Anticonvulsant drugs and hematological disease

Verrotti, Alberto; Scaparrotta, Alessandra; Grosso, Salvatore; Chiarelli, Francesco; Coppola, Giangennaro

doi:10.1007/s10072-014-1701-0

Cited by 68 publications

(79 citation statements)

References 90 publications

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“…Though rare, the association between phenytoin and megaloblastic anemia secondary to folate-deficiency has been well described 44–46 . (44-46) Several mechanisms have been proposed for this observation, including inhibition of folate transport proteins and induction of hepatic metabolism by phenytoin 47,48 .…”

Section: Discussionmentioning

confidence: 99%

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Greenberg

et al. 2016

Therapeutic Drug Monitoring

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Background Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Methods Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. Results For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 μg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7–1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. Conclusions This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration–response relationships.

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Section: Discussionmentioning

confidence: 99%

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Greenberg

et al. 2016

Therapeutic Drug Monitoring

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“…The neutropenia and thrombocytopenia resolved after discontinuation of phenobarbital (8 days and 15 days after discontinuation, respectively). This is the first case report in Korea to demonstrate blood dyscrasia associated with idiosyncratic adverse effects of phenobarbital.Keywords : leukopenia, neutropenia, phenobarbital, thrombocytopenia Phenobarbital (PB) is a long-acting barbiturate that enhances γ-aminobutyric acid-mediated increases in chloride conductance by opening chloride channels [11,12]. PB is a well-tolerated and effective anticonvulsant for various seizures and certain types of clinical epilepsy in dogs and cats [9,11,12].…”

mentioning

confidence: 99%

“…PB is a well-tolerated and effective anticonvulsant for various seizures and certain types of clinical epilepsy in dogs and cats [9,11,12].…”

mentioning

confidence: 99%

Drug-induced blood cell dyscrasia associated with phenobarbital administration in a dog

Jung¹,

Kang²,

Park³

2015

Korean Journal of Veterinary Research

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: A 13-year-old, spayed, female Chihuahua dog was referred for evaluation of fever, lethargy, and dyspnea. Hematologic evaluation revealed severe neutropenia, thrombocytopenia, and mild anemia. The dog had been undergoing phenobarbital therapy for the past 7 weeks because of generalized seizures due to meningoencephalomyelitis of unknown etiology. After ruling out other possible causes of cytopenias, a tentative diagnosis was made of drug-induced blood cell dyscrasia. The neutropenia and thrombocytopenia resolved after discontinuation of phenobarbital (8 days and 15 days after discontinuation, respectively). This is the first case report in Korea to demonstrate blood dyscrasia associated with idiosyncratic adverse effects of phenobarbital.Keywords : leukopenia, neutropenia, phenobarbital, thrombocytopenia Phenobarbital (PB) is a long-acting barbiturate that enhances γ-aminobutyric acid-mediated increases in chloride conductance by opening chloride channels [11,12]. PB is a well-tolerated and effective anticonvulsant for various seizures and certain types of clinical epilepsy in dogs and cats [9,11,12].PB has infrequent complications including hyperactivity, restlessness, excessive sedation, ataxia, polyuria, polydipsia, and polyphagia; these typically occur during the initial phase of therapy [9,10]. In most dogs, these side effects usually are tolerated after 2 to 4 weeks of therapy [10]. No actual hepatocellular damage during PB treatment has been confirmed; however, PB administration can contribute to the induction of serum liver enzyme activities in dogs [2,8]. In addition, PB has infrequently been associated with hematologic adverse drug events (ADEs) in dogs, including reversible neutropenia, thrombocytopenia, and anemia [5,6]. Long term use of PB can also lead to bone marrow necrosis [13].This case report describes the clinical and laboratory features of PB-related cytopenia and treatment outcomes. To the best of authors' knowledge, this is the first case report demonstrating blood dyscrasia associated with idiosyncratic ADE of PB in our country (South Korea).A 13-year-old, spayed female Chihuahua dog, weighing 2.8 kg, was referred to Konkuk University Veterinary Teaching Hospital for evaluation of fever, lethargy, and anorexia. About 9 months previously, the dog had been admitted for evaluation of generalized seizure and diagnosed with meningoencephalomyelitis of unknown etiology (MUE), based on magnetic resonance imaging findings (Fig. 1), and cerebrospinal fluid (CSF) analysis showing mononuclear pleocytosis (208 cells/µL; reference range: 0-5 cells/µL). Further test results including a polymerase chain reaction test for canine distemper virus and CSF culture were negative. Despite the diagnosis of MUE in this dog, the owner was unable to administer any medication due to personal circumstances. Since that visit, the frequency of seizures had increased, so PB (2.5 mg/kg, per orally [po], quarter [q] 12 h, Hana Pharm, Korea) had been prescribed by the referring veterinarian approximately 7 weeks...

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“…Severe hematological disorders are associated with CBZ treatment, including rare but severe aplastic anemia, agranulocytosis, and pancytopenia [19]. Mild anemia is possible in less than 5 % of patients on CBZ, persistent leukopenia in 2 % of patients [19,20] Fatal aplastic anemia is a rare but dangerous event, with a prevalence of 1 out of 50,000 patients [21].…”

Section: Carbamazepine and Oxcarbazepinementioning

confidence: 99%

“…Mild anemia is possible in less than 5 % of patients on CBZ, persistent leukopenia in 2 % of patients [19,20] Fatal aplastic anemia is a rare but dangerous event, with a prevalence of 1 out of 50,000 patients [21]. CBZ-induced thrombocytopenia is also described although rare, and developed shortly after treatment initiation: it is often asymptomatic, but it can present also with skin rashes, fever, and arthralgia [22].…”

Section: Carbamazepine and Oxcarbazepinementioning

confidence: 99%

Management of Adverse Effects of Mood Stabilizers

Murru

Popović

Pacchiarotti

et al. 2015

Curr Psychiatry Rep

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Mood stabilizers such as lithium and anticonvulsants are still standard-of-care for the acute and long-term treatment of bipolar disorder (BD). This systematic review aimed to assess the prevalence of their adverse effects (AEs) and to provide recommendations on their clinical management. We performed a systematic research for studies reporting the prevalence of AEs with lithium, valproate, lamotrigine, and carbamazepine/oxcarbazepine. Management recommendations were then developed. Mood stabilizers have different tolerability profiles and are eventually associated to cognitive, dermatological, endocrine, gastrointestinal, immunological, metabolic, nephrogenic, neurologic, sexual, and teratogenic AEs. Most of those can be transient or dose-related and can be managed by optimizing drug doses to the lowest effective dose. Some rare AEs can be serious and potentially lethal, and require abrupt discontinuation of medication. Integrated medical attention is warranted for complex somatic AEs. Functional remediation and psychoeducation may help to promote awareness on BD and better medication management.

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Anticonvulsant drugs and hematological disease

Cited by 68 publications

References 90 publications

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Drug-induced blood cell dyscrasia associated with phenobarbital administration in a dog

Management of Adverse Effects of Mood Stabilizers

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