Quetiapine-Induced Hypomania and its Association with Quetiapine/Norquetiapine Plasma Concentrations : A Case Series of Bipolar Type 2 Patients

International guidelines consider quetiapine at medium doses (300-400 mg/day) as valid options for the treatment of bipolar depression for the supposed lower risk of a switch to hypomania/mania than antidepressants. Norquetiapine is an active metabolite with antidepressant action. We describe three cases of induced hypomania in bipolar type 2 subjects who received quetiapine extended-release monotherapy (300 mg/day) for a mild/moderate major depressive episode. Quetiapine and norquetiapine plasma concentrations were measured after 1 week of treatment. Hypomania appeared after 7-10 days of quetiapine extended-release monotherapy and all subjects had a quetiapine/norquetiapine plasma concentration ratio <1. We propose a ratio value <1 as a predictor of risk for a switch to hypomania in bipolar depressed subjects receiving quetiapine extended-release monotherapy. Future research should ascertain the validity of this laboratory parameter to assess the risk of quetiapine-induced hypomania in large samples of bipolar patient

Lessons learned from SARS-CoV and MERS-CoV : FDA-approved Abelson tyrosine-protein kinase 2 inhibitors may help us combat SARS-CoV-2

SARS-CoV-2 is a newly emerging infectious disease, which originated from Wuhan in the Hubei province of China in late December 2019 [1]. Since then, it has rapidly spread all over the world, and at the time of writing this letter, WHO statistics show more than 1,696,588 cases and 105,952 deaths confirmed across the world [2]. Although there is no specific therapy for SARS-CoV-2 infection [3], combination therapy with antiviral and anti-inflammatory drugs accompanied by supportive treatment have been used for SARS-CoV-2 patients [4]. The combination of well-known HIV protease inhibitors, such as ritonavir with lopinavir, has also been a common approach to treat SARS-CoV-2. Insufficient outcome in severe cases is, however, one of the main challenges associated with the current antiviral-based therapy for SARS-CoV-2 [5]. In view of the long period required for novel drug discovery and the desperate need for a prompt response to this pandemic infection, one must resort to repurposing FDA-approved drugs. In this direction, our experience with other close members of coronaviruses such as SARS and MERS has taught us that repurposing the current drugs is a reasonable strategy. Abelson tyrosine-protein kinase 2 (Abl2), the imatinib target, was required for efficient SARS-CoV and MERS-CoV replication in vitro [6]. Coleman et al. have shown that the imatinib target Abl2 is indispensable for efficient replication of SARS-CoV and MERS-CoV in vitro

Late Post-traumatic Epilepsy in Children and Young Adults : Impropriety of Long-Term Antiepileptic Prophylaxis and Risks in Tapering

Background: After traumatic brain injury, epilepsy affects up to 20\uc2 % of children. It is a risk factor, for both clinical recovery and cognitive performance; therefore pharmacological therapy is advisable. Current guidelines recommend prophylaxis to be initiated as soon as possible and tapered 1\uc2 week after trauma. However, no guideline exists for paediatric patients and the clinical practice is heterogeneous. Objective: In our institute, prophylaxis was routinely tapered 6\uc2 months after trauma. Therefore we investigated whether this prophylaxis or its tapering influenced the development of post-traumatic epilepsy, together with several clinical-demographic factors. Methods: The study population comprised all patients with post-traumatic brain injury referred to this institute between 2002 and 2009 who consented to participate. Clinical, epileptological and pharmacological data were collected. The role of prophylaxis and several other predictors on occurrence of post-traumatic epilepsy was analysed through logistic regressions. Results: Two hundred and three patients (145 paediatric) were followed for 57\uc2 months on average. Risk factors for epilepsy were past neurosurgery [odds ratio (OR)\uc2 =\uc2 2.61, 95\uc2 % confidence interval (CI) 1.15\u20135.96], presence of epileptiform anomalies (OR\uc2 =\uc2 6.92, 95\uc2 % CI 3.02\u201315.86) and the presence of prophylaxis (OR\uc2 =\uc2 2.49, 95\uc2 % CI 1.12\u20135.52), while higher intelligence quotient (IQ) was protective (OR\uc2 =\uc2 0.96, 95\uc2 % CI 0.95\u20130.98). While evaluating possible different effects within and after 6\uc2 months (tapering, for those under prophylaxis), we found that epileptiform anomalies (OR\uc2 =\uc2 7.61, 95\uc2 % CI 2.33\u201324.93, and OR\uc2 =\uc2 8.21, 95\uc2 % CI 3.00\u201322.44) and IQ (OR\uc2 =\uc2 0.96, 95\uc2 % CI 0.94\u20130.98, and OR\uc2 =\uc2 0.97, 95\uc2 % CI 0.95\u20130.98) were always significant predictors of epilepsy, while neurosurgery (OR\uc2 =\uc2 4.38, 95\uc2 % CI 1.10\u201317.45) was significant only within 6\uc2 months from trauma, and prophylaxis (OR\uc2 =\uc2 3.98, 95\uc2 % CI 1.62\u20139.75) only afterwards. Conclusions: These results suggest that prophylaxis was irrelevant when present; furthermore its tapering increased the risk of epilepsy. Since the presence of epileptiform anomalies was the main predictor of post-traumatic epilepsy, such anomalies may be useful to better direct the choice of prophylaxis

Peroxynitrite mobilizes calcium ions from ryanodine-sensitive stores, a process associated with the mitochondrial accumulation of the cation and the enforced formation of species mediating cleavage of genomic DNA

Peroxynitrite does not directly cause strand scission of genomic DNA. Rather, as we previously reported, the DNA cleavage is largely mediated by H2O2 resulting from the dismutation of superoxide generated in the mitochondria upon peroxynitrite-dependent inhibition of complex III. The present study demonstrates that this process is strictly controlled by the availability of Ca2+ in the mitochondrial compartment. Experiments using intact as well as permeabilized U937 cells showed that the DNA-damaging response evoked by peroxynitrite is enhanced by treatments causing an increase in mitochondrial Ca2+ uptake and remarkably reduced under conditions leading to inhibition of mitochondrial Ca2+ accumulation. An additional, important observation was that the source of the Ca2+ mobilized by peroxynitrite is the ryanodine receptor; preventing the mobilization of Ca2+ with ryanodine suppressed the mitochondrial formation of reactive oxygen species and the ensuing DNA strand scission. Identical results were obtained using PC12, C6, and THP-1 cells. These results, along with our previous findings indicating that the DNA damage induced by peroxynitrite is also suppressed by inhibition of the electron flow through complex I, e.g., by rotenone, or by the respiration-deficient phenotype, demonstrate that the mitochondrial formation of DNA-damaging species is critically regulated by the inhibition of complex III and by the availability of Ca2+

Determination of linezolid in human plasma by high-performance liquid chromatography with ultraviolet detection

A high-performance liquid chromatographic method for the determination of linezolid in human plasma was developed and validated. After precipitation of plasma proteins with perchloric acid, the protein-free supernatant was separated by isocratic reverse-phase chromatography on a X Bridge C18 column. The mobile phase consisted of a mixture of phosphoric acid 0.05%: acetonitrile (75:25, v/v) with a flow rate of 1 mL/min. The column elute was monitored at 254 nm. The method was linear from 0.2 to 48 mg/L (mean r = 0.9996, n = 10). The observed intra-and inter-day assay imprecision ranged from 2.83% to 8.16% (18.80% at the lower limit of quantification); inaccuracy varied between-0.33% and 8.18%. Mean drug recovery was 99.8% for linezolid and 90.0% for the internal standard (para-toluic acid). The method was found to be precise and accurate and suitable for therapeutic drug monitoring of linezolid in routine clinical practice

Exposure-related effects of atazanavir on the pharmacokinetics of raltegravir in HIV-1-infected patients

Raltegravir (RAL) is primarily metabolized by uridine diphosphate- glucorunosyl transferase 1A1 (UGT1A1). Atazanavir (ATV), a strong inhibitor of UGT1A1, has been shown to increase plasma concentrations of RAL by approximately 50% in healthy volunteers. However, the extent of this interaction has not been studied in HIV-infected patients. A pharmacokinetic study was performed in 22 HIV-infected adults treated with 400 mg RAL plus 300 mg ATV 300 twice a day. Both drugs showed high pharmacokinetic variability (RAL AUC0-12 7649 \ub1 4862 ng*h/mL; ATV AUC0-12 = 19237 \ub1 13136 ng*h/mL). Notably, RAL trough concentrations were significantly higher compared with those measured in HIV subjects (n = 24) on RAL plus nucleoside reverse transcriptase inhibitors (506 \ub1 411 versus 177 \ub1 262 ng/mL, P < 0.01). A significant correlation was found between RAL and ATV area under the curve (AUC) (r = 0.611, P = 0.005). Notably, patients with ATV AUC0-12 above the mean or with concentrations exceeding the half maximal inhibitory concentration for UGT1A1 had twofold higher RAL AUCs compared with patients with lower ATV exposure. Coadministration of ATV significantly increased plasma concentrations of RAL, especially in HIV-1-infected patients exposed to high concentrations of the protease inhibitor. This pharmacokinetic drug interaction could be handled by routine measurements of ATV trough concentrations and by the assessment of plasma RAL concentrations 2 to 3 hours after the morning drug intake

A case of atrial fibrillation induced by inhaled fluticasone propionate

Atrial fibrillation (AF) is the most common rhythm disorder observed in clinical practice. Several case reports and case-control studies have associated this condition with the use of systemic corticosteroids. However, to our knowledge, no case of AF induced by inhaled corticosteroids has been reported in the literature. We describe here the case of a 15-year-old boy who reported a paroxysmal AF with fast ventricular response after the administration of fluticasone propionate, which resolved after discontinuation of the drug. Use of the Naranjo adverse-drug-reaction probability scale indicated a possible relationship between the patient's development of AF and fluticasone propionate therapy. More studies are needed to confirm the association between this arrhythmia and the use of high doses of inhaled corticosteroids. Data from this report already suggest that clinicians should be aware of the possibility of adverse cardiovascular reactions when corticosteroids are prescribed also as inhaled preparations