Treatment of benzodiazepine-resistant status epilepticus: Systematic review and network meta-analyses.

PURPOSE: Multiple interventions have been studied for benzodiazepine-resistant status epilepticus (SE) in children and adults. This review aimed to summarize the available evidence and provide estimates of comparative effectiveness and ranking of treatment effects. METHODS: All randomized controlled trials studying patients (>1 month of age) with benzodiazepine-resistant SE were included. Outcomes including seizure cessation within 60 min, seizure freedom for 24 h, death, respiratory depression warranting intubation and cardiovascular instability were studied. Conventional and network meta-analyses (NMA) were done. RESULTS: Seventeen studies were included (16 in NMA). Phenobarbital and high-dose levetiracetam were significantly superior to phenytoin with respect to seizure cessation within 60 min. Network ranking demonstrated that phenobarbital had the highest probability of being the best among the studied interventions followed by high-dose levetiracetam and high-dose valproate. Network meta-analysis was limited by predominant indirect evidence and high heterogeneity.On pairwise comparisons, phenobarbital was found to be associated with a higher risk of need for intubation and cardiovascular instability. Levetiracetam had a better safety profile than fosphenytoin. CONCLUSIONS: Based on low quality evidence, phenobarbital appears to be the most effective agent for seizure cessation within 60 min of administration in patients with benzodiazepine resistant status epilepticus. High-dose levetiracetam, high-dose valproate and fosphenytoin are probably equally effective. Choice of medication may be guided by effectiveness, safety concerns, availability, cost and systemic co-morbidities.

The Prevention and Reversal of a Phenytoin-Resistant Model by N-acetylcysteine Therapy Involves the Nrf2/P-Glycoprotein Pathway at the Blood-Brain Barrier.

The transporter hypothesis is one of the most popular hypotheses of drug-resistant epilepsy (DRE). P-glycoprotein (P-gp), a channel protein at the blood-brain barrier (BBB), plays an important role in the transport of some anti-seizure drugs from brain tissue into vessels, which reduces drug concentrations and diminishes the effects of drug treatment. We performed this study to test whether P-gp is overexpressed in DRE and identify ways to prevent and reverse DRE. In this study, we established a phenytoin (PHT)-resistant mouse model and revealed that P-gp was overexpressed at the BBB in PHT-resistant mice. The P-gp inhibitor nimodipine decreased the resistance of phenytoin. Antioxidative preventive treatment with N-acetylcysteine (NAC) prevented the mice from entering a PHT-resistant state, and NAC therapy tended to reverse PHT resistance into sensitivity. We were also able to induce PHT resistance by activating the Nrf2/P-gp pathway, which indicates that oxidative stress plays an important role in drug resistance. Taken together, these findings suggest that antioxidative therapy may be a promising strategy for overcoming DRE.

The interplay of epilepsy with impaired mitophagy and autophagy linked dementia (MAD): A review of therapeutic approaches.

The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aß), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.

Evaluation of combination use of phenytoin cream 1% and fractional CO2 laser in treatment of stable nonsegmental vitiligo: A pilot study.

Vitiligo is an autoimmune disorder of melanocyte characterized by macular and depigmented patches. There are several treatment modalities for this disease, including the use of corticosteroids, calcineurin inhibitors, vitamin D analogous and topical phenytoin. Combination therapy utilizing fractional CO2 laser with different topical agents has been used to enhance treatment response with promising results. In this study, we aimed to evaluate the effect of fractional CO2 laser in combination with topical phenytoin. In this study, 25 patients (11 females and 14 males) with age of 18-59 (mean age of 31.12) with nonsegmental stable vitiligo were recruited with insufficient response to at least 1-year treatment with a monotherapy using topical corticosteroids, calcineurin inhibitors, and/or NB-UVB phototherapy. Patients were treated with a combination of fractional CO2 laser (10,600 nm, pulse energy 30-50 mJ, MIXEL, South Korea, Rating: 220VAC, 3A, 50/60 Hz) with monthly intervals for six sessions and application of phenytoin 1% cream twice daily. Photography was done before and after treatment with Wood's lamp. The severity of disease using VASI score was calculated and compared before and after treatment. The mean VASI score before treatment was 0.55, and sixth month after treatment increased to 1.97 (p-value < 0.001). Patients were divided into three groups based on the vitiligo subtype: acral, upper extremities, and trunk. VASI score was measured in each group: VASI score before and after treatment was 0.50 and 1.48 in acral areas, 0.45 and 2.04 in upper extremities and 0.79 and 3.39 in trunk, respectively. This study revealed that combination therapy with phenytoin and fractional CO2 laser is effective in treatment of vitiligo not only in the upper extremities and trunk, but also interestingly in the acral areas.

Anti-epileptic drug and folic acid usage during pregnancy, seizure and malformation outcomes: Changes over two decades in the Kerala Registry of Epilepsy and Pregnancy.

BACKGROUND: This study was carried out to determine changes over time in use of folic acid, anti-epileptic drugs (AED), seizures during pregnancy and malformation rate over two decades in women with epilepsy enrolled in the Kerala registry of Epilepsy and Pregnancy (KREP). METHODS: All completed pregnancies with known outcome between 1998 and 2017 (n = 1962) were analyzed for the use of folic acid and AEDs in the first trimester, seizure count for the entire pregnancy and the presence of major congenital malformation (MCM). The results were presented for three epochs (1998-2004, 2005-2011 and 2012-2017). RESULTS: There was significant increase (p = .001) in the use of folic acid 5 mg/day or more in pre-pregnancy month (43.9 to 81 %) and first trimester (52.7 to 86.6 %). Occurrence of seizures during pregnancy had declined significantly (57.2 to 32.9 %, p = 0.001) over time. Those who were off AEDs during pregnancy declined from 17.4 to 8.5 % (p = .001). Newer AEDs - lamotrigine, levetiracetam, oxcarbazepine and topiramate) were increasingly preferred in the last seven years instead of older AEDs (phenobarbitone, phenytoin and clonazepam). There was no significant change in the use of carbamazepine or valproate. MCM rates did not show any significant change (7.5 to 7.3 %). CONCLUSION: Seizure control and high dose folic acid usage during pregnancy had improved over two decades. Despite the changes in the AED usage over time the MCM rates had remained unchanged probably due to continued use of valproate, increased use of topiramate and clobazam that are associated with higher MCM rates and lack of reduction in polytherapy.

Narrative review of acute post-craniotomy pain. Concept and strategies for prevention and treatment of pain. / Revisión narrativa del dolor agudo poscraneotomía. Concepto y estrategias de prevención y tratamiento del dolor.

The aim of this narrative review is to confirm that acute pain after craniotomy is frequent and presents with moderate to severe intensity. We also highlight the importance of not only treating post-craniotomy pain, but also of preventing it in order to reduce the incidence of chronic pain. Physicians should be aware that conventional postoperative analgesics (non-steroidal anti-inflammatory, paracetamol, cyclooxygenase inhibitors 2, opioids) are not the only options available. Performing a scalp block prior to surgical incision or after surgery, the use of intraoperative dexmedetomidine, and the perioperative administration of pregabalin are just some alternatives that are gaining ground. The management of post-craniotomy pain should be based on perioperative multimodal analgesia in the framework of an "enhaced recovery after surgery" (ERAS) approach.

Antiepileptic Drug Treatment Patterns in Women of Childbearing Age With Epilepsy.

Importance: Limited population-based data are available on antiepileptic drug (AED) treatment patterns in women of childbearing age with epilepsy; the current population risk is not clear. Objectives: To examine the AED treatment patterns and identify differences in use of valproate sodium and topiramate by comorbidities among women of childbearing age with epilepsy. Design, Setting, and Participants: A retrospective cohort study used a nationwide commercial database and supplemental Medicare as well as Medicaid insurance claims data to identify 46 767 women with epilepsy aged 15 to 44 years. The eligible study cohort was enrolled between January 1, 2009, and December 31, 2013. Data analysis was conducted from January 1, 2017, to February 22, 2018. Exposures: Cases required an International Classification of Diseases, Ninth Revision, Clinical Modification-coded epilepsy diagnosis with continuous medical and pharmacy enrollment. Incident cases required a baseline of 2 or more years without an epilepsy diagnosis or AED prescription before the index date. For both incident and prevalent cases, focal and generalized epilepsy cohorts were matched by age, payer type, and enrollment period and then compared. Main Outcomes and Measures: Antiepileptic drug treatment pattern according to seizure type and comorbidities. Results: Of the 46 767 patients identified, there were 8003 incident cases (mean [SD] age, 27.3 [9.4] years) and 38 764 prevalent cases (mean [SD] age, 29.7 [9.0] years). Among 3219 women in the incident epilepsy group who received AEDs for 90 days or more, 3173 (98.6%) received monotherapy as first-line treatment; among 28 239 treated prevalent cases, 18 987 (67.2%) received monotherapy. In 3544 (44.3%) incident cases and 9480 (24.5%) prevalent cases, AED treatment was not documented during 180 days or more of follow-up after diagnosis. Valproate (incident: 35 [5.81%]; prevalent: 514 [13.1%]) and phenytoin (incident: 33 [5.48%]; prevalent: 178 [4.53%]) were more commonly used for generalized epilepsy and oxcarbazepine (incident: 53 [8.03%]; prevalent: 386 [9.89%]) was more often used for focal epilepsy. Levetiracetam (incident: focal, 267 [40.5%]; generalized, 271 [45.0%]; prevalent: focal, 794 [20.3%]; generalized, 871 [22.2%]), lamotrigine (incident: focal, 123 [18.6%]; generalized, 106 [17.6%]; prevalent: focal, 968 [24.8%]; generalized, 871 [22.2%]), and topiramate (incident: focal, 102 [15.5%]; generalized, 64 [10.6%]; prevalent: focal, 499 [12.8%]; generalized, 470 [12.0%]) were leading AEDs prescribed for both focal and generalized epilepsy. Valproate was more commonly prescribed for women with comorbid headache or migraine (incident: 53 of 1251 [4.2%]; prevalent: 839 of 8046 [10.4%]), mood disorder (incident: 63 of 860 [7.3%]; prevalent: 1110 of 6995 [15.9%]), and anxiety and dissociative disorders (incident: 57 of 881 [6.5%]; prevalent: 798 of 5912 [13.5%]). Topiramate was more likely prescribed for those with comorbid headache or migraine (incident: 335 of 1251 [26.8%]; prevalent: 2322 of 8046 [28.9%]). Conclusions and Relevance: Many women appear to be treated with valproate and topiramate despite known teratogenicity risks. Comorbidities may affect selecting certain AEDs despite their teratogenicity risks.

Aqueous Extract of Wood Ear Mushroom, Auricularia polytricha (Agaricomycetes), Demonstrated Antiepileptic Activity against Seizure Induced by Maximal Electroshock and Isoniazid in Experimental Animals.

Auricularia polytricha is a popular mushroom found all over the world. This article describes a study of the antiepileptic effect of A. polytricha, a mushroom that is used traditionally for treating asthma, rheumatism, tumors, cough, fever, and epilepsy, and for its antimicrobial effect. We carried out toxicity studies to identify a standard dose of A. polytricha aqueous extract; maximal electroshock (MES)- and isoniazid (INH)-induced seizures in albino mice were used to screen for the extract's antiepileptic activity. Per Organisation for Economic Co-operation and Development Guideline 423, up to 2000 mg/kg body weight of extract was toxic. Animals were treated with aqueous extract at doses of 200, 400, and 600 mg/kg body weight. Phenytoin was used as the reference anticonvulsant drug for comparison. The investigation found a significant interruption in INH-induced clonic seizure. During MES, we found a reduction in the period of hind leg extensor phase; mice exhibited a significant decrease in the duration of hind limb extension after being treated with 400 and 600 mg/kg doses of A. polytricha. Comparable results were obtained in the INH group, as the extract seemed to delay the onset of a clonic seizure. The aqueous extract of A. polytricha showed antiepileptic action against MES- and INH-induced epilepsy in the mice. This extract, however, requires additional study in order to completely explain its active ingredients and their mechanisms of action.

Réplica: Interacciones potenciales con ivermectina como tratamiento coadyuvante en la epilepsia refractaria / Reply: Potential interactions with ivermectin as adjuvant therapy for refractory epilepsy

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Evaluation of the effect and mechanism of action of local phenytoin in treatment of vitiligo.

There are many theories explaining vitiligo such as genetic, autoimmune, neural, free radicals, biochemical, intrinsic defect, melanocytorrhagy, and convergent theories. Phenytoin is a widely used anticonvulsant, which is used in cutaneous medicine for treatment of ulcers and epidermolysis bullosa. The aim of this study is to assess the effectiveness of topical phenytoin gel in the treatment of vitiligo patients and explaining the underlying mechanism using immunohistochemistry for evaluation of HMB45, CD4, and CD8. Only 9 patients out of 28 experienced response to phenytoin in the form of dull, white color change and light brown color. Post-phenytoin treatment biopsies showed decreased density of inflammation, increased melanin and increased HMB45 positive cells together with an increased number of CD4 positive lymphocytes and decreased number of CD8 positive lymphocytes. These observations did not reach significant level (P > 0.05). A high percentage of CD4 positive lymphocytes was significantly associated with a long duration of vitiligo (p = 0.03) and segmental vitiligo type (p = 0.02). The current study applied phenytoin as 2% concentrated gel for 3 months, which is a relatively short duration without observed side effects throughout the period. These results indicate that topical phenytoin of low concentrations may have beneficial effects through immunomodulatory activity by affecting CD4 and CD8 counts and subsequently the ratio between them. Further studies are recommended to combine phenytoin with other antivitiligo agents as local corticosteroids or phototherapy to clarify if it could potentiate their effects.

Dressings and topical agents for treating pressure ulcers.

BACKGROUND: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and promote healing, and there are many options to choose from including alginate, hydrocolloid and protease-modulating dressings. Topical agents have also been used as alternatives to dressings in order to promote healing.A clear and current overview of all the evidence is required to facilitate decision-making regarding the use of dressings or topical agents for the treatment of pressure ulcers. Such a review would ideally help people with pressure ulcers and health professionals assess the best treatment options. This review is a network meta-analysis (NMA) which assesses the probability of complete ulcer healing associated with alternative dressings and topical agents. OBJECTIVES: To assess the effects of dressings and topical agents for healing pressure ulcers in any care setting. We aimed to examine this evidence base as a whole, determining probabilities that each treatment is the best, with full assessment of uncertainty and evidence quality. SEARCH METHODS: In July 2016 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses, guidelines and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of at least one of the following interventions with any other intervention in the treatment of pressure ulcers (Stage 2 or above): any dressing, or any topical agent applied directly to an open pressure ulcer and left in situ. We excluded from this review dressings attached to external devices such as negative pressure wound therapies, skin grafts, growth factor treatments, platelet gels and larval therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. We conducted network meta-analysis using frequentist mega-regression methods for the efficacy outcome, probability of complete healing. We modelled the relative effectiveness of any two treatments as a function of each treatment relative to the reference treatment (saline gauze). We assumed that treatment effects were similar within dressings classes (e.g. hydrocolloid, foam). We present estimates of effect with their 95% confidence intervals for individual treatments compared with every other, and we report ranking probabilities for each intervention (probability of being the best, second best, etc treatment). We assessed the certainty (quality) of the body of evidence using GRADE for each network comparison and for the network as whole. MAIN RESULTS: We included 51 studies (2947 participants) in this review and carried out NMA in a network of linked interventions for the sole outcome of probability of complete healing. The network included 21 different interventions (13 dressings, 6 topical agents and 2 supplementary linking interventions) and was informed by 39 studies in 2127 participants, of whom 783 had completely healed wounds.We judged the network to be sparse: overall, there were relatively few participants, with few events, both for the number of interventions and the number of mixed treatment contrasts; most studies were small or very small. The consequence of this sparseness is high imprecision in the evidence, and this, coupled with the (mainly) high risk of bias in the studies informing the network, means that we judged the vast majority of the evidence to be of low or very low certainty. We have no confidence in the findings regarding the rank order of interventions in this review (very low-certainty evidence), but we report here a summary of results for some comparisons of interventions compared with saline gauze. We present here only the findings from evidence which we did not consider to be very low certainty, but these reported results should still be interpreted in the context of the very low certainty of the network as a whole.It is not clear whether regimens involving protease-modulating dressings increase the probability of pressure ulcer healing compared with saline gauze (risk ratio (RR) 1.65, 95% confidence interval (CI) 0.92 to 2.94) (moderate-certainty evidence: low risk of bias, downgraded for imprecision). This risk ratio of 1.65 corresponds to an absolute difference of 102 more people healed with protease modulating dressings per 1000 people treated than with saline gauze alone (95% CI 13 fewer to 302 more). It is unclear whether the following interventions increase the probability of healing compared with saline gauze (low-certainty evidence): collagenase ointment (RR 2.12, 95% CI 1.06 to 4.22); foam dressings (RR 1.52, 95% CI 1.03 to 2.26); basic wound contact dressings (RR 1.30, 95% CI 0.65 to 2.58) and polyvinylpyrrolidone plus zinc oxide (RR 1.31, 95% CI 0.37 to 4.62); the latter two interventions both had confidence intervals consistent with both a clinically important benefit and a clinically important harm, and the former two interventions each had high risk of bias as well as imprecision. AUTHORS' CONCLUSIONS: A network meta-analysis (NMA) of data from 39 studies (evaluating 21 dressings and topical agents for pressure ulcers) is sparse and the evidence is of low or very low certainty (due mainly to risk of bias and imprecision). Consequently we are unable to determine which dressings or topical agents are the most likely to heal pressure ulcers, and it is generally unclear whether the treatments examined are more effective than saline gauze.More research is needed to determine whether particular dressings or topical agents improve the probability of healing of pressure ulcers. The NMA is uninformative regarding which interventions might best be included in a large trial, and it may be that research is directed towards prevention, leaving clinicians to decide which treatment to use on the basis of wound symptoms, clinical experience, patient preference and cost.

Simultaneous triple therapy for the treatment of status epilepticus.

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

Efficacy of sodium channel blockers in SCN2A early infantile epileptic encephalopathy.

BACKGROUND: Recent clinical evidence supports a targeted therapeutic approach for genetic epileptic encephalopathies based on the molecular dysfunction. PATIENT DESCRIPTION: A 2-day-old male infant presented with epileptic encephalopathy characterized by burst-suppression EEG background and tonic-clonic migrating partial seizures. The condition was refractory to phenobarbital, pyridoxine, pyridoxal phosphate and levetiracetam, but a dramatic response to an intravenous loading dose of phenytoin was documented by video-EEG monitoring. Over weeks phenytoin was successfully switched to carbamazepine to prevent seizure relapses associated with difficulty in maintaining proper blood levels of phenytoin. Genetic analysis identified a novel de novo heterozygous mutation (c.[4633A>G]p.[Met1545Val]) in SCN2A. At two years and three months of age the patient is still seizure-free on carbamazepine, although a developmental delay is evident. CONCLUSIONS: Sodium channel blockers represent the first-line treatment for confirmed or suspected SCN2A-related epileptic encephalopathies. In severe cases with compatible electro-clinical features we propose a treatment algorithm based on a test trial with high dose intravenous phenytoin followed in case of a positive response by carbamazepine, more suitable for long-term maintenance treatment. Because of their rarity, collaborative studies are needed to delineate shared therapeutic protocols for EIEE based on the electro-clinical features and the presumed underlying genetic substrate.

Comparative trial of Aloe vera/olive oil combination cream versus phenytoin cream in the treatment of chronic wounds.

OBJECTIVE: Aloe vera is a medicinal plant that has been traditionally used to accelerate wound healing. Olive oil is also a natural product that may contribute to wound healing owing to its antimicrobial and anti-inflammatory effects. The present study aimed to evaluate the effect of an Aloe vera-olive oil (AVO) combination cream on the healing process of chronic wounds. METHOD: In this randomised, double-blind, comparator-controlled, parallel-group trial, patients with chronic wounds were treated with either AVO cream or phenytoin cream as the standard treatment for a period of 30 days. Wound healing was evaluated using Bates-Jensen assessment tool and the severity of pain was assessed using a visual analogue scale (VAS). RESULTS: After initial assessment, 60 patients with chronic wounds (41 with pressure ulcer, 13 with diabetic wounds and 6 with venous ulcers), were recruited and randomised into 2 groups of 30. After 30 days of treatment, significant improvements in the wound size, depth, and edges; necrotic tissue type and amount; exudate type and amount; colour of wound surroundings; and peripheral tissue oedema score were observed in the AVO cream group (p<0.001). The total score of wound healing showed significant improvement with both AVO (p<0.001) and phenytoin (p<0.01) creams, although AVO was more efficacious (p<0.001). Likewise, although both treatments reduced the initial VAS score, the efficacy of AVO was significantly greater (p<0.001). CONCLUSION: AVO cream significantly accelerates biological healing of chronic wounds and helps to reduce pain severity with a higher efficacy compared with phenytoin cream.

Reversal of P-glycoprotein overexpression by Ginkgo biloba extract in the brains of pentylenetetrazole-kindled and phenytoin-treated mice.

The purpose of this study was to investigate the combined effects of Ginkgo biloba extract and phenytoin (PHT) sodium as a dose regimen simulating the clinical treatment of patients with epilepsy, on P-glycoprotein (P-GP) overexpression in a pentylenetetrazole-kindled mouse model of epilepsy. Epilepsy was induced by intraperitoneal administration of pentylenetetrazole (40 mg/kg) for 7 days followed by intragastric administration of PHT (40 mg/kg) for 14 days. Thirty mice that developed seizures were randomly divided into three groups and administered PHT as well as the following treatments: saline (negative control); verapamil (20 mg/kg, positive control); and G. biloba (30 mg/kg). Seizure severity was recorded 30 minutes after treatment on Day 4 of drug administration, after which the mice were euthanized, and their brains isolated. Western blots and immunohistochemistry were performed to analyze the expression of P-GP and caspase-3, respectively, in the brain tissue. High-performance liquid chromatography was used to measure the concentrations of PHT in the brains of the treated mice. After 4 consecutive days of treatment, the seizure severity in the mice in the G. biloba extract group was more significantly reduced than the seizure severity in the saline control group, and a significant difference was observed between the G. biloba extract and verapamil control groups (p < 0.05). P-GP expression in the brain more significantly decreased in the mice treated with G. biloba extract and verapamil than it did in the saline-treated control group (p < 0.05). Compared with the saline-treated control group, the mice treated with G. biloba extract and verapamil showed significantly increased brain PHT concentrations (p < 0.05). Furthermore, caspase-3 expression in the brain tissue of the G. biloba extract group was significantly lower than that in the vehicle control group (p < 0.05); this finding demonstrated the neuroprotective effects of G. biloba. Therefore, this study showed that treatment with G. biloba extract in combination with PHT prevented the upregulation of P-GP expression in mice. Moreover, G. biloba extract decreased seizure severity in pentylenetetrazole-kindled/PHT-treated mice through a mechanism that might be related to the reduction of P-GP expression in the brain.

Modulatory role of kolaviron in phenytoin-induced hepatic and testicular dysfunctions in Wistar rats.

Phenytoin, an anticonvulsant agent used for the treatment of epilepsy has been reported to exhibit toxic side effects on the liver and testes. The present study investigated the protective effects of kolaviron (KV, a bioflavonoid from Garcinia kola seeds) against hepatic and testicular damage in rats exposed to phenytoin. The study consisted of four groups of six rats per group. Group I rats received 2 mL/kg of corn alone while group II received 75 mg/kg of phenytoin (PHT) alone. Groups III and IV were co-treated with kolaviron (200 mg/kg KV) and vitamin E (500 mg/kg VTE), respectively, for 14 days. The antioxidant status, hepatic and reproductive functional parameters were subsequently determined. PHT treatment significantly (p < 0.05) increased superoxide dismutase (SOD) and catalase (CAT) activities, elevated lipid peroxidation (LPO) and hydrogen peroxide (H2O2) levels along with significant reduction in the hepatic and testicular levels of glutathione (GSH). Moreover, PHT exposure elicited significant increases in alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels. The significant reduction in seminal epithelium thickness and the diameter of seminiferous tubules was accompanied with marked decrease in sperm motility, sperm count, and viability in PHT-treated rats. However, antioxidant status and the functional indices of liver and testes were restored to near control levels in rats co-treated with KV and VTE. In conclusion, KV and VTE protect the liver and testes against functional impairment due to PHT treatment.

Acupuncture for epilepsy.

BACKGROUND: Acupuncture is increasingly used in people with epilepsy. It remains unclear whether existing evidence is rigorous enough to support its use. This is an update of a Cochrane review first published in 2008. OBJECTIVES: To determine the effectiveness and safety of acupuncture in people with epilepsy. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5), MEDLINE, EMBASE, CINAHL, AMED and other databases (from inception to June 2013). We reviewed reference lists from relevant trials. We did not impose any language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing acupuncture with placebo or sham treatment, antiepileptic drugs or no treatment; or comparing acupuncture plus other treatments with the same other treatments, involving people of any age with any type of epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 17 RCTs with 1538 participants that had a wide age range and were suffering mainly from generalized epilepsy. The duration of treatment varied from 7.5 weeks to 1 year. All included trials had a high risk of bias with short follow-up. Compared with Chinese herbs, needle acupuncture plus Chinese herbs was not effective in achieving at least 50% reduction in seizure frequency (80% in control group versus 90% in intervention group, RR 1.13, 95% CI 0.97 to 1.31, 2 trials; assumed risk 500 per 1000, corresponding risk 485 to 655 per 1000). Compared with valproate, needle acupuncture plus valproate was not effective in achieving freedom from seizures (44% in control group versus 42.7% in intervention group, RR 0.97, 95% CI 0.72 to 1.30, 2 trials; assumed risk 136 per 1000, corresponding risk 97 to 177 per 1000) or at least 50% reduction in seizure frequency (69.3% in control group versus 81.3% in intervention group, RR 1.34, 95% CI 0.52 to 3.48, 2 trials; assumed risk 556 per 1000, corresponding risk 289 to 1000 per 1000) but may have achieved better quality of life (QOL) after treatment (QOLIE-31 score (higher score indicated better QOL) mean 170.22 points in the control group versus 180.32 points in the intervention group, MD 10.10 points, 95% CI 2.51 to 17.69 points, 1 trial). Compared with phenytoin, needle acupuncture was not effective in achieving at least 50% reduction in seizure frequency (70% in control group versus 94.4% in intervention group, RR 1.43, 95% CI 0.46 to 4.44, 2 trials; assumed risk 700 per 1000, corresponding risk 322 to 1000 per 1000). Compared with valproate, needle acupuncture was not effective in achieving seizure freedom (14.1% in control group versus 25.2% in intervention group, RR 1.75, 95% CI 0.93 to 3.27, 2 trials; assumed risk 136 per 1000, corresponding risk 126 to 445 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (55.3% in control group versus 73.7% in intervention group, RR 1.32, 95% CI 1.05 to 1.66, 2 trials; assumed risk 556 per 1000, corresponding risk 583 to 923 per 1000) and better QOL after treatment (QOLIE-31 score mean 172.6 points in the control group versus 184.64 points in the intervention group, MD 12.04 points, 95% CI 4.05 to 20.03 points, 1 trial). Compared with antiepileptic drugs, catgut implantation at acupoints plus antiepileptic drugs was not effective in achieving seizure freedom (13% in control group versus 19.6% in intervention group, RR 1.51, 95% CI 0.93 to 2.43, 4 trials; assumed risk 127 per 1000, corresponding risk 118 to 309 per 1000) but may be effective in achieving at least 50% reduction in seizure frequency (63.1% in control group versus 82% in intervention group, RR 1.42, 95% CI 1.07 to 1.89, 5 trials; assumed risk 444 per 1000, corresponding risk 475 to 840 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated worse quality of life) mean 53.21 points in the control group versus 45.67 points in the intervention group, MD -7.54 points, 95% CI -14.47 to -0.61 points, 1 trial). Compared with valproate, catgut implantation may be effective in achieving seizure freedom (8% in control group versus 19.7% in intervention group, RR 2.82, 95% CI 1.61 to 4.94, 4 trials; assumed risk 82 per 1000, corresponding risk 132 to 406 per 1000) and better QOL after treatment (QOLIE-31 score (higher score indicated better quality of life) mean 172.6 points in the control group versus 191.33 points in the intervention group, MD 18.73 points, 95% CI 11.10 to 26.36 points, 1 trial) but not at least 50% reduction in seizure frequency (65.6% in control group versus 91.7% in intervention group, RR 1.31, 95% CI 0.94 to 1.84, 4 trials; assumed risk 721 per 1000, corresponding risk 677 to 1000 per 1000). Acupuncture did not have excess adverse events compared to control treatment in the included trials. AUTHORS' CONCLUSIONS: Available RCTs are small, heterogeneous and have high risk of bias. The current evidence does not support acupuncture for treating epilepsy.

Anticonvulsant effect of the essential oil and methanolic extracts of Zataria multiflora Boiss.

UNLABELLED: Zataria multiflora is an Iranian endemic plant with a variety of uses. Anticonvulsant effect of the plant has not been studied yet. We aimed to evaluate the anticonvulsant effect of the essential oil and methanolic extract of the plant on chemical and electrically seizures. METHODS: Essential oil (EO) and methanolic extract (ME) were prepared by hydrodistillation and maceration method respectively and administered for evaluating the anticonvulsant activity against pentylenetetrazole (PTZ) and maximal electroshock (MES) convulsions in mice. Different doses of the EO and ME of Zataria multiflora were administered intraperitoneally (i.p), thirty minutes before induction of chemical (PTZ, 100 mg/kg) and electrical (50 mA, 50 Hz, 1 s duration) convulsions. Neurotoxicity was evaluated using rota-rod test. Mortality was determined after 24 hours for determining LD50. RESULTS: EO significantly increased the onset time of clonic seizures at doses of 0.2, 0.25 and 0.35ml/kg and significantly prevented tonic convulsions induced by PTZ at the same doses. No increase in onset time of tonic convulsions was observed. Methanolic extract of Z. multiflora was not effective in PTZ model. Neither EO nor ME was effective against MES convulsions; however both of them significantly reduced the time spent on rota-rod at doses of 0.6 ml/kg and 3 g/kg respectively. LD50 value of the EO was determined as 1.30 (1.0-1.5) ml/kg. No mortality was seen for the ME until dose of 5 g/kg. CONCLUSION: EO would be a good candidate for more investigations to determine its active constituent(s) and also its mechanism against PTZ-induced seizures.

Which medical devices and/or local drug should be curatively used, as of 2012, for PU patients? How can granulation and epidermidalization be promoted? Developing French guidelines for clinical practice.

INTRODUCTION: Management of a patient with pressure ulcer sore(s) must associate local and general treatment. OBJECTIVES: To determine which medical devices other than supports and which treatments may be used for pressure sore healing (granulation tissue and epithelization/epidermidalization) as of 2012. METHODS: Systematic review of the literature querying the databases: PASCAL Biomed, PubMed, and Cochrane library from 2000 through 2010. RESULTS: Data in the literature on granulation tissue and epithelisation/epidermidalization in pressure sore healing are poor. The level of evidence regarding the relative effectiveness of one modern dressing compared to another has remained low. However, the study data on the interest of hydrocolloid dressing compared with impregnated gases are more significant. DISCUSSION: Studies with heterogeneous results and populations have shown low power. Meta-analyses are difficult due to the wide range of therapeutic aims. Further clinical studies with adequate methodology are needed prior to elaboration of more specific recommendations. CONCLUSION: The use of hydrocolloid dressing may be recommended to improve granulation tissue development and epithelization/epidermidalization in pressure sore (Level B).