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BACKGROUND. Pathophysiology of type 1 diabetes (T1D) is illustrated by pancreatic islet infiltration of inflammatory lymphocytes, including CD8(+) T cells; however, the molecular factors mediating their recruitment remain unknown. We hypothesized that single-cell RNA-sequencing (scRNA-Seq) analysis of immune cell populations isolated from islets of NOD mice captured gene expression dynamics providing critical insight into autoimmune diabetes pathogenesis. METHODS. Pancreatic sections from human donors were investigated, including individuals with T1D, autoantibody-positive (aAb(+)) individuals, and individuals without diabetes who served as controls. IHC was performed to assess islet hormones and both novel and canonical immune cell markers that were identified from unbiased, state-of-the-art workflows after reanalyzing murine scRNA-Seq data sets. RESULTS. Computational workflows identified cell adhesion molecule 1-mediated (Cadm1-mediated) homotypic binding among the most important intercellular interactions among all cell clusters, as well as Cadm1 enrichment in macrophages and DCs from pancreata of NOD mice. Immunostaining of human pancreata revealed an increased number of CADM1(+)glucagon(+) cells adjacent to CD8(+) T cells in sections from T1D and aAb(+) donors compared with individuals without diabetes. Numbers of CADM1(+)CD68(+) peri-islet myeloid cells adjacent to CD8(+) T cells were also increased in pancreatic sections from both T1D and aAb(+) donors compared with individuals without diabetes. CONCLUSION. Increased detection of CADM1(+) cells adjacent to CD8(+) T cells in pancreatic sections of individuals with T1D and those who were aAb(+) validated workflows and indicated CADM1-mediated intercellular contact may facilitate islet infiltration of cytotoxic T lymphocytes and serve as a potential therapeutic target for preventing T1D pathogenesis.

Background: Anorexia nervosa (AN) is a serious mental disorder with a high mortality rate and often a chronic course. In contrast to many other common mental disorders, there is no drug therapy approved for AN. Methods: We performed a narrative literature review to consider whether a choline-containing molecule, such as phosphatidylcholine (PC), with an omega (ω)-3 long chain polyunsaturated fatty acid (LCPUFA) could be a potential future medicinal treatment for AN. Results: Choline and LCPUFAs have individually shown benefit for mental health. Case series and pilot studies suggest ω -3 LCPUFAs may be effective in eating disorders. However, pharmacodynamic and pharmacokinetic considerations suggest a greater benefit from the combination of both components. Conclusion: The combination of a choline-containing molecule with an ω-3 LCPUFA may be clinically effective and well tolerated. This idea is supported by the current literature on the role of inflammation, the microbiome, the gut-brain-axis, hormonal, neurotransmitter and intracellular signalling, and on the structure and fluidity of nerve cells membranes in patients with AN.

Frank MC Besag,1–3 Philip N Patsalos4,51East London Foundation NHS Trust, 2Institute of Psychiatry, Psychology and Neuroscience, 3UCL School of Pharmacy, 4Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, NIHR University College London Hospitals Biomedical Research Centre, London, 5Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter, UKBackground and purpose: Perampanel, a selective noncompetitive antagonist at the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is highly effective in a wide range of experimental models. Although initially licensed as adjunctive therapy for partial seizures with or without secondary generalization in patients aged 12 years or older, the US Food and Drug Administration has recently approved its use in the treatment of primary generalized tonic–clonic seizures (PGTCS). This paper reviews the pharmacokinetics, efficacy, and tolerability of perampanel as an antiepileptic drug.Results: After oral ingestion, perampanel is rapidly absorbed (Tmax, 0.5–2.5 hours), has a bioavailability of ~100%, and is highly protein bound (~95%) in plasma. It undergoes extensive (>90%) hepatic metabolism, primarily via cytochrome P450 3A4 (CYP3A4), with a half-life of 48 hours. Carbamazepine and other antiepileptic drugs can enhance its metabolism via induction of CYP3A4. Efficacy of perampanel in focal seizures has been extensively evaluated in Phase II and randomized, placebo-controlled Phase III trials. The efficacy in PGTCS has been reported in one class I study. In the treatment of focal seizures, perampanel showed significant dose-dependent median seizure reductions: 4 mg/d, 23%; 8 mg/d, 26%–31%; 12 mg/d, 18%–35%; and placebo, 10%–21%. The 50% responder rates were 15%–26%, 29%, 33%–38%, and 34%–36% for placebo, 4 mg/d, 8&

Frank MC Besag,1,2 Philip N Patsalos3,41South Essex Partnership University NHS Foundation Trust (SEPT), Mid Beds Clinic, Bedford, Bedfordshire, UK; 2Institute of Psychiatry, London, UK; 3Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, UCL-Institute of Neurology, London, UK; 4Epilepsy Society, Chalfont Centre for Epilepsy, Chalfont St Peter, Buckinghamshire, UKAbstract: Although most people presenting with partial-onset seizures will achieve control with antiepileptic medication, a considerable minority will have difficult-to-treat epilepsy that is resistant to existing medication. Over the last few years, a large number of new antiepileptic drugs have been developed. Some of these have a novel mode of action. Many of the older antiepileptic drugs act through sodium channels or by enhancement of gamma amino butyric acid (GABA). Lamotrigine has sodium-channel blocking properties but also has other important modes of action, indicated by efficacy in treating not only partial-onset but also generalized seizures. Vigabatrin and tiagabine both increase GABA activity, by inhibiting GABA transaminase and limiting GABA reuptake, respectively. The main mode of action of gabapentin and pregabalin is not via GABA but through a selective inhibitory effect on voltage-gated calcium channels containing the α2δ-1 subunit. Levetiracetam inhibits the recycling of SV2A (synaptic vesicle protein 2A) neurotransmitter vesicles but also has other effects, including inhibition of voltage-dependent calcium channels. Some drugs, eg, felbamate, zonisamide, and topiramate, have multiple modes of action. In many cases, although the main mode of action may have been identified, other modes of action also play a role. Two recently developed antiepileptic drugs appear to have completely novel primary modes of action; retigabine (ezogabine) and perampanel act on the potassium channel and on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazo

Item does not contain fulltext, Long-term anti-epileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to effectively control seizures, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. Also, the fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients needs to be considered. Therefore, the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and upon drug withdrawal. Whilst pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine and valproic acid; these drugs exhibit synergistic efficacy when co-administered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions and enzyme-inducing drugs such as phenytoin, phenobarbitone and carbamazepine will readily enhance the metabolism of other AEDs (e.g. lamotrigine, topiramate and tiagabine). The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g. oral contraceptives, antidepressants and warfarin) so that therapeutic efficacy of co-administered drugs is lost unless the dosage is increased. Valproate inhibits the metabolism of phenobarbitone and lamotrigine, resulting in an elevation in the plasma levels of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of carba

Item does not contain fulltext, Long-term anti-epileptic drug (AED) therapy is the reality for the majority of patients diagnosed with epilepsy. One AED will usually be sufficient to effectively control seizures, but a significant proportion of patients will need to receive a multiple AED regimen. Furthermore, polytherapy may be necessary for the treatment of concomitant disease. Also, the fact that over-the-counter drugs and nutritional supplements are increasingly being self-administered by patients needs to be considered. Therefore, the probability of patients with epilepsy experiencing drug interactions is high, particularly with the traditional AEDs, which are highly prone to drug interactions. Physicians prescribing AEDs to patients with epilepsy must, therefore, be aware of the potential for drug interactions and the effects (pharmacokinetic and pharmacodynamic) that can occur both during combination therapy and upon drug withdrawal. Whilst pharmacokinetic interactions are numerous and well described, pharmacodynamic interactions are few and usually concluded by default. Perhaps the most clinically significant pharmacodynamic interaction is that of lamotrigine and valproic acid; these drugs exhibit synergistic efficacy when co-administered in patients with refractory partial and generalised seizures. Hepatic metabolism is often the target for pharmacokinetic drug interactions and enzyme-inducing drugs such as phenytoin, phenobarbitone and carbamazepine will readily enhance the metabolism of other AEDs (e.g. lamotrigine, topiramate and tiagabine). The enzyme-inducing AEDs also enhance the metabolism of many other drugs (e.g. oral contraceptives, antidepressants and warfarin) so that therapeutic efficacy of co-administered drugs is lost unless the dosage is increased. Valproate inhibits the metabolism of phenobarbitone and lamotrigine, resulting in an elevation in the plasma levels of the inhibited drugs and consequently an increased risk of toxicity. The inhibition of the metabolism of carba

Item does not contain fulltext, Vigabatrin and diazepam both are GABAergic drugs. Vigabatrin enhances the concentration of endogenous GABA by inhibiting GABA-transaminase, while diazepam enhances the efficacy of the endogenous GABA present. As may be expected, the clinical effects of the two drugs overlap: e.g. both have anti-epileptic effects and both decrease the level of vigilance. The similarity of the effects on the EEG is however less clear. During slow-wave sleep, in drug-free rats, the EEG consists of high-voltage delta waves. Despite the induction of sleep, diazepam enhances the power of the high frequency beta band. This phenomenon is called pharmacological dissociation. In contrast, vigabatrin has been shown to slow down the EEG; the power in the delta and theta bands increases while that of the beta band decreases. However in those studies behavioural changes were not taken into consideration. The aim of the present study was to investigate, in the rat, the effect of vigabatrin on behaviour and on behaviour-related EEG.

Item does not contain fulltext, Vigabatrin and diazepam both are GABAergic drugs. Vigabatrin enhances the concentration of endogenous GABA by inhibiting GABA-transaminase, while diazepam enhances the efficacy of the endogenous GABA present. As may be expected, the clinical effects of the two drugs overlap: e.g. both have anti-epileptic effects and both decrease the level of vigilance. The similarity of the effects on the EEG is however less clear. During slow-wave sleep, in drug-free rats, the EEG consists of high-voltage delta waves. Despite the induction of sleep, diazepam enhances the power of the high frequency beta band. This phenomenon is called pharmacological dissociation. In contrast, vigabatrin has been shown to slow down the EEG; the power in the delta and theta bands increases while that of the beta band decreases. However in those studies behavioural changes were not taken into consideration. The aim of the present study was to investigate, in the rat, the effect of vigabatrin on behaviour and on behaviour-related EEG.

Item does not contain fulltext, Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried so as to improve effectiveness, by improving either efficacy, or tolerability, or both. We have reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis have been used in these studies it was also necessary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Results: 39 papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only endpoint. Conclusions: There is some evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with a NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and for advantageous combinations to be subsequently evaluated in clinical trials. Testing procedures in animals should include the isobologram method and the concept of drug load sho

Item does not contain fulltext

Item does not contain fulltext, Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried so as to improve effectiveness, by improving either efficacy, or tolerability, or both. We have reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis have been used in these studies it was also necessary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Results: 39 papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only endpoint. Conclusions: There is some evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with a NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and for advantageous combinations to be subsequently evaluated in clinical trials. Testing procedures in animals should include the isobologram method and the concept of drug load sho

Item does not contain fulltext

Item does not contain fulltext

Item does not contain fulltext, Purpose: When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried so as to improve effectiveness, by improving either efficacy, or tolerability, or both. We have reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis have been used in these studies it was also necessary to evaluate the appropriateness of these approaches. Methods: Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers. Results: 39 papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only endpoint. Conclusions: There is some evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with a NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and for advantageous combinations to be subsequently evaluated in clinical trials. Testing procedures in animals should include the isobologram method and the concept of drug load sho