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Background: Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods: This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion: NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz’s capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.

Additional file 2. MRI acquisition protocols.

Additional file 1: Supplementary Figure 1. Study flow chart. Description of data: flow chart of included and excluded subjects. Footnote: ID, intellectual disability; mCRT, modified Cued Recall Test; MRI, magnetic resonance imaging; OCD, obsessive compulsive disorder.

Additional file 1. Consent form

Background Adults with Down syndrome are at an ultra-high risk of developing early-onset Alzheimer’s disease. Episodic memory deficits are one of the earliest signs of the disease, but their association with regional brain atrophy in the population with Down syndrome has not been explored. We aimed to investigate the neuroanatomical correlates of episodic memory in adults with Down syndrome and symptomatic Alzheimer’s disease. Methods Single-center, cross-sectional study. A total of 139 adults with Down syndrome (85 asymptomatic and 54 with symptomatic Alzheimer’s disease) were included in the study (mean age 43.6 ± 10.9 years, 46% female). Episodic memory was assessed using the modified Cued Recall Test. Immediate (trial 1 free immediate recall, trial 3 free immediate recall, total free immediate recall score, and total immediate score) and delayed scores (free delayed recall score and total delayed score) were examined. Cortical thickness from magnetic resonance imaging was determined with surface-based morphometry using the FreeSurfer 6.0 software package. The clusters of reduced cortical thickness were compared between symptomatic and asymptomatic participants to create a cortical atrophy map. Then, the correlation between cortical thickness and the modified Cued Recall Test subscores were separately assessed in symptomatic and asymptomatic subjects, controlling for age, sex, and severity of intellectual disability. Results Compared with asymptomatic participants, those with symptomatic Alzheimer’s disease showed a pattern of cortical atrophy in posterior parieto-temporo-occipital cortices. In symptomatic subjects, trial 1 immediate free recall significantly correlated with cortical atrophy in lateral prefrontal regions. Trial 3 free immediate recall and total free immediate recall were associated with the most widespread cortical atrophy. Total immediate score was related to posterior cortical atrophy, including lateral parietal and temporal cortex, posterior cingulate cortex, precuneus, and medial temporal lobe areas. Delayed memory scores were associated with cortical atrophy in temporoparietal and medial temporal lobe regions. No significant relationships were observed between episodic memory measures and cortical atrophy in asymptomatic subjects. Conclusions Different episodic memory measures were associated with cortical atrophy in specific brain regions in adults with Down syndrome and Alzheimer’s disease. These results overlap with those described in sporadic Alzheimer’s disease and further support the similarities between Down syndrome-associated Alzheimer’s disease and that in the general population.

Background: Cemented hip arthroplasty requires applying a layer of polymethylmethacrylate (cement) in the space between the bone and the prosthetic stem. This can be achieved using 2 techniques: the thick-layer technique (requires a layer of at least 2 mm to surround an undersized prosthetic stem), and the thin-layer technique (requires a thin layer of cement, so that the prosthetic stem fills the femoral medullary canal). Both approaches have excellent long-term clinical and radiological outcomes, although an implant's insertion into the bone generates inevitable bone mass and bone metabolic changes around it. Combination of single photon emission computed tomography and computed tomography scan (SPECT-CT) imaging combines the single photon emission computed tomography's ability to provide detailed bone metabolism assessment with the computed tomography scan's capacity to provide a meticulous anatomical study. Methods: This is a single center, open label, randomized clinical trial, performed in the premises of the Bellvitge University Hospital. Participants will be randomly assigned to the Thick-layer technique group (Exeter V40 Cemented Femoral Stem) or to the French paradox technique group (Müller Straight Stem). All participants will have a SPECT-CT scan study at 3, 6, 12, and 24 months after the surgery. Discussion: Surgical distress itself and the implant's insertion into the bone may cause microvascular changes that alter periprosthetic bone mass and bone metabolism. To the best of our knowledge, there are no studies using SPECT-CT to compare bone metabolism evolution in the postoperative period between these 2 surgical cementation techniques. We aim to provide information in this regard that could help decision making in complicated implant cases and, maybe, pave the way for larger, and methodologically improved studies. Trial registration: NCT05010733 (August 18, 2021).

Eva M Sobas,1,2 Amanda Vázquez,1,2 Sebastián Videla,3 Roberto Reinoso,1,4,5 Itziar Fernández,1,5 Carmen Garcia-Vazquez,1 Miguel J Maldonado,1,6 J Carlos Pastor1,6,7 1IOBA Eye Institute, University of Valladolid, Valladolid, Spain; 2Nursery Faculty, University of Valladolid, Valladolid, Spain; 3Clinical Research Support Unit, Clinical Pharmacology Department, Bellvitge University Hospital/Bellvitge Biomedical Research Institute (IDIBELL)/University of Barcelona, L’Hospitalet de Llobregat, Barcelona; 4Visión I+D, University of Valladolid, Valladolid, Spain; 5Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Valladolid, Spain; 6Department of Surgery, Ophthalmology, Otorhinolaryngology and Physiotherapy, Faculty of Medicine, University of Valladolid, Valladolid, Spain; 7Department of Ophthalmology, Hospital Clínico Universitario, Valladolid, SpainCorrespondence: Eva M Sobas Email eva@ioba.med.uva.esPurpose: To evaluate the evolution of a set of proposed pain biomarkers in the saliva of subjects following Advanced Surface Ablation (ASA), in order to determine their validity as objective pain measures.Methods: A multicenter, prospective, and descriptive study was carried out to assess the variations between biomarkers and perceived pain. The Inclusion criteria were healthy subjects who underwent a bilateral, alcohol-assisted surface ablation with epithelial removal (ASA). Pain intensity before and after surgery was assessed by Visual Analog Scale (VAS) and the Numeric Pain Rating Scale (NPRS). Cortisol, sAA, sIgA, testosterone, and sTNFαRII were assayed at four-time points (V0, baseline; V1, pre-surgery; V2, 1hr post-surgery, and V3, 72hrs post-surgery). Comorbidities and Hospital Anxiety and Depression (HADS) questionnaires were administrated before and at 6 hrs after the surgery. All patients were treated with cold patches, topical steroids, topical cold antibiotics, and benzodiazepines after ASA surgery. A descriptive analysis of biomarkers and pain intensity evolution and the agreement between biomarkers and pain was performed.Results: Concentration of sIgA and sTNFαRII post-surgery was significantly higher at each visit compared to baseline (p-value: 0.053, p-value:< 0.001, respectively). Relations between VAS scale score and putative biomarker variations were not statistically significant except for the sIgA but only at visit 0 (p-value: 0.024). The HADS questionnaire showed anxiety scores between 0 and 7 in all patients before and at 6 hrs after surgery.Conclusion: In this study, sIgA and sTNFαRII are the two potential biomarkers that present correlation with the VAS and these salivary substances showed acceptable levels of reproducibility in healthy subjects.Keywords: biomarkers, ocular pain, advanced surface ablation

Aim We compared the pharmacokinetic (PK) profiles of co‐crystal of tramadol–celecoxib (CTC) vs. each reference product (alone and in open combination) after single (first dose) and multiple dosing. Methods Healthy adults aged 18–50 years received, under fasted conditions, 15 twice‐daily doses of the following treatments (separated by ≥14‐day washout): 200 mg immediate‐release (IR) CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; treatment 1); 100 mg IR tramadol (treatment 2), 100 mg celecoxib (treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (treatment 4). The treatment sequence was assigned by computer‐generated randomization. PK parameters were calculated using non‐compartmental analysis. Parameters for CTC were adjusted according to reference product dose. Results A total of 30 subjects (20 males, mean age 35 years) were included. Multiple‐dose tramadol PK parameters for treatments 1, 2 and 4, respectively, were 551, 632 and 661 ng ml−1 [mean maximum plasma concentration (C max)]; 4796, 4990 and 5284 ng h ml−1 (area under the plasma concentration–time curve over the dosing interval at steady state); and 3.0, 2.0 and 2.0 h (median time to C max at steady state). For treatments 1, 3 and 4, multiple‐dose celecoxib PK parameters were 445, 536 and 396 ng ml−1; 2803, 3366 and 2897 ng h ml−1; and 2.0, 2.0 and 3.0 h. Single‐dose findings were consistent with multiple‐dose data. Types of adverse events were consistent with known reference product safety profiles. Conclusion After single (first dose) and multiple dosing, PK parameters for each active pharmaceutical ingredient in CTC were modified by co‐crystallization compared with reference products alone or in open combination.

Background Co-crystal of tramadol–celecoxib (CTC), containing equimolar quantities of the active pharmaceutical ingredients (APIs) tramadol and celecoxib (100 mg CTC = 44 mg rac–tramadol hydrochloride and 56 mg celecoxib), is a novel API-API co-crystal for the treatment of pain. We aimed to establish the effective dose of CTC for treating acute pain following oral surgery. Methods A dose-finding, double-blind, randomised, placebo- and active-controlled, multicentre (nine Spanish hospitals), phase II study (EudraCT number: 2011-002778-21) was performed in male and female patients aged ≥ 18 years experiencing moderate to severe pain following extraction of two or more impacted third molars requiring bone removal. Eligible patients were randomised via a computer-generated list to receive one of six single-dose treatments (CTC 50, 100, 150, 200 mg; tramadol 100 mg; and placebo). The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 8 h assessed in the per-protocol population. Results Between 10 February 2012 and 13 February 2013, 334 patients were randomised and received study treatment: 50 mg (n = 55), 100 mg (n = 53), 150 mg (n = 57), or 200 mg (n = 57) of CTC, 100 mg tramadol (n = 58), or placebo (n = 54). CTC 100, 150, and 200 mg showed significantly higher efficacy compared with placebo and/or tramadol in all measures: SPID (0–8 h) (mean [standard deviation]): − 90 (234), − 139 (227), − 173 (224), 71 (213), and 22 (228), respectively. The proportion of patients experiencing treatment-emergent adverse events was lower in the 50 (12.7% [n = 7]), 100 (11.3% [n = 6]), and 150 (15.8% [n = 9]) mg CTC groups, and similar in the 200 mg (29.8% [n = 17]) CTC group, compared with the tramadol group (29.3% [n = 17]), with nausea, dizziness, and vomiting the most frequent events. Conclusion Significant improvement in the benefit–risk ratio was observed for CTC (doses ≥ 100 mg) over tramadol and placebo in the treatment of acute pain following oral surgery. Funding Laboratorios del Dr. Esteve, S.A.U.

Introduction: We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer's disease (AD) (early-onset AD [EOAD]). Methods: Neuroimaging features of CAA, apolipoprotein (APOE), and cerebrospinal fluid amyloid beta (A beta) 40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n 5 42), and healthy controls (n = 68). Results: CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE epsilon 4 genotype was borderline significantly associated with CAA in sporadic EOAD (P = .06) but not with DS or ADAD. There were no differences in A beta 040 levels between groups or between subjects with and without CAA. Discussion: CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid A beta 40 levels are not a useful biomarker for CAA in AD. (C) 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

1 We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. 2 Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K(+) (35 mM) or by blocking Ca(2)(+)-activated K(+) channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses. 3 Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 micro M) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K(+) or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg(-1) i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. 5 EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.