左乙拉西坦添加治疗对难治性部分性癫痫患者生活质量影响的研究

目的：评价新型抗癫痫药物左乙拉西坦（Lev）作为添加治疗对难治性部分性癫痫患者生活质量的影响。方法：43例确诊有癫痫部分性发作的成年患者随机分为两组：Lev治疗组与安慰剂组,Lev治疗16周后比较两组的有效率和不良反应,并用QOLIE-31量表对两组癫痫患者进行生活质量评定,所有患者在转入Lev开放性治疗6个月后再次进行QOLIE评估。结果：16周治疗期末Lev组癫痫部分性发作的治疗有效率明显高于安慰剂组,两组不良反应的发生率相当;Lev组生活质量明显高于安慰剂组,两组患者转入开放性治疗6个月后,生活质量均显著改善。结论：Lev作为添加用药治疗成人难治性部分性癫痫发作,显著减少发作频率、安全耐受性较好,能够提高癫痫患者的生活质量。     

多中心、随机、双盲、安慰剂对照评价普瑞巴林添加治疗部分性癫发作的疗效和安全性

目的评价普瑞巴林添加治疗部分性癫发作的疗效和安全性。方法采用随机、双盲、安慰剂对照、多中心平行设计添加治疗的方法,确诊为有部分性癫发作的225例癫患者,被随机分配入普瑞巴林治疗组(114例)与安慰剂组(111例)。在6周前瞻性基线期后,采用灵活剂量的普瑞巴林(150~600 mg·d-1)添加治疗成人部分性癫发作。主要疗效指标:部分性癫发作28 d-反应率。次要疗效指标:部分性癫发作28d-减少率、临床疗效评价、16周内癫无发作和发作减少率≥50%的病例比例、第13~16周癫无发作和发作减少率≥50%的病例比例以及临床疗效总评量表评分;并观察研究药物的安全性与不良反应情况。结果普瑞巴林组部分性癫发作28 d-反应率(-40.24±37.88)%,显著高于安慰剂组(-22.84±37.61)%(F=15.063 9,P=0.000 1)。普瑞巴林组和安慰剂组的不良事件发生率分别为60.53%和47.75%,组间无显著差异;但普瑞巴林组的不良反应发生率较安慰剂组高(45.61%vs 23.42%,P=0.000 7),主要不良反应有头晕、嗜睡、视物模糊、乏力等。结论普瑞巴林组的疗效显著优于安慰剂组。普瑞巴林作为部分性癫发作的添加药物有确定的疗效,安全耐受性较好,具有一定临床应用价值。     

醋甲唑胺添加治疗成人难治性癫部分性发作研究

目的探讨醋甲唑胺添加治疗成人难治性癫部分性发作的疗效及耐受性。方法采用自身对照方法,对63例难治性癫患者在原抗癫药的基础上添加醋甲唑胺(25 mg,3次/d)治疗。12周后评价其疗效及耐受性。结果 63例难治性癫患者,完成观察62例,其中复杂部分性发作患者失访1例,显效15例(24.2%),有效3例(21.0%),无效31例(50.0%),加重3例(4.84%),总显效率24.2%,总有效率45.2%。其中单纯部分性发作总有效率73.3%,明显高于其他两种类型,差异有统计学意义(P<0.05),所有病例均无严重不良反应及肾结石发生。结论醋甲唑胺添加治疗成人难治性癫部分性发作有一定疗效且以单纯部分性发作效果最佳,耐受性好,价格便宜,值得临床推广应用。     

左乙拉西坦添加治疗对部分性癫患者认知及生活质量的影响

目的探讨左乙拉西坦添加治疗对部分性癫患者认知及生活质量的影响。方法选取2011-01—2012-06就诊于本院神经内科的部分性癫患者40例,按照随机对照原则分为观察组和对照组,每组各20例。在常规治疗基础上,观察组患者加用左乙拉西坦治疗,对照组给予安慰剂治疗。治疗6个月,对2组患者的认知及生活质量情况进行比较。结果 (1)治疗6个月后,观察组治疗有效率高于对照组,差异有统计学意义(χ2=8.64,P<0.01);(2)左乙拉西坦添加治疗6个月后,在对发作的担心、精力/疲乏、认知、药物影响、社会功能及生活质量总分均高于对照组,差异有统计学意义(P<0.05)。结论左乙拉西坦添加治疗部分性癫发作,可有效减少发作次数,提高患者的生活质量,改善患者的认知。     

多中心双盲、随机、安慰剂对照评价左乙拉西坦添加治疗难治性部分性癫(癎)发作的疗效及安全性

目的 评价左乙拉西坦(LEV)添加用药治疗难治性部分性癫(癎)发作的临床疗效及安全性.方法 随机、双盲、安慰剂对照、多中心平行设计添加治疗,确诊为有癫(癎)部分性发作的202例癫(癎)患者,平均年龄(32.8±12.7)岁,随机分配入LEV治疗组(n=102)与安慰剂组(n=100).在回顾8周基线期的癫(癎)发作频率后,进入逐量加药期.初始用药剂量为0.5 g,每日2次,2周后增加至1.0 g,每日2次服用,4周后加量至1.5 g,每日2次,随后维持该剂量治疗12周,最后逐渐减量并转入LEV开放治疗期.主要评价指标为16周治疗期内每周癫(癎)发作频率的比较、得出药物治疗发作频率减少50%有效率、安全性和药物不良反应.结果 在16周治疗期内,LEV组每周癫(癎)发作频率明显减少,较安慰剂组减少26.8%;每周发作频率较基线期下降数在LEV组与安慰剂组的组间差异为42.2%;部分性发作频率减少50%有效率为55.9%,与安慰剂组比的OR值为3.6;有11例治疗后完全无发作,两组相比均有显著统计学意义(P＜0.001).LEV组的主要不良事件为嗜睡、头晕、无力及血小板减少,但与安慰剂组比差异无统计学意义.结论 LEV添加用药治疗成人难治性部分性癫(癎)发作,可以显著减少癫(癎)发作频率,安全性良好.     

左乙拉西坦添加治疗对青年癫(癎)患者生活质量影响的研究

目的 评价新型抗癫(癎)药物左乙拉西坦添加治疗青年难治性部分性癫(癎)患者的疗效,以及对患者生活质量的影响.方法 30例诊断明确的部分性发作青年患者随机分为左乙拉西坦组和吡拉两坦组,计算左乙拉西坦治疗第12周末时治疗有效率;依据癫(癎)生活质量量表-31分别评价两组患者在左乙拉西坦剂量维持期(12周)和开放性治疗期(12周)的生活质量.结果 治疗第12周末时,左乙拉西坦组治疗有效率(43.75%,7/16)高于吡拉两坦组(35.72%,5/14;Fisher精确概率法:P=0.031),生活质最明显改善(与基线比较:t=3.905.P=0.001).治疗第24周末时,两组患者生活质量较治疗前均显著改善(左乙拉西坦组:t=4.940,P:0.021;吡拉西坦组:t=2.575.P=0.023).结论 左乙拉两坦作为抗癫(癎)药的添加治疗药物,能够显著减少青年难治性部分性癫(癎)患者的发作频率,快速有效地提高患者生活质量.     

妥泰添加治疗难治性癫的临床观察

目的观察妥泰作为治疗难治性癫的添加剂的疗效及不良反应。方法临床选取13例难治性癫患者,其中3例全面性强直阵挛发作,9例复杂部分性发作,1例单纯部分性发作。病程均在2年以上;经一线抗癫药物正规治疗1年以上仍频繁发作,每月发作频率均为4次以上;影响日常工作、生活;妥泰用药方法:成人用25mg开始,以后每周加25mg或50mg至发作控制或达到200mg/d;儿童1mg/(kg.d),以后每周增加1mg/(kg.d)至发作控制或达到5mg/(kg.d),以后维持观察12周,共20周。结果经治疗5例发作减少75%以上(显效),3例发作减少50%(有效),2例发作减少25%以下(无效),1例发作增加25%以上(恶化),2例退出。总有效率61.5%。主要不良反应有厌食、恶心、呕吐、体重减轻、记忆力下降。结论妥泰作为添加药物对难治性癫疗效较好,特别是对复杂部分性发作,有效率达77.8%。     

多中心、随机、双盲、安慰剂对照评价普瑞巴林添加治疗部分性癫癎发作的疗效和安全性

目的 评价普瑞巴林添加治疗部分性癫（癎）发作的疗效和安全性.方法采用随机、双盲、安慰剂对照、多中心平行设计添加治疗的方法,确诊为有部分性癫（癎）发作的225例癫（癎）患者,被随机分配入普瑞巴林治疗组（114例）与安慰剂组（111例）.在6周前瞻性基线期后,采用灵活剂量的普瑞巴林（150～600 mg·d-1）添加治疗成人部分性癫（癎）发作.主要疗效指标：部分性癫（癎）发作28 d-反应率.次要疗效指标：部分性癫（癎）发作28d-减少率、临床疗效评价、16周内癫（癎）无发作和发作减少率≥50％的病例比例、第13～16周癫（癎）无发作和发作减少率≥50％的病例比例以及临床疗效总评量表评分;并观察研究药物的安全性与不良反应情况.结果 普瑞巴林组部分性癫（癎）发作28 d-反应率（-40.24±37.88）％,显著高于安慰剂组（-22.84±37.61）％（F=15.063 9,P=0.000 l）.普瑞巴林组和安慰剂组的不良事件发生率分别为60.53％和47.75％,组间无显著差异;但普瑞巴林组的不良反应发生率较安慰剂组高（45.61％ vs 23.42％,P=0.000 7）,主要不良反应有头晕、嗜睡、视物模糊、乏力等.结论 普瑞巴林组的疗效显著优于安慰剂组.普瑞巴林作为部分性癫（痈）发作的添加药物有确定的疗效,安全耐受性较好,具有一定临床应用价值.     

小儿颞叶癫的临床表现及脑电图分析

目的探讨小儿颞叶癫的临床特征及脑电图特点。方法收集16例颞叶癫患儿,对其发作的临床特点及脑电图资料进行分析,对比难治性癫的脑电图变化规律。结果患儿的癫发作形式主要表现为单纯部分性发作、复杂部分性发作、继发全面性发作。单纯部分发作频率高而持续时间短,复杂部分发作持续时间长但发作频率低并常见发作后朦胧状态。颞叶癫的脑电图特点:背景正常者约占62.5%(10/16);背景异常约占37.5%(6/16);异常放电及部位:颞叶棘波或慢波放电,表现为单侧或双侧同步或不同步放电。结论小儿颞叶癫是一组部分性症状性癫综合征,多表现为复杂部分发作,临床发作及同步脑电图特点可为临床诊治提供帮助。     

左乙拉西坦治疗难治性癫痫48例的临床研究

目的：探讨左乙拉西坦（Lev）添加剂量治疗难治性癫痫的疗效和安全性。方法：采用开放性自身对照方法,对48例（儿童23例,成人25例）难治性癫痫患者进行Lev添加治疗,并随访1年以上,收集治疗后患者发作频率变化、无发作情况、不良反应以及退出原因。结果：Lev治疗难治性癫痫总有效率为64．58％,成人有效率高于儿童,对部分性癫痫综合征有效率高;3、6和12个月无发作率分别为6．25％、18．75％和16．67％,保留率为81．25％、56．25％和43．75％。总不良反应发生率为39．58％,无严重不良反应,退出的最主要原因为对疗效欠满意。结论：LEV是一种安全有效的难治性癫痫治疗药物,对部分性和全面性癫痫发作均有效。     

传统抗癫痫药物和妥泰对成年癫痫患者生活质量的影响

目的 评价传统抗癫痫药物和妥泰对成年癫痫患者生活质量的影响。方法 102例临床新确诊的成年癫痫患者被随机分为两组：一组予以传统抗癫痫药物单药系统治疗(AEDs组)，另一组予以妥泰单药治疗(TPM组)。1个月后比较两组的发作频率和不良反应。并用QOLIE-30表对这102例癫痫患者进行生活质量评定。结果 TPM组的发作频率和不良反应均明显低于AEDs组，而生活质量总分明显高于AEDs组，尤其在前五项的评分中更加明显。结论 TPM能提高癫痫患者的生活质量，其改善生活质量的作用主要是通过控制发作和减轻不良反应实现的。     

Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. European Levetiracetam Study Group

PURPOSE: To evaluate the efficacy and tolerability of levetiracetam (LEV, Keppra) as add-on therapy in patients with refractory partial seizures. METHODS: In this European multicenter, double-blind, randomized, placebo-controlled trial, LEV (500 or 1,000 mg twice daily) was compared with placebo as add-on therapy in 324 patients with uncontrolled simple or complex partial seizures, or both, with or without secondary generalization. After enrollment, three parallel groups were assessed during a baseline period of 8 or 12 weeks, followed by a 4-week titration interval and a 12-week evaluation period. RESULTS: LEV significantly decreased partial seizure frequency compared with placebo. A reduction in seizure frequency of > or =50% occurred in 22.8% of patients in the 1,000-mg group and 31.6% of patients in the 2,000-mg group, compared with 10.4% of patients in the placebo group. Administration of LEV did not affect plasma concentrations of concomitant antiepileptic drugs or alter vital signs or laboratory parameters. No significant difference in the incidence of adverse events was observed between treatment groups (70.8% for the 1,000-mg group and 75.5% for the 2,000-mg group), or between the LEV and placebo groups (73.2% for placebo group). The most commonly reported adverse effects in the LEV group were asthenia, headache, and somnolence. CONCLUSIONS: The antiepileptic efficacy and tolerability of LEV (1,000 mg/d and 2,000 mg/d, administered in two divided doses) as add-on therapy was established in patients with refractory partial seizures in this clinical study.     

Normalization of quality of life three years after temporal lobectomy: a controlled study

PURPOSE: The goal of epilepsy surgery is not merely to control previously intractable seizures, but also to improve quality of life (QOL). Our goals were to assess, in our Middle Eastern population, the QOL of adults with temporal lobe epilepsy (TLE) 3 years after temporal lobectomy as compared with matched TLE patients who did not undergo surgery and with healthy individuals in the same community. METHODS: Twenty consecutive TLE patients who underwent temporal lobectomy 3 years previously were matched in the following variables: age, sex, seizure frequency, seizure duration, age at onset of epilepsy, duration of epilepsy, and number of medications, with 17 TLE patients who underwent the presurgical evaluation and subsequent optimization of medical therapy but did not undergo surgery. They were also matched for age, sex, educational level, income, and residence with 20 healthy individuals. All groups were interviewed by using the ESI-55 questionnaire. RESULTS: Compared with the nonsurgery group, QOL was significantly better in the surgery group (85% seizure free) in the well-being, functioning, and role-limitation domains. QOL was similar in the surgery and healthy control groups in all domains and scales. The nonsurgery group scored significantly lower than healthy controls in the functioning and role-limitation domains. CONCLUSIONS: Intractable TLE was associated with marked impairments in QOL despite continued attempts to optimize medical therapy. Three years after temporal lobectomy QOL in our patient population achieved levels similar to those of matched healthy individuals. To our knowledge, this is the first study to report normalization of QOL after temporal lobectomy, in any population.     

Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial

OBJECTIVE: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. METHODS: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. RESULTS: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p /=10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. CONCLUSION: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.     

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

Purpose:  To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial‐onset seizures. Methods:  Data from 1,049 patients enrolled from 125 centers, in 23 countries, in three phase III double‐blind, randomized, placebo‐controlled studies were pooled and analyzed. Following a 2‐week titration period, ESL was administered at 400 mg, 800 mg, and 1,200 mg once‐daily doses for 12 weeks. Key Findings:  Seizure frequency was significantly reduced with ESL 800 mg (p < 0.0001) and 1,200 mg (p < 0.0001) compared to placebo. Median relative reduction in seizure frequency was, respectively, 35% and 39% (placebo 15%) and responder rate was 36% and 44% (placebo 22%). ESL was more efficacious than placebo regardless of gender, geographic region, epilepsy duration, age at time of diagnosis, seizure type, and number and type of concomitant antiepileptic drugs (AEDs). Incidence of adverse events (AEs) and AEs leading to discontinuation were dose dependent. AEs occurred mainly during the first weeks of treatment, with no difference between groups after 6 weeks. Most common AEs (>10% patients) were dizziness, somnolence, and headache. The incidence of AEs in ESL groups compared to placebo was generally consistent among different subpopulations. Significance:  Once‐daily ESL 800 mg and 1,200 mg showed consistent results across all efficacy and safety end points. Results were independent of study population characteristics and type and number of concomitant AEDs.     

Efficacy and safety of Losigamone in partial seizures: a randomized double-blind study

The objective of the study was to investigate the efficacy and safety of two different dosages of Losigamone (LSG) in add-on treatment of partial seizures. In a multi-center, double-blind, randomized clinical trial, patients received one of three 12-week treatments: placebo, LSG 1200 mg/day, or 1500 mg/day, in addition to up to three standard anticonvulsants after a prospective period of 12 weeks to assess baseline seizure frequency. The primary efficacy measure was the relative reduction of seizure frequency per 4 weeks in the double-blind phase as compared to baseline. In the intention-to-treat population of 264 patients, the relative median reduction of partial seizure frequency was 3.3% for placebo, 19.7% for LSG 1200 mg/day, and 25.3% for LSG 1500 mg/day. The differences of both LSG groups versus placebo were significant (P<0.01, two-tailed). In the responder analysis, 11.8% of the patients in the placebo group, 17.2% in the LSG 1200 mg/day group, and 29.3% in the LSG 1500 mg/day group showed a seizure reduction versus baseline of at least 50%. A positive association between dosage and response was observed (P=0.003). Adverse events during treatment were reported by 58.8% of the patients for placebo, by 62.1% for LSG 1200 mg/day and by 76.1% for LSG 1500 mg/day. Most events in the LSG groups occurred during the first 4 weeks of double-blind (during or immediately after up-titration) and subsided quickly. Over the last 4 weeks of treatment, the incidence of adverse events in the LSG groups was close to the placebo level. Based on the study's results, LSG is an effective and safe add-on drug for refractory partial epilepsy in adults.     

Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: A randomized, double-blind, placebo-controlled, parallel-group phase III study

Purpose: To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with ≥4 partial‐onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1–2 antiepileptic drugs (AEDs). Methods: This multicenter, parallel‐group study had an 8‐week, single‐blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once‐daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double‐blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400‐mg steps to the full maintenance dose (12 weeks). Results: Seizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200‐mg (p = 0.0003) and 800‐mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of log‐transformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56–62% of patients), lamotrigine (25–27%), and valproic acid (22–28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate. Discussion: ESL, 800 and 1,200 mg once‐daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.     

传统抗癫疒间药物与托吡酯对成年癫疒间患者生活质量影响的对比研究

目的 探讨传统抗癫癎药物(AEDs)与托吡酯(TPM)对成年癫癎患者生活质量(QOL)的影响。方法 102例临床确诊的成年癫癎患者随机分为AEDs组和TPM组,井用QOL IE-30表对102例癫癎患者和62名正常人(对照组)进行评定。结果 AEDs组较对照组QOL明显降低(P<0.05),表现惧怕发作,对日常生活不满意,情绪差,精力不足,认知功能下降,对长期服用抗癫癎药物的顾虑较多,社交、工作受限等;而TPM组的QOL虽然低于对照组(P<0.05),但在前5项的评分中明显高于AEDs组(P<0.05)。TPM组的发作频率明显低于AEDs组(P<0.05)。发作频率对癫癎患者QOL的影响较大,癫癎发作越频繁,QOL越差。结论 成年癫癎患者的QOL较正常人显著降低,TPM能提高癫癎患者的QOL,其改善QOL的作用主要是通过控制发作实现的。因此,合适的药物控制癎性发作是提高癫癎患者QOL的关键。     

Improved quality of life in patients with partial seizures after conversion to oxcarbazepine monotherapy

OBJECTIVE: Quality of life (QOL) was assessed in patients who switched to oxcarbazepine monotherapy because of the lack of efficacy or poor tolerability of their current antiepileptic drug (AED). METHOD: This open-label, single-arm study consisted of patients aged 12 >or= years with partial onset seizures. Oxcarbazepine (8-10mg/kg/day for children, 600 mg/day for adults) was titrated up over 4 weeks while the existing AED was tapered off. QOL was evaluated at baseline and end of study (Week 16) using the validated-in-epilepsy QOLIE-31 questionnaire. RESULTS: For all patients who completed the QOLIE-31 at baseline and completion, a statistically significant improvement was noted for both the composite and multi-item subscale QOL scores (P<0.05 vs baseline). Statistically significant mean percentage improvements of >or=10% from baseline (range=10.8-50.1%) were also noted. Significant improvements were seen in health-related QOL for patients who experienced seizure freedom or >or=50% reductions in seizure frequency with oxcarbazepine monotherapy. CONCLUSIONS: Patients with partial seizures who switched to oxcarbazepine monotherapy showed statistically significant, clinically relevant improvements in QOL.     

A double-blind, placebo-controlled evaluation of the efficacy and safety of loreclezole as add-on therapy in patients with uncontrolled partial seizures

Sixty-two patients with uncontrolled partial seizures participated in a 12-week, double-blind, placebo-controlled add-on-trial. Thirty-two patients received loreclezole and 30 a placebo as add-on therapy. Loreclezole was targeted at a plasma level of 1-2 mg/l. In spite of an antiepileptic therapy, usually with 2 or 3 antiepileptic drugs, these patients had at least 4 seizures a month during the baseline period. At the end of the treatment phase with loreclezole and placebo, individual responses varied widely. The median change in the daily seizure frequency was not significantly different in the 2 groups. However, when individual responses are considered, 6 patients in the verum group (19%) experienced a seizure reduction of 50% or more, compared with no patients in the placebo group. During the trial, only mild adverse events were reported in both the loreclezole and the placebo group, nor were any clinically relevant abnormalities seen in the haematological and biochemical analysis. The efficacy and safety of higher loreclezole plasma concentrations were studied in a long-term follow-up trial, the results of which are presented in the following article.