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      A systematic review of phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets in China

      review-article
      , MMed, , MD, , MMed, , MMed, , MMed, , MMed, , MD
      Medicine
      Wolters Kluwer Health
      CPEHTT, nervous system, phenytoin poisoning, systematic review

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          Abstract

          Objective:

          In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets (CPEHTT).

          Method:

          A literature search was performed in the following databases: WANFANG DATA, HowNet, National Library Reference and Consultation Alliance, Full-text Database of Foreign Medical Journals, PubMed and Ovid. The search terms were “Compound Phenytoin Sodium, ephedrine Hydrochloride and Theophylline Tablets,” and “poisoning,” or “toxicity,” in Chinese and in English.

          Result:

          Ten articles including 104 patients with CPEHTT intoxication were identified. The ages of the patients ranged from 52 to 82 years. Sixty-seven patients were male and thirty-seven patients were female (the male/female ratio, approximately 2:1). The most common clinical manifestations were dizziness (85%) and ataxia (85%), followed by limb weakness (65%), diplopia (25%), binocular horizontal nystagmus (24%), limb numbness (13%), nausea and vomiting (12%), somnolence (10%), tremor and high muscle tension (7%), lag in response (5%), dysarthria (6%), choking cough (2%), auditory hallucination and visual fantasy (1%), and involuntary movement (1%). All patients had chronic lung disease, and the most common disease was chronic bronchitis. The dosage ranged 4 to 15 tablets per day with medication duration of more than 1 year for most patients.

          Conclusion:

          The CPEHTT intoxication caused by phenytoin toxicity represents a drug safety problem in China. The common clinical manifestations, serum phenytoin concentrations, and associated factors of CPEHTT intoxication are important for diagnosis and prevention. These findings may help guide clinicians to correctly attend to the use of CPEHTT and avoid its toxicity.

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          Most cited references18

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          Phenytoin poisoning.

          Phenytoin toxicity may result from intentional overdose, dosage adjustments, drug interactions, or alterations in physiology. Intoxication manifests predominantly as nausea, central nervous system dysfunction (particularly confusion, nystagmus, and ataxia), with depressed conscious state, coma, and seizures occurring in more severe cases. Cardiac complications such as arrhythmias and hypotension are rare in cases of phenytoin ingestion, but they may be seen in parenteral administration of phenytoin or fosphenytoin. Deaths are unlikely after phenytoin intoxication alone. A greatly increased half-life in overdose due to zero-order pharmacokinetics can result in a prolonged duration of symptoms and thus prolonged hospitalization with its attendant complications. The mainstay of therapy for a patient with phenytoin intoxication is supportive care. Treatment includes attention to vital functions, management of nausea and vomiting, and prevention of injuries due to confusion and ataxia. There is no antidote, and there is no evidence that any method of gastrointestinal decontamination or enhanced elimination improves outcome. Activated charcoal should be considered if the patient presents early; however, the role of multiple-dose activated charcoal is controversial. Experimental studies have proven increased clearance rates, but this effect has not been translated into clinical benefit. There is no evidence that any invasive method of enhanced elimination (such as plasmapheresis, hemodialysis, or hemoperfusion) provides any benefit. This article provides an overview of phenytoin pharmacokinetics and the clinical manifestations of toxicity, followed by a detailed review of the various treatment modalities.
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            Cerebellar volume and long-term use of phenytoin.

            To perform MRI cerebellum volumetry in patients exposed to phenytoin and to identify factors associated with cerebellar atrophy (CA). From 100 consecutive epilepsy patients we selected those with phenytoin use for more than 2 months and with MRI scan available for volumetric studies. We obtained cerebellar volumes corrected for total intracranial volume. Volumes below 2 standard deviations from the mean of control group were considered abnormal. We studied 56 patients (33 women). Mean age was 33.6 years and mean duration of epilepsy was 17.6 years. Mean daily dose of phenytoin was 301 mg. CA was detected in 20 (35.7%) patients. CA was not associated with frequent generalised seizures. CA correlated with duration of epilepsy (r=-0.34; P=0.01) and years of treatment with phenytoin (r=-0.48; P=0.001), but not with age and mean daily dosage of phenytoin (P>0.05). However, a multiple correlation analysis as well as a backward stepwise multiple regression analysis including all variables showed that only duration of treatment was significantly associated with CA (P=0.001). CA is frequently associated with long-term use of phenytoin. Although duration of epilepsy may have an influence in the CA, this is clearly less important than the time of exposure to phenytoin.
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              Acute phenytoin intoxication: causes, symptoms, misdiagnoses, and outcomes.

              Phenytoin is a commonly prescribed antiepileptic drug. Due to its saturation (zero-order) pharmacokinetics, phenytoin carries a special risk of dose-related toxicity that is an important issue in emergency medicine. The purpose of this cross-sectional case-series study was to investigate the causes, symptoms, misdiagnoses, and outcomes of acute phenytoin intoxication. It was based on a retrospective chart review of 30 inpatients (mean age, 41.6 +/- 22.8 years) with 36 episodes of acute phenytoin intoxication at our university hospital in the past 13 years. The average initial serum phenytoin level was 47.3 +/- 9.7 microg/mL (range, 27.9-70.4 microg/mL). Excessive self-medication, misunderstanding of the prescription order, and probable drug interaction were the three leading causes of acute phenytoin intoxication. Unsteady gait, dizziness/vertigo, nausea/vomiting, general weakness, and drowsiness were the most common presenting symptoms. The tentative diagnostic accuracy was 67%. The most common initial misdiagnosis was brainstem or cerebellum stroke (14%). The clinical course in all patients was uneventful under temporary withdrawal of phenytoin and supportive care. We concluded that acute phenytoin intoxication was relatively under-diagnosed in the emergency service. Although acute phenytoin intoxication causes no mortality and has a good outcome, the unsteady gait increases the risk of injuries caused by falls. The management of acute phenytoin intoxication includes temporary withdrawal of phenytoin and supportive care.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                December 2018
                21 December 2018
                : 97
                : 51
                : e13689
                Affiliations
                Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
                Author notes
                []Correspondence: Liping Chen, Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China (e-mail: chenliping301@ 123456163.com ).
                Article
                MD-D-18-00089 13689
                10.1097/MD.0000000000013689
                6320048
                30572493
                d2764b5d-dbe7-439d-92bc-3b5367c5c1d2
                Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

                History
                : 23 January 2018
                : 22 November 2018
                Categories
                5300
                Research Article
                Systematic Review and Meta-Analysis
                Custom metadata
                TRUE

                cpehtt,nervous system,phenytoin poisoning,systematic review

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