Patch testing and cross sensitivity study of adverse cutaneous drug reactions due to anticonvulsants: A preliminary report

AIM To evaluate the utility of patch test and cross-sensitivity patterns in patients with adverse cutaneous drug reactions(ACDR) from common anticonvulsants. METHODS Twenty-four(M:F = 13:11) patients aged 18-75 years with ACDR from anticonvulsants were patch tested 3-27 mo after complete recovery using carbamazepine, phenytoin, phenobarbitone, lamotrigine, and sodium valproate in 10%, 20% and 30% conc. in pet. after informed consent. Positive reactions persisting on D3 and D4 were considered significant. RESULTS Clinical patterns were exanthematous drug rash with or without systemic involvement(DRESS) in 18(75%), Stevens-Johnsons syndrome/toxic epidermal necrolysis(SJS/TEN) overlap and TEN in 2(8.3%) patients each, SJS and lichenoid drug eruption in 1(4.2%) patient each, respectively. The implicated drugs were phenytoin in 14(58.3%), carbamazepine in 9(37.5%), phenobarbitone in 2(8.3%), and lamotrigine in 1(4.7%) patients,respectively. Twelve(50%) patients elicited positive reactions to implicated drugs; carbamazepine in 6(50%), phenytoin alone in 4(33.3%), phenobarbitone alone in 1(8.3%), and both phenytoin and phenobarbitone in 1(8.33%) patients, respectively. Cross-reactions occurred in 11(92%) patients. Six patients with carbamazepine positive patch test reaction showed cross sensitivity with phenobarbitone, sodium valproate and/or lamotrigine. Three(75%) patients among positive phenytoin patch test reactions had cross reactions with phenobarbitone, lamotrigine, and/or valproate. CONCLUSION Carbamazepine remains the commonest anticonvulsant causing ACDRs and cross-reactions with other anticonvulsants are possible. Drug patch testing appears useful in DRESS for drug imputability and cross-reactions established clinically.

Risk of Autism Spectrum Disorder According to the Dose and Trimester of Exposure to Antiseizure Medications: A Systematic Review and Meta-Analysis

Background: The association between prenatal exposure to antiseizure medications (ASM) and autism spectrum disorder has been documented. This study sought to examine and synthesize evidence from studies that have evaluated these associations, with particular focus on the trimester of pregnancy and dosage of exposure. Methodology: PubMed, Embase, and PsycINFO databases were searched following strict inclusion/exclusion criteria. 10 studies were recruited involving children born to mothers with epilepsy who took ASM during pregnancy as cases, and those with epilepsy who did not take any ASM in pregnancy. Results: The relative risk of developing ASD among children exposed to valproic acid (RR, 3.90 [95% CI: 2.36 - 6.44], p < 0.006), was twice higher than that of carbamazepine (RR, 1.65 [95% CI: 0.62 - 4.37], p < 0.0001), or lamotrigine (RR, 1.60 [95% CI: 0.77 - 3.32], p = 0.006). The trimester of exposure and dosage of ASM administered were not significant. Conclusion: In summary, prenatal exposure to ASM increased the risk of developing ASD in children. The relative risk was twice as high in those exposed to valproic acid compared to those exposed to carbamazepine or lamotrigine. Trimester of pregnancy and dosage of ASM used by the mothers were not significant.

Synergistic effect of pinellia total alkaloids and uncaria total alkaloids on anticonvulsant action in mice and rats

Aim To investigate the synergistic effect of the combination of pinellia total alkaloid （PTA） and uncaria total alkaloid （UTA）, and explore the mechanism of anticonvulsant action. Methods Anticonvulsant and toxic effect profiles of combinations of PTA with UTA, alone and at three fixed ratios of 1：4, 1 ：1, 4：1, were evaluated in maximal electroshock （MES）-induced seizures and acute toxicity test in mice. Respective ED50 and LD50 were calculated with Bliss＇s method. Their synergistic effect were evaluated by isobolographic analysis and allowed the determination of benefit indices （BI） for respective combinations. The model of convulsive rats kindled by penicillin topically injected into cortex was used to investigated the content of Glu, Asp, Gly and GABA in hippocampus using high performance liquid chromatography （HPLC）. Results Combinations of PTA and UTA at the ratio of 4：1 were synergistic in MES test and antagonistic in acute toxicity test, showing the best profile for combinations of PTA with UTA. In contrast, the ratios of 1 ：4 and 1 ： 1, despite synergistic in MES test, were additive in acute toxicity test. The 4：1 combination and two drugs alone significantly decreased Glu level and increased GABA level in the hippocampus, but the GABA level in the 4：1 combination group was higher than that in the two drugs alone groups. They did not have significant influence on the levels of ASp and Gly. Conclusion Combinations of PTA and UTA at 4：1 ratio demonstrated synergistic effect in anticonvulsant action and antagonistic effect in toxicity. The anticonvulsant mechanism might be related to decreasing the excitability of Glutamatergic neurons and increasing the inhibition of GABAergic neurons.

Diabetic neuropathic pain:Physiopathology and treatment

Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes,which affects over 90% of the diabetic patients.Although pain is one of the main symptoms of diabetic neuropathy,its pathophysiological mechanisms are not yet fully known.It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication,but several other hypotheses have been postulated.The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy,improving glycemic control as a prophylactic therapy and using medications to alleviate pain.First line drugs for pain relief include anticonvulsants,such as pregabalin and gabapentin and antidepressants,especial y those that act to inhibit the reuptake of serotonin and noradrenaline.In addition,there is experimental and clinical evidence that opioids can be helpful in pain control,mainly if associated with first line drugs.Other agents,including for topical application,such as capsaicin cream and lidocaine patches,have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain,but the clinical evidence is insufficient to support their use.In conclusion,a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies,but also to the improvement of the guidelines to optimize pain control with the drugs currently available.

Clinical Observation on 930 Child Epilepsy Cases Treated with Anti-epilepsy Capsules

1090 cases of child epilepsy were divided randomly into two groups: the treatment group (930 cases treated with anti-epilepsy capsules) and the control group (160 cases treated with luminal). The results showed that in the treatment group, 534 cases were markedly effective, 241 effective, 96 improved, 46 ineffective, and 13 aggravated, with a total effective rate of 83.33%; while in the control group, 64 cases were markedly effective, 19 effective, 38 improved, 29 ineffective, and 10 aggravated, with a total effective rate of 51.88%. The treatment group showed an obviously higher total effective rate than that in the control group (P<0.01). After treatment, cases in the two groups all had lower frequency of epilepsy attacks and shorter duration of each attack as compared with that before treatment (P<0.01), but the situation was obviously better in the treatment group. The anti-epilepsy capsules had very good effect on various types of epilepsy, especially on autonomic epilepsy and on epilepsies due to wind, phlegm, or terror as differentiated in TCM. After treatment, the recovery rate shown by EEG examination was 54.3% in the treatment group, while 38.4% in the control group, the former being obviously higher than the latter (P<0.01).

A Study of the Relationship Between the Chemical Structure and the Anticonvulsant Activity of the 3-Pyrazolidinones

The Hansch approach was used in the quantitative structure anticonvulsant activity studies of the previously synthesized 1-substituted-and 1.5-disubstituted-3-pyrazo- lidinones.Correlation analysis predicted that 1.5-disubstituted-3-pyrazoljdinones in which 1- substituent is n-propyl but not benzyl.with the total hydrophobic constant of 1-and 5-sub- stituents(∑л)equals to 4.5(optimum value)will have the most potent activity.On the basis of this analysis eleven 5-substituted and I-n-butyl-5-substituted-3-pyrazolidinones were syn- thesized.Pharmacological tests indicated that the prediction of the Hansch analysis of the 3- pyrazolidinones is correct.The Hansch analysis,by including these 11 compounds,gives an almost identical correlation with that previously obtained.

Studies on the Synthesis, Anticonvulsant Activity, and the Structure-Activity Relationships of Phenyl Pyridazinones and their GABA Derivatives

In searching for effective anticonvulsant agents,fourteen 6-aryl-4.5-di- hydro-3(2H)pyridazinones.fifteen 6-aryl-3(2H)pyridazinones,and seventeen 3-GABA derivatives of 6-aryIpyridazines have been synthesized,and evaluated in mice for the ability to antagonize maximal electroshock seizure(MES).The ED_(50) values showed that 6-(2′,4′- dichlorophenyt)-3(2H)pyridazinone was the most potent anticonvulsant among these corn- pounds(ED_(50)=10.15 mg/kg).The structure-activity relationships of the aryl pyridazinones were studied.The result showed that:(1)the higher the value of the hydrophobic parameter л of the substituent on the phenyl ring.the more potent the anticonvulsant activity of the corn- pound.and(2)only the compounds with an electron withdrawing substituent on the phenyl ring exhibited appreciable anticonvulsant activity.

新仿牛黄的抗惊厥作用

牛黄为脊椎动物哺乳纲牛科牛BostaursdomesticusGmelin的胆结石。由于天然牛黄极为短缺,价格昂贵,因而许多学者都在进行人工牛黄的研究。五十年代,唐德煊首先进行了人工合成牛黄的研究并获得成功。后经朱颜进行的药理实验表明,人工牛黄对古柯碱和咖啡碱引起的小鼠惊厥有对抗作用,此点与天然牛黄的药理作用是一致的。1971年,卫生部组织了人工牛黄药理实验协作小组进行了实验,观察到人工牛黄对戊四氮引起的小鼠惊厥也有较好的对抗作用。同年年底。

Microwave-assisted synthesis,anticonvulsant activity and quantum mechanical modelling of N-(4-bromo-3-methylphenyl) semicarbazones

Objective: To study the effect of halo substitution on disubstituted aryl semicarbazones on the anticonvulsant potential and model the activity based on quantum mechanics. Methods: A series of twenty-six compounds of N4-(4-bromo-3-methylphenyl) semicarbazones were synthesized and evaluated for the anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Some potential compounds were also tested in the subcutaneous strychnine (scSTY) and subcutaneous picrotoxin (scPIC) seizure threshold tests. The synthesized compounds were tested for behavioral impairment and CNS (central nervous system) depression in mice. Quantum mechanical modelling was carried out on these compounds to gain understanding on the structural features essential for activity. Results: Some compounds possessed broad spectrum anticonvulsant activity as indicated by their effect in pentylenetetrazole, strychnine, picrotoxin and maximal electro- shock seizures models in resemblance to other aryl semicarbazone derivatives reported earlier. The higher the difference in HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy levels was, the greater was the activity profile. Conclusion: The pharmacophoric requirements for compounds to exhibit anticonvulsant activity that includes one aryl unit in proximity to a hydrogen donor-acceptor domain and an electron donor have been justified with the molecular orbital surface analysis of the synthesized compounds.

Gabapentin for the treatment of behavioral and psychological symptoms of dementia

Objective: To examine the efficacy of gabapentin for the treatment of behavioral and psychological symptoms of dementia (BPSD). Design: A retrospective chart review. Settings: Tertiary care geriatric psychiatry inpatient unit. Participants: 230 patients with BPSD. Measurements: The socio-demographic information, type of behaviors, co-morbid psychiatric and medical diagnoses, daily doses of medications and side-effects were recorded. Results: Of the 230 patients, 22 were treated with gabapentin. Twenty of these patients were on a combination of gabapentin and an antipsychotic medication while two patients were treated with gabapentin monotherapy. Eighteen of the 20 patients in the combination group tolerated the treatments with little or no side effects as did the two patients in the monotherapy group. Conclusions: Gabapentin may be a safe option for the treatment of BPSD in combination with antipsychotic medications. Gabapentin may also be effective as monotherapy in certain patients with BPSD.

Problems of Rational Therapy for Epilepsy during Pregnancy

Epilepsy is one of the most frequent neurological disorders. In these circumstances, more than 25% of the patients are women of reproductive age. The aim of our research was to analyze the effectiveness and safety of antiepileptic therapy in women with epilepsy during pregnancy and to analyze the pregnancies’ outcomes. We included in our research 121 pregnancies of 101 women aged at the moment of childbearing about 26.9 ± 4.57 years old. Idiopathic forms of epilepsy were predominant among all causes—47.1% (р < 0.01). Of all cases, 65.4% remained seizure-free from generalized tonic-clonic seizures (GTCS), including 69.6% of all idiopathic epilepsy cases and 68.6% among symptomatic ones. The antiepileptic drugs (AED) dosages were exceeding teratogenic level at the moment of conception in 54.7% of the cases. Worse control of epileptic seizures was associated with Benzobarbital (66.7%) and Lamotrigine (50.0%). Women with epilepsy did not receive specialized neurological therapy before conception in most cases, which leaded to the usage of AED teratogenic doses and less effectiveness of AED during pregnancy. It is necessary to plan the pregnancy and prescribe rational treatment for epilepsy starting at the stage of planning and during gestation in order to obtain a better seizures control and to decrease congenital disorders risk in fetus.

Phenytoin Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Case Report

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening condition. It presents a long prodromal period, extensive rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia with or without atypical lymphocytosis), and internal organ involvement. Purpose: To describe a case of phenytoin induced DRESS syndrome, presenting diagnostic and management challenges of clinical interest. Methods: The Consensus-based Clinical Case Reporting Guideline Development (CARE) was observed for data analysis in case reports. Case Report: A 22-year-old man, using phenytoin for 60 days, sought medical attention due to fever and maculopapular cutaneous lesions. He presented lymphocytosis with eosinophilia and severe acute hepatitis 24 hours after admission day. Hepatic transaminases returned to reference levels after phenytoin withdrawal, and eosinophilia and cutaneous manifestations did not respond well to systemic steroids. A forearm biopsy showed findings suggestive of severe cutaneous adverse reaction. The patient’s microscopic and clinical characteristics meet all criteria in the scoring systems of Bocquet et al., Registry of Severe Cutaneous Adverse Reaction (RegiSCAR), and Japanese Research Committee on Severe Cutaneous Adverse Reaction (J-SCAR), being highly suggestive of DRESS syndrome very probably caused by phenytoin. The complete remission of symptoms was achieved weeks after admission. Conclusions: DRESS syndrome is a defiant reaction. Clinicians must be aware of potential causative drugs and perform a complete clinical examination using the available resources, including laboratory tests and histopathological assessment. The clinical remission relies on the withdrawal of the culprit drug. Particular attention should be given to the involvement of internal organs.

Comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury:a randomized clinical trial

BACKGROUND： Liver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries （DILI） in children. Although withdrawal of the causative agent is the only proved treatment for DILI, in some dinical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with antioxidant actions for the management of DILl. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy. METHODS： This randomized, open-label, clinical trial evalu- ated 55 children with epilepsy who were on antiepileptic treat- ment and experienced DILL The children were randomized to receive either silymarin （5 mg/kg per day） or folic acid （1 mg per day） for one month and were followed up for three months. RESULTS： Liver enzymes significantly decreased in both groups. The decrease trend in alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were stronger in the folic acid group compared to silymarin group （P=0.04 and P=0.007, respectively）. At the end of the study patients in the folic acid group had significantly lower ALT （P=0.04）, AST （P=0.02）, and gamma-glntamyl transferase （GGT） （P〈0.001） levels and also higher percentage of normal ALT （30.7% vs 3.4%, P=0.009） and AST （42.3% vs 0%, P〈0.001）, and GGT （23.1% vs 0%, P=0.008） values compared to the patients in the silymarin group. No rebound elevations in ALT, AST and GGT levels or adverse reactions were noted in neither of the study groups.CONCLUSION： Although both treatments were safe and effective in decreasing liver enzymes, folic acid seems to be superior to silymarin in the management of DILl.

Arrhythmogenic epilepsy and pacing need: A matter of controversy

There is increasing awareness among the cardiology community regarding ictal bradyarrhythmias as a cause of loss of consciousness. A high degree of suspicion is necessary when diagnosing ictal bradyarrhythmias, and delay in diagnosing this condition may lead to morbidity associated with falls and trauma. Ictal bradyarrhythmias have also been suggested to be associated with sudden unexplained death in epilepsy, although evidence related to this association is limited. There is no guidelinedirected therapy for symptomatic ictal bradyarrhythmias due to a lack of randomized, controlled trials. Cardiac pacemaker therapy is commonly used for these patients; however, currently, there is no universal agreement on the pacing indications for these patients. In this review, we focus on the pathophysiology and clinical presentation of ictal bradyarrhythmias and then discuss the pacing need based on the available literature data.

Potent Anticonvulsant 1H-Imidazol-5(4H)-One Derivatives with Low Neurotoxicity

We report here the synthesis and in vivo anticonvulsant/neurotoxicity activities of a series of compounds belonging to 2-aryl-4-arylidene-1-phenyl-1H-imidazol-5(4H)-one. The scaffold is based on the commonality of 5-membered lactam ring structures as successful anticonvulsant agents. The present compounds exhibited a range of anticonvulsant activity in pentylenetetrazole (PTZ)-induced seizure test. In particular, the protection was excellent by compounds bearing furylmethylidene on C4, possibly due to good pharmacokinetic properties. It was found that high lipophilicity and/or electron deficient aryl ring substitution at C4 compromised the anticonvulsant activities. For example, chloro analogues were found much less active than unsubstituted phenyl or furyl derivatives. Regarding side effects, active compounds exerted no observable neurotoxic effect at their therapeutic doses in Chimney test.

A novel series of 2,5-disubstituted 1,3,4-thiadiazoles as potential anticonvulsant agent

In pursuit for better antiepileptic drug and the importance of semicarbazones and 2,5-disubstituted 1,3,4-thiadiazoles as anticonvulsant pharmacophore, a series of novel N-（{5-[（6-methyl-l-benzofuran-3-yl）methyl]-l,3,4-thiadiazol-2-yl}carba- mothioyl）-2/3/4-substitutedbenzamide were designed, synthesized and evaluated for their anticonvulsant activity. The findings of the present studies confirmed that the pharmacophore model with four binding sites is crucial for anticonvulsant activity. Structure-activity relationships among synthesized compounds were also established.

Evaluation of the anticonvulsant and muscle relaxant effects of the methanol root bark extracts of Annona senegalensis

Objective:To investigate the potentials of the root bark of Annona（A.） senegalensis in the control of seizure and related hypnotic and motor incoordination effects in mice using experimental models.Methods:The methanol extract（ME） of the root bark of A.senegalensis was studied in mice using pentylenetetrazole（PTZ） induced convulsions,phenobarbitone induced sleeping time and motor coordination test on rota-rod performance.Acute toxicity and lethality（LD50） lest as well as phytochemical analysis were also carried out.Results:The extract（200,400,800 mg/ kg） exhibited a non- dose dependent significant（P【0.05） delay in the onset of both tonic and clonic phases of seizure induced by PTZ（60 mg/kg,s.c.） as well as offered a 100%protection （200 mg/kg） in mice from PTZ induced seizures.The extract significantly（P【0.05） decreased the latency and increased the duration of phenobarbitone induced sleeping time.At 200 mg/kg, the extract exhibited a significant（P【0.05） motor incoordination.The acute toxicity test revealed an oral LD50 of 1 2%mg/kg,while the phytochemical studies showed the presence of alkaloids, resins,glycosides,carbohydrate,reducing sugar,flavonoids,terpenoids,saponins and tannins. Conclusion:The extract of A senegalensis possessed anticonvulsant activity with pronounced hypnotic and muscle relaxant effects.

Antipyretic and anticonvulsant activity of n-hexane fraction of viola betonicifolia

Objective:To investigate the antipyretic and anticonvulsant activities of n-hexane fraction of Viola betonicifolia(V.betonicifolia).Methods:The antipyretic effect was scrutinized using brewer's yeast induced pyrexia and anticonvlsion effect was tested using pentylenetetrazol and strychnine induced convulsion in mice.Results:N-hexane fraction of V.betonicifolia demonstrated highly significant antipyretic activity during various assessment times(1-5 h)when challenged in yeast induced pyrexia test.The effect was in a dose dependent manner with maximum attenuation(82.50%)observed at 300 mg/kg i.p.When tested in pentylenetetrazol induced convulsion test,the 1st stage(Ear and facial twitching)and 2nd stage(Convulsive wave through the body)was 100%protected during 24 h at all the test doses(300,400 and 500 mg/kg i.p.),while the latency time of remaining stages was significantly increased.The maximum effect was observed by n-hexane fraction of V.betonicifolia at 400 and 500 mg/kg i.p.,as the latency time for generalized clonic-tonic seizure(5th stage)was increased up to 25.34 min.However,n-hexane fraction of V.betonicifolia had no protection in strychnine induced convulsion test.Conclusions:In conclusion,phytopharmacological studies provide scientific foundation to the folk uses of the plant in the treatment of pyrexia and neurological disorders.

Studies on the Relationship Between the Structure and Anticonvulsant Activity of Cinnamamides and Their Analogs

On the basis of systematic modification of the structure of componds of antiepilepsirine type, more than 200 cinnamamides were synthesized and tested by animal assay (maximal electroshock seizure, MES). Pharmacological evaluation showed that the configuration and the substituents on the phenyl ring and the nitrogen of amides, and substituents on the double bond displayed an important effect on the anticonvulsant activity.For studying the effect of the modification of structure to anticonvulsant activity, Hansch approach was employed to study the QSAR among 38 cinnamamides, and Hopfinger' s MSA was employed to study the MSA-QSAR among 26 cinnamamides.

Anticonvulsant effects of medicinal plants with emphasis on mechanisms of action

Epilepsy is a disorder in brain in which clusters of nerve cells, or neurons, occasionally signal abnormally and cause strange emotions, sensations, and behavior, or sometimes muscle spasms, convulsions, and loss of consciousness. Neurotransmitters in central nervous system greatly affect and play a very important part in neuronal excitability.Traditional treatments are still a component of health care system in many communities despite the fact that well-established alternatives are available. In this review article, we addressed epilepsy and its treatments with emphasis on medical plants and introduction of antiepileptic plants and their action mechanisms. Relevant articles published since 2010 were retrieved using the search terms including epileptic seizure, anticonvulsant, medicinal plants, and oxidative stress. Most plants/herbal preparations that are ethnomedically used to treat epilepsy or those which have been tested for anticonvulsant activity were reported. Overall, the results of the published articles show that the symptoms of epilepsy seizure can be inhibited or treated by active ingredients derived from medicinal plants.