New "drugs and targets" in the GWAS era of bipolar disorder.

OBJECTIVE: Due to the phenotypic heterogeneity and etiological complexity of bipolar disorder (BD), many patients do not respond well to the current medications, and developing novel effective treatment is necessary. Whether any BD genome-wide association study (GWAS) risk genes were targets of existing drugs or novel drugs that can be repurposed in the clinical treatment of BD is a hot topic in the GWAS era of BD. METHODS: A list of 425 protein-coding BD risk genes was distilled through the BD GWAS, and 4479 protein-coding druggable targets were retrieved from the druggable genome. The overlapped genes/targets were subjected to further analyses in DrugBank, Pharos, and DGIdb datasets in terms of their FDA status, mechanism of action and primary indication, to identify their potential for repurposing. RESULTS: We identified 58 BD GWAS risk genes grouped as the druggable targets, and several genes were given higher priority. These BD risk genes were targets of antipsychotics, antidepressants, antiepileptics, calcium channel antagonists, as well as anxiolytics and analgesics, either existing clinically-approved drugs for BD or the drugs than can be repurposed for treatment of BD in the future. Those genes were also likely relevant to BD pathophysiology, as many of them encode ion channel, ion transporter or neurotransmitter receptor, or the mice manipulating those genes are likely to mimic the phenotypes manifest in BD patients. CONCLUSIONS: This study identifies several targets that may facilitate the discovery of novel treatments in BD, and implies the value of conducting GWAS into clinical translation.

Non-CGRP Antagonist/Non-Triptan Options for Migraine Disease Treatment: Clinical Considerations.

PURPOSE OF REVIEW: Although the association between CGRP and migraine disease is well-known and studied, therapies can target other pathways to minimize migraine symptoms. It is important to understand the role of these medications as options for migraine treatment and the varied mechanisms by which symptoms can be addressed. In the present investigation, the role of non-CGRP antagonist/non-triptan options for migraine disease therapy is reviewed, including NSAIDs, ß-blockers, calcium channel blockers, antidepressants, and antiepileptics. Pharmacologic therapies for both acute symptoms and prophylaxis are evaluated, and their adverse effects are compared. RECENT FINDINGS: At present, the Food and Drug Association has approved the beta-blockers propranolol and timolol and the anti-epileptic drugs topiramate and divalproex sodium for migraine prevention. Clinicians have other options for evidence-based treatment of episodic migraine attacks. Treatment decisions should consider contraindications, the effectiveness of alternatives, and potential side effects. NSAIDs are effective for the acute treatment of migraine exacerbations with caution for adverse effects such as gastrointestinal upset and renal symptoms. Beta-blockers are effective for migraine attack prophylaxis but are associated with dizziness and fatigue and are contraindicated in patients with certain co-morbidities, including asthma, congestive heart failure, and abnormal cardiac rhythms. Calcium channel blockers do not show enough evidence to be recommended as migraine attack prophylactic therapy. The anti-epileptic drugs topiramate and divalproex sodium and antidepressants venlafaxine and amitriptyline are effective for migraine exacerbation prophylaxis but have associated side effects. The decision for pharmacologic management should ultimately be made following consideration of risk vs. benefit and discussion between patient and physician.

Antiseizure Properties of Histamine H3 Receptor Antagonists Belonging 3,4-Dihydroquinolin-2(1H)-Ones.

H3R is becoming an attractive and promising target for epilepsy treatment as well as the discovery of antiepileptics. In this work, a series of 6-aminoalkoxy-3,4-dihydroquinolin-2(1H)-ones was prepared to screen their H3R antagonistic activities and antiseizure effects. The majority of the target compounds displayed a potent H3R antagonistic activity. Among them, compounds 2a, 2c, 2h, and 4a showed submicromolar H3R antagonistic activity with an IC50 of 0.52, 0.47, 0.12, and 0.37 µM, respectively. The maximal electroshock seizure (MES) model screened out three compounds (2h, 4a, and 4b) with antiseizure activity. Meanwhile, the pentylenetetrazole (PTZ)-induced seizure test gave a result that no compound can resist the seizures induced by PTZ. Additionally, the anti-MES action of compound 4a fully vanished when it was administrated combined with an H3R agonist (RAMH). These results showed that the antiseizure role of compound 4a might be achieved by antagonizing the H3R receptor. The molecular docking of 2h, 4a, and PIT with the H3R protein predicted their possible binding patterns and gave a presentation that 2h, 4a, and PIT had a similar binding model with H3R.

Development and Use of an Ex-Vivo In-Vivo Correlation to Predict Antiepileptic Drug Clearance in Patients Undergoing Continuous Renal Replacement Therapy.

OBJECTIVES: Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations. METHODS: Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2 g/dL, 3 g/dL, and 4 g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr). Blood and effluent/dialysate concentrations were collected after circuit priming. ECs were calculated for each drug, modality, vehicle, and experimental arm combination. RESULTS: The calculated average EC for levetiracetam and lacosamide was approximated to the fraction unbound from plasma protein. Human plasma and ALB-NS vehicles demonstrated adequate prediction of in-vivo CRRT clearance. Geometric mean ratios indicated similarity in extraction coefficients when comparing between hemofiltration and hemodiafiltration modalities and between filtration and dialysis modalities at effluent flow rates ≤ 2L/hr. Evaluation of phenytoin provided inconsistent findings with regards to extraction coefficient similarity across different CRRT modalities. CONCLUSION: The findings indicate that an ex-vivo study can be used as a surrogate to predict in-vivo levetiracetam and lacosamide clearance in patients receiving CRRT.

Association between human leukocyte antigens and cutaneous adverse drug reactions to antiepileptics and antibiotics in the Iranian population.

In this case-control study, class І and ІІ human leukocyte antigen (HLA) alleles in Iranian patients with benign and severe cutaneous adverse drug reactions (CADRs) due to aromatic anticonvulsants and antibiotics were evaluated. Patients diagnosed with CADRs (based on clinical and laboratory findings) with a Naranjo score of ≥ 4 underwent blood sampling and HLA-DNA typing. The control group comprised 90 healthy Iranian adults. Alleles with a frequency of more than two were reported. Deviations from Hardy-Weinberg equilibrium were not observed. Eighty patients with CADRs including 54 females and 26 males with a mean age of 41.49 ± 16.08 years were enrolled in this study. The culprit drugs included anticonvulsants (lamotrigine, carbamazepine, and phenytoin) and antibiotics (ciprofloxacin and co-trimoxazole). The comparison of allele frequencies in the Iranian healthy control group and the group with benign CADRs revealed that HLA-Cw*04, and HLA-A*24 were significantly associated with lamotrigine-induced maculopapular CADRs. Furthermore, HLA-B*51 showed a significant correlation with carbamazepine-induced maculopapular CADRs. Significant associations were also detected between ciprofloxacin-induced urticarial CADRs with HLA-B*40, and HLA-DRB1*14. In the severe group, HLA-B*38 and HLA-DRB1*13 were significantly associated with lamotrigine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Moreover, HLA-A*31 and HLA-Cw*04 were significantly correlated with carbamazepine-induced drug reactions with eosinophilia and systemic symptoms (DRESS). HLA-B*08 also showed a significant correlation with ciprofloxacin-induced acute generalized exanthematous pustulosis (AGEP). In conclusion, Lamotrigine-induced MPE was significantly correlated with HLA-Cw*04, and HLA-A*24. Similarly, lamotrigine-induced SJS/TEN was significantly associated with HLA-B*38 and HLA-DRB1*13. Additionally, HLA-A*31 was associated with DRESS caused by carbamazepine. The most frequent CADR-inducing drugs were anticonvulsants.

Perioperative routine EEG can reliably predict de novo seizures after supratentorial craniotomy.

BACKGROUND: The contributing risk factors in development of seizure after supratentorial craniotomy, the optimal duration of prophylactic antiepileptic therapy, the high-risk patient to treat, and the drug of choice are subjects of debate as is the gold standard diagnostic tool for patient screening. Combining routine electroencephalography (EEG) with clinical data to identify high-risk patients and determine the ideal time of recording after surgery was the goal of this study. METHODS: In this prospective cohort, 59 patients were evaluated with three EEG recordings after different intervals of supratentorial craniotomy due to different etiologies and were followed for 9 months for development of seizures. Demographic and disease-related variables as well as EEG results were analyzed to determine the contributing risk factors for development of seizures. RESULTS: Neoplastic etiology and abnormal perioperative EEG (performed before surgery or in the first postoperative week) were the only independent variables associated with development of de novo seizure. CONCLUSION: Routine EEG in the perioperative period and neoplastic etiology are two independent powerful predictors of developing seizure after supratentorial craniotomy and may help deciding whether to continue prophylactic antiepileptic medications for an extended period or not.

Trends in the consumption and cost of antiepileptics in Morocco between 2008 and 2018.

INTRODUCTION: Epilepsy is one of the most common chronic neurological diseases. In Morocco, it is the second most common reason for consulting a neurologist. Its prevalence was estimated in Casablanca in 1998 at 1.1%. This study was carried out with the aim of evaluating, on the one hand, the consumption of antiepileptics and, on the other hand, the impact of their generic drugs on the pharmaceutical market between 2008 and 2018 in Morocco. MATERIALS AND METHODS: We used sales data for antiepileptic drugs collected from the Moroccan subsidiary of IQVIA, a multinational healthcare data science company, and we converted them into a defined daily dose (DDD/1000 inhabitants). RESULTS: The consumption of antiepileptic drugs increased from 442 to 641 DDD/1000 inhabitants between 2008 and 2018, all molecules combined, recording a 45% increase in the period studied. From an economic point of view, the calculation of the average cost of DDD, all molecules combined, gives an average cost of 2.42 dollars/DDD in 2018 versus 3.53 dollars/DDD in 2008 (1 dirham = 0.11 dollar), which corresponds to a decrease of -30%. This is due mainly to the introduction of generic drugs. CONCLUSION: These results show that while the average cost of a DDD has decreased, the consumption of antiepileptics has increased in Morocco over the years. Several events that have marked the drug market in Morocco have contributed to this trend, including the arrival on the market of several new molecules indicated for the treatment of epilepsy, the decrease in drug prices in 2014 and the policy of promoting generic drugs.

Features of the choice and the use of antiepileptic drugs as analgesics in elderly.

High prevalence of chronic pain in elderly results in active search of new approaches for the effective and safe management of this category of patients. Antiepileptic drugs may provide analgesic affect in different types of chronic pain (mainly, in neuropathic pain). Variety of antiepileptics used as analgesics have variable efficacy and safety profile in elderly. «Old¼ antiepileptics (phenobarbital, clonazepam, ethosuximide, carbamazepine, phenytoin, valproate, etc.) and «new¼ (gabapentin, pregabalin, oxcarbazepine, lamotrigine, levetiracetam, topiramate, zonisamide, tiagabine) are considered in this review with insights on pharmacokinetic features of these drugs in elderly, profile of side effects, parameters of analgesic efficacy.

Post hoc analysis of a phase 3, multicenter, open-label study of cenobamate for treatment of uncontrolled focal seizures: Effects of dose adjustments of concomitant antiseizure medications.

OBJECTIVE: To report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long-term, open-label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention. METHODS: Patients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut-off, on or after September 1, 2019. RESULTS: A total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut-off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut-off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)-related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months. SIGNIFICANCE: Concomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs.

Interictal autonomic changes in persons with epilepsy (PWE) on carbamazepine (CBZ) versus other anti-seizure drug monotherapy: A cross-sectional study.

OBJECTIVE: Epilepsy is one of the most prevalent neurological conditions and carbamazepine is a commonly used anti-seizure drug (ASD), especially in developing nations. There are reports of carbamazepine causing atrioventricular conduction defects and autonomic dysfunctions and its implication in Sudden Unexpected Death in Epilepsy (SUDEP) is controversial. We planned this study to assess the effect of carbamazepine (CBZ) on autonomic function compared to other ASDs in persons with epilepsy. METHODS: In this cross-sectional study, we assessed the sympathetic and parasympathetic autonomic functions in persons with epilepsy (PWE) on CBZ versus other anti-seizure monotherapy using tests of heart rate variability including its time-, frequency- and non-linear domains, heart rate response to deep breathing, valsalva maneuver, and blood pressure response to isometric handgrip. RESULTS: Persons with epilepsy on CBZ monotherapy did not show a significant reduction in the time domain parameter SDRR compared to other ASDs used as monotherapy (mean ±â€¯SD, 38.04 ±â€¯18.75 ms vs 44.37 ±â€¯20.35 ms; p = 0.125). However, PWE on CBZ had significantly lower time-domain measurements including RMSSD (mean ±â€¯SD 31.95 ±â€¯17.29 ms vs 42.02 ±â€¯22.29 ms; p = 0.018), SDSD (mean ±â€¯SD 31.91 ±â€¯17.26 ms vs 41.96 ±â€¯22.27 ms; p 0.018), and pNN50 [median (IQR) 05.45(0.69-25.37) vs 16.38(2.32-36.83); p = 0.030]. Frequency domain measures of HRV, heart rate responses to deep breathing, valsalva maneuver and tilt-testing and BP responses to valsalva and tilt-testing were not significantly different between the groups. CONCLUSION: The findings of our study indicate reduced parasympathetic activity in persons on CBZ monotherapy compared to other ASDs, which may pose risk of SUDEP. Carbamazepine may thus be avoided in those at risk of autonomic dysfunction and SUDEP.

Serum concentrations of antidepressants, antipsychotics, and antiepileptics over the bariatric surgery procedure.

PURPOSE: As a substantial proportion of bariatric surgery patients use psychotropic/antiepileptic drugs, we investigated the impact of this procedure on serum concentrations. METHODS: In a naturalistic, longitudinal, prospective case series, we compared dose-adjusted trough concentrations of antidepressants, antipsychotics, or antiepileptics in consecutive patients before and after bariatric surgery. Adherence to treatment over 2 weeks preceding each sampling was considered. RESULTS: In all, 85 participants were included (86% female, median age 45 years, median body mass index 42 kg/m2). They were being treated with 18 different psychotropic/antiepileptic drugs (7 substances: 6-17 individuals, 11 substances: 1-4 individuals) and contributed 237 samples over a median of 379 days after surgery. For four out of seven substances with pre-/post-surgery samples available from six or more individuals, the dose-adjusted concentration was reduced (sertraline: 51%, mirtazapine: 41%, duloxetine: 35%, citalopram: 19%). For sertraline and mirtazapine, the low-calorie-diet before surgery entirely explained this reduction. A consistent finding, irrespective of drug, was the association between the mean ratio of the post-/pre-diet dose-adjusted concentration and the lipophilicity of the drug (logD; correlation coefficient: -0.69, P = 0.0005), the low-calorie diet often affecting serum concentration more than the surgery itself. CONCLUSIONS: Serum concentrations of psychotropic/antiepileptic drugs vary after bariatric surgery and can be hard to predict in individual patients, suggesting that therapeutic drug monitoring is of value. Conversely, effects of the pre-surgery, low-calorie diet appear generalizable, with decreased concentrations of highly lipophilic drugs and increased concentrations of highly hydrophilic drugs. Interaction effects (surgery/dose/concentration) were not evident but cannot be excluded.

Evaluation of Time to Administration, Benzodiazepine Use, and Safety of Intravenous Push Levetiracetam in a Neuro-Spine Intensive Care Unit.

PURPOSE: The purpose of this study was to evaluate the time to medication administration, clinical effect, and safety of a recent Pharmacy and Therapeutics Committee-approved change in the administration of levetiracetam from intravenous piggyback (IVPB) over 15 min to undiluted intravenous push (IVP) over 2-5 min at a large academic medical center. METHODS: The primary outcome was the time from order verification to the administration of IVP levetiracetam versus IVPB levetiracetam. The secondary outcome was any benzodiazepine administered in the time between levetiracetam order verification and administration in both groups. Adult patients admitted to the neuro-spine intensive care unit in the 6 months prior to and after the policy change, and who received at least one dose of 1000 mg or higher of IVP or IVPB levetiracetam for active seizures, were included in this retrospective, observational, institutional review board-approved study. Data were analyzed using descriptive statistics, χ2, and the Mann-Whitney U-test as appropriate. RESULTS: Of the 2055 hospital-wide levetiracetam doses ordered within the study period, 316 doses were screened for enrollment and 160 were enrolled with 60 and 100 patients assigned to the IVP and IVPB groups, respectively. There were no differences between the groups at baseline. The majority of the population was male, 57 years old, had no significant renal dysfunction (defined as a creatinine clearance of less than 60 ml/min), and had a seizure etiology of malignancy or traumatic brain injury. A significant reduction in the time to administration of levetiracetam was found with IVP compared with IVPB administration (28 vs. 80 min, p < 0.0001). A subsequent reduction in patients who received benzodiazepines in the interim of levetiracetam order verification and administration was also associated with IVP compared with IVPB (2% vs. 13%, p = 0.042). There were no differences found in the rates of adverse effects between groups. CONCLUSIONS: Administration of levetiracetam doses up to 2000 mg via IVP is a safe method of administration that results in a reduction of time to medication administration and a reduction of benzodiazepine use.

[S2k guidelines: status epilepticus in adulthood : Guidelines of the German Society for Neurology]. / S2k-Leitlinie: Status Epilepticus im Erwachsenenalter : Leitlinie der Deutschen Gesellschaft für Neurologie.

This S2k guideline on diagnosis and treatment of status epilepticus (SE) in adults is based on the last published version from 2021. New definitions and evidence were included in the guideline and the clinical pathway. A seizures lasting longer than 5 minutes (or ≥ 2 seizures over more than 5 mins without intermittend recovery to the preictal neurological state. Initial diagnosis should include a cCT or, if possible, an MRI. The EEG is highly relevant for diagnosis and treatment-monitoring of non-convulsive SE and for the exclusion or diagnosis of psychogenic non-epileptic seizures. As the increasing evidence supports the relevance of inflammatory comorbidities (e.g. pneumonia) related clinical chemistry should be obtained and repeated over the course of a SE treatment, and antibiotic therapy initiated if indicated.Treatment is applied on four levels: 1. Initial SE: An adequate dose of benzodiazepine is given i.v., i.m., or i.n.; 2. Benzodiazepine-refractory SE: I.v. drugs of 1st choice are levetiracetam or valproate; 3. Refractory SE (RSE) or 4. Super-refractory SE (SRSE): I.v. propofol or midazolam alone or in combination or thiopental in anaesthetic doses are given. In focal non-convulsive RSE the induction of a therapeutic coma depends on the circumstances and is not mandatory. In SRSE the ketogenic diet should be given. I.v. ketamine or inhalative isoflorane can be considered. In selected cased electroconvulsive therapy or, if a resectable epileptogenic zone can be defined epilepsy surgery can be applied. I.v. allopregnanolone or systemic hypothermia should not be used.

Prevalence and correlates of depression in patients with epilepsy in Sri Lanka.

Background: Depression is one of the most common psychiatric disorders in patients with epilepsy and it is often associated with poor quality of life, increased risk of suicide and poor seizure control, yet remains underdiagnosed and undertreated. The prevalence and associations for depression in patients with epilepsy vary between studies reflecting regional and cultural influences. Therefore, it is important to identify unique attributes within a community on this phenomenon This is the first study from Sri Lanka on the prevalence and correlates of depression in patients with epilepsy. Method: We conducted this cross-sectional study at the Epilepsy clinic, Colombo North Teaching Hospital, Ragama. All consenting patients with a diagnosis of epilepsy followed up at the clinic, during study period, were enrolled. Symptoms of depression were screened with Beck Depression Inventory II and diagnosis was confirmed with a clinical assessment by psychiatrist. Results: Of 150 participants, majority were female 63.3%. (95) and 36.7% (55) of the sample were between 26-45 years. The prevalence of depressive disorder was 22% (33). The prevalence of depression was significantly associated with the recent diagnosis of epilepsy, use of multiple antiepileptic medications and duration of seizure free period (p<0.05). There is a statistically significant association between prevalence of depression with the use of carbamazepine, topiramate, clobazam and phenobarbitone. Regression analysis revealed higher the duration individuals suffering from epilepsy were at lower odds of having depression compared with that of individuals suffering from lower duration of epilepsy. For each year in increase of duration of epilepsy, the odds of depression decreased by 2% (95% CI 0.3% to 5.1%). Conclusion: The prevalence of depression is high in patients with epilepsy. Risk of having depression is higher during the early phase of the illness. Therefore, it is important to screen patients with epilepsy for depressive disorder during the early course of the illness.

Epilepsy management in pregnant HIV+ women in sub-Saharan Africa, clinical aspects to consider: a scoping review.

BACKGROUND: Since the introduction of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome (AIDS) related mortality has markedly declined. As HAART is becoming increasingly available, the infection with human immunodeficiency virus (HIV+) in sub-Saharan Africa (SSA) is becoming a chronic condition. While pregnancy in HIV+ women in SSA has always been considered a challenging event for the mother and the fetus, for pregnant HIV+ women also diagnosed with epilepsy (WWE), there are additional risks as HIV increases the odds of developing seizures due to the vulnerability of the central nervous system to other infections, immune dysfunction, and overall metabolic disturbances. In light of a growing proportion of HIV+ WWE on HAART and an increasing number of pregnant women accessing mother-to-child transmission of HIV programs through provision of HAART in SSA, there is a need to develop contextualized and evidenced-based clinical strategies for the management of epilepsy in this population. In this study, we conduct a literature scoping review to identify issues that warrant consideration for clinical management. RESULT: Twenty-three articles were retained after screening, which covered six overarching clinical aspects: status epilepticus (SE), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), dyslipidemia, congenital malformation (CM), chronic kidney disease (CKD), and neurological development. No studies for our population of interest were identified, highlighting the need for a cautionary approach to be employed when extrapolating findings. CONCLUSION: High risks of CM and drug interactions with first-line antiepileptic drugs (AEDs) warrant measures to increase the accessibility and choices of safer second-line AEDs. To ensure evidence-based management of epilepsy within this population, the potential high prevalence of SE, CKD, dyslipidemia, and SJS/TEN and the cumulative effect of drug-drug interactions should be considered. Further understanding of the intersections between pregnancy and drug-drug interactions in SSA is needed to ensure evidenced-based management of epilepsy in pregnant HIV+ WWE. To prevent SE, the barriers for AED treatment adherence in pregnant HIV+ women should be explored. Our review underscores the need to conduct cohort studies of HIV+ WWE in reproductive age over time and across pregnancies to capture the cumulative effect of HAART and AED to inform clinical management.

A Double Blind, Placebo Controlled, Randomized Trial to Evaluate the Efficacy and Tolerability of On-Demand Oral Pregablin (150 mg and 75 mg) in Treatment of Premature Ejaculation.

INTRODUCTION: Although premature ejaculation (PE) is a common sexual dysfunction, the available options for PE treatment remain unsatisfactory. AIM: To evaluate the effect of on-demand oral pregabalin on the intravaginal ejaculation latency time (IELT). METHOD: We conducted a multiarm double-blinded placebo-controlled randomized clinical trial that enrolled 120 patients with PE who were divided equally into 3 groups (A, B, and C). 4 patients were excluded, 39 patients received 150 mg pregabalin (group A), 39 patients received 75 mg pregabalin (group B), and 38 patients received placebo (group C). All patients were encouraged to engage in sexual relations twice per week for 2 weeks and to take the medication 1-2 hours before sexual intercourse. A stopwatch was used to evaluate IELT. MAIN OUTCOME MEASURE: The main outcome measure are the improvement of IELT and the reported adverse events. RESULTS: IELT significantly improved in patients who received 150 mg pregabalin, but there was no change in the other groups. CLINICAL IMPLICATIONS: Most PE patients showed a significant improvement after receiving on-demand pregabalin (150 mg). STRENGTH & LIMITATIONS: The strength of this study is that it is the first randomized controlled trial to evaluate the efficacy of pregabalin in treatment of PE. The main limitations were the small number of patients, IELT was the only primary outcome of the study, and the pregabalin cap can be identified by the patient. CONCLUSION: Oral pregabalin seems to be a promising drug for additional evaluation as a new treatment for PE. More studies are needed to evaluate the suitable dose, duration, timing, and its safety profile. El Najjar MR, El Hariri M, Ramadan A, et al. A Double Blind, Placebo Controlled, Randomized Trial to Evaluate the Efficacy and Tolerability of On-Demand Oral Pregablin (150 mg and 75 mg) in Treatment of Premature Ejaculation. J Sex Med 2020;17:442-446.

Prevalence trends and individual patterns of antiepileptic drug use in pregnancy 2006-2016: A study in the five Nordic countries, United States, and Australia.

PURPOSE: To describe recent international trends in antiepileptic drug (AED) use during pregnancy and individual patterns of use including discontinuation and switching. METHODS: We studied pregnancies from 2006 to 2016 within linked population-based registers for births and dispensed prescription drugs from Denmark, Finland, Iceland, Norway, Sweden, and New South Wales, Australia and claims data for public and private insurance enrollees in the United States. We examined the prevalence of AED use: the proportion of pregnancies with ≥1 prescription filled from 3 months before pregnancy until birth, and individual patterns of use by trimester. RESULTS: Prevalence of AED use in almost five million pregnancies was 15.3 per 1000 (n = 75 249) and varied from 6.4 in Sweden to 34.5 per 1000 in the publicly-insured US population. AED use increased in all countries in 2006-2012 ranging from an increase of 22% in Australia to 104% in Sweden, and continued to rise or stabilized in the countries in which more recent data were available. Lamotrigine, clonazepam, and valproate were the most commonly used AEDs in the Nordic countries, United States, and Australia, respectively. Among AED users, 31% only filled a prescription in the 3 months before pregnancy. Most filled a prescription in the first trimester (59%) but few filled prescriptions in every trimester (22%). CONCLUSIONS: Use of AEDs in pregnancy rose from 2006 to 2016. Trends and patterns of use of valproate and lamotrigine reflected the safety data available during this period. Many women discontinued AEDs during pregnancy while some switched to another AED.

Brivaracetam: First Canadian Experience in an Intractable Epilepsy Population.

OBJECTIVE: To evaluate the effectiveness and tolerability of brivaracetam (BRV) in a refractory epilepsy population in an outpatient clinical setting. METHODS: Retrospective medical information system review and self-report questionnaire for all patients treated with BRV until the end of 2017. RESULTS: Thirty-eight patients were included, 73.7% female and mean age 36.2. The mean number of antiepileptic drugs (AEDs) for previous use was 8.9, and for current use was 2.5. Mean seizure frequency in the last 3 months was 12 per month. At 3, 6, 12, and 15 months, the 50% responder rates were 36.1%, 32%, 41.2%, and 45.5%, respectively. Patients took BRV for a median duration of 8.25 months, ranging from 7 days to 60 months. Retention rate was 75.0%, 72.0%, 59.2%, and 47.9% at 3, 6, 12, and 15 months, respectively. Overall, the main reasons for discontinuation were adverse events (AEs) (52.3%), lack of efficacy (35.3%), or both (11.8%). The rate of total AEs was 60.5% according to medical records and 85.7% according to questionnaire, including mostly tiredness, psychiatric, and memory complaints. Psychiatric side effects occurred in 31.6% according to medical records and 47.4% according to questionnaire results, which is higher than previously reported and persisted throughout the study period. CONCLUSIONS: BRV appears to be a useful and safe add-on treatment, even in a very refractory group of patients. In this real-life clinical setting, psychiatric AEs were found at a higher rate than previously published.

Drug-associated hyperthermia: A longitudinal analysis of hospital presentations.

WHAT IS KNOWN AND OBJECTIVE: Hyperthermia occurs when heat accumulation surpasses the body's ability for heat dissipation. Many drugs can affect thermoregulation through mechanisms including altering the neurotransmitters that cause increased heat production or decreased heat loss and may, therefore, be associated with hyperthermia. This study aimed to examine hospitalizations and emergency department (ED) presentations due to hyperthermia and to investigate the potential association with drug therapy. METHODS: A retrospective analysis of ED presentations and hospitalizations due to hyperthermia in all four major hospitals in Tasmania, Australia, between July 2010 and December 2018 was performed. Data of patients aged ≥18 years were extracted from the hospital digital medical records and analysed for the prevalence, trends and various potential risk factors for hyperthermia, such as age, environmental temperature and drug therapy. RESULTS: This study included 224 patients. The data illustrated a trend with time, albeit not statistically significant, towards increasing hospital presentations due to hyperthermia. Antiepileptics (P = .03) and furosemide (P = .04) were the most frequently used drugs in patients with primary hyperthermia. The high use of levothyroxine in the study population (6.7%) stood out compared with the estimated national average (2.1%). Various drug classes associated with hyperthermia were used significantly more in the age group ≥60 years, suggesting polypharmacy in the elderly as a contributing factor for hyperthermia. WHAT IS NEW AND CONCLUSION: This study reports a possible association of some drugs, particularly diuretics (furosemide), antiepileptics and levothyroxine, with hyperthermia. Healthcare professionals should be aware of the increasing prevalence of hyperthermia and the possible involvement of drugs.

Carbamazepine adversely altered the pituitary-testicular axis with resultant reproductive dysfunctions than levetiracetam or carbamazepine-levetiracetam adjuvant treatment in male Wistar rat.

This study investigated the on-toward reactions of individual or adjunctive treatment with carbamazepine (CBZ) and levetiracetam (LEV) on the pituitary-testicular axis in male rats. Twenty-four male Wistar rats were randomised into 4 groups (n = 6) and received daily intraperitoneal (i.p) treatment of normal saline (0.1 ml/day); CBZ (25 mg/kg i.p); LEV (50 mg/kg i.p); or combination of CBZ (12.5 mg/kg) and LEV (25 mg/kg) for 4 weeks. The serum concentration of luteinising hormone (LH), follicle-stimulating hormone (FSH), and testosterone was determined. Also, the seminal profile and histomorphological status of the testis were determined. Data were analysed using descriptive and inferential statistics. The control and test groups were compared using Student's t test, analysis of variance (ANOVA), and Student-Newman-Keuls post hoc analysis where appropriate, while the results presented as mean ± SEM in graphs or tables. The level of significance was taken at p < .05. The percentage motility, viability, and concentration of FSH decreased significantly in all the treatment groups, while the testis was presented with various forms of histomorphological aberrations. This study concludes that CBZ, and CBZ + LEV adjunctive treatments alter the pituitary-testicular axis with evidence of hormonal deregulation and alteration in the reproductive functions' indices, while LEV treatment remains the safest.