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Objective: In the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small‐molecule, highly lipid‐soluble drug, CBD is likely to be distributed into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short‐term placental effects, we conducted an ex vivo perfusion study in human placentas. Methods: Placentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD‐containing medium (250 ng/mL,.796 μmol·L−1; representative of a low therapeutic concentration; n = 8). CBD concentrations were determined at 180 min in the medium and placental tissue using liquid chromatography–tandem mass spectrometry. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 μmol·L−1; high therapeutic concentration; n = 8) and in those exposed to the vehicle. Results: CBD was sequestered in the placental tissue, exhibiting significant variability across samples (median = 5342 ng/g tissue, range = 1066–9351 ng/g tissue). CBD concentrations in the fetal compartment were one fifth of those measured in the maternal compartment (median = 59 ng/mL, range = 48–72 ng/mL vs. 280 = ng/mL, range = 159–388 ng/mL, respectively; p <.01). Placental gene expression was not significantly altered by CBD. Significance: The placenta acts as a depot compartment for CBD, slowing down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD. [ABSTRACT FROM AUTHOR]

The marketed and nonmarketed ASM drug lists are based on Odi et al.[1] and includes bumetanide (see text for further details).[10] The other drug lists are based on the World Health Organization's Collaborating Center for Drug Statistics Methodology, and the numbers in brackets refer to drug classes as defined in this database.[6] Drug combinations, gases, local anesthetics, drugs not approved for use by the US Food and Drug Administration (except for nonmarketed ASMs), and those that do not necessarily have to cross the blood-brain barrier to exert their effects (e.g., antiemetics and antimigraine drugs) were excluded. Keywords: antiepileptic drugs; efficacy; molecular weight; physicochemical properties; topological polar surface area EN antiepileptic drugs efficacy molecular weight physicochemical properties topological polar surface area 311 319 9 02/08/23 20230201 NES 230201 Key Points We found differences between physicochemical properties of antiseizure medications with proven clinical efficacy and those of other CNS drugs. MARKETED ASMS ARE MORE POLAR THAN OTHER CNS DRUGS ASMs additionally differ from other CNS drugs by generally having more surface area over polar atoms, as indicated by the higher TPSA values of the marketed ASM group relative to the nonmarketed ASMs and other CNS drugs (Figure 1B, Table 2). [Extracted from the article]

Objective: Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus. Methods: Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 μg/ml (10 μmol·L−1, n = 7) or 10 μg/ml (40 μmol·L−1, n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 μg/ml, 500 μmol·L−1, n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. Results: Following a 3‐h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 μg/ml lacosamide (50%) as compared with the vehicle (p <.05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 μg/ml lacosamide, 83 μg/ml valproate, and 2.5 μg/ml lacosamide, respectively; p <.05). Significance: Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy. [ABSTRACT FROM AUTHOR]

Therapeutic monoclonal antibodies (mAbs) have emerged as the fastest growing drug class. As such, mAbs are increasingly being co‐prescribed with other drugs, including antiseizure medications (ASMs). Although mAbs do not share direct targets or mechanisms of disposition with small‐molecule drugs (SMDs), combining therapeutics of both types can increase the risk of adverse effects and treatment failure. The primary goal of this literature review was identifying mAb‐ASM combinations requiring the attention of professionals who are treating patients with epilepsy. Systematic PubMed and Embase searches (1980–2021) were performed for terms relating to mAbs, ASMs, drug interactions, and their combinations. Additional information was obtained from documents from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Evidence was critically appraised ‐ key issues calling for clinicians' consideration and important knowledge gaps were identified, and practice recommendations were developed by a group of pharmacists and epileptologists. The majority of interactions were attributed to the indirect effects of cytokine‐modulating antibodies on drug metabolism. Conversely, strong inhibitors or inducers of drug‐metabolizing enzymes or drug transporters could potentially interact with the cytotoxic payload of antibody‐drug conjugates, and ASMs could alter mAb biodistribution. In addition, mAbs could potentiate adverse ASM effects. Unfortunately, few studies involved ASMs, requiring the formulation of class‐based recommendations. Based on the current literature, most mAb‐ASM interactions do not warrant special precautions. However, specific combinations should preferably be avoided, whereas others require monitoring and potentially adjustment of the ASM doses. Reduced drug efficacy or adverse effects could manifest days to weeks after mAb treatment onset or discontinuation, complicating the implication of drug interactions in potentially deleterious outcomes. Prescribers who treat patients with epilepsy should be familiar with mAb pharmacology to better anticipate potential mAb‐ASM interactions and avoid toxicity, loss of seizure control, or impaired efficacy of mAb treatment. [ABSTRACT FROM AUTHOR]

Background Studies on benzodiazepine (BZDs) as well as Zopiclone and Zolpidem (Z-drugs) utilization are important for estimating the prevalence of medical conditions, providing the basis for pharmacovigilance, and identifying temporal trends of consumption. Such studies that involve the Israeli population have not been conducted yet. Purpose Identify trends over time in utilization of BZDs and Z-drugs in a nationwide population in Israel. Methods Data on BZD and Z-drugs utilization (for all indications) for the period 2005 to 2013 were obtained from pharmaceutical companies that distribute BZDs in Israel. Prevalence of BZD utilization was reported as defined daily doses (DDD)/1000 inhabitants/day. Results The utilization of BZDs and Z-drugs aimed to treat sleeping disorders increased over the period of the study from 10.22 to 22.49 DDD/1000 inhabitants/day. The greatest increases in utilization of drugs established in Israel were observed for brotizolam (83%), zopiclone (59%), and zolpidem (94%). Decreases in use were recorded for lorazepam (14%), diazepam (16%), and oxazepam (27%). Use of hypnotic BZDs appeared to be relatively high, compared with the use of non-BZD hypnotics ('Z-drugs') such as zolpidem or zopiclone. Nationwide stressful conditions did not appear to be reflected in the annual BZD sales. Conclusions Conventional BZDs and Z-drugs remained the treatment of choice for sleeping disorders in Israel during the study period. These results are, in certain cases, in contrast to current practice recommendations and guidelines and point at a need in better dissemination of these guidelines among prescribers in Israel. [ABSTRACT FROM AUTHOR]

The human leukocyte antigen ( HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome ( SJS)- and toxic epidermal necrolysis ( TEN)-related hospitalizations were obtained from the Israeli Ministry of Health ( MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin. [ABSTRACT FROM AUTHOR]