P.106 Intravenous lacosamide use in pre-school children

Background: Data on intravenous lacosamide use in young pediatric patients is scarce, especially of pre-school age. Methods: We retrospectively reviewed the medical records of all patients less than 6 years old who received intravenous lacosamide at our tertiary pediatric hospital. Data on dose, timing and order of administration was collected. Clinical and electrographic response was independently assessed with EEG interpretation blinded to time of administration. For adverse effects surveillance, heart rate was noted before and 1 hour after dose. Results: Eleven patients (8 boys), received lacosamide between 2013 and 2018. Mean age was 2 years (11 days – 5,3 years). Medical indications were: refractory status epilepticus (n=6), repetitive seizures (n=4), and inability to take oral lacosamide (n=1). On average, lacosamide was the fifth (1st-8th) IV antiepileptic drug administered 78 hours (SD 11 hours) after presentation. The most frequent dose was 5 mg/kg. Clinical response was confirmed in 7 patients, while electrographic response was proven in 3 patients. Seizure relapse at 24 hours was noted in 6 patients. No bradycardia occurred post-lacosamide. Conclusions: Although very safe, therapeutic response to lacosamide in young pediatric patients was inconclusive, mostly due to delay in administration, suboptimal dose, and high number of other IV antiepileptic drugs previously given.

Predictors of inappropriate dosing of direct oral anticoagulants in nonagenarian patients with atrial fibrillation

Background Direct oral anticoagulants (DOACs) are presented as a good option for older patients owing to their safety profile. However, the dosing can become challenging especially in this population. Objective Our aim is to evaluate the predictors of inappropriate dosing of DOACs. Methods The authors analyzed the use of DOACs in 726 patients aged ≥90 years with a diagnosis of atrial fibrillation (AF) from a retrospective multicenter registry from 3 health areas in Spain. We studied the dosing, differentiating between appropriate dose, underdosing or overdosing. To evaluate the best predictive model, the Akaike information criterion (AIC) was used. Results Follow-up was 27.7±18.3 months. Mean age was 93.0±5.2 years, and 60.1% of patients were female. 339 patients received rivaroxaban (47.3%), 237 apixaban (33.1%), 105 dabigatran (14.7%) and 35 edoxaban (4.9%). An important proportion of patients received a suboptimal dose (41.5%, n=297): 35.3% underdosed and 6.1% overdosed. The rate of suboptimal dosing was higher for apixaban and lower for dabigatran (Figure 1A). In our registry we found as a predictors of inappropriate dosing: kidney function (Chronic Kidney Disease Epidemiology Collaboration), odds Ratio (OR) 1.04; 95% CI: 1.03–1.05, P<0.001; weight measured in kilograms, OR 1.04; 95% CI: 1.01–1.07, P=0.012; and high blood pressure (HBP), OR 1.61; 95% CI: 1.02–2.53, P=0.041 (Figure 1B). Other variables such as HASBLED, CHADSVASc, anemia, prior bleeding, or concomitant use of antiplatelet therapy, were not significantly associated. Conclusions We want to highlight that the use of an inappropriate dose of DOAC in older patients is common, about 40% in our study. Apixaban was the most frequently underdosed DOAC. HBP, weight, and kidney function were associated with an inappropriate dosing prescription. Therefore, it is important to carefully evaluate the characteristics of the patient to prescribe the appropriate dose that guarantees a correct action. FUNDunding Acknowledgement Type of funding sources: None. Dosing of DOACs Predictors of inappropriate dosing

Treatment With Suboptimal Dose of Benznidazole Mitigates Immune Response Molecular Pathways in Mice With Chronic Chagas Cardiomyopathy

Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe form of Chagas disease, a neglected tropical illness caused by the protozoan Trypanosoma cruzi, and the main cause of morbimortality from cardiovascular problems in endemic areas. Although efforts have been made to understand the signaling pathways and molecular mechanisms underlying CCC, the immunological signaling pathways regulated by the etiological treatment with benznidazole (Bz) has not been reported. In experimental CCC, Bz combined with the hemorheological and immunoregulatory agent pentoxifylline (PTX) has beneficial effects on CCC. To explore the molecular mechanisms of Bz or Bz+PTX therapeutic strategies, C57BL/6 mice chronically infected with the T. cruzi Colombian strain (discrete typing unit TcI) and showing electrocardiographic abnormalities were submitted to suboptimal dose of Bz or Bz+PTX from 120 to 150 days postinfection. Electrocardiographic alterations, such as prolonged corrected QT interval and heart parasite load, were beneficially impacted by Bz and Bz+PTX. RT-qPCR TaqMan array was used to evaluate the expression of 92 genes related to the immune response in RNA extracted from heart tissues. In comparison with non-infected mice, 30 genes were upregulated, and 31 were downregulated in infected mice. Particularly, infection upregulated the cytokines IFN-γ, IL-12b, and IL-2 (126-, 44-, and 18-fold change, respectively) and the T-cell chemoattractants CCL3 and CCL5 (23- and 16-fold change, respectively). Bz therapy restored the expression of genes related to inflammatory response, cellular development, growth, and proliferation, and tissue development pathways, most probably linked to the cardiac remodeling processes inherent to CCC, thus mitigating the Th1-driven response found in vehicle-treated infected mice. The combined Bz+PTX therapy revealed pathways related to the modulation of cell death and survival, and organismal survival, supporting that this strategy may mitigate the progression of CCC. Altogether, our results contribute to the better understanding of the molecular mechanisms of the immune response in the heart tissue in chronic Chagas disease and reinforce that parasite persistence and dysregulated immune response underpin CCC severity. Therefore, Bz and Bz+PTX chemotherapies emerge as tools to interfere in these pathways aiming to improve CCC prognosis.

mRNA-based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus-neutralising antibodies and mediates protection in rodents

AbstractmRNA technologies have recently proven clinical efficacy against coronavirus disease 2019 and are among the most promising technologies to address the current pandemic. Here, we show preclinical data for our clinical candidate CVnCoV, a lipid nanoparticle-encapsulated mRNA vaccine that encodes full-length, pre-fusion stabilised severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein. In contrast to previously published approaches, CVnCoV is exclusively composed of naturally occurring nucleotides. Immunisation with CVnCoV induced strong humoral responses with high titres of virus-neutralising antibodies and robust T-cell responses. CVnCoV vaccination protected hamsters from challenge with wild-type SARS-CoV-2, demonstrated by the absence of viral replication in the lungs. Hamsters vaccinated with a suboptimal dose of CVnCoV leading to breakthrough viral replication exhibited no evidence of vaccine-enhanced disease. Overall, data presented here provide evidence that CVnCoV represents a potent and safe vaccine candidate against SARS-CoV-2.

GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.

InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation

The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of lentiviral vector enabling expression of insulinB9-23 (LV.InsB) in hepatocytes, arrests β cell destruction in pre-diabetic NOD mice, by generating InsB9-23-specific FoxP3+T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 mAb (combined therapy, 1X5µg CT5) reverts diabetes and prevents recurrence of autoimmunity following islets transplantation in ~50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, allo-islets were transplanted after optimized CT tolerogenic conditioning (1X25µg CT25). Diabetic NOD mice conditioned with CT25 when glycaemia was <500mg/dL, remained normoglycaemic for 100 days after allo-islets transplantation, displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T cell unresponsiveness to InsB9-23 stimulation and increased Tregs frequency in islets infiltration and pancreatic LN. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 co-stimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before allo-islets transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous β cell mass.

InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation

The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of lentiviral vector enabling expression of insulinB9-23 (LV.InsB) in hepatocytes, arrests β cell destruction in pre-diabetic NOD mice, by generating InsB9-23-specific FoxP3+T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 mAb (combined therapy, 1X5µg CT5) reverts diabetes and prevents recurrence of autoimmunity following islets transplantation in ~50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, allo-islets were transplanted after optimized CT tolerogenic conditioning (1X25µg CT25). Diabetic NOD mice conditioned with CT25 when glycaemia was <500mg/dL, remained normoglycaemic for 100 days after allo-islets transplantation, displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T cell unresponsiveness to InsB9-23 stimulation and increased Tregs frequency in islets infiltration and pancreatic LN. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 co-stimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before allo-islets transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous β cell mass.

In Vitro and In Vivo Evaluation of an Adamantyl-Based Phenyl Sulfonyl Acetamide against Cutaneous Leishmaniasis Models of Leishmania amazonensis

ABSTRACT Phenotypic assay against Leishmania amazonensis in vitro and in vivo led to identification of an adamantyl-based phenyl sulfonyl acetamide (compound 1) as a promising antileishmanial agent. Compound 1 inhibited the growth of intracellular forms of L. amazonensis (50% inhibitory concentration [IC50] = 4 μM) and exhibited low toxicity to host cells, with a selectivity index (SI) of >125. However, in a cutaneous leishmaniasis (CL) mouse model, compound 1 did not reduce lesions and parasite load when administered as monotherapy or when given simultaneously with a suboptimal dose of miltefosine.

Stimulant prescribing for attention deficit hyperactivity disorder (ADHD): what guides clinicians in their choice of an upper limit for dose titration?

Objective: There is little evidence to support the current stimulant dose upper limit restrictions in the treatment of attention deficit hyperactivity disorder (ADHD). Within Australasia, there is inconsistency in dose maxima in different jurisdictions. Clinician experience in this area may be worth gauging when trying to improve the understanding of optimal maximal dosing. Our objective was to survey prescribers’ experience of whether the current stimulant maximum doses ever conflict with dose optimisation and how such conflicts are managed. Method: We conducted an anonymous online survey of health professionals treating children, adolescents and adults with ADHD. Results: Responses were received from 128 prescribers, mainly paediatricians (52%) and adult psychiatrists (39%). The designated maximum dose of stimulant was a constraint to dose optimisation experienced by 91% for the Product Information maxima and 82% for their respective state/territory regulations maxima. When clinically indicated, 72% would exceed the designated maxima, either with or without obtaining a second opinion or applying for special authority. Of the remaining 28%, the majority (16%) would opt for polypharmacy, with only two accepting a suboptimal dose. Conclusion: The current stimulant dose maxima act as a constraint to stimulant dose optimisation and may promote undertreatment and polypharmacy.