Evidence for sodium valproate toxicity in mitochondrial diseases: a systematic analysis.

Background: We aimed to determine whether sodium valproate (VPA) should be contraindicated in all mitochondrial diseases, due to known VPA-induced severe hepatotoxicity in some mitochondrial diseases. Methods: We systematically reviewed the published literature for mitochondrial DNA (mtDNA) and common nuclear genotypes of mitochondrial diseases using PubMed, Ovid Embase, Ovid Medline and MitoPhen databases. We extracted patient-level data from peer-reviewed articles, published until July 2022, using the Human Phenotype Ontology to manually code clinical presentations for 156 patients with genetic diagnoses from 90 publications. Results: There were no fatal adverse drug reactions (ADRs) in the mtDNA disease group (35 patients), and only 1 out of 54 patients with a non-POLG mitochondrial disease developed acute liver failure. There were fatal outcomes in 53/102 (52%) POLG VPA-exposed patients who all harboured recessive mutations. Conclusions: Our findings confirm the high risk of severe ADRs in any patient with recessive POLG variants irrespective of the phenotype, and therefore recommend that VPA is contraindicated in this group. However, there was limited evidence of toxicity to support a similar recommendation in other genotypes of mitochondrial diseases.

Real-world data on siponimod-related lymphopenia among people with secondary progressive multiple sclerosis.

BACKGROUND: Siponimod-related lymphopenia in real-world clinical practice has implications for dose adjustment and infection risk. OBJECTIVE: To characterise siponimod-related lymphopenia in people with secondary progressive multiple sclerosis (pwSPMS). METHODS: This is a retrospective cohort of 188 pwSPMS. The development of grade 4 lymphopenia was interrogated with Kaplan-Meier survival analysis and binary logistic regression. RESULTS: Lymphopenia develops soon after commencing siponimod. In total, 15 (8.5%) of 176 experienced grade 4 lymphopenia at 1 month after initiation. There were no clinically significant associations between patient characteristics and development of grade 4 lymphopenia. CONCLUSION: Grade 4 lymphopenia can occur soon after siponimod initiation and cannot be predicted.

Interaction of cannabidiol with other antiseizure medications: A narrative review.

OBJECTIVE: Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs). METHODS: A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded. RESULTS: Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same. CONCLUSION: Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.

Cyanobacteria Respond to Low Levels of Ethylene.

Ethylene is a gas that has long been known to act as a plant hormone. We recently showed that a cyanobacterium, Synechocystis sp. PCC 6803 (Synechocystis) contains an ethylene receptor (SynEtr1) that regulates cell surface and extracellular components leading to altered phototaxis and biofilm formation. To determine whether other cyanobacteria respond to ethylene, we examined the effects of exogenous ethylene on phototaxis of the filamentous cyanobacterium, Geitlerinema sp. PCC 7105 (Geitlerinema). A search of the Geitlerinema genome suggests that two genes encode proteins that contain an ethylene binding domain and Geitlerinema cells have previously been shown to bind ethylene. We call these genes GeiEtr1 and GeiEtr2 and show that in air both are expressed. Treatment with ethylene decreases the abundance of GeiEtr1 transcripts. Treatment of Geitlerinema with 1000 nL L-1 ethylene affected the phototaxis response to white light as well as monochromatic red light, but not blue or green light. This is in contrast to Synechocystis where we previously found ethylene affected phototaxis to all three colors. We also demonstrate that application of ethylene down to 8 nL L-1 stimulates phototaxis of both cyanobacteria as well as biofilm formation of Synechocystis. We formerly demonstrated that the transcript levels of slr1214 and CsiR1 in Synechocystis are reduced by treatment with 1000 nL L-1 ethylene. Here we show that application of ethylene down to 1 nL L-1 causes a reduction in CsiR1 abundance. This is below the threshold for most ethylene responses documented in plants. By contrast, slr1214 is unaffected by this low level of ethylene and only shows a reduction in transcript abundance at the highest ethylene level used. Thus, cyanobacteria are very sensitive to ethylene. However, the dose-binding characteristics of ethylene binding to Geitlerinema and Synechocystis cells as well as to the ethylene binding domain of SynEtr1 heterologously expressed in yeast, are similar to what has been reported for plants and exogenously expressed ethylene receptors from plants. These data are consistent with a model where signal amplification is occurring at the level of the receptors.

A comparison of the short-term settling of three scleral lens designs.

PURPOSE: Scleral gas-permeable lenses are rapidly gaining international popularity. Unlike corneal gas-permeable lenses, scleral lenses are fitted to the bulbar conjunctiva and settle into the tissue after insertion. To date, we are unaware of any studies examining the settling behavior of three varying scleral lens designs. The purpose of this study was to quantify the mean total settling and mean rates of settling for three scleral lens designs: Onefit P&A (Blanchard Contact Lens, Inc), Mini Scleral Design (msd) (Blanchard Contact Lens, Inc), and Jupiter (Visionary Optics). METHODS: A randomized, repeated-measures study of Onefit P&A, msd, and Jupiter was performed. Subjects were fitted from a trial lens set, according to the manufacturer's guidelines. After insertion, lens settling was measured at 0 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours. Statistical analyses were performed using analysis of variance and two-stage, nonlinear regression analyses of settling over time. RESULTS: On average, the Onefit P&A, msd, and Jupiter lenses settled a total of 113.7, 133.7, and 88.1 µm, respectively. Although the rates of settling were not linear, analysis of variance revealed a significant difference in the average settling rates (p < 0.05) among the groups. Tukey analyses revealed a significant difference in the settling rates for msd and Jupiter comparison (p < 0.05). Nonlinear regression analyses predicted that the lenses settled to about 80% of the final estimated values for the Onefit P&A lens, 90% for msd, and 99% for the Jupiter, after 8 hours. CONCLUSION: We concluded that the amount of settling varied significantly among the three lens designs. Settling rates were greatest shortly after insertion. Larger lenses were estimated to be settled by 8 hours. Based on the results of this short-term study, careful consideration to the settling patterns of individual scleral lens designs should be given.