Are Psychiatric Adverse Events of Antiepileptic Drugs a Unique Entity? A Study on Topiramate and Levetiracetam

PURPOSE: To investigate the hypothesis that some patients with epilepsy are generally prone to develop psychiatric adverse events (PAEs) during antiepileptic drug (AED) therapy irrespective of the mechanism of action of the drugs. METHODS: From a large case registry of patients prescribed topiramate (TPM) and levetiracetam (LEV), data of patients who had a trial with both drugs were analyzed. Demographic and clinical variables of those who developed PAEs with both drugs (group 1) were compared with those who did not (group 2). Subsequently, from the whole case registry, psychopathological features, demographic, and clinical variables of patients developing PAEs with TPM were compared with those of patients developing PAEs with LEV. RESULTS: The case registry included over 800 patients. Among 108 patients having a trial with both drugs, we identified 9 patients in group 1 and 71 in group 2. Previous psychiatric history, family psychiatric history and history of febrile convulsions showed to be significant clinical correlates. Comparing patients who developed PAEs with LEV with those who developed PAEs with TPM, there were no differences in epilepsy related variables. Well-defined DSM-IV disorders were more frequent with TPM than with LEV. Seizure freedom was associated with psychosis. Conclusions: This study suggests that a subgroup of patients is generally prone to develop PAEs during AED therapy, despite different pharmacological properties of the AEDs. A particular clinical profile and relevant variables have been identified.     

The role of titration schedule of topiramate for the development of depression in patients with epilepsy

Purpose:   To determine whether a fast titration schedule of topiramate (TPM) has different effects on the occurrence of depression, in relation to other risk factors for TPM-induced depression, including history of depression (HxDEP), febrile seizures (FS), and hippocampal sclerosis (HS).
Methods:   Using data from a large case registry of patients prescribed TPM, two models were constructed: Model 1 examined the independent effect of rapid TPM titration after separate adjustment for FS, HxDEP, and HS. Model 2 examined effect of the cooccurrence of rapid titration on the development of depression with each of these risk factors.
Results:   A total of 423 patients were included (51.8% females), mean age (SD) 35.5 (11.8) years, mean duration of epilepsy of 22.2 (11.5) years. Forty-four patients (10.4%) developed depression during TPM therapy. A rapid TPM titration was associated with 5-fold increased risk of depression that increased to 12.7-fold in the presence of both FS and rapid TPM titration, 23.3-fold in the presence of both HxDEP and rapid TPM titration, and 7.6-fold in the presence of both HS and rapid TPM titration schedule.
Conclusions:   Our study suggests that a rapid titration schedule is associated with an increased risk of developing depression during TPM therapy. HxDEP and FS are major contraindications to the use of a rapid titration, with a 23.3-fold and 12.7 fold increased risk, respectively.     

Reclaiming freshwater sustainability in the Cadillac Desert

Increasing human appropriation of freshwater resources presents a tangible limit to the sustainability of cities, agriculture, and ecosystems in the western United States. Marc Reisner tackles this theme in his 1986 classic Cadillac Desert: The American West and Its Disappearing Water. Reisner's analysis paints a portrait of region-wide hydrologic dysfunction in the western United States, suggesting that the storage capacity of reservoirs will be impaired by sediment infilling, croplands will be rendered infertile by salt, and water scarcity will pit growing desert cities against agribusiness in the face of dwindling water resources. Here we evaluate these claims using the best available data and scientific tools. Our analysis provides strong scientific support for many of Reisner's claims, except the notion that reservoir storage is imminently threatened by sediment. More broadly, we estimate that the equivalent of nearly 76% of streamflow in the Cadillac Desert region is currently appropriated by humans, and this figure could rise to nearly 86% under a doubling of the region's population. Thus, Reisner's incisive journalism led him to the same conclusions as those rendered by copious data, modern scientific tools, and the application of a more genuine scientific method. We close with a prospectus for reclaiming freshwater sustainability in the Cadillac Desert, including a suite of recommendations for reducing region-wide human appropriation of streamflow to a target level of 60%.     

The impact of cytokines on the expression of drug transporters,cytochrome P450 enzymes and chemokine receptors in human PBMC

Background and purpose:

The function of transporters in peripheral blood mononuclear cells (PBMC) has been characterized, but less is known about cytochrome P450 (CYP) enzyme function in these cells. Given that cytokines are dysregulated in many diseases, the purpose of this work was to assess the impact of cytokines on the expression of CYPs, transporters and chemokine receptors in PBMC.

Experimental approach:

Human PBMC were incubated with cytokines for 48 h. ATP-binding cassette (ABC)B1, ABCC1, ABCC2, CYP2B6, CYP3A4, CXCR4 and CCR5 expression were measured by quantitative polymerase chain reaction and flow cytometry at 0, 4, 8, 24 and 48 h. Enzyme activity was assessed using fluorescent probes.

Key results:

We show here functional activity of CYP3A4 and CYP2B6 in PBMC. Furthermore, cytokines had a significant impact on the mRNA and protein expression of all proteins. For example, interleukin-2 (IL-2) had a marked impact on ABCB1 mRNA (% control 4745 ± 11961) and protein (% control 200 ± 57). Increases in drug efflux transporter expression, in response to cytokines, resulted in reduced cellular accumulation of digoxin [decrease of 17% and 26% for IL-2 and interferon-γ (IFNγ) respectively] and saquinavir (decrease of 28% and 30% for IL-2 and IFNγ respectively). The degree to which drug transporter and chemokine receptor expression changed in response to cytokines was positively correlated (e.g. ABCB1 and CXCR4, r² = 0.545).

Conclusions and implications:

These data have important implications for diseases in which cytokines are dysregulated and for which pharmacological intervention targets immune cells.     

On the prevalence of bipolar disorder in epilepsy

Although mood disorders represent a frequent psychiatric comorbidity in epilepsy, data on bipolar disorder (BD) are still limited, and the role of possible specific confounding variables (seizures and antiepileptic drug therapy) has never been considered. Data for 143 adult outpatients with epilepsy assessed with the Mini International Neuropsychiatric Interview Plus Version 5.0.0 using the Epilepsy Addendum for Psychiatric Assessment, the Mood Disorder Questionnaire, and the Interictal Dysphoric Disorder Inventory revealed that 11.8% had the Diagnostic and Statistical Manual of Mental Disorders-based diagnosis of BD, only 1.4% of whom could be considered as having “pure” BD, because in all other cases BD symptoms were related to phenotype copies of BD such as interictal dysphoric disorder of epilepsy, postictal manic or hypomanic states, and preictal dysphoria.     

Isolation and structure elucidation by LC-MS-SPE/NMR: PR toxin- and cuspidatol-related eremophilane sesquiterpenes from Penicillium roqueforti

Three eremophilane sesquiterpenes (1, 2, and 3) were isolated from Penicillium roqueforti DAOM 232127, and their structures were established. The new (3S)-3-acetoxyeremophil-1(2),7(11),9(10)-trien-8-one (3) is a likely biosynthetic precursor of PR toxin. 1-Hydroxyeremophil-7(11),9(10)-dien-8-one (1) is related to the immunosuppressant cuspidatol. The application of semihyphenated LC-MS-SPE/NMR to rapidly identify, purify, and elucidate the structures of 1, 2, and 3 is described.     

Epigallocatechin-3-gallate enhances CD8+ T cell-mediated antitumor immunity induced by DNA vaccination

Immunotherapy and chemotherapy are generally effective against small tumors in animal models of cancer. However, these treatment regimens are generally ineffective against large, bulky tumors. We have found that a multimodality treatment regimen using DNA vaccination in combination with chemotherapeutic agent epigallocatechin-3-gallate (EGCG), a compound found in green tea, is effective in inhibiting large tumor growth. EGCG was found to induce tumor cellular apoptosis in a dose-dependent manner. The combination of EGCG and DNA vaccination led to an enhanced tumor-specific T-cell immune response and enhanced antitumor effects, resulting in a higher cure rate than either immunotherapy or EGCG alone. In addition, combined DNA vaccination and oral EGCG treatment provided long-term antitumor protection in cured mice. Cured animals rejected a challenge of E7-expressing tumors, such as TC-1 and B16E7, but not a challenge of B16 7 weeks after the combined treatment, showing antigen-specific immune responses. These results suggest that multimodality treatment strategies, such as combining immunotherapy with a tumor-killing cancer drug, may be a more effective anticancer strategy than single-modality treatments.     

Comparison of the effects of frontal and temporal lobe partial seizures on prolactin levels.

The acute effects of partial (focal) epileptic seizures on serum prolactin levels were studied in two groups of patients: (1) 10 with temporal lobe seizures and (2) 11 with seizures that arose from the frontal lobes, recorded on cable video-electroencephalographic telemetry. Six of the eight complex partial seizures of temporal lobe origin were associated with a marked rise in prolactin levels at 10 minutes after onset (rise in levels, from a mean of 279 to 534 mU/L), compared with a rise in only one of the eight frontal lobe complex partial seizures. None of the five simple partial seizures (two of temporal and three of frontal lobe origin) was associated with a marked rise in prolactin levels. This difference in prolactin response following complex partial seizures of frontal and temporal lobe origin may help in the clinical differentiation of these seizures. A failure of prolactin levels to rise does not, however, exclude a diagnosis of complex partial seizures; thus, this measurement will not help in the clinical differentiation of frontal lobe complex partial seizures from psychogenic attacks.