+,K+-ATP酶和Ca2+-ATP酶的活性逐渐升高(P < 0.05);训练6周,仅有氧运动组升高(P < 0.05),无氧运动组则活性降低(P < 0.05)。结果提示有氧训练更有利于保护大鼠骨骼肌肌浆网Na+,K+-ATP酶和Ca2+-ATP酶的活性,但需要一定的时间累积。     

Sustained efficacy and long-term safety of oxcarbazepine: one-year open-label extension of a study in refractory partial epilepsy

PURPOSE: To evaluate the long-term efficacy, tolerability, and safety of oxcarbazepine (OXC) in medically refractory partial epilepsy. METHODS: This study is the open-label extension phase that followed a multicenter, randomized, double-blind, dose-response clinical study of OXC monotherapy in patients with medically refractory partial epilepsy. We analyzed the efficacy, tolerability, and safety of OXC during the first 48 weeks of open-label therapy. To evaluate efficacy, we compared the change in seizure frequency throughout the 48 weeks of treatment with OXC with the baseline seizure frequency that preceded the double-blind phase of the core study by an intent-to-treat and completer analysis. Safety and tolerability were evaluated by using an intent-to-treat analysis. RESULTS: Of the 87 patients enrolled in the double-blind study, 76 patients participated in the open-label extension phase. Fifty-five (72%) patients completed 48 weeks of open-label treatment on a median OXC dose of 2,400 mg/day. Based on an intent-to-treat analysis, the median reduction in seizure frequency was 47%(p = 0.0054); the 50 and 75% responder rates were 46.1 and 25.0%, respectively, with 6.6% of patients remaining seizure free. The completer analysis yielded comparable efficacy results. OXC was well tolerated, with 13% of patients exiting because of adverse events. The six most common adverse events, irrespective of their causal relation to OXC, were dizziness, headache, fatigue, diplopia, nausea, and rash. For the most part, these adverse events tended to be transient. CONCLUSIONS: The efficacy of OXC is sustained with good safety and tolerability profiles during long-term treatment of patients with medically refractory partial epilepsy.     

硬脑膜动静脉瘘单次血管内栓塞治疗的安全性和有效性分析

目的 探讨单次血管内栓塞治疗硬脑膜动静脉瘘（DAVF）的安全性和有效性。方法 回顾性分析2005年4月至2018年12月采用血管内栓塞治疗的46例DAVF的临床资料。所有病例均尝试进行单次瘘口栓塞术,对部分残余分流或软脑膜静脉逆行引流（RLVD）的病例则择期二次手术。结果 42例（91.3%）单次手术治疗后实现完全闭塞或仅轻微残余分流。34例Borden分型Ⅱ、Ⅲ型病例中,33例（97.1%）首次治疗后RLVD明显改善,仅4例需要二次治疗。所有病例最终均完全闭塞,术后未发生与DAVF相关的卒中和死亡事件。术后随访7~96个月,平均23个月;4例（8.7%）复发。结论 单次血管内手术治疗DAVF是安全、有效的,能有效预防卒中事件。     

Caregiver measures for seizure control, efficacy, and tolerability of antiepileptic drugs for childhood epilepsy: results of a preference survey

We sought to identify and quantify caregiver-defined characteristics of efficacy related to the perceived success of antiepileptic drug (AED) use. A 22-question survey was designed using physician input, focus groups, and clinical trial endpoints. Responses were pooled and analyzed with regard to seizure type and treatment, categorized as controlled (exposure to 1 AED), adjunctive (exposure to 2 AEDs), or refractory (exposure to ≥ 3 AEDs). Two hundred ninety-five surveys were completed: 109 (37%) controlled, 84 (28%) adjunctive, and 102 (35%) refractory. Seizure freedom and median seizure reduction > 90% maintained for > 1 year were reported as the most important indicators of medication efficacy by the majority of respondents. These measures were the same regardless of seizure type or treatment category. Our results demonstrate that current trial design may be inadequate to address the expectations of patients. Incorporating patient-defined AED efficacy measures may improve satisfaction and informed decision making regarding epilepsy treatment.     

Different protection of K252a and N-acetyl-L-cysteine against amyloid-beta peptide-induced cortical neuron apoptosis involving inhibition of MLK3-MKK7-JNK3 signal cascades

Amyloid-beta peptide (Abeta) has been implicated in the etiopathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms underlying Abeta neurotoxicity remain to be elucidated. This study showed that Abeta treatment resulted in the increased phosphorylation (activation) of MLK3, MKK7, and JNK3 in cultured cortical neurons, which characterized as biphasic activation (first peaked at 1 hr and second peaked at 12 hr after Abeta treatment). K252a blocked Abeta-induced neuronal apoptosis, both early and late phases of MLK3-MKK7-JNK3 activation, as well as downstream signal events involving p-JNKs nuclear translocation, c-Jun phosphorylation, and Bad translocation to the mitochondria. The neuroprotective effect of K252a on Abeta-induced apoptosis was partially dependent on Akt activation. In contrast, antioxidant N-acetyl-L-cysteine (NAC) reduced early, but not late, MLK3-MKK7-JNK3 activation by Abeta treatment and provided a weak neuroprotective ability in Abeta-induced apoptosis. Taken together, Abeta neurotoxicity is mainly due to MLK3-MKK7-JNK3 signal cascades. The late signal events of MLK3 activation after Abeta treatment may play an important role in AD neuronal loss and will be a promising pharmacological target for AD therapeutic intervention.     

Comparison of the effect of edoxaban,a direct factor Xa inhibitor,with a direct thrombin inhibitor,melagatran, and heparin on intracerebral hemorrhage induced by collagenase in rats

Introduction

Intracerebral hemorrhage (ICH) is a major clinical concern with anticoagulation therapy. The effect of a new oral direct FXa inhibitor, edoxaban, was determined in a rat model of ICH and compared with a direct thrombin inhibitor, melagatran, and heparin.

Methods

To induce ICH, 0.1 U collagenase type VII was injected into the striatum of male Wistar rats under anesthesia with thiopental or halothane. Immediately after ICH induction, edoxaban, melagatran, or heparin were infused intravenously. Five hours after ICH induction, the brain was removed and ICH size was measured. To estimate the margin of safety, antithrombotic effects were evaluated in a rat venous thrombosis model.

Results

Edoxaban at 6 mg/kg/h significantly increased ICH volume (1.8-fold) and prolonged prothrombin time (PT) 2.8-fold compared to the vehicle group. No deaths were observed with edoxaban. Melagatran at 1 mg/kg/h increased ICH volume at 1 mg/kg/h (2.8-fold) with 6.1-fold PT prolongation. At 3 mg/kg/h, all rats died due to severe ICH (3.9-fold). Heparin at both 100 and 500 U/kg/h significantly increased ICH. At 500 U/kg/h, 5 out of 8 rats died. The doses required for 50% inhibition of thrombosis of edoxaban, melagatran, and heparin were 0.045 mg/kg/h, 0.14 mg/kg/h, and 55 U/kg/h, respectively. The safety margins between antithrombotic and ICH exacerbation effects of these anticoagulants were 133, 7.1, and 1.8, respectively.

Conclusion

The safety margin of edoxaban was wider than that of melagatran or heparin. These results suggest that edoxaban may be preferable from the perspective of ICH exacerbation risk.     

Duloxetine for the treatment of major depressive disorder: a closer look at efficacy and safety data across the approved dose range

OBJECTIVE: This analysis focuses on efficacy and safety data obtained from studies of duloxetine for the treatment of major depressive disorder (MDD) within the approved dose range of 40-60 mg/day. METHOD: Efficacy and safety data were obtained from the acute phase portions of four randomized, double-blind, placebo-controlled clinical trials in patients meeting DSM-IV criteria for MDD. In Studies 1 and 2, patients were randomized to duloxetine 60 mg once daily (QD) (n=123 [Study 1]; n=128 [Study 2]) or placebo (n=122 [Study 1]; n=139 [Study 2]) for 9 weeks. In Studies 3 and 4, patients were randomized to duloxetine 20 mg twice daily (BID) (n=91 [Study 3]; n=86 [Study 4]) or placebo (n=90 [Study 3]; n=89 [Study 4]) for 8 weeks. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD17) total score (primary outcome), HAMD17 subscales, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, and Visual Analog Scales (VAS) for pain. Safety assessments included rates of discontinuation due to adverse events, spontaneously reported treatment-emergent adverse events, and changes in vital signs. RESULTS: In both studies of duloxetine 60 mg QD, mean change in HAMD17 total score was significantly greater in duloxetine-treated patients compared with placebo (Study 1, p<.001; Study 2, p=.024). At a dose of 20 mg BID, duloxetine demonstrated significant superiority over placebo on the HAMD17 total score in one of the two studies (Study 4, p=.034). Probabilities of remission among patients receiving duloxetine 60 mg QD were 44.2% in Study 1 (p<.001 vs. placebo) and 43.0% in Study 2 (NS), while for patients receiving duloxetine 20 mg BID the probabilities of remission were 27.2% in Study 3 (NS) and 36.1% in Study 4 (NS). Across the six assessed VAS measures of pain severity and interference, the main effect of treatment for duloxetine 60 mg QD was significantly superior to placebo on 7 of the 12 outcomes in Studies 1 and 2, while duloxetine 20 mg BID was not superior to placebo on any of the 12 outcomes in Studies 3 and 4. The rate of discontinuation due to adverse events was 13.1% among patients receiving duloxetine 60 mg QD, and 11.9% at a dose of 20 mg BID. The most frequently reported treatment-emergent adverse events at both doses included nausea, headache, dry mouth, dizziness, and insomnia. The incidence of treatment-emergent nausea among patients receiving duloxetine 60 mg QD was 37.8%, compared with 16.4% among patients receiving 20 mg BID. CONCLUSION: Duloxetine provides safe and effective acute phase treatment of MDD at doses of 40-60 mg/day. Compared with placebo, the 60 mg QD dose was more consistently effective than the 20 mg BID dose. However, the incidence of certain treatment-emergent adverse events is likely to be lower at the 40 mg dose.     

Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons

Objective:An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury,and that regulating autophagy can enhance recovery from spinal cord injury.However,the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear.Therefore,in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison,in an effort to provide a basis for further research.Data source:Relevant literature published from inception to February 1,2018 were included by searching Wanfang,CNKI,Web of Science,MEDLINE(OvidSP),PubMed and Google Scholar in English and Chinese.The keywords included"autophagy","spinal cord injury",and"rat".Data selection:The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury(including intervention pre-and post-spinal cord injury).Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy,and subgroup analyses were also conducted.Outcome measure:Basso,Beattie,and Bresnahan scores.Results:Of the 622 studies,33 studies of median quality were included in the analyses.Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=1.80,95%CI:0.81-2.79,P=0.0004),3 days(MD=0.92,95%CI:0.72-1.13,P<0.00001),1 week(MD=2.39,95%CI:1.85-2.92,P<0.00001),2 weeks(MD=3.26,95%CI:2.40-4.13,P<0.00001),3 weeks(MD=3.13,95%CI:2.51-3.75,P<0.00001)and 4 weeks(MD=3.18,95%CI:2.43-3.92,P<0.00001)after spinal cord injury with upregulation of autophagy compared with the control group(drug solvent control,such as saline group).Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=6.48,95%CI:5.83-7.13,P<0.00001),2 weeks(MD=2.43,95%CI:0.79-4.07,P=0.004),3 weeks(MD=2.96,95%CI:0.09-5.84,P=0.04)and 4 weeks(MD=4.41,95%CI:1.08-7.75,P=0.01)after spinal cord injury with downregulation of autophagy compared with the control group.Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso,Beattie,and Bresnahan scores at 1 day(MD=-4.68,95%CI:-5.840 to-3.496,P=0.94644),3 days(MD=-0.28,95%CI:-2.231-1.671,P=0.99448),1 week(MD=1.83,95%CI:0.0076-3.584,P=0.94588),2 weeks(MD=0.81,95%CI:-0.850-2.470,P=0.93055),3 weeks(MD=0.17,95%Cl:-2.771-3.111,P=0.99546)or 4 weeks(MD=-1.23,95%Cl:-4.647-2.187,P=0.98264)compared with the control group.Conclusion:Regulation of autophagy improves neurological function,whether it is upregulated or downregulated.There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury.The variability in results among the studies may be associated with differences in research methods,the lack of clearly defined autophagy characteristics after spinal cord injury,and the limited autophagy monitoring techniques.Thus,methods should be standardized,and the dynamic regulation of autophagy should be examined in future studies.     

一种新发现的双孔钾通道-TRESK在疼痛及全身麻醉中的作用

TRESK是最近新发现的一种双孔钾通道,其在基因、分子结构、生理药理学特性方面不同于其他类别的双孔钾通道。本文总结了TRESK的研究现状,并根据目前的研究资料推测TRESK有可能通过激活钙调神经磷酸酶参与了急性和慢性疼痛的发生,是吸入性全身麻醉药的作用靶点,有可能通过对钙调神经磷酸酶的激活影响记忆,从而参与吸入性全身麻醉药的术后遗忘效应。对TRESK的深入研究有可能揭示某些病理生理状态的内在机制。     

Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile

Purpose: To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies.
Methods: Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB.
Results: Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p < 0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency > 50% ) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p < 0.027) and longer total time on VGB (p < 0.045) was associated with better IQ- developmental quotient ( DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52% . VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings.
Conclusion: We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.     

Comparing efficacy and side effects of a weekly intramuscular biogeneric/biosimilar interferon beta-1a with Avonex in relapsing remitting multiple sclerosis: a double blind randomized clinical trial

Objective

We compared the efficacy and safety of two biosimilar forms of interferon beta-1a in the treatment of multiple sclerosis: Avonex (Biogen Idec, USA) and CinnoVex (CinnaGen, Iran).

Methods

In a double blind randomized clinical trial study 84 patients with relapsing remitting multiple sclerosis (RRMS) with Expanded Disability Status Scale (EDSS) score of 0–5.5 were randomly allocated to two groups of 42 subjects.

Results

Twenty-four patients lost to follow-up. Finally, 31 patients (mean ± SD of age = 33.7 ± 7.0; 7 males and 24 females) in the Avonex and 29 patients (mean ± SD of age = 32.2 ± 9.2; 8 males and 21 females) in the CinnoVex group completed full 24 months of study period. Decrease in EDSS was 1.05 ± 0.24, p = 0.62 in the Avonex and 0.16 ± 0.88, p = 1.0 in the CinnoVex group after 12 months and 0.27 ± 1.05, p = 0.46 in the Avonex and 0.16 ± 1.06, p = 1.0 in the CinnoVex group after 24 months. There was no statistically significant difference in attack number between two groups (1.0 ± 1.2 in Avonex and 1.2 ± 1.3 in CinnoVex; p = 0.46). Volume of T2-weighted lesions on MRI showed a progressive significant increase in the 12th month (28056 ± 23693) in Avonex treated patients compared with first image (16353 ± 11172) (p = 0.01). But number of gadolinium-enhancing lesions in CinnoVex showed statistically significant decrease after 12 months (0.08 ± 0.28 vs. 1.00 ± 1.22; p = 0.03). However, there were no significant differences between groups after 24 months. There were no significant differences between 2 groups regarding frequency and duration of most considerable side effects, as well. Neutralizing antibodies were not positive in any patients.

Conclusion

CinnoVex can be used as a safe and effective alternative to Avonex in treatment of RRMS.     

Clearance of activity‐evoked K+ transients and associated glia cell swelling occur independently of AQP4: A study with an isoform‐selective AQP4 inhibitor

The mammalian brain consists of 80% water, which is continuously shifted between different compartments and cellular structures by mechanisms that are, to a large extent, unresolved. Aquaporin 4 (AQP4) is abundantly expressed in glia and ependymal cells of the mammalian brain and has been proposed to act as a gatekeeper for brain water dynamics, predominantly based on studies utilizing AQP4‐deficient mice. However, these mice have a range of secondary effects due to the gene deletion. An efficient and selective AQP4 inhibitor has thus been sorely needed to validate the results obtained in the AQP4^?/? mice to quantify the contribution of AQP4 to brain fluid dynamics. In AQP4‐expressing Xenopus laevis oocytes monitored by a high‐resolution volume recording system, we here demonstrate that the compound TGN‐020 is such a selective AQP4 inhibitor. TGN‐020 targets the tested species of AQP4 with an IC₅₀ of ~3.5 μM, but displays no inhibitory effect on the other AQPs (AQP1‐AQP9). With this tool, we employed rat hippocampal slices and ion‐sensitive microelectrodes to determine the role of AQP4 in glia cell swelling following neuronal activity. TGN‐020‐mediated inhibition of AQP4 did not prevent stimulus‐induced extracellular space shrinkage, nor did it slow clearance of the activity‐evoked K⁺ transient. These data, obtained with a verified isoform‐selective AQP4 inhibitor, indicate that AQP4 is not required for the astrocytic contribution to the K⁺ clearance or the associated extracellular space shrinkage.     

Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: a putative mechanism of antiseizure action

PURPOSE: Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known. METHODS: To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (beta-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes. RESULTS: We found that PUFAs at concentrations down to 21microM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing. CONCLUSIONS: These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels.     

The Drosophila Mutant tetanic Interacts with a Gene Complex Including the Structural Locus of K+ Channels and Shows Altered Dephosphorylation and Learning

The tetanic (tta; X.-52.6) mutation has been isolated on the basis of its sensitivity to extradoses of the normal Shaker gene complex (ShC) where the K+ channel la is encoded. The mutant shows up to threefold elevation of the membrane bound protein phosphatase type 1 (PP1) activity in body extracts, probably due to reduced levels of the PP1 specific inhibitor 2 (I-2). By contrast, PP1 activity in the head is only half of the normal value. In addition, tta fails to perform normally in a negative reinforcement olfactory paradigm. The functional relationships between phosphorylation, K+ currents, phosphatase activity and modulation of synaptic activity during learning and memory are discussed in the light of their possible genetic links.     

Japanese Creutzfeldt-Jakob disease patients exhibiting high incidence of the E200K PRNP mutation and located in the basin of a river

Abstract

Seven cases with Creutzfeldt-jakob disease (CJD) located in the basin of the Fuji river (Fuji area) in japan were examined genetically and clinicopathologically. The onset of the disease was between 7989 and 1995. All cases Were from different families, although 3.cases were family members of previously reported CJD patients. They had clinical and,or neuropathological features, corresponding to suba.cute spongiform encephalopathy. Five of the 7 cases, including the 3 familial cases, had the E200K mutation in the gene encoding prion protein (PRNP). It is suggested that there is a small cluster of CJD patients with a founder effect of the E200K mutation in the Fuji area, because the incidence of CJD with the E200K mutation appears to be much higher in this area than other areas in japan. The disease penetrance of the 5 cases with the E200K mutation seems to be low, and they may have an age-related incidence in the Fuji area. These findings support the hypothesis that the phenotypes of CJD patients with the PRNP mutations are linked to the position of the mutation, but not related to ethnic or environmental factors. [Neural Res 1998; 20: 684-688]