Prescription Of Carbamazepine Research Articles

Molecular identification of HLA-B75 serotype markers by qPCR: A more inclusive pharmacogenetic approach before carbamazepine prescription.

Genetic screening for HLA-B*15:02 before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These reactions are associated not only with this allele but also with closely related HLA-B75 serotype markers-HLA-B*15:11 and HLA-B*15:21-which are prevalent in several Asian countries. However, a reliable method for identifying HLA-B75 serotype markers is still not available. We developed an in-house quantitative PCR (qPCR) for HLA-B75 screening and validated it using 303 anonymized DNA samples. Due to inadequate quality control, the qPCR results for 11 samples were excluded. We analyzed the sensitivity and specificity of the test using 93 HLA-typed samples. The concordance between the qPCR method and an established screening method was assessed using 199 HLA-screened samples tested for HLA-B*15:02 at Songklanagarind Hospital, Songkhla, Thailand. All discordant results were confirmed by Sanger sequencing. The qPCR method demonstrated a sensitivity of 100% (95% confidence interval = 83.16%-100.00%) and a specificity of 100% (95% confidence interval = 95.07%-100.00%). Concordance analysis revealed a 96.5% agreement between methods (192/199; 44 positive and 148 negative results). All discordant results were due to HLA-B75 markers not being HLA-B*15:02 (two samples with HLA-B*15:11 and five samples with HLA-B*15:21). In conclusion, this qPCR method could be useful for identifying HLA-B75 carriers at risk of carbamazepine-induced reactions in Asian populations where carriers of HLA-B*15:02, HLA-B*15:11, or HLA-B*15:21 are common.

Toxic Epidermal Necrolysis: A Case Report in Azal hospital, Sana'a, Yemen

Toxic epidermal necrosis (TEN) is a life-threatening connective tissue disorder also known as Lyell's syndrome, characterized by erythema, and epidermal detachment, manifests as blisters, and raw skin patches. Adverse drug reactions are the most common risk factors. TEN is identical with Steven-Johnson's syndrome (SJS), differs from the latter in that greater area of the skin is involved. In this article, we report a case of a 20 years old male patient who presented with complaints of lethargy, red eyes and blisters after prescription of carbamazepine. Following this, the drug was taken off immediately. The treatment included the administration of fluids and appropriate antibiotics for treating the fluid-filled vesicles. The treatment regimen continued for three weeks and was stopped when the skin lesions were minimal and there was an improvement in the overall health of the patient.

Drug-induced Stevens Johnson syndrome and toxic epidermal necrolysis: Interpreting the systematic reviews on immunomodulatory therapies.

Drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are non-immunoglobulin E-mediated severe cutaneous adverse reactions with a high risk of morbidity, mortality, and physical and mental health impact. These are associated with certain high-risk drugs, human leukocyte antigen (HLA)-specific genotypes and ethnicities. HLA class I-restricted oligoclonal CD8 cytotoxic T-cell responses occur at the tissue level in SJS/TEN. Cytotoxic T cells are the T effector cells that result in keratinocyte apoptosis (cell death) mediated by T effector molecules granzyme B, perforin, granulysin, gamma interferon, tumor necrosis factor-alpha, and lipocalin-2. The clinical hallmarks of SJS/TEN include fever, ≥2 mucosal involvements (ocular, oral, and genital), and positive Nikolsky sign with epidermal detachment. Systematic reviews on immunomodulatory treatments remain limited by the paucity of randomized controlled trials, heterogeneity of studies, and non-standardization of outcome measures. Preventive HLA genotype screening before the prescription of carbamazepine and allopurinol may further reduce the incidence of SJS/TEN. The role of immunomodulatory treatments in SJS/TEN is at present not supported by robust evidence from systematic reviews given the lack of randomized controlled trials. The evidence for improved survival with off-label use of corticosteroids plus intravenous immunoglobulins, ciclosporin plus intravenous immunoglobulins, and ciclosporin alone has not been demonstrated by network meta-analyses and meta-regression. In the real-world clinical setting, systemic corticosteroids (in SJS and overlap SJS/TEN), ciclosporin, and etanercept (in TEN) appear to be the off-label treatments currently most widely used.

Foreign Objects in Stool

A pathology consult was initiated regarding a 75-year-old female with a chief complaint of pea-sized yellow balls in her stool (Fig. 1). Her medical history included irritable bowel syndrome, multiple sclerosis, and trigeminal neuralgia with prescriptions for extended-release carbamazepine, atenolol, buspirone, and gabapentin. The patient noted that the ball-shaped objects retrieved from the stool contained white fluid when opened. Her physician placed an order for “stool microscopic.” ... Potential foreign objects in stool include parasite structures (1), dietary plant material (2), illicit drug packing, accidentally ingested foreign bodies, capsule endoscopy, and undigested coatings of modified-release (-ER/-XR/-EC/-SR/-CR) medication (3, 4). While the patient and clinician claimed no changes to diet or medication, the carbamazepine prescription had recently changed to Tegretol-XR (extended-release) (see online Supplemental Fig. 1). The medication package insert states: “…tablet coating is not absorbed and is excreted in the feces…” (5). Supplementary material is available at Clinical Chemistry online.

Single Nucleotide Variants as Proxies for HLA-A*31:01 in Native American Populations.

Carbamazepine triggers dermatologic hypersensitivity reactions, associated with specific human leukocyte antigens (HLAs), especially HLA-B*15:02 and HLA-A*31:01. Previous efforts to identify single nucleotide variants (SNVs) with high predictive value as HLA proxies, revealed that rs1061235 and rs17179220 fulfill these requirements for HLA-A*31:01 in some but not all populations. Herein we explored the predictive performance of rs1061235 and rs17179220 as HLA-A*31:01 tags in populations of Native American ancestry, which are largely underrepresented in pharmacogenomic studies. The study cohorts comprised the overall Admixed American superpopulation of the 1000 Genomes Project (1 KG_AMR), a subcohort of individuals with predominant Native American ancestry (1 KG_NAT), the Native American population of the Human Genome Diversity Project (HGDP), plus Kaingang (KRC) and Guarani (GRC and GKW) adults from indigenous reservation areas in Brazil. The diversity of cohorts is reflected in the range of frequencies of HLA-A*31:01 (0.02–0.65), rs1061235 (0.03–0.13) and rs17179220 (0.12–0.66), as well as in the predictive performance of these SNVs as HLA-A*31:01 proxies. NPV (negative predictive value), the metric of primary interest for pharmacogenetic-informed carbamazepine prescription was maximal (NPV = 1.0) for both SNVs in 1 KG_AMR and 1 KG_NAT, for rs17179220, but not rs1061235 (NPV = 0.91) in HGDP, and for rs17179220 in GWK, but not GRC (NPV = 0.88) or KRC (NPV = 0.80). Collectively, the data support the notion that rs1061235 and rs17179220 are not optimal proxies for HLA-A*31:01 across populations of Native American ancestry.

Effect of alendronate on the femoral metaphyseal defect under carbamazepine in ovariectomized rats

BackgroundThe use of antiepileptic drugs and estrogen deficiency put forward higher requirements for bone defect regeneration. The present study investigated the effects of alendronate (ALN) on femoral bone defect in ovariectomized (OVX) rats under the influence of carbamazepine (CBZ).MethodsOne hundred female SD rats at 3 months of age were either sham-operated or OVX and divided into four groups: sham control (CON); OVX control (OVX); ovariectomized rats treated with CBZ via gavage (75 mg/kg/day; CBZ); ovariectomized rats treated with CBZ plus ALN (2 mg/kg/day; CBZ-ALN). A critical-sized femoral metaphyseal bone defect was established in all female SD rats. Animals from the CBZ and CBZ-ALN groups received drugs by gavage the day after bone defect surgery was performed. After the rats were sacrificed, the defected area located in the distal femur was harvested for evaluation by microcomputed tomography (micro-CT), hematoxylin and eosin (HE) staining, and Masson’s trichrome staining. The samples were also analyzed by biomechanics and immunohistochemical evaluation (IHC). Besides, biochemical analysis evaluates all serum samples.ResultsThe present study showed that ovariectomy changed the microstructural parameters of bone. The use of CBZ further decreased femur bone mass while treatment with ALN prevented bone loss. Compared to OVX and CBZ groups, CBZ-ALN group promoted bone neoformation and enhanced the ultimate load of the femur bone. However, the group of CBZ-ALN did not return to normal levels compared with the CON group. Besides, we noticed that CBZ-ALN group reduced tartrate-resistant acid phosphatase-5b (Tracp-5b) expression and had no significant effect on the expression of osteocalcin (OCN) and type I collagen (Col-I) in IHC compared with CBZ group. Biochemical analysis results presented that systemic delivery of CBZ showed pernicious effects on bone formation and resorption in ovariectomized rats, with the worse effects on C-terminal crosslinked telopeptide of type I collagen (CTX-1). Besides, a significant decrease in CTX-1 levels was observed in CBZ-ALN group as compared to the group of CBZ.ConclusionThese results demonstrated that ALN can effectively reverse the effects of CBZ on the microarchitectural properties of bone, and thus can have a positive effect on local bone neoformation in rats with osteoporosis.Clinical relevanceThe dose of 2 mg/kg ALN improves the negative effect of prescription of CBZ at 75 mg/kg and promotes bone neoformation of femoral bony deficits.

A proof of concept study demonstrating that environmental levels of carbamazepine impair early stages of chick embryonic development

Carbamazepine (CBZ) is an anticonvulsant drug used for epilepsy and other disorders. Prescription of CBZ during pregnancy increases the risk for congenital malformations. CBZ is ubiquitous in effluents and persistent during wastewater treatment. Thus, it is re-introduced into agricultural ecosystems upon irrigation with reclaimed wastewater. People consuming produce irrigated with reclaimed wastewater were found to be exposed to CBZ. However, environmental concentrations of CBZ (μgL−1) are magnitudes lower than its therapeutic levels (μgml−1), raising the question of whether and how environmental levels of CBZ affect embryonic development.The chick embryo is a powerful and highly sensitive amniotic model system that enables to assess environmental contaminants in the living organism. Since the chick embryonic development is highly similar to mammalians, yet, it develops in an egg, toxic effects can be directly analyzed in a well-controlled system without maternal influences. This research utilized the chick embryo to test whether CBZ is embryo-toxic by using morphological, cellular, molecular and imaging strategies. Three key embryonic stages were monitored: after blastulation (st.1HH), gastrulation/neurulation (st.8HH) and organogenesis (st.15HH).Here we demonstrate that environmental relevant concentrations of CBZ impair morphogenesis in a dose- and stage- dependent manner. Effects on gastrulation, neural tube closure, differentiation and proliferation were exhibited in early stages by exposing embryos to CBZ dose as low as 0.1μgL−1. Quantification of developmental progression revealed a significant difference in the total score obtained by CBZ-treated embryos compared to controls (up to 5-fold difference, p<0.05). Yet, defects were unnoticed as embryos passed gastrulation/neurulation.This study provides the first evidence for teratogenic effect of environmental-relevant concentrations of CBZ in amniotic embryos that impair early but not late stages of development. These findings call for in-depth risk analysis to ensure that the environmental presence of CBZ and other drugs is not causing irreversible ecological and public-health damages.

Prevalence of Anticonvulsants Utilization at a Tertiary Hospital in Southeast Nigeria; Bridging the Gaps Between Facilities Outcomes and Policies Through Evidence-Based Reports

The World Health Organization (WHO) recommended regular drug utilization studies in health facilities as a tool in generating information on disease pattern, and as a guide for policy in healthcare systems. These information help in assessing disease patterns, population health status, quality of care, quality of prescribers, and treatment practices. The choice of anticonvulsants depends on individual tolerance, affordability, and efficacy. This study assessed the proportions of anticonvulsants used and determined the most commonly used anticonvulsants. The study was a retrospective cross sectional analysis of prescription records. Study lasted between June to December 2016. Data were analyzed based on frequency of prescribed drugs, number of drugs, defined daily dose (DDD), number and frequency of anticonvulsants used. The number of prescriptions analyzed was 1393.0. Of these prescriptions, 7700.0 drugs were prescribed with each prescription containing an average of 5.5±0.9 drugs per prescription. The mean age of patients was 46±4.3 years. Anticonvulsant drugs accounted for 19.0 (0.25%) of the entire drugs prescribed. Carbamazepine was the most prescribed anticonvulsant 12.0 (63.2%) at a dose of 200mg daily, followed by diazepam 6.0 (31.6%), while the least was pregabalin 1.0 (5.2%). Generic prescription of carbamazepine was 84.0% while that of diazepam was 100.0%. Prescription of anticonvulsants monotherapy was 100.0%. Study suggested low anticonvulsants use an indication of low prevalence of seizure related disorders in the population. Patients were controlled on monotherapy. Carbamazepine was the most used anticonvulsant and suggested good tolerance, efficacy, affordability, and acceptability. The study provided baseline information for further studies to provide timely information for promoting anticonvulsant drugs utilization in healthcare facilities in Nigeria. Policy issues on the use of newer agents should be dependent on facility-based studies. Newer agents can be introduced when they match and exceed already existing ones based on key indicators.

HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis

HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action.

Clinical study of myoclonic epileptic syndromes

Background: Incidence of different myoclonic epileptic syndromes is variable in different regions. Here in as there is very few literature available internationally being inclusive of all myoclonic epilepsies together. Very few studies are available which describe all characteristics in a given study population. The aim of the study was to find incidence of different types of myoclonic epilepsies among patients presenting with myoclonic seizures their characteristics and to study all myoclonic epilepsies and juvenile myoclonic epilepsy in the study population. Methods: In this study conducted in neurological unit at Ruby hall clinic, a total of 188 case of epileptic disorder were enrolled irrespective of age and sex, among 136 were new case of epileptic disorder were classified based on seizure pattern, 23 were new cases of myoclonic epilepsy, these 23 new case of myoclonic epilepsy along with 52 old cases of myoclonic epilepsy attending to neurological unit were clubbed, a total of 75 cases myoclonic epilepsy were studied. All cases of myoclonic epilepsy and juvenile myoclonic epilepsy were studied with respect to age of onset different seizures, relation with family history, response to treatment, EEG findings. Results: Out of 136 cases 23 were new cases of myoclonic epilepsy, these 23 newly diagnosed cases of myoclonic epilepsies along with 52 already diagnosed myoclonic epilepsy are clubbed together, total of 75 cases were further studied. Incidence of myoclonic epilepsy among epileptic patients found to be 16.9%. Incidence of JME among myoclonic epilepsies is 75-80%, in all myoclonic epilepsies and JME association with GTCS, family history, EEG abnormalities were common finding, valproate and leviteracetam are good therapeutic options, carbamazepine aggravated myoclonus. Conclusions: For diagnosis of myoclonic epilepsy proper clinical history stress laid to ask history of myoclonic jerk in case of all seizure disorder, diagnosis basically depends on proper knowledge of myoclonic epileptic syndrome, eliciting history, EEG as an ancillary testing when in doubt always expert opinion is required as misdiagnosis of the myoclonus as partial seizure leads to wrong prescription of carbamazepine which exacerbates the myoclonus.

Human Leukocyte Antigen (HLA) Pharmacogenomic Tests: Potential and Pitfalls

Adverse drug reactions involving a range of prescribed drugs and affecting the skin, liver and other organs show strong associations with particular HLA alleles. For some reactions, HLA typing prior to prescription, so that those positive for the risk allele are not given the drug associated with the reaction, shows high positive and negative predictive values. The best example of clinical implementation relates to the hypersensitivity reaction induced by the anti-HIV drug abacavir. When this reaction is phenotyped accurately, 100% of those who develop it are positive for HLA-B*57:01. Drug regulators worldwide now recommend genotyping for HLA-B*57:01 before abacavir is prescribed. Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrosis can be induced by carbamazepine and other anticonvulsant drugs. In certain East Asians, these reactions are significantly associated with HLA-B*15:02, and typing for this allele is now recommended prior to carbamazepine prescription in these populations. Other HLA associations have been described for skin rash induced by carbamazepine, allopurinol and nevirapine and for liver injury induced by flucloxacillin, amoxicillin-clavulanate, lapatanib, lumiracoxib and ticlopidine. However, the predictive values for typing HLA alleles associated with these adverse reactions are lower. Clinical implementation therefore seems unlikely. Performing HLA typing is relatively complex compared with genotyping assays for single nucleotide polymorphisms. With emphasis on HLA-B*57:01, the approaches used commonly, including use of sequence-specific oligonucleotide PCR primers and DNA sequencing are considered, together with their successful implementation. Genotyping single nucleotide polymorphisms tagging HLA alleles is a simpler alternative to HLA typing but appears insufficiently accurate for clinical use.

A World Allergy Organization International Survey on Diagnostic Procedures and Therapies in Drug Allergy/Hypersensitivity

Objective To study the diagnostic and treatment modalities used in drug allergy/hypersensitivity among members of the World Allergy Organization (WAO).Methods A questionnaire comprising 39 questions was circulated electronically to member societies, associate member societies, and regional and affiliate organizations of WAO between June 29, 2009, and August 9, 2009.Results Eighty-two responses were received. Skin testing was used by 74.7%, with only 71.4% having access to penicillin skin test reagents. In vitro-specific IgE tests were used by 67.4%, and basophil activation test was used by 54.4%. Lymphocyte transformation tests were used by 36.8% and patch tests by 54.7%. Drug provocation tests were used by 68.4%, the most common indication being to exclude hypersensitivity where history/symptoms were not suggestive of drug hypersensitivity/allergy (76.9%). Rapid desensitization for chemotherapy, antibiotics, or biologic agents was used by 69.6%. Systemic corticosteroid was used in the treatment of Stevens-Johnson syndrome by 72.3%, and high-dose intravenous immunoglobulins in toxic epidermal necrolysis by 50.8%. Human leukocyte antigen screening before prescription of abacavir was used by 92.9% and before prescription of carbamazepine by 21.4%.Conclusions Results of this survey form a useful framework for developing educational and training needs and for improving access to drug allergy diagnostic and treatment modalities across WAO member societies.

Wicket spikes misinterpreted as focal abnormalities in idiopathic generalized epilepsy with prescription of carbamazepine leading to paradoxical aggravation

Wicket spikes (WS) are a normal variant EEG pattern that sometimes can be mistaken for epileptiform activity. We present a patient with WS and idiopathic generalized epilepsy who had been wrongly diagnosed with focal epilepsy, which leads to the prescription of carbamazepine with severe aggravation of generalized tonic-clonic seizures. She was referred for presurgical assessment of refractory focal epilepsy but long-term video-EEG showed sharp theta waves over the temporal regions during awakening, with a typical aspect of WS during drowsiness, nREM sleep stages I-II, and rapid eye movements (REM) sleep. There were a few generalized spike-waves during sleep but interictal changes were increased in frequency at awakening with bursts of fast-generalized spike-waves. Carbamazepine was progressively withdrawn and the patient was progressively switched to zonisamide. The patient no longer complained of generalized tonic-clonic seizures. At one year follow-up, this patient receives zonisamide with valproate. She has remained seizure-free.

Anticonvulsant medication in a mental handicap hospital: 1972-1982.

The prescription sheets for all patients in a mental handicap hospital on one day in 1972 and on the same date in 1982 were examined to identify trends in anticonvulsant medication over a 10-year period. There was a reduction in size of the hospital population associated with fewer very young and milder handicapped persons. Prescription of anticonvulsants fell slightly during the decade under study with a dramatic fall in the use of phenobarbitone, and a parallel increase in the prescription of carbamazepine. Other changes included the use of sodium valproate in a significant minority of patients and the occasional use of clonazepam in 1982, while phenytoin remained a first-rank anticonvulsant throughout the period under review. The proportions of patients on polytherapy did not change over the 10-year period, though the contribution of phenobarbitone to the combined drug regimes was significantly reduced.