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Clinical Neuropharmacology 2016Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs):... (Review)
Review
OBJECTIVES
Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate.
METHODS
We performed a literature search using PubMed and EMBASE to collect published safety, efficacy, and therapeutic monitoring data for 5 AEDs and extracted all relevant information into a drug- and study-specific drug database. For each AED, we summarized (1) type, severity, and incidence of toxicity-related adverse events and toxicity-associated range of drug doses or concentrations; (2) effective versus toxic concentration and dose (therapeutic range); and (3) therapeutic drug monitoring practices. We defined therapeutic index as the ratio of the minimum toxic concentration to the minimum effective concentration.
RESULTS
We reviewed a total of 810 full-text articles and extracted data from 163. The literature suggests that the therapeutic index of phenytoin is 2. The therapeutic indices of phenobarbital and valproate exceed 2. There were insufficient data to precisely quantify the therapeutic indices of carbamazepine and lamotrigine.
CONCLUSIONS
For some drugs, this approach offers a low-cost method of therapeutic index estimation. Our results can serve as preliminary data for future trials and as guidance for US Food and Drug Administration decision making regarding narrow therapeutic index classification.
Topics: Anticonvulsants; Databases, Bibliographic; Drug Monitoring; Epilepsy; Humans; Treatment Outcome
PubMed: 27428884
DOI: 10.1097/WNF.0000000000000172 -
The Canadian Journal of Hospital... 2022Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line... (Review)
Review
BACKGROUND
Status epilepticus (SE) is a neurologic emergency with potential for substantial mortality and morbidity. Parenteral benzodiazepine is the established first-line treatment but fails to control SE in about one-third of patients. Levetiracetam may be used for SE that is refractory to benzodiazepine therapy.
OBJECTIVE
To examine, by means of a systematic review, the role of IV levetiracetam for the treatment of SE in adults.
DATA SOURCES
MEDLINE, Embase, CENTRAL, and CINAHL databases were searched, from inception to August 18, 2020.
STUDY SELECTION AND DATA EXTRACTION
Included in this review were prospective randomized controlled trials comparing levetiracetam with another antiepileptic drug, given with or after a benzodiazepine, in adult patients with SE. The primary outcome was cessation of SE. Quality of evidence was assessed with the Cochrane risk-of-bias tool. Characteristics of the included studies were reported using descriptive statistics.
DATA SYNTHESIS
Five studies compared IV levetiracetam with valproic acid, phenytoin (or its prodrug fosphenytoin), or both. All 5 studies found no statistically significant differences in efficacy or safety end points. There were numerically more cases of hypotension and respiratory failure with phenytoin, and more cases of psychiatric adverse effects (e.g., post-ictal psychosis) with levetiracetam.
CONCLUSIONS
Available evidence suggests that levetiracetam is as effective as valproic acid or phenytoin for the cessation of SE in adults. Other factors should therefore dictate the choice of antiepileptic drug for patients with SE, such as adverse effect profile, logistics of administration, drug cost, inclusion on hospital formularies, and drug availability.
PubMed: 34987263
DOI: 10.4212/cjhp.v75i1.3254 -
Journal of Clinical Pharmacy and... Jun 2018Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key... (Meta-Analysis)
Meta-Analysis Review
WHAT IS KNOWN AND OBJECTIVE
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that can be induced by phenytoin (PHT). CYP2C9*3 is the key enzyme in PHT metabolism. The aim of this meta-analysis was to evaluate the association between CYP2C9*3 and PHT-induced SJS/TEN.
METHODS
An extensive search was performed in multiple databases, including the Cochrane Library, EMBASE, PubMed, OVID and EBSCO. Studies exploring the relationship between CYP2C9*3 and PHT-induced SJS and TEN were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CI) were calculated for dichotomous data. Data analysis was performed using Review Manager (version 5.3).
RESULTS AND DISCUSSION
Four studies, with 117 PHT-induced SJS/TEN cases and 338 matched controls (PHT-tolerant patients) or 4231 population controls (general population), were identified. SJS and TEN were found to be significantly associated with the CYP2C9*3 allele, comparing both matched controls (OR, 8.93; 95% CI, 2.63-30.36; P = .0005) with substantial heterogeneity (I = 46%) and population controls (OR, 8.88; 95% CI, 5.01-15.74; P < .00001).
WHAT IS NEW AND CONCLUSION
A significant association between CYP2C9*3 and PHT-induced SJS/TEN was identified, especially in a Thai population. CYP2C9*3 is thus a credible predictive genetic marker of PHT-induced SJS/TEN. Further multicenter studies and large prospective observational studies are, however, still required to determine the influence of CYP2C*3 on blood levels of PHT and its metabolites, and their association with SJS/TEN.
Topics: Alleles; Anticonvulsants; Cytochrome P-450 CYP2C9; Genetic Markers; Humans; Phenytoin; Stevens-Johnson Syndrome
PubMed: 29274302
DOI: 10.1111/jcpt.12660 -
Seizure Feb 2017Posttraumatic epileptic seizures (PTS) are a serious complication in patients with subdural haematoma (SDH). However, to date, several studies have shown discordances... (Review)
Review
BACKGROUND
Posttraumatic epileptic seizures (PTS) are a serious complication in patients with subdural haematoma (SDH). However, to date, several studies have shown discordances about SDH-associated seizures in terms of incidence, risk factors and prophylactic antiepileptic treatment.
OBJECTIVE
The aim of this study was to analyse the incidence, risk factors of PTS and the role of prophylactic antiepileptic treatment in patients with SDH.
DATA SOURCES
A systematic literature review examining PTS in patients with SDH was performed using PubMed gateway, Cochrane Central Register of Controlled Trials, and Excerpta Medica dataBASE between September 1961 and February 2016. Search terms included subdural haematoma, seizure, epilepsy, prophylactic antiepileptic drugs, anticonvulsive medication, and risk factors.
DATA SELECTION
Human-based clinical studies focusing on epileptic seizures in patients with SDH.
DATA EXTRACTION AND SYNTHESIS
PRISMA statements were used for assessing data quality. Two independent reviewers extracted data from included studies and disagreement was solved by consensus. Twenty-four studies were identified for inclusion into the study.
RESULTS
Overall incidence of early PTS (ePTS) and late PTS (lPTS)/2 years was 28% and 43% in acute SDH (aSDH) whereas the incidence of e- and lPTS was lower in chronic SDH (cSDH; 5.3% vs. 10%). Overall risk factors for PTS in patients with aSDH were: 24h postoperative Glasgow Coma Score (GCS) score below 9 (OR 10.5), craniotomy (OR 3.9), preoperative GCS below 8 (OR 3.1). In patients with cSDH the risk factors were alcohol abuse (OR 14.3), change of mental status (OR 7.2), previous stroke (OR 5.3) and density of haematoma in computer tomography (OR 3.8). Age, sex, haematoma size/side and midline shifts were not significant risk factors for PTS in both types of SDH. In prevention of PTS phenytoin and levetiracetam showed similar efficacy (OR 1.3), whereas levetiracetam was associated with significantly lower adverse effects (OR 0.1).
LIMITATIONS
Most of the studies were of retrospective nature with a small sample size. Due to the inclusion criteria, some studies had to be excluded and that might lead to selection bias.
CONCLUSIONS
PTS are a serious complication in patients with SDH, particularly in aSDH. The "prophylactic use" of antiepileptic drugs might be beneficial in patients with cumulative risk factors.
Topics: Adult; Anticonvulsants; Epilepsy; Hematoma, Subdural; Humans; Incidence; PubMed; Risk Factors
PubMed: 27914224
DOI: 10.1016/j.seizure.2016.11.017 -
Acute Medicine & Surgery 2022Status epilepticus (SE) is a life-threatening neurological emergency. There is insufficient evidence regarding which antiepileptic therapy is most effective in patients... (Review)
Review
AIM
Status epilepticus (SE) is a life-threatening neurological emergency. There is insufficient evidence regarding which antiepileptic therapy is most effective in patients with benzodiazepine-refractory convulsive SE. Therefore, this study aimed to evaluate intravenous phenytoin (PHT) and other intravenous antiepileptic medications for SE.
METHODS
We searched PubMed, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for published randomized controlled trials (RCTs) in humans up to August 2019. We compared outcomes between intravenous PHT and other intravenous medications. The important primary composite outcomes were the successful clinical cessation of seizures, mortality, and neurological outcomes at discharge. The reliability of the level of evidence for each outcome was compared using the Grading of Recommendations Assessment, Development, and Evaluation approach.
RESULTS
A total of 1,103 studies were identified from the databases, and 10 RCTs were included in the analysis. The ratio of successful clinical seizure cessation was significantly lower (risk ratio [RR] 0.89; 95% confidence interval [CI], 0.82-0.97) for patients treated with intravenous PHT than with other medications. When we compared mortality and neurological outcomes at discharge, we observed no significant differences between patients treated with PHT and those treated with other medications. The RRs were 1.07 (95% CI, 0.55-2.08) and 0.91 (95% CI, 0.72-1.15) for mortality and neurological outcomes at discharge, respectively.
CONCLUSIONS
Our findings showed that intravenous PHT was significantly inferior to other medications in terms of the cessation of seizures. No significant differences were observed in mortality or neurological outcomes between PHT and other medications.
PubMed: 35028156
DOI: 10.1002/ams2.717 -
The International Journal of Lower... Jun 2023There are a variety of dressings for wound healing. For this reason, research can assist in the choice and proper use of the intervention. This current view of the... (Review)
Review
There are a variety of dressings for wound healing. For this reason, research can assist in the choice and proper use of the intervention. This current view of the effectiveness of dressing on diabetic foot ulcers (DFUs) in patients with type 2 diabetes mellitus. This study is a systematic review of clinical trials selected in 4 databases: PubMed, Scopus, Web of Science, and Cochrane. Studies without language restriction, published between 2009 and 2020, were included. The search resulted in the identification of 5651 articles, of which 58 met all inclusion criteria. Among these, 2 biomaterials (D-acellular dermal matrix and keratinocyte) and phenytoin were highlighted for achieving healing rates of 100% and 95.82% ± 2.22%, respectively. The literature presents several alternatives with different actions, cure rates, reduction rates, and varied cost benefits. The growth in the use of biomaterials for the treatment of DFU can be seen in this study.
Topics: Humans; Bandages, Hydrocolloid; Diabetes Mellitus, Type 2; Diabetic Foot; Wound Healing
PubMed: 33949242
DOI: 10.1177/15347346211013189 -
The Cochrane Database of Systematic... Aug 2019More than three million persons are disabled by leprosy worldwide. The main complication of sensory nerve damage is neuropathic ulceration, particularly of the feet. In... (Review)
Review
BACKGROUND
More than three million persons are disabled by leprosy worldwide. The main complication of sensory nerve damage is neuropathic ulceration, particularly of the feet. In this review we explored interventions that can prevent and treat secondary damage to skin and limbs.
OBJECTIVES
To assess the effects of self-care, dressings and footwear in preventing and healing secondary damage to the skin in persons affected by leprosy.
SEARCH METHODS
We searched the Cochrane Skin Group Specialised Register (April 2008), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2008), MEDLINE (from 2003 to April 2008), EMBASE (from 2005 to April 2008), CINAHL (1982-2006) and LILACS (1982- April 2008 ) as well as online registers of ongoing trials (April 2008).
SELECTION CRITERIA
Randomised controlled trials involving anyone with leprosy and damage to peripheral nerves treated with any measures designed to prevent damage with the aim of healing existing ulcers and preventing development of new ulcers.
DATA COLLECTION AND ANALYSIS
Two authors assessed trial quality and extracted data.
MAIN RESULTS
Eight trials with a total of 557 participants were included. The quality of the trials was generally poor. The interventions and outcome measures were diverse. Although three studies that compared zinc tape to more traditional dressings found some benefit, none of these showed a statistically significant effect. One trial indicated that topical ketanserin had a better effect on wound healing than clioquinol cream or zinc paste, RR was 6.00 (95% CI 1.45 to 24.75). We did not combine the results of the two studies that compared topical phenytoin to saline dressing, but both studies found statistically significant effects in favour of phenytoin for healing of ulcer (SMD -2.34; 95% CI -3.30 to -1.39; and SMD -0.79; 95% CI -1.20 to 0.39). Canvas shoes were not much better than PVC-boots, and double rocker shoes did not promote healing much more than below-knee plasters.
AUTHORS' CONCLUSIONS
One study suggested that topical ketanserin is more effective than clioquinol cream or zinc paste. Topical phenytoin (two studies) may be more effective than saline dressing regarding ulcer healing. For the other dressings the results were equivocal. Canvas shoes were a little better than PVC-boots, but not significantly, and the effect of double rocker shoes compared to below-knee plasters was no different in promoting the healing of ulcers. No side effects were documented.There is a lack of high quality research in the field of ulcer prevention and treatment in leprosy. New trials should follow the current standards for design and reporting of randomised controlled trials.
PubMed: 31425616
DOI: 10.1002/14651858.CD004833.pub4 -
The Cochrane Database of Systematic... Oct 2014There is a need to expand monotherapy options available to a clinician for the treatment of new partial-onset or generalized-onset seizures. A Cochrane systematic review... (Review)
Review
BACKGROUND
There is a need to expand monotherapy options available to a clinician for the treatment of new partial-onset or generalized-onset seizures. A Cochrane systematic review for clobazam monotherapy is expected to define its place in the treatment of new-onset or untreated seizures and highlight gaps in evidence.
OBJECTIVES
To evaluate the efficacy, effectiveness, tolerability and safety of clobazam as monotherapy in people with new-onset partial or generalized seizures.
SEARCH METHODS
We searched the following databases: Cochrane Epilepsy Group Specialized Register (5 March 2013), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, January 2013, Issue 1), MEDLINE (Ovid, 1946 to July 1, 2014), Database of Abstracts of Reviews of Effectiveness (DARE, January 2013, Issue 1), BIOSIS Previews (all years, searched on 5 March 2013). There were no language restrictions.
SELECTION CRITERIA
Randomized or quasi-randomised controlled trials comparing clobazam monotherapy versus placebo or other anti-seizure medication in people with two or more unprovoked seizures or single acute symptomatic seizure requiring short-term continuous anti-seizure medication, were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Primary outcome measure was time on allocated treatment (retention time), reflecting both efficacy and tolerability. Secondary outcomes included short- and long-term effectiveness measures, tolerability, quality of life, and tolerance measures. Two authors independently extracted the data.
MAIN RESULTS
We identified two trials fulfilling the review criteria, which included 163 participants. None of the identified studies reported the preselected primary outcome measure. A meta-analysis was not possible. Lack of detail regarding concealment of allocation and a high risk of performance and detection bias in one study prompted us to downgrade the quality of evidence for some of our results due to risk of bias.Regarding retention at 12 months, we detected no evidence of a statistically significant difference between clobazam and carbamazepine (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.61 to 1.12); low quality evidence. There was low quality evidence that clobazam led to better retention compared with phenytoin (RR 1.43, 95% CI 1.08 to 1.90). We could not determine whether participants receiving clobazam were found to be less likely to discontinue it due to adverse effects as compared to phenytoin (RR 0.10, 95% CI 0.01 to 1.65, low quality evidence).
AUTHORS' CONCLUSIONS
We found no advantage for clobazam over carbamazepine for retention at 12 months in drug-naïve children and a slight advantage of clobazam over phenytoin for retention at six months in adolescents and adults with neurocysticercosis in a single clinical trial each. At present, the available evidence is insufficient to inform clinical practice.
Topics: Adolescent; Adult; Anticonvulsants; Benzodiazepines; Carbamazepine; Child; Clobazam; Epilepsies, Partial; Epilepsy, Generalized; Humans; Phenytoin; Randomized Controlled Trials as Topic; Seizures
PubMed: 25280512
DOI: 10.1002/14651858.CD009258.pub2 -
Progress in Neuro-psychopharmacology &... Jun 2023Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a...
OBJECTIVE
Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a series of matrices from combined samples of pregnant/breastfeeding women treated with anticonvulsants or lithium.
METHODS
We conducted a systematic literature search in PubMed/EMBASE for studies with concentrations of anticonvulsants/lithium from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal concentrations. When data from multiple studies were available, we calculated combined penetration ratios, weighting studies' mean by study size.
RESULTS
Ninety-one eligible studies for brivaracetam, carbamazepine, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, lithium, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproate, vigabatrin and zonisamide were identified. For amniotic fluid, the highest penetration ratios were estimated for levetiracetam (mean 3.56, range 1.27-5.85, n = 2) and lowest for valproate (mean 0.11, range 0.02-1.02, n = 57). For umbilical cord plasma, oxcarbazepine had the highest ratio (mean 1.59, range 0.11-4.33, n = 12) with clonazepam having the lowest (mean 0.55, range 0.52-0.59, n = 2). For breast milk, the highest ratios were observed for oxcarbazepine (mean 3.75, range 0.5-7.0, n = 2), whereas the lowest were observed for valproate (mean 0.04, range 0.01-0.22, n = 121).
DISCUSSION
We observed substantial variability between anticonvulsants and lithium regarding their ability to enter fetal/newborn circulation. Assessing concentrations of anticonvulsants and lithium in maternal samples can provide a surrogate of fetal/infant exposure, although patterns of concentration-dependent effects for maternal/neonatal safety are lacking.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Amniotic Fluid; Anticonvulsants; Fetal Blood; Lithium; Maternal-Fetal Exchange; Milk, Human
PubMed: 36805301
DOI: 10.1016/j.pnpbp.2023.110733 -
The Cochrane Database of Systematic... Apr 2016Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures (with or without other generalised seizure types). This review is one in a series of Cochrane reviews investigating pair-wise monotherapy comparisons. This is the latest updated version of the review first published in 2001 and updated in 2013.
OBJECTIVES
To review the time to withdrawal, remission and first seizure of phenytoin compared to valproate when used as monotherapy in people with partial onset seizures or generalised tonic-clonic seizures (with or without other generalised seizure types).
SEARCH METHODS
We searched the Cochrane Epilepsy Group's Specialised Register (19 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2015, Issue 4), MEDLINE (1946 to 19 May 2015), SCOPUS (19 February 2013), ClinicalTrials.gov (19 May 2015), and WHO International Clinical Trials Registry Platform ICTRP (19 May 2015). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy.
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) review. Outcomes were time to: (a) withdrawal of allocated treatment (retention time); (b) achieve 12-month remission (seizure-free period); (c) achieve six-month remission (seizure-free period); and (d) first seizure (post-randomisation). We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs), and the generic inverse variance method to obtain the overall pooled HR and 95% CI.
MAIN RESULTS
IPD were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to partial onset seizures (simple, complex and secondary generalised tonic-clonic seizures), and generalised tonic-clonic seizures, but not other generalised seizure types (absence or myoclonus seizure types). For remission outcomes: HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes: HR > 1 indicates an advantage for valproate.The main overall results (pooled HR adjusted for seizure type) were time to: (a) withdrawal of allocated treatment 1.09 (95% CI 0.76 to 1.55); (b) achieve 12-month remission 0.98 (95% CI 0.78 to 1.23); (c) achieve six-month remission 0.95 (95% CI 0.78 to 1.15); and (d) first seizure 0.93 (95% CI 0.75 to 1.14). The results suggest no overall difference between the drugs for these outcomes. We did not find any statistical interaction between treatment and seizure type (partial versus generalised).
AUTHORS' CONCLUSIONS
We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. However misclassification of seizure type may have confounded the results of this review. Results do not apply to absence or myoclonus seizure types. No outright evidence was found to support or refute current treatment policies.
Topics: Anticonvulsants; Epilepsies, Partial; Epilepsy, Generalized; Epilepsy, Tonic-Clonic; Humans; Phenytoin; Randomized Controlled Trials as Topic; Seizures; Valproic Acid
PubMed: 27123830
DOI: 10.1002/14651858.CD001769.pub3