Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk.

Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis of a hypersensitivity reaction was corroborated by in vitro rechallenge for each drug (phenytoin, n = 34; phenobarbital, n = 22; carbamazepine, n = 25) when cytotoxicity (% dead cells) exceeded 3 SD above the mean result for controls. Cross-reactivity among the drugs was noted. 7 out of 10 patients who had received all three anticonvulsants had adverse reactions to each. 40 out of 50 patients tested to all three drugs in vitro were positive to each. Adverse reactions were indistinguishable among anti-convulsants. Skin rash (87%), fever (94%), hepatitis (51%), and hematologic abnormalities (51%) were common clinical features of each drug. 62% of reactions involved more than two organs. Cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients. In vitro testing can help diagnose hypersensitivity to anticonvulsants. Cells from patients may also be used for prospective individualization of therapy to decrease risk of adverse reaction. Cross-reactivity among the major anticonvulsants is common and should be considered before deciding on alternative therapy.     

Anticonvulsant therapy. Approaches to some common clinical problems.

The anticonvulsants generally preferred for initial therapy of most seizure disorders are phenytoin for adults and phenobarbital for children. If seizures continue despite a high serum level of drug or the patient has symptoms of toxicity, another anticonvulsant may be added. A patient who is taking three or four drugs but still having seizures may benefit from adjustments in dosage, or if an epileptogenic focus is present, from surgical excision. Anticonvulsant therapy is usually continued indefinitely because of the continued risk of seizures. Newer drugs are becoming available, but none is free from side effects. Increasing attention is being given to the effect of anticonvulsants on the fetus.     

DRUG-RELATED HOSPITALIZATION IN PAEDIATRIC PATIENTS

A survey, to estimate drug-related hospitalization, was conducted by a clinical pharmacist who participated in medical rounds on a paediatric ward. Data were collected from patients' medical charts and verified by the attending physicians and the patients and/or their guardians. Adverse drug reactions and inappropriate therapy were defined with criteria supported by medical publications. Approximately 18% of the 906 studied admissions were found to be drug-related; 11·0% as a result of inappropriate drug therapy, 3·4% as a result of patient non-compliance and 3· 2% because of adverse reactions. Antineoplastic agents were responsible for most adverse reactions that led to hospital admission. They were followed by corticosteroids, antimicrobials and by anticonvulsants. The last two groups of drugs were also responsible for hospitalization because of inappropriate drug therapy and patient non-compliance. Adverse drug reactions were more prevalent in females, in 6–10-year-old children, in patients of Ashkenazic origin and in patients who have experienced similar reactions in the past. Non-compliance was more prevalent in patients of Sephardic origin.     

Nursing interventions for anticonvulsant drug interactions

The management of epilepsy or seizure disorder commonly includes drug therapy. Optimal treatment may involve single-drug regimens, but multiple agents are often required. Although any pharmacological agent can be involved in a drug interaction, anticonvulsants are often implicated. As more drugs are prescribed for the patient, the potential for drug interactions increases. This article reviews the background of anticonvulsant drug interactions, the most common interactions encountered, and nursing interventions useful in monitoring potential interactions. Suggestions for nursing research are given.     

Plasma total glutathione concentrations in epileptic patients taking anticonvulsants

Glutathione plays an important role in protecting cells against oxidative damage as a free radical scavenger. Since several anticonvulsants have been associated with decreased intrahepatic glutathione levels, we investigated plasma concentrations of total glutathione (including reduced and oxidized forms, tGSH=GSH+GSSG) in 45 epileptic patients taking anticonvulsant drugs. Plasma tGSH concentrations were significantly lower than in controls in patients treated with carbamazepine or phenytoin monotherapy, or with multiple drugs. Plasma tGSH concentrations in patients treated with valproic acid and in patients treated with phenobarbital did not differ significantly from those in controls. In no patient group was a significant correlation evident between duration of treatment or drug concentration and plasma tGSH concentration. No significant differences in plasma total cysteine concentrations were found between any patient group and controls. We conclude that some anticonvulsant drugs can lower plasma tGSH levels, reflecting treatment-related oxidative stress.     

Characterization of drug overdoses in an Ohio incarcerated population

Context: Literature exists about drug overdose following release of recently incarcerated individuals and mortality among prisoners in the United States, but little information exists about drug overdoses in the imprisoned population. Objective: This study aims to quantify and describe prisoner medication overdose requiring inpatient admission or assessment at a tertiary care facility and to assess the associated hospital charges. Materials and methods: A single-center, retrospective cohort study was conducted on all Ohio Department of Rehabilitation and Correction inmates who presented to The Ohio State University Wexner Medical Center with drug overdose between 15 October 2011 and 14 October 2014. Demographic information, overdose substances, exposure reason, clinical effects, lengths of stay, outcomes, and hospital charges were collected. Results: Of the 130 patients included in the study, there were 100 intentional overdoses, 7 unintentional overdoses, 3 adverse drug reactions, and 20 unknown intentions. The most common drug in prisoner overdose was phenytoin (n?=?29, 22%). While anticonvulsants were the most common drug class overall, anticonvulsants, antidepressants, and cardiovascular medications accounted for equal numbers of intensive care unit (ICU) admissions. Most patients exhibited multiple symptoms on arrival, most commonly neurologic, cardiovascular, and gastrointestinal symptoms. Patients were seen from 21 of the 28 Ohio Department of Rehabilitation and Correction facilities, of which five facilities, that largely house minimum and medium security prisoners, accounted for 61% of patients sent to our institution. The total sum of charges was $2,606,942 with 55% of charges from ICU stays. Conclusion: Our study shows that drug overdoses within our incarcerated population were largely intentional overdoses of anticonvulsants, cardiovascular drugs, and antidepressants. Opportunities exist to target intentional drug overdoses that accounted for 80% of prisoner overdoses for potential cost-savings.     

Misuse of therapeutic drug monitoring: an analysis of causes and methods for improvement

The quantification of serum drug levels provides physicians with an indication of attainment of the desired pharmacologic goals. However, based on the preceding evidence, therapeutic drug monitoring (TDM), which is commonly used in conjunction with the prescribing of anticonvulsants, antiarrythmics, cardiac glycosides, antibiotics, antineoplastics, bronchodilators, lithium, antidepressants, neuroleptics, benzodiazepines, and other psychotropic drugs, is not used effectively for therapeutic intervention in the elderly. In addition to determining if a blood level is within the therapeutic range, TDM can also be helpful in identifying the reasons why a patient is not responding to a prescribed drug or is exhibiting toxic signs or symptoms, as well as in elucidating causes of coma, patient noncompliance, poor absorption, and excessively rapid metabolism. Furthermore, drug blood levels can be an asset in the diagnosis and monitoring of treatment programs for alcohol and drug abuse. Despite the existence of computerized programs for drug level determination in clinical laboratories, and the existence of individualized computer programs for optimizing the choice and dosage of drugs for many categories of patients with a multitude of metabolic and pathophysiologic problems, most physicians still rely on tradition, imitation, and information provided by drug advertising and sales representatives to choose therapeutic regimens for patients. To make proper use of TDM, a physician has to have at least a working knowledge of the basic concepts of pharmacokinetics. This advancing medical science also demands a thorough knowledge of the routes of absorption, distribution, metabolism, and excretion of drugs. Results from TDM determinations indicate how effectively the appropriate amount of drug is delivered to the desired location of action from the site of administration. One of the most common reasons for misuse of TDM results is that physicians order specimens for drug monitoring to be drawn at inappropriate times. Accurate TDM requires that (most) specimens be drawn at trough levels, after steady-state levels have been attained. Trough levels occur immediately prior to the administration of the next dose. Such measurements avoid the absorptive peaking levels that occur shortly (usually) after drug administration. Steady-state levels are attained when the amount of drug absorbed and the amount excreted are essentially equal. This usually occurs after the drug has been administered for approximately five half-lives.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review

To determine the relative efficacy and adverse effects of antidepressants and anticonvulsants in the treatment of diabetic neuropathy and postherpetic neuralgia, published reports were identified from a variety of electronic databases, including Medline, EMBASE, the Cochrane Library and the Oxford Pain Relief Database, and from two previously published reviews. Additional studies were identified from the reference lists of retrieved reports. The relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief was calculated from available dichotomous data, as was the relative risk (RR) and number-needed-to-harm (NNH) for minor adverse effects and drug related study withdrawal. In diabetic neuropathy, 16 reports compared antidepressants with placebo (491 patient episodes) and three compared anticonvulsants with placebo (321). The NNT for at least 50% pain relief with antidepressants was 3.4 (95% confidence interval 2.6–4.7) and with anticonvulsants 2.7 (2.2–3.8). In postherpetic neuralgia, three reports compared antidepressants with placebo (145 patient episodes) and one compared anticonvulsants with placebo (225), giving an NNT with antidepressants of 2.1 (1.7–3) and with anticonvulsants 3.2 (2.4–5). There was little difference in the incidence of minor adverse effects with either antidepressants or anticonvulsants compared with placebo, with NNH (minor) values of about 3. For drug-related study withdrawal, antidepressants had an NNH (major) of 17 (11–43) compared with placebo, whereas with anticonvulsants there was no significant difference from placebo. Antidepressants and anticonvulsants had the same efficacy and incidence of minor adverse effects in these two neuropathic pain conditions. There was no evidence that selective serotonin reuptake inhibitors (SSRIs) were better than older antidepressants, and no evidence that gabapentin was better than older anticonvulsants. In these trials patients were more likely to stop taking antidepressants than anticonvulsants because of adverse effects.     

A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes

OBJECTIVES: To validate the novel lymphocyte toxicity assay (LTA) based on the mitochondrial succinate dehydrogenase (SDH) activity vs. the LTA by using trypan blue exclusion and to determine the utility of the assay to confirm drug hypersensitivity syndrome (DHS) to sulphonamides (SMX) and aromatic anticonvulsants. METHODS: Incubation of patient lymphocytes, with or without murine hepatic microsomes with anticonvulsants or SMX. The viability of lymphocytes was based on SDH activity that can be measured spectrophotometrically. The percentage of cells displaying cytotoxicity compared to controls (cells treated only with drug) was calculated. Seventy-two immunocompetent and 16 immunocompromised (HIV) patients with DHS to SMX were sampled. The results were validated vs. 26 controls that had not experienced DHS to SMX. Sixty-two patients who had DHS to anticonvulsants were compared with 24 controls that did not have any DHS to the same anticonvulsants. RESULTS: The results showed a very good percentage of sensitivity 98 and specificity 96 with a kappa-score of 0.96. LTA higher than 13.5% was considered positive for the immunocompetent population and LTA higher than 22% was positive for the immunocompromised population. In two of the 26 controls, LTA was positive. CONCLUSION: The high quantitative kappa-value 0.96 emphasizes that the novel LTA is at least as good as the trypan blue assay. The latter is labor intensive, time consuming, and prone to human error. The new assay is objective, faster, and has been reproducible in assessing cytotoxicity.     

住院精神疾病患者诊断和药物使用情况调查

目的 调查我院住院精神疾病患者的诊断和药物使用情况,提高医院临床合理用药水平.方法 于2019年10月6日对我院住院的218例精神疾病患者的临床诊断及用药情况进行统计分析.统计入组患者疾病诊断与分类情况,抗精神病药物联合使用情况,单一抗精神病药物使用情况,药物使用频率及剂量,缓解药物副反应用药情况.结果 入组患者中,精...     

Neuromodulating drugs for the symptomatic treatment of neuropathic pain

Significant improvement of neuropathic pain has been achieved with studies that have demonstrated efficacy of newer anticonvulsants in relieving this type of pain, by having a neuromodulatory effect on the hyperexcitable damaged nervous system. Two drugs from this class, gabapentin and lamotrigine, have been submitted to a number of clinical trials. Ease of use and broad therapeutic range, in addition to demonstrated efficacy, make gabapentin the drug of choice for most neuropathic pain disorders. Lamotrigine is well tolerated when it is titrated slowly, which also is the way to avoid the development of a rash. Pregabalin, the newest agent that has demonstrated efficacy in the treatment of post-herpetic neuralgia, is awaiting approval. A number of available anticonvulsants are undergoing clinical trials and many drugs with neuromodulatory properties are being considered for further development.     

Usefulness of monitoring free (unbound) concentrations of therapeutic drugs in patient management

Drugs are bound to various serum proteins in different degrees and only unbound or free drug is pharmacologically active. Although free drug concentration can be estimated from total concentration, for strongly bound drugs, prediction of free level is not always possible. Conditions like uremia, liver disease and hypoalbuminemia can lead to significant increases in free drug resulting in drug toxicity even if the concentration of total drug is within therapeutic range. Drug-drug interactions may also lead to a disproportionate increase in free drug concentrations. Elderly patients may have increased free drug concentrations due to hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS and pregnancy. Currently free drug concentrations of anticonvulsants such as phenytoin, carbamazepine and valproic acid are widely measured in clinical laboratories. Newer drugs such as mycophenolic acid mofetil and certain protease inhibitors are also considered as candidates for monitoring free drug concentration.     

Drug interactions of cyclosporine. Literature review

The cyclosporine is widely used as an immuno-suppressive agent in association with others drugs. Its narrow therapeutic range requires frequent monitoring. We suggest a literature review of suspected or confirmed drug interactions. The classification is presented as: absorption interactions; pharmacokinetic interactions in antiinfectious, anticonvulsants, cardiovascular drugs, H2 antagonists agents, hormonotherapy; pharmacodynamic interactions associated to increased cyclosporine nephrotoxicity.     

Anticonvulsant drugs for pediatric migraine prevention: An evidence‐based review

Background: The use of anticonvulsant drugs for the prevention of migraine in children and adolescents has been supported in the past. Aims: To evaluate the available evidence for the efficacy and safety of anticonvulsants drugs in the prevention of migraine attacks in children and adolescents. Methods: Studies were selected through a comprehensive literature search. We included all types of study designs (controlled and uncontrolled) due to the limited evidence. Monthly migraine frequency was used as the primary outcome measure in most of the studies. Studies were classified into levels of evidence according to their design. Results: Fourteen studies were included with a total of 939 patients. Topiramate (4 randomized controlled trials [RCT], two uncontrolled trials), sodium valproate/divalproex sodium (two RCTs, one uncontrolled trial, two retrospective chart reviews) levetiracetam and zonisamide (both only uncontrolled studies) are the anticonvulsants that have been reported in the literature. The findings show that valproate is not different from placebo and topiramate may not be different but further randomized trials are needed. All drugs were well tolerated in this age group with no serious events reported. Conclusions: The use of anticonvulsants in the prevention of migraine in children and adolescents is not adequately supported by methodologically sound RCTs. More research is needed in the future to establish the efficacy and safety of specific agents.