CYP2C9 polymorphisms in epilepsy: influence on phenytoin treatment

Carlos Eduardo Silvado,1 Vera Cristina Terra,1 Carlos Alexandre Twardowschy2 1Comprehensive Epilepsy Program, Hospital de Clinicas, Federal University of Parana (UFPR), Curitiba, Brazil; 2Department of Neurology, Catholic University of Parana (PUCPR), Curitiba, Brazil Abstract: Phenytoin (PHT) is an antiepileptic drug widely used in the treatment of focal epilepsy and status epilepticus, and effective in controlling focal seizures with and without tonic–clonic generalization and status epilepticus. The metabolization of PHT is carried out by two oxidative cytochrome P450 enzymes CYP2C9 and CYP2C19; 90% of this metabolization is done by CYP2C9 and the remaining 10% by CYP2C19. Genetic polymorphism of CYP2C9 may reduce the metabolism of PHT by 25–50% in patients with variants *2 and *3 compared to those with wild-type variant *1. The frequency distribution of CYP2C9 polymorphism alleles in patients with epilepsy around the world ranges from 4.5 to 13.6%, being less frequent in African-Americans and Asians. PHT has a narrow therapeutic range and a nonlinear pharmacokinetic profile; hence, its poor metabolization has significant clinical implications as it causes more frequent and more serious adverse effects requiring discontinuation of treatment, even if it had been effective. There is evidence that polymorphisms of CYP2C9 and the use of PHT are associated with an increase in the frequency of some side effects, such as cerebellar atrophy, gingival hypertrophy or acute cutaneous reactions. The presence of HLA-B*15:02 and CYP2C9 *2 or *3 in the same patient increases the risk of Stevens–Johnson syndrome and toxic epidermal necrolysis; hence, PHT should not be prescribed in these patients. In patients with CYP2C9 *1/*2 or *1/*3 alleles (intermediate metabolizers), the usual PHT maintenance dose (5–10 mg/kg/day) must be reduced by 25%, and in those with CYP2C9 *2/*2, *2/*3 or *3/*3 alleles (poor metabolizers), the dose must be reduced by 50%. It is controversial whether CYP2C9 genotyping should be done before starting PHT treatment. In this paper, we aim to review the influence of CYP2C9 polymorphism on the metabolization of PHT and the clinical implications of poor metabolization in the treatment of epilepsies. Keywords: phenytoin, antiepileptics, CYP2C9, cytochrome P450, epilepsy, polymorphisms, adverse effect

Non-ceruloplasmin copper and urinary copper in clinically stable Wilson disease: Alignment with recommended targets.

BACKGROUND & AIMS: Wilson disease (WD) is caused by accumulation of copper primarily in the liver and brain. During maintenance therapy of WD with D-penicillamine, current guidelines recommend on-treatment ranges of urinary copper excretion (UCE) of 200-500 μg/24 h and serum non-ceruloplasmin-bound copper (NCC) of 50-150 μg/L. We compared NCC (measured by two novel assays) and UCE from patients with clinically stable WD on D-penicillamine therapy with these recommendations. METHODS: This is a secondary analysis of data from the Chelate trial (NCT03539952) that enrolled physician-selected patients with clinically stable WD on D-penicillamine maintenance therapy (at an unaltered dose for at least 4 months). We analyzed laboratory samples from the first screening visit, prior to interventions. NCC was measured by either protein speciation (NCC-Sp) using anion exchange high-performance liquid chromatography protein speciation followed by copper determination with inductively coupled plasma mass spectroscopy or as exchangeable copper (NCC-Ex). NCC-Sp was also analyzed in healthy controls (n = 75). RESULTS: In 76 patients with WD with 21.3±14.3 average treatment-years, NCC-Sp (mean±SD: 56.6±26.2 μg/L) and NCC-Ex (mean±SD: 57.9±24.7 μg/L) were within the 50-150 μg/L target in 61% and 54% of patients, respectively. In addition, 36% and 31%, respectively, were even below the normal ranges (NCC-Sp: 46-213 μg/L, NCC-Ex: 41-71 μg/L). NCC-Ex positively correlated with NCC-Sp (r2 = 0.66, p <0.001) but with systematic deviation. UCE was outside the 200-500 μg/24 h target range in 58%. Only 14/69 (20%) fulfilled both the NCC-Sp and UCE targets. Clinical or biochemical signs of copper deficiency were not detected. CONCLUSION: Clinically stable patients with WD on maintenance D-penicillamine therapy frequently have lower NCC-Sp or higher UCE than current recommendations without signs of overtreatment. Further studies are warranted to identify appropriate target ranges of NCC-Sp, NCC-Ex and UCE in treated WD. IMPACT AND IMPLICATIONS: Chelator treatment of patients with Wilson disease (WD) is currently guided by measurements of non-ceruloplasmin-bound copper (NCC) and 24 h urinary copper excretion (UCE) but validation is limited. In 76 adults with ≈21 years history of treated WD and clinically stable disease on D-penicillamine therapy, NCC was commonly found to be below normal values and recommended target ranges whether measured by protein speciation (NCC-Sp) or as exchangeable copper (NCC-Ex), while UCE values were above the recommended target range in 49%. Common wisdom would suggest overtreatment in these cases, but no clinical or biochemical signs of copper deficiency were observed. Exploratory analysis of liver enzymes suggested that NCC below levels seen in controls may be beneficial, while the relation to UCE was less clear. The data calls for critical re-evaluation of target ranges for treatment of WD, specific for drug and laboratory methodology. CLINICAL TRIAL NUMBER: (NCT03539952)

Pontine and extrapontine osmotic myelinolysis after the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with fluoxetine: case report Mielinólise osmótica pontina e extrapontina após a síndrome da secreção inapropriada de hormônio antidiurético associada com fluoxetina: relato de caso

Osmotic demyelination syndrome (ODS) may be precipitated by aggressive correction of a hypo or hyper-osmolar states. We describe the case of a 53-year-old woman that was started on fluoxetine 20 mg/day for depression and nine days later was found to have fluoxetine-induced syndrome of inappropriate secretion of antidiuretic hormone. After hyponatremia correction the mental status of the patient gradually improved, but subsequently she had intermittent difficulty in speaking, naming objects, memory deficits and psychomotor slowness. Magnetic resonance revealed bilateral symmetric hyperintense lesions in the basal ganglia, temporal lobe and hippocampal formation compatible with ODS. These symptoms gradually resolved and she was discharged home without any deficits. Two months later, a new image showed lesion in pons and the other lesions had disappeared. Fluoxetine therapy had never been related with a complication like that.<br>A síndrome de desmielinização osmótica (SDO) pode ser precipitada pela correção agressiva de um estado hiper ou hipoosmolar. Nós descrevemos o caso de mulher de 53 anos que havia iniciado o uso de fluoxetina 20 mg/dia para depressão e que nove dias depois foi diagnosticada como tendo síndrome da secreção inapropriada de hormônio antidiurético induzida por fluoxetina. Depois da correção da hiponatremia o estado mental da paciente gradualmente melhorou, mas subsequentemente ela apresentou dificuldade intermitente para fala e para nomear objetos, déficits de memória recente e lentidão psicomotora. Ressonância magnética revelou lesões hiperintensas bilaterais e simétricas na região dos gânglios da base, lobo temporal e hipocampo compatíveis com SDO. Estes sintomas gradualmente se resolveram e a paciente foi de alta sem qualquer déficit. Dois meses mais tarde uma nova imagem cerebral mostrou lesão na ponte e ausência das lesões antigas. Até onde sabemos a terapia com fluoxetina nunca foi relacionada a uma complicação tardia como esta

A case of asymptomatic pontine myelinolysis

Central pontine myelinolysis is an acquired, non-inflammatory demyelinating lesion usually localized in the brainstem pons basis; it usually affects patients with a history of chronic alcoholism, malnutrition or dysionemia. The exact pathogenesis of myelinolysis is still unclear. A 69-year-old Caucasian male presented intensive headache and underwent cranial MRI that showed the typical feature of central pontine myelinolysis. Neurological valuation was negative. Other examinations included extensive blood tests, electroencephalogram and multimodal evoked potentials which all gave normal results. Alcohol abuse and malabsorption syndrome were excluded. The medical history revealed a continuative use of anti-depressive drugs and exposure to glue for years. Our patient may represent one of the rare cases of asymptomatic CPM. The actual reason why he presented this lesion is not clear, but we discuss the possible role in the etiopathogenesis of his chronic use of anti-depressive drugs and the exposure to glue and chemical agents

Adverse Skin Reactions to Plants and Plant Products

Plants are a significant cause of skin reactions worldwide. Because most affected individuals do not present to a dermatologist, it is likely that skin reactions to plants are under-reported. Plants may induce mechanical irritant reactions, e.g., due to spines or hairs. Trauma to the plant may release chemical irritants such as calcium oxalate crystals or phorbol esters. Skin contact with furocoumarins in some plants, notably members of the Apiaceae, followed by exposure to ultraviolet A, induces a characteristic streaky rash leading to hyperpigmentation (phototoxicity). A few plant species including nettles (Urtica spp.) inject toxins into unsuspecting predators, a form of chemical warfare. These toxins include histamine, inducing nettle rash (urticaria). Other nonprotein plant constituents such as cinnamic acid derivatives may induce urticaria by a pharmacological mechanism. However, some individuals may develop immunologically mediated urticaria and even anaphylaxis caused by immediate hypersensitivity to plants or plant products, including fruit, vegetables, and nuts. Finally, a few plant families have the potential to induce allergic contact dermatitis; these include the daisy family (Asteraceae/Compositae) and poison ivy family (Anacardiaceae)