Neurodevelopmental Effects of Antiepileptic Drugs

Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.

     

The Effects of Levosimendan Exposure on Oxidant/Antioxidant Status and Trace Element Levels in the Pulmonary Artery of Rats

We investigated both the effect of levosimendan and the role of oxidant/antioxidant status and trace element levels in the pulmonary artery of rats. Fourteen male Wistar albino rats were randomly divided into two groups of seven animals each. Group 1 was not exposed to levosimendan and served as a control. Levosimendan (12 μg/kg) diluted in 10 ml 0.9 % NaCl was administered intraperitoneally to group 2. Animals of both groups were killed after 3 days, and their pulmonary arteries were harvested to determine changes in tissue oxidant/antioxidant status and trace element levels. The animals in both groups were killed 72 h after the levosimendan exposure treatment, and pulmonary arteries were harvested to determine levels of the lipid peroxidation product MDA and the antioxidant GSH as well as the decreased activity of antioxidant enzymes such as SOD, GSH-Px and CAT. It was found that MDA levels increased in pulmonary artery tissues of rats after levosimendan administration. The GSH level decreased in the pulmonary artery of rats after levosimendan treatment. Co, Mn, Fe, Cd and Pb levels were significantly higher (P < 0.001) and Mg, Zn and Cu levels significantly lower (P < 0.001) in the levosimendan group compared to the control group. These results suggest that levosimendan treatment caused an increase in free radical production and a decrease in antioxidant enzyme activity in the pulmonary artery of levosimendan-treated rats. It also caused a decrease or increase in the levels of many minerals in the pulmonary artery, which is an undesirable condition for normal pharmacological function.     

Trace Element Levels and Oxidant/Antioxidant Status in Patients with Alcohol Abuse

Biological Trace Element Research - Alcohol abuse is a well-known cause of imbalance in trace element levels and oxidant/antioxidant status of individuals with long time consumption. However, the...     

Nutraceutical Effect of Trace Elements as Additional Injectable Doses to Modulate Oxidant and Antioxidant Status,and Improves the Quality of Lamb Meat

Our study aimed to evaluate whether zinc, copper, selenium, and manganese subcutaneous mineral application (trace elements) reduced mortality, improved performance, and modulated oxidant and antioxidant balance in lamb meat, thereby improving its quality. We divided the 110 newborn Lacaune lambs into two groups: non-treated (control), and treated (application of minerals) with three doses of 0.33 mL/kg of body weight mineral complex on days of life 1, 30, and 60. All animals were weighed on day of life 1, 30, 60, 90, and 150. At the end of the experiment, 12 animals were slaughtered for physical and chemical analysis of meat, oxidant, and antioxidant status, and for allometric analysis. Mineral-application animals had greater live-weight (P < 0.05) on days of life 60 and 90. There was an increase in fat thickness (P = 0.004); pH levels (P = 0.002) were lower in mineral-application animal meat than in that of the control group. Meat was paler (according to lightness (L color)) in the control group (P = 0.04). Weight loss from cooking was greater in control animals (P = 0.004). Shear strength values were lower in the meat of treated lambs (P = 0.008) suggesting that mineral application was associated with increased meat tenderness. In addition, catalase and superoxide dismutase activities were higher (P = 0.01) in mineral-treated animals, associated with a reduction in reactive oxygen species levels (P < 0.01), and lipid peroxidation products (P = 0.02). These data suggest that mineral application modulated oxidant and antioxidant status, reflecting better meat quality.

     

NO Synthase and NO-Dependent Signal Pathways in Brain Aging and Neurodegenerative Disorders: The Role of Oxidant/Antioxidant Balance

Nitric oxide and other reactive nitrogen species appear to play several crucial roles in the brain. These include physiological processes such as neuromodulation, neurotransmission and synaptic plasticity, and pathological processes such as neurodegeneration and neuroinflammation. There is increasing evidence that glial cells in the central nervous system can produce nitric oxide in vivo in response to stimulation by cytokines and that this production is mediated by the inducible isoform of nitric oxide synthase. Although the etiology and pathogenesis of the major neurodegenerative and neuroinflammatory disorders (Alzheimer's disease, amyothrophic lateral sclerosis, Parkinson's disease, Huntington's disease and multiple sclerosis) are unknown, numerous recent studies strongly suggest that reactive nitrogen species play an important role. Furthermore, these species are probably involved in brain damage following ischemia and reperfusion, Down's syndrome and mitochondrial encephalopathies. Recent evidence also indicates the importance of cytoprotective proteins such as heat shock proteins (HSPs) which appear to be critically involved in protection from nitrosative and oxidative stress. In this review, evidence for the involvement of nitrosative stress in the pathogenesis of the major neurodegenerative/ neuroinflammatory diseases and the mechanisms operating in brain as a response to imbalance in the oxidant/antioxidant status are discussed.     

沈阳地区MRSA血浆凝固酶流行型别监测分析

为了掌握MRSA在沈阳地区流行病学特点 ,采用血浆凝固抑制试验检测 87株MRSA血浆凝固酶型别。结果显示 ,87株MRSA中血浆凝固酶Ⅱ型有 47株 (5 4% ) ,Ⅳ型 2 4株 (2 7.5 % ) ,Ⅶ型 7株 ,Ⅲ型 7株。按菌株来源分析 ,门诊患者MRSA血浆凝固酶型别分布散乱 ,而病房医护人员和住院患者的MRSA血浆凝固酶型别以Ⅱ型居多 ,Ⅳ型次之 ,有明显的偏重集中现象。可见 ,沈阳地区城市大医院MRSA感染蔓延较为严重 ,流行的主要血浆凝固酶型别为Ⅱ和Ⅳ型     

Neurology: Use of Antiepileptic Drugs in Pregnancy

The Scientific Board of the California Medical Association presents the following inventory of items of progress in neurology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items of progress in neurology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Neurology of California Medical Association, and the summaries were prepared under its direction.     

Antioxidant Enzymes and Related Trace Elements in Aging Brain Capillaries and Choroid Plexus

The activities of superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase, and catalase were measured in isolated brain capillaries, choroid plexus, cerebrum, and cerebellum from rats of 2, 6, 12, and 24 months. The contents of copper, zinc, and manganese were determined in capillaries, cerebrum, and cerebellum, and the profile of fatty acids was studied in brain capillaries. In brain capillaries, the activities of glutathione peroxidase and glutathione reductase did not change with age. The activities of the two enzymes increased in cerebrum and cerebellum. In choroid plexus, glutathione peroxidase activity increased, but glutathione reductase activity remained unchanged. Catalase activity in brain capillaries declined, whereas in choroid plexus, cerebrum, and cerebellum, it did not change. The activities of the three enzymes were significantly higher in brain capillaries and choroid plexus than in cerebrum and cerebellum. SOD activity increased in the four tissues. Copper content in the capillaries increased initially and then levelled off, whereas it continued to increase in cerebrum and cerebellum. Zinc increased in brain capillaries, but did not vary in cerebrum and cerebellum. Manganese content remained constant in all tissues studied. The percent of saturated fatty acids in brain capillaries did not change with age, whereas those of mono- and polyunsaturated fatty acids increased and decreased, respectively. The possibility that a deficiency of enzymes protective against free radicals causes blood-brain barrier and blood-cerebrospinal fluid barrier degeneration is ruled out.     

Effects of Soil Trace Elements on Longevity Population in China

Based on background concentrations of elements in soils and the sixth population census data of China, this study discussed the distribution characteristics of soil elements and longevity population at province level in China. Percentages of the aging population are high in Southwest China and the eastern coastal region but low in western and northwestern regions. Provinces in South and Southwest China gain a high level of longevity, while the northern part of China has a low level of longevity. The background concentration of Se in soil has a significant positive correlation with longevity index, while Ba and Ni have a significant negative correlation with longevity indexes. By regression analysis, longevity index C/100,000 can be expressed as C/100,000?=?1.679?0.205 Ni?+?0.413 Co?+?0.006 Se (with R ²?=?0.402 and p?<?0.01), C/65+ can be expressed as C/65+=3.425?0.262 Ni?+?0.435 Co?+?0.006 Se (with R ²?=?0.369 and p?<?0.01).     

微量元素对大肠杆菌生长和乙酸生成的影响研究

大肠杆菌DA19的代谢特性与培养基中添加微量元素有较大的关系。在基本培养基中,当氮源限制时,添加微量元素可以在一定程度上改善DA19菌体的生长,提高菌体得率YX/G,大大减少乙酸的生成;当氮源充分时,与不添加微量元素相比,DA19在添加微量元素后,菌体浓度大大增加,虽然葡萄糖消耗速率加快,但产乙酸仍然很少,只有不添加时的13％,YX/G提高至少60％。基本培养基中添加0.1～1mL/L的微量元素混合溶液对DA19菌体生长、乙酸生成及葡萄糖消耗没有显著影响。在单独添加不同种类的微量元素时, BO33-、Zn2+、MoO42+、Cu2+没有特别明显的影响,Al3+会抑制菌体生长和葡萄糖利用,而Co2+、Mn2+、Fe2+可以改善细胞生长,特别是添加Fe2+时,细胞生长及乙酸生成等培养结果与添加微量元素混合溶液几乎相同。     

Topotecan Treatment and Its Toxic Effects on Hematologic Parameters and Trace Elements

The aim of this study was to investigate the effects of topotecan, a topoisomerase I-inhibiting anticancer agent, on hematologic parameters and serum levels of trace elements. The study was conducted on three groups consisting of 16 and 18 rabbits in the study groups and 15 rabbits in the control group. Rabbits in group I (n = 16) received high-dose topotecan intravenously (i.v.; 0.5 mg/kg once daily), while rabbits in group II (n = 18) received low-dose topotecan i.v. (0.25 mg/kg once daily) for 3 days. The 15 rabbits comprising the control group did not receive topotecan. Serum samples were collected from each rabbit on the first day, before the treatment, and on the 15th day of treatment. Erithrocytes, hemoglobin, white blood cell count, thrombocyte count, and trace elements such as selenium, copper, lead, zinc, and cobalt were analyzed. Hemoglobin levels and erythrocyte counts were lower in both study groups than in the control group. However, thrombocyte and leukocyte counts were similar in all three groups (p > 0.005). Serum trace element levels (copper, lead, zinc, and cobalt) did not differ significantly between groups. However, serum selenium levels were significantly lower in both study groups than the control group (p < 0.001). The results revealed that topotecan treatment causes a decrease in erythrocyte counts and hemoglobin levels due to bone marrow suppression, and these effects must be taken into account during treatment. In addition, selenium supplementation might be helpful in cancer patients receiving topotecan to increase the effect of the chemotherapeutic agent.     

Pediatrics: New Antiepileptic Drugs for the Treatment of Childhood Epilepsies

The Council on Scientific Affairs of the California Medical Association presents the following epitomes of progress in pediatrics. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and clinical importance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of progress in medicine, whether in their own field of special interest or another.The epitomes included here were selected by the Advisory Panel to the Section on Pediatrics of the California Medical Association, and the summaries were prepared under the direction of Susan B. Conley, MD, and the panel.     

Role of Oxidative Stress and Ca2+ Signaling on Molecular Pathways of Neuropathic Pain in Diabetes: Focus on TRP Channels

Diabetes mellitus, a debilitating chronic disease, affects ~100?million people. Peripheral neuropathy is one of the most common early complications of diabetes in ~66?% of these patients. Altered Ca(2+) handling and Ca(2+) signaling were detected in a huge variety of preparations isolated from animals with experimentally induced type 1 and 2 diabetes as well as patients suffering from the disease. We reviewed the role of Ca(2+) signaling through cation channels and oxidative stress on diabetic neuropathic pain in sensory neurons. The pathogenesis of diabetic neuropathy involves the polyol pathway, advanced glycation end products, oxidative stress, protein kinase C activation, neurotrophism, and hypoxia. Experimental studies with respect to oxidative stress and Ca(2+) signaling, inhibitor roles of antioxidants in diabetic neuropathic pain are also summarized in the review. We hypothesize that deficits in insulin, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca(2+) homeostasis and oxidative stress and associated mitochondrial dysfunction. The transient receptor potential channels are a large family of proteins with six main subfamilies. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging in diabetic neuropathic pain and it seems that the TRPC, TRPM and TRPV groups are mostly responsible from diabetic neuropathic pain. In conclusion, the accumulating evidence implicating Ca(2+) dysregulation and over production of oxidative stress products in diabetic neuropathic pains, along with recent advances in understanding of genetic variations in cation channels such as TRP channels, makes modulation of neuronal Ca(2+) handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many diabetic neuropathies.     

Mexiletine and its Interactions with Classical Antiepileptic Drugs: An Isobolographic Analysis

Using the mouse maximal electroshock test, the reference model of tonic–clonic seizures, the aim of the present study was to determine the type of interaction between mexiletine (a class IB antiarrhythmic drug) and classical antiepileptics: valproate, carbamazepine, phenytoin, and phenobarbital. Isobolographic analysis of obtained data indicated antagonistic interactions between mexiletine and valproate (for fixed ratio combinations of 1:1 and 3:1). Additivity was observed between mexiletine and valproate applied in proportion of 1:3 as well as between mexiletine and remaining antiepileptics for the fixed ratios of 1:3, 1:1, and 3:1. Neither motor performance nor long-term memory were impaired by mexiletine or antiepileptic drugs regardless of whether they were administered singly or in combination. Mexiletine did not significantly affected brain concentrations of carbamazepine, phenobarbital or phenytoin. In contrast, the antiarrhythmic drug decreased by 23 % the brain level of valproate. This could be, at least partially, the reason of antagonistic interaction between the two drugs. In conclusion, the observed additivity suggests that mexiletine can be safely applied in epileptic patients treated with carbamazepine, phenytoin or phenobarbital. Because of undesirable pharmacodynamics and pharmacokinetic interactions with valproate, mexiletine should not be used in such combinations.

     

三种抗癫痫药对癫痫患者脑电图的背景影响比较研究

目的:研究对比三种抗癫痫药(苯妥因钠、丙戊酸钠、卡马西平)对癫痫患者脑电图的背景影响。方法:选取我院于2009年3月至2011年2月收治的60例癫痫患者,随机分为苯妥因钠(PHT)、卡马西平(CBZ)和丙戊酸钠(SVP)组各20例,动态观察各组患者于治疗期间痫样波放电的频度和EEG背景的变化。结果:EEG痫样波放电的抑制率以SVP最为明显,而CBZ在EEG背景活动影响方面均比其他两组显著。结论:三种药物对癫痫波放电的抑制顺序是SVP>PHT>CBZ,SVP组明显优于其他两组。     

三种抗癫痫药对癫痫患者脑电图的背景影响比较研究

目的：研究对比三种抗癫痫药（苯妥因钠、丙戊酸钠、卡马西平）对癫痫患者脑电图的背景影响。方法：选取我院于2009年3月至2011年2月收治的60例癫痫患者,随机分为苯妥因钠（PHT）、卡马西平（CBZ）和丙戊酸钠（SVP）组各20例,动态观察各组患者于治疗期间痫样波放电的频度和EEG背景的变化。结果：EEG痫样波放电的抑制率以SVP最为明显,而CBZ在EEG背景活动影响方面均比其他两组显著。结论：三种药物对癫痫波放电的抑制顺序是SVP〉PHT〉CBZ,SVP组明显优于其他两组。     

Antioxidant Status in Blood of Obese Children: The Relation between Trace Elements,Paraoxonase, and Arylesterase Values

Obesity is known to lead to complications involving several systems. The basic mechanism in obesity-related complications is chronic inflammation and increased oxidative stress. Trace element levels in obese children may vary due to poor nutritional habits. The purpose of this study was to investigate the relation between serum paraoxonase (PON1) and arylesterase (ARE) levels, markers of the oxidant–antioxidant balance in the body, and serum zinc (Zn), copper (Cu), manganese (Mn), and selenium (Se) concentrations in obese children. Fifty-seven overweight patients aged 6–17 and 48 age- and sex-matched healthy children were included in the study. Serum PON1 and ARE activity levels were measured, together with Cu, Zn, Mn, Se, total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, glucose, aspartate amino transferase, and alanine amino transferase levels. PON1 and ARE activity levels were significantly lower in obese patients compared to those in healthy individuals (P?<?0.05). Various changes were determined in Cu, Zn, Mn, and Se levels between the study and control groups (P?<?0.05). In terms of the relation between trace elements and PON1 and ARE levels, a significant positive correlation was determined between serum Se and PON1 levels in the study group (P?<?0.05, r?=?0.31). No significant correlation was determined between other trace element levels and PON1 and ARE levels (P?>?0.05). In conclusion, the detection in our study of a positive correlation between Se and PON1 levels in obese children may be significant in terms of showing a relation between Se and antioxidant systems in obese children.