Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2.
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L-Carnitine is essential for the translocation of acyl-carnitine into the mitochondria for beta-oxidation of long-chain fatty acids. It is taken up into the cells by the recently cloned Na(+)-driven carnitine organic cation transporter OCTN2. Here we expressed hOCTN2 in Xenopus laevis oocytes and investigated with two-electrode voltage- clamp and flux measurements its functional and pharmacological properties as a Na(+)-carnitine cotransporter. L-carnitine transport was electrogenic. The L-carnitine-induced currents were voltage and Na(+) dependent, with half-maximal currents at 0.3 +/- 0.1 mM Na(+) at -60 mV. Furthermore, L-carnitine-induced currents were pH dependent, decreasing with acidification. In contrast to other members of the organic cation transporter family, hOCTN2 functions as a Na(+)-coupled carnitine transporter. Carnitine transport was stereoselective, with an apparent Michaelis-Menten constant (K(m)) of 4.8 +/- 0.3 microM for L-carnitine and 98.3 +/- 38.0 microM for D-carnitine. The substrate specificity of hOCTN2 differs from rOCT-1 and hOCT-2 as hOCTN2 showed only small currents with classic OCT substrates such as choline or tetraethylammonium; by contrast hOCTN2 mediated transport of betaine. hOCTN2 was inhibited by several drugs known to induce secondary carnitine deficiency. Most potent blockers were the antibiotic emetine and the ion channel blockers quinidine and verapamil. The apparent IC(50) for emetine was 4.2 +/- 1.2 microM. The anticonvulsant valproic acid did not induce a significant inhibition of carnitine transport, pointing to a different mode of action. In summary, hOCTN2 mediates electrogenic Na(+)-dependent stereoselective high-affinity transport of L-carnitine and Na(+). hOCTN2 displays transport properties distinct from other members of the OCT family and is directly inhibited by several substances known to induce systemic carnitine deficiency. (+info)
Central nervous system paracoccidioidomycosis. Report of a case successfully treated with itraconazol.
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Paracoccidioidomycosis (PCM) is a primary pulmonary infection that often disseminates to other organs and systems. Involvement of the central nervous system (CNS) is rare and due to the fact that both clinical alertness and establishment of the diagnosis are delayed, the disease progresses causing serious problems. We report here a case of neuroparacoccidioidomycosis (NPCM), observed in a 55 year-old male, who consulted due to neurological symptoms (left hemiparesis, paresthesias, right palpebral ptosis, headache, vomiting and tonic clonic seizures) of a month duration. Upon physical examination, an ulcerated granulomatous lesion was observed in the abdomen. To confirm the diagnosis a stereotactic biopsy was taken; additionally, mycological tests from the ulcerated lesion and a bronchoalveolar lavage were performed. In the latter specimens, P. brasiliensis yeast cells were visualized and later on, the brain biopsy revealed the presence of the fungus. Treatment with itraconazole (ITZ) was initiated but clinical improvement was unremarkable; due to the fact that the patient was taking sodium valproate for seizure control, drug interactions were suspected and confirmed by absence of ITZ plasma levels. The latter medication was changed to clonazepam and after several weeks, clinical improvement began to be noticed and was accompanied by diminishing P. brasiliensis antigen and antibody titers. In the PCM endemic areas, CNS involvement should be considered more often and the efficacy of itraconazole therapy should also be taken into consideration. (+info)
Nonconvulsive status epilepticus causing acute confusion.
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PRESENTATION: an elderly patient presented with acute confusion and was found to have nonconvulsive status epilepticus. She responded to treatment with anti-epileptic drugs. OUTCOME: this case illustrates an important, under-recognized and reversible cause of acute prolonged confusion. (+info)
Characteristics of valproic acid resistant juvenile myoclonic epilepsy.
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Juvenile myoclonic epilepsy (JME) is often exquisitely responsive to treatment with valproic acid (VPA). However, a subset of patients does not respond to this medication and often has intractable seizures. We wanted to identify differences between these two subsets of JME patients. Charts of all JME patients followed at the Duke Epilepsy Center were reviewed. Clinical parameters, electroencephalogram (EEG) findings and magnetic resonance imaging (MRI) data were reviewed. These features were compared between patients with VPA sensitive and VPA resistant JME. Thirty-three patients with JME were identified: 23 (70%) were VPA sensitive (13 females, 10 males; mean age of onset 15.9 years) and 10 (30%) were VPA resistant (5 females, 5 males; mean age of onset 14.1 years). The VPA resistant group had a higher frequency of EEG asymmetries (40% vs. 10%); atypical seizure characteristics including auras and post-ictal confusion (30% vs. 4%); and intellectual deficiency (20% vs. 0%). Clinical characteristics combined with EEG data may help in predicting which JME patients will respond favorably to VPA. This study also raises the issue whether VPA resistant JME is in fact a localization-related epilepsy. (+info)
Management of bipolar disorder.
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Bipolar disorder most commonly is diagnosed in persons between 18 and 24 years of age. The clinical presentations of this disorder are broad and include mania, hypomania and psychosis. Frequently associated comorbid conditions include substance abuse and anxiety disorders. Patients with acute mania must be evaluated urgently. Effective mood stabilizers include lithium, valproic acid and carbamazepine. A comprehensive management program, including collaboration between the patient's family physician and psychiatrist, should be implemented to optimize medical care. (+info)
Influence of chronic barbiturate administration on sleep apnea after hypersomnia presentation: case study.
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When sleepiness is excessive, undesirable, inappropriate or unexplained, it often indicates a clinical disorder that is generically termed hypersomnia. One of the leading causes of hypersomnia is sleep apnea. We present the case of a 44-year-old woman with a history of bipolar spectrum disorder and epilepsy who initially showed evidence of hypersomnia. The hypersomnia settled with changes to her medication, but the patient was subsequently found to have severe obstructive sleep apnea. The relation between the patient's medication and sleep apnea is discussed, and the possible respiratory-suppressant effects of chronic barbiturate treatment are considered. The role of other evoking factors within the context of this case and the mechanisms by which drug interactions and psychotropic treatment may worsen, obscure or perpetuate sleep apnea are also examined. (+info)
Valproate-induced alterations in testosterone, estradiol and progesterone secretion from porcine follicular cells isolated from small- and medium-sized ovarian follicles.
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The aim of the present study was to investigate whether long-term exposure to valproate (VPA) alters follicular steroidogenesis and whether or not this effect is dependent on the degree of follicular development. Small- and medium-sized follicles were obtained from pig ovaries collected, respectively, at days 8-10 and 14-16 of oestrus cycle. Theca interna and granulosa cells were isolated from follicles and placed in the same well in the ratio 1 : 3 with or without the VPA in doses of 100, 300 and 500 micro g ml(-1). The culture medium was changed after 2, 4, 6 and 8 days. In both types of follicles, VPA caused a significant and dose-dependent reduction in both testosterone and estradiol secretion from follicular cells. In small-sized follicles, the testosterone to oestrogen ratio increased at all doses used and after all lengths of time in culture. In medium-sized follicles, a significant increase in the testosterone to oestrogen ratio was only observed at the highest dose level. All doses of VPA caused a marked inhibition of progesterone secretion after 48 hours while during long-term VPA exposure progesterone gradually increased demonstrating luteinization of cells. In conclusion, the present study demonstrates a direct effect of VPA on steroidogenesis. The effect seems to differ to some extent depending on the follicular stage of development. The elevated ratio of testosterone to estradiol suggests that VPA inhibits the conversion of testosterone to estradiol. (+info)
Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy.
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Lamotrigine is a broad-spectrum antiepileptic drug that blocks sodium channels, thereby inhibiting the pre-synaptic release of excitatory neurotransmitters. The primary aim of the study was to evaluate lamotrigine add-on therapy and consecutive monotherapy in patients with epilepsy whose seizures were not controlled by carbamazepine or valproate. One hundred and twenty six epilepsy patients at 18 centres in Poland were recruited into a lamotrigine substitution study. In all patients, existing seizures were poorly controlled with valproate (n= 63) or carbamazepine (n= 63) monotherapy. The study consisted of four phases: (1) a 4-week lamotrigine dose-escalation phase, (2) an 8-week lamotrigine add-on phase, (3) an 8-week carbamazepine/valproate withdrawal phase, and (4) an 8-week lamotrigine monotherapy phase. Of 126 patients recruited into the study, 107 (85%) completed dose-escalation and add-on therapy with lamotrigine and 85 (68%) completed lamotrigine monotherapy. Fifty percent of patients during add-on therapy and 53% during lamotrigine monotherapy experienced at least 50% reduction in total seizures (responders) compared to the pre-study period. Approximately 20% of patients during add-on therapy and 27% during lamotrigine monotherapy were seizure free. Total well-being was assessed using a Visual Analogue Scale with 62% of patients during add-on therapy and 60% in lamotrigine monotherapy reporting improvement in scores. Lamotrigine was generally well tolerated. Treatment was discontinued in 7% because of adverse events. In conclusion, lamotrigine is an effective AED in add-on therapy and monotherapy, it is safe and well tolerated, and successful conversion from add-on to monotherapy can be achieved in many cases. An additive effect between lamotrigine and valproate was observed. (+info)