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BACKGROUND: Osteoporosis is a common concern in the elderly that leads to fragile bones. Calcium supplementation plays a crucial role in improving bone health, reducing fracture risk, and supporting overall skeletal strength in this vulnerable population. However, there is conflicting evidence on the safety of calcium supplements in elderly individuals. AIM: The aim of this study was to evaluate the adherence, safety and tolerability of calcium citrate supplementation in elderly osteopenic subjects. METHODS: In this non-interventional, prospective, multicenter study, subjects received daily 500 mg calcium citrate supplementation for up to one year. Adherence was calculated based on compliance and persistence. Safety was assessed through adverse reactions (ARs), deaths, and clinical laboratory evaluations. RESULTS: A total of 268 Caucasian subjects (91.4% female, mean age 70 ± 4.5 years) participated in the study. Mean adherence to treatment was 76.6 ± 29.5% and half of subjects had an adherence of 91% and ~ 33% of participants achieved complete (100%) adherence. ARs were reported by nine (3.9%) subjects, primarily gastrointestinal disorders, with no serious ARs. The frequency of all adverse events (including ARs) was significantly higher in subjects with adherence of < 80% (41.6%; 32/77) vs. those with adherence ≥ 80% (11%; 16/145, p < 0.0001). Both systolic and diastolic blood pressure decreased from baseline to follow-up visit (change of -2.8 ± 13.9 mmHg, p = 0.0102 and -2.1 ± 10.4 mmHg, p = 0.0116, respectively). CONCLUSION: This study demonstrated favorable adherence to calcium citrate supplementation in elderly osteopenic subjects. The occurrence of ARs, though generally mild, were associated with lower adherence to calcium supplementation.
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Citrato de Cálcio , Osteoporose , Humanos , Feminino , Idoso , Masculino , Citrato de Cálcio/efeitos adversos , Cálcio , Estudos Prospectivos , Osteoporose/tratamento farmacológico , Cálcio da Dieta , Suplementos Nutricionais/efeitos adversosRESUMO
INTRODUCTION: Few studies have explored the intricate connections between vitamin D receptor (VDR) gene polymorphisms, VDR, tight junction (TJ) protein expression and clinical features of atopic dermatitis (AD). METHODS: From 43 adult AD patients, VDR polymorphisms were genotyped from peripheral blood samples using polymerase chain reaction-restriction fragment length polymorphism. VDR, occludin, claudin-1 and ZO-1 protein expression from skin lesion biopsies were assessed by immunohistochemistry. RESULTS: The A1012G heterozygous VDR polymorphism exhibited a lower odds ratio (OR) for juvenile AD onset (OR: 0.046, 95% CI 0.004-0.51, p=0.012). In contrast, the presence of ≥2 homozygous VDR polymorphisms were significantly associated with positive skin prick test (SPT) (10/20, 50%) vs. negative SPT (1/23, 4.3%; p=0.0003). The most highly expressed TJ proteins in lesions of AD patients were claudin-1 and zonulin-1 (ZO-1), while VDR and occludin were less prevalent. A significant correlation was observed between ZO-1 expression and a body mass index ≥30 kg/m2 (OR: 12.1, 95% CI 1.06-137.9, p=0.045). Claudin-1 expression was associated with a positive SPT (OR: 8.23, 95% CI 1.04-65.5, p=0.046) and serum 25(OH)D levels were negatively correlated with ZO-1 expression (rho= -0.43, p=0.0058). CONCLUSION: This study provides novel insights into the relationship between VDR gene polymorphisms, VDR, TJ protein expression, and clinical features in adult AD patients, highlighting a significant role of vitamin D in the pathophysiology of this disease.
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Few studies have evaluated the association between circulating levels of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), and the endocrine disruptor bisphenol A (BPA), with risk of cardiovascular (CV) disease in elderly individuals. This was a cross-sectional study in a subgroup of elderly people from the InCHIANTI Biobank in Italy. We examined the association between circulating serum vitamin D metabolites, 1,25(OH)2D, 25(OH)D, and the endocrine disrupting agent BPA, with an arbitrary CV risk score and the European Society of Cardiology-based 10-year CV risk (SCORE2/SCORE2-OP) using univariate and multiple regression. In 299 individuals, blood samples were tested for serum values of 25(OH)D, 1,25(OH)2D and urinary BPA levels. One hundred eighty individuals (60.2%) were deficient (< 20 ng/ml) in 25(OH)D. Levels of 25(OH)D and 1,25(OH)2D were negatively correlated with CV risk score (p < 0.0001 for both) as well as SCORE2/SCORE2-OP (p < 0.0001 for both) while BPA levels were positively correlated with both CV risk scores (p < 0.0001 for both). In a logistic regression model, male gender (odds ratio; OR: 2.1, 95% CI:1.1-3.8, p = 0.022), obesity (OR:2.8, 95% CI:1.2-6.5, p = 0.016) and BPA levels ≥ 110 ng/dl (OR:20.9, 95% CI:9.4-46.8, p < 0.0001) were associated with deficient levels of 25(OH)D. 1,25(OH)2D levels < 41 ng/dl and 25(OH)D levels < 20 ng/ml were associated with CV risk score ≥ 3 (OR: 4.16, 95% CI: 2.32-7.4, p < 0.0001 and OR: 1.86, 95% CI: 1.02-3.39, p = 0.044) respectively and 1,25(OH)2D levels < 41 ng/dl were associated with SCORE2/SCORE2-OP of ≥ 20% (OR:2.98, 95% CI: 1.7-5.2, p = 0.0001). In this cross-sectional analysis, BPA exposure was associated with significantly reduced levels of vitamin D that in turn were significantly associated with increased CV risk.
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PURPOSE: Low vitamin D in COVID-19 have been related to worse outcomes. However, most of the studies conducted so far were not-controlled and retrospective, including biases potentially influencing this association. We evaluated 25(OH)vitamin D levels of patients with both severe and non-severe disease at hospital-admission, and in a cohort of control subjects. Moreover, we evaluated sACE-2 levels to investigate the mechanisms underlying the association between vitamin D and COVID-19. METHODS: COVID-19 patients were enrolled in a matched for age, sex and comorbidities 1:1-ratio based on the presence/or not of respiratory-distress/severe-disease at hospital-admission. Control matched subjects were enrolled from an outpatient-setting. RESULTS: Seventy-three COVID-19 patients (36 severe and 37 non-severe) and 30 control subjects were included. We observed a higher vitamin D deficiency (<20 ng/mL) prevalence in COVID-19 patients than control subjects (75% vs 43%). No differences were found regarding 25(OH)vitamin D and sACE-2 levels between patients with and without severe-disease at study entry. During the disease-course, in the severe group a life-threatening disease occurred in 17 patients (47.2%), and, in the non-severe group, a worsening disease occurred in 10 (27%). 25(OH)vitamin D levels, at admission, were negatively correlated with sACE-2 levels, and were lower in patients whose disease worsened as compared to those in whom it did not, independently from the disease severity at admission. In multivariate-analysis, lower 25(OH)vitamin D resulted as an independent risk factor for disease worsening. CONCLUSIONS: 25(OH)vitamin D levels at hospital-admission strongly predicted the occurrence of worsening outcomes in COVID-19 independently of the disease severity at presentation.
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COVID-19 , Deficiência de Vitamina D , Humanos , Estudos Retrospectivos , Vitamina D , Vitaminas , Pacientes Ambulatoriais , Hospitalização , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologiaRESUMO
CONTEXT: Long COVID is an emerging syndrome affecting 50% to 70% of COVID-19 survivors that still lacks predicting factors. OBJECTIVE: Due to the extraskeletal effects of vitamin D, we retrospectively assessed the association between 25(OH) vitamin D levels and long COVID in COVID-19 survivors 6 months after hospitalization. METHODS: Long COVID was defined according to NICE guidelines. Fifty long COVID and 50 non-long-COVID subjects matched on a 1:1 basis were enrolled from an outpatient clinic post-COVID cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin D/bone metabolism, and/or admission to the intensive care unit during hospitalization were exclusion criteria. 25(OH) Vitamin D was measured at hospital admission and 6 months after discharge. RESULTS: We observed lower 25(OH) vitamin D levels, evaluated at follow-up, in subjects with long COVID than those without (20.1 vs 23.2 ng/mL, P = .03). Regarding the affected health areas evaluated in the entire cohort, we observed lower 25(OH) vitamin D levels in those with neurocognitive symptoms at follow-up (n = 7) than those without (n = 93) (14.6 vs 20.6 ng/mL, P = .042). In patients presenting vitamin D deficiency (<20 ng/mL), both at admission and at follow-up (n = 42), those affected by long COVID (n = 22) presented lower 25(OH) vitamin D levels at follow-up than those not affected (n = 20) (12.7 vs 15.2 ng/mL, P = .041). In multiple regression analyses, lower 25(OH) vitamin D levels at follow-up were the only variable significantly associated with long COVID in our cohort (P = .008, OR 1.09, CI 1.01-1.16). CONCLUSION: COVID-19 survivors with long COVID have lower 25(OH) vitamin D levels than matched patients without long COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital discharge. The role of vitamin D supplementation as a preventive strategy of COVID-19 sequelae should be tested in randomized controlled trials.
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COVID-19 , Deficiência de Vitamina D , Humanos , COVID-19/complicações , COVID-19/epidemiologia , Síndrome de COVID-19 Pós-Aguda , Estudos Retrospectivos , Vitamina D , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/diagnóstico , Vitaminas , SobreviventesRESUMO
PURPOSE: Low vitamin D levels were reported to negatively influence the outcome of acute COVID-19, as well as to be linked to Long-COVID. However, few studies have investigated, so far, its effects on humoral-response to anti-SARS-CoV-2 vaccination, reporting conflicting results. We aimed to evaluate the impact of baseline 25(OH)vitamin D (25(OH)D) levels on humoral-response to a two-dose cycle of Pfizer-BioNTech-vaccine up to 9-10 months after immunization. METHODS: We retrospectively included 119 consecutive healthcare-workers (median age 53 years) without a previous history of acute COVID-19 or anti-SARS-CoV-2 immunoglobulins presence immunized with two doses of Comirnaty-vaccine from January to February 2021. 25(OH)D was measured at time of first-immunization. Immune response was evaluated at: time 0 (T0), before the first-dose; T1, time of second-dose (21 days after T0); T2, T3, T4 at 1, 5 and 9 months after T1, respectively. RESULTS: Median 25(OH)D levels were 25.6 ng/mL, and vitamin D deficiency (25(OH)D <20 ng/mL) was observed in 29 subjects (24.8%). In those with vitamin D deficiency, we found a non-significant trend towards lower antibody-titers at T3, and significantly lower titers at T4 as compared to those not vitamin D-deficient, also observing a more pronounced antibody-titers negative drop from peak-T2 and T4 in those with vitamin D deficiency. A positive correlation between 25(OH)D levels and antibody-titers at T4 (p = 0.043) was found. In multiple linear-regression analysis, 25(OH)D deficiency and older-age resulted as negative independent factors associated with antibody titer at T4 (p = 0.026, p = 0.004; respectively). CONCLUSION: In our relatively young cohort presenting low prevalence of hypovitaminosis D, the long-term humoral response to anti-SARS-CoV-2 vaccination was negatively influenced by low baseline 25(OH)D. Vitamin D supplementation could be tested as a strategy to optimize the vaccination campaigns to prevent severe COVID-19.
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COVID-19 , Deficiência de Vitamina D , Humanos , Pessoa de Meia-Idade , Vitamina D , Vacinas contra COVID-19 , Síndrome de COVID-19 Pós-Aguda , Estudos Retrospectivos , COVID-19/prevenção & controle , Vitaminas , Vacinação , ImunidadeRESUMO
Background: No data on the permanent and curative effect of bisphosphonate treatment in patients with complex regional pain syndrome type-1 (CRPS-1) are currently available. The aim of this pre-specified, open-label, observational study was to evaluate the long-term efficacy and safety of neridronate treatment. Design: A pre-specified, open-label, extension study. Methods: Patients treated with intramuscular (IM) placebo in the double-blind phase of the study were assigned to 100 mg intravenous (IV) neridronate treatment administered 4 times over 10 days. These patients, together with those previously treated with 400 mg IM neridronate, were followed for 1 year. Efficacy was assessed using a visual analogue scale (VAS) pain score. Changes in clinical signs and symptoms, quality of life (QoL) using the Short Form Health Survey (SF-36), and the McGill Pain Questionnaire were also assessed. Results: Benefits on pain, clinical and functional measures were maintained and further improved over 12 months in most patients treated with neridronate administered either IM or IV. In IM-treated patients, the percentage of those defined as responders (VAS score reduction ≥ 50%) progressively increased up to day 360 to 32 of 35 patients (91.4%). Among the 27 patients referred to as responders at the end of the double-blind phase, 26 reported the same result at day 360 (96.3%). In IV-treated patients, a responder rate of 88% (22 out 25) was found at day 360 (p = 0.66 between groups). Consistent improvements were also observed for all clinical signs and functional questionnaire. No drug-related adverse events were reported during the study. Conclusion: In patients with acute CRPS-1, the benefit in pain, clinical, and functional measures observed a few weeks after neridronate treatment administered either IM or IV is maintained and further improved over 12 months. Parenteral neridronate induces permanent disease remission preventing chronic pain and motor dysfunction. Trial registration: EU Clinical Trials Register (EudraCT Number): 2014-001156-28.
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Previous studies have shown a relationship between vitamin D and celiac disease (CD), however little evidence is available examining the direct effects of vitamin D on pathological features of this disease. In this study we evaluated the effect of oral administration of different doses of native vitamin D3 (cholecalciferol) in enteropathic mice. Female non-obese diabetic (NOD)/ShiLt.J mice were fed standard or gluten-free diet and administered gliadin (5 µg/kg) to induce a celiac pathology. Healthy control (gluten-free diet, without gliadin) and control for pathology (standard diet, with gliadin) were administered olive oil. All other experimental groups received gliadin and standard diet plus oral cholecalciferol (5, 10, 20, 50 and 130 µg/kg). Serum levels of 25(OH)D3, calcium and zonulin and expression of vitamin D receptor (VDR), CD3 and zonula occludens-1 (ZO-1) by immunohistochemistry as well as intestinal histological and histomorphometric analyses were undertaken. Although no difference in serum levels of 25(OH)D3, calcium or zonulin was observed in cholecalciferol-treated mice vs. healthy controls, a significant improvement in intestinal mucosa pathological features in mice administered cholecalciferol was observed by histological analysis. Villi length was also significantly increased by cholecalciferol in a dose-dependent manner. Immunohistochemical staining revealed increased expression of CD3 and ZO-1 in celiac mice compared to mice receiving high dose (130 µg/kg) cholecalciferol. These findings show the effect of oral cholecalciferol on signature features of CD in a mouse model of CD. Further dose-ranging studies to investigate the efficacy of cholecalciferol for the treatment of CD are warranted.
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Doença Celíaca , Colecalciferol , Animais , Calcifediol , Cálcio , Cálcio da Dieta , Doença Celíaca/tratamento farmacológico , Colecalciferol/farmacologia , Colecalciferol/uso terapêutico , Modelos Animais de Doenças , Feminino , Gliadina/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Vitamina DRESUMO
Sarcopenia is a complex process characterized by a progressive decrease in muscle mass and strength. Various nutrients have been shown to be effective in supporting muscular performance. This randomized clinical trial aimed to evaluate the effectiveness of a 2-month administration of food for special medical purposes composed of omega-3 fatty acids (500 mg), leucine (2.5 g), and probiotic Lactobacillus paracasei PS23 (LPPS23), on appendicular lean mass (ALM), muscle performance, inflammatory status, and amino acid profile in sarcopenic patients. A total of 60 participants (aged 79.7 ± 4.8 years and a body mass index of 22.2 ± 2.1 kg/m2) were enrolled and randomly assigned to either intervention (n = 22) or placebo group (n = 28). Comparing the differences in effects between groups (intervention minus placebo effects), ALM increased significantly in the intervention group (p < 0.05), with no discernible change in the placebo group. Similarly, significant differences were also observed for the Tinetti scale (+2.39 points, p < 0.05), the SPPB total score (+2.22 points, p < 0.05), and the handgrip strength (4.09 kg, p < 0.05). Visceral adipose tissue significantly decreased in the intervention group compared to the placebo group at 60 days −0.69 g (95% CI: −1.09, 0.29) vs. 0.27 g (95% CI: −0.11, 0.65), groups difference −0.96 (95% CI: −1.52, 0.39, p = 0.001). A statistically significant increase in levels of valine, leucine, isoleucine, and total amino acid profiles was observed in the intervention group compared with the placebo group at 60 days (p = 0.001). When taken together, these beneficial effects may be attributed to the innovative composition of this special medical-purpose food which could be considered for the treatment of sarcopenia in the elderly.
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Ácidos Graxos Ômega-3 , Lacticaseibacillus paracasei , Probióticos , Sarcopenia , Idoso , Humanos , Sarcopenia/tratamento farmacológico , Leucina , Lacticaseibacillus paracasei/fisiologia , Força da Mão , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Probióticos/uso terapêutico , Método Duplo-CegoRESUMO
Objective: This study aimed to evaluate the association between the endocrine-disrupting chemical, bisphenol A (BPA) on circulating levels of 25-hydroxy vitamin D (25(OD)D) and other vitamin D metabolites in an elderly population in Italy. Methods: This was a retrospective analysis of the InCHIANTI Biobank in Italy. The association between vitamin D metabolites namely 1,25(OH)D, 25(OH)D, parathyroid hormone (PTH) and BPA levels were evaluated. Multiple regression models were used to examine the association between predictor variables with 1,25(OH)D or 25(OH)D levels. Results: Samples from 299 individuals aged 72.8 ± 15.7 years were examined. Mean levels of BPA, 1,25(OH)D and 25(OH)D were 351.2 ± 511.6 ng/dL, 43.7 ± 16.9 pg/mL and 20.2 ± 12.1 ng/mL, respectively. One hundred eighty individuals (60.2%) were deficient (<20 ng/mL) in 25(OH)D and this population also presented higher BPA levels (527.9 ± 1289.5 ng/dL vs 86.9 ± 116.8 ng/dL, P < 0.0001). Univariate analysis revealed that BPA levels were negatively correlated with both 1,25(OH)D (r= -0.67, P < 0.0001) and 25(OH)D (r= -0.69, P < 0.0001). Multivariate regression revealed that PTH (ß: -0.23, 95% CI: -0.34, -0.13, P < 0.0001) and BPA (ß: -0.25, 95% CI: -0.3, -0.19, P < 0.0001) remained significantly associated with 25(OH)D levels while BPA was also associated with 1,25(OH)D levels (ß: -0.19, 95% CI: -0.22, -0.15, P < 0.0001). Receiver operating characteristic curve analysis showed that a BPA concentration of >113 ng/dL was the best cut-off to predict individuals deficient in 25(OH)D (area under the curve: 0.87, 95% CI: 0.82-0.90, P < 0.0001). Conclusion: The strong negative association between BPA and vitamin D in this elderly population warrants further investigation, particularly since this population is already at greatest risk of hypovitaminosis and fracture.
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BACKGROUND: Complex regional pain syndrome type-1 (CRPS-1) is a severely disabling painful disease challenging to treat. This multicenter, randomized, double-blind placebo-controlled trial examined the efficacy of intramuscular (i.m.) neridronate in CRPS-1 patients. METHODS: A total of 78 patients diagnosed with CRPS-1 (aged 59.5 ± 10.3, 66.7% female) were randomly assigned to 25 mg (i.m.) neridronate (N = 41) given once daily for 16 consecutive days or placebo control (N = 37). Efficacy was assessed after 30 days using a visual analogue scale (VAS) pain score and the number of patients achieving ⩾50% reduction in VAS score. Change in clinical signs and symptoms, quality of life (QoL) using Short Form Health Survey (SF-36) and the McGill Pain Questionnaire were also assessed. RESULTS: After 30 days, VAS score decreased significantly to a greater extent in neridronate-treated patients versus placebo (31.9 ± 23.3 mm versus 52.3 ± 27.8 mm, p = 0.0003). Furthermore, the proportion of patients achieving a VAS reduction of ⩾50% was greater in the neridronate group (65.9% versus 29.7%, p = 0.0017). Clinical signs and symptoms were improved significantly in the neridronate group versus placebo for edema (72.5% versus 79.9%, p = 0.03), pain during motion (70% versus 83.3%, p = 0.0009), allodynia (20% versus 63.3%, p = 0.0004), and hyperalgesia (20% versus 56.7%, p = 0.0023). Whereas no difference was observed for QoL measures using the SF-36 questionnaire, three of the four pain variables using the McGill Pain Questionnaire improved significantly in the neridronate group. No serious drug-related adverse events were reported during the study. CONCLUSION: In patients with acute CRPS-1, i.m. injections of 25 mg neridronate were associated with clinically relevant benefit compared with placebo controls. TRIAL REGISTRATION: EU Clinical Trials Register: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001156-28.
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BACKGROUND: Transplantation (Tx) is an effective therapeutic option in patients with end-stage organ failure and osteoporosis and related fractures are a recognized complication in these patients. Aim of this study was to evaluate the efficacy of neridronate in patients with reduced bone mass after Tx of the heart, liver or lung. METHODS: In this multicenter randomized double-blind controlled trial (RCT), 22 patients were treated with neridronate (25 mg i.m./month) and 17 received placebo. All patients received daily oral calcium (500 mg) and vitamin D (400 IU). Dual-energy X-ray absorptiometry (DXA) was evaluated at 0, 6 and 12 months and markers of bone turnover at 0, 3, 6, 9 and 12 months. RESULTS: Thirty-nine patients (11 heart Tx, 21 liver Tx, 7 lung Tx), aged 49.3±9.1 years, with a T-score <-2.0 SD at lumbar spine or femoral level were included. In neridronate-treated patients, a significant increase in lumbar bone mineral density (BMD) was observed after 12 months vs. placebo control (0.92±0.13 g/cm2 vs. 0.84±0.08 g/cm2; P=0.005). Femur and hip BMD remained unchanged between groups. Total alkaline phosphatase, bone alkaline phosphatase and beta-cross-laps significantly decreased over the 12 months in neridronate-treated patients vs. placebo, respectively (107.4±74 U/L vs. 157.6±107.1 U/L, P=0.002; 5.7±3.3 µg/L vs. 11.7±4.3 µg/L, P<0.001 and 0.25±0.13 ng/mL vs. 0.73±0.57 ng/mL, P<0.001). No difference was observed between neridronate and placebo groups regarding safety profile. CONCLUSIONS: This is the first RCT that demonstrates the efficacy of neridronate in increasing bone density and reducing bone turnover in organ Tx recipients with significant skeletal morbidity.
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Difosfonatos/uso terapêutico , Transplante de Coração , Transplante de Fígado , Transplante de Pulmão , Osteoporose/tratamento farmacológico , Absorciometria de Fóton , Fosfatase Alcalina/sangue , Fosfatase Alcalina/metabolismo , Remodelação Óssea , Osso e Ossos/efeitos dos fármacos , Difosfonatos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Resultado do TratamentoRESUMO
Effects of ABIO-08/01, a new potentially anxiolytic isoxazoline, on regional electrical brain generators were investigated by 3-dimensional EEG tomography. In a double- blind, placebo-controlled, multiple-ascending-dose study, 16 healthy males (30.2 +/- 5.7 years) received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (8-day wash-out) in a randomized non-balanced design for phase-1 studies. A 3-min vigilance-controlled (V) EEG, a 4-min resting (R) EEG with eyes closed, a 1-min eyes-open (EO) EEG and psychometric tests were performed 0, 1 and 6 h after taking the drug on days 1 and 5. Low-resolution brain electromagnetic tomography (LORETA) was computed from the spectrally analyzed EEG data, and differences between drug and placebo were displayed as statistical parametric maps. Data were registered to the Talairach-Tournoux Human Brain Atlas available as a digitized MRI. An overall omnibus significance test followed by a voxel-by-voxel t test demonstrated significant regional EEG changes after ABIO-08/01 versus placebo, dependent on recording condition, dose and time. While in the EO-EEG specifically the lowest dose of ABIO-08/01 induced pronounced sedative effects (delta/theta and beta increase) 1 h after acute and slightly less so after superimposed administration, in the 6th hour a decrease in alpha and beta activity signaled less sedative and more relaxant action. In the V-EEG these changes were less pronounced, in the R-EEG partly opposite. Hemisphere-specific changes were observed, suggesting increases in LORETA power over the left temporal, parietal, superior frontal regions and decreases over the right prefrontal, temporal pole and occipital regions. These LORETA changes are discussed in the light of neuroimaging findings on anxiety and anxiolytics.
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Ansiolíticos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Isoxazóis/farmacologia , Tomografia/métodos , Adulto , Mapeamento Encefálico , Córtex Cerebral/fisiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Hipocampo/fisiologia , Humanos , Masculino , Placebos , Desempenho Psicomotor/efeitos dos fármacos , Fatores de TempoRESUMO
In a double-blind, placebo-controlled, multiple-ascending-dose study, the encephalotropic and psychotropic properties of ABIO-08/01, a new potentially anxiolytic and nootropic isoxazoline, were studied in 16 young healthy males. In a randomized nonbalanced phase 1 study, they received 3 oral drug doses (10, 20, 40 mg) and placebo for 7 days (washout period 8 days). EEG mapping and psychometry were carried out at hours 0, 1, 6 of day 1 (acute effect) and day 5 (subacute and superimposed effects). MANOVA/ Hotelling T(2) test demonstrated significant central effects of ABIO-08/01 versus placebo after acute, subacute and superimposed administration of all doses in the resting, vigilance-controlled and eyes-open EEG. Univariate analysis revealed activating patterns in the resting EEG (40 mg > 20 mg > 10 mg), and sedative patterns in the eyes-open EEG (10 mg > 20 mg > 40 mg). In the vigilance-controlled EEG, 40 mg of ABIO-08/01 induced activating patterns, whereas 10 mg induced sedative patterns. Concerning psychometry, ABIO-08/01 improved concentration (40 mg > 20 mg > 10 mg; activating effect) and deteriorated well-being (10 mg > 20 mg > 40 mg; sedative effect). Ten milligrams also improved reaction time performance and psychomotor activity. ABIO-08/01 is well-tolerated and is of interest in anxiety disorders.
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Ansiolíticos/efeitos adversos , Ansiolíticos/farmacologia , Transtornos de Ansiedade/tratamento farmacológico , Eletroencefalografia/efeitos dos fármacos , Isoxazóis/efeitos adversos , Isoxazóis/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Adulto , Ansiolíticos/administração & dosagem , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Isoxazóis/administração & dosagem , Masculino , Placebos , Fatores de TempoRESUMO
Early pharmacological studies in animals demonstrated that ABIO-08/01, a new isoxazoline, exerted anxiolytic and anticonvulsant, but also cognition-enhancing properties. Thus, the aim of the present double-blind, placebo-controlled multiple-ascending-dose study was to investigate the effect of the new compound on event-related potentials (ERPs). In a randomized ascending-dose design for phase-1 studies, 16 young healthy male subjects aged 30.2 +/- 5.7 years received three ascending drug doses (10, 20, and 40 mg) and placebo for 7 days, with a washout period of 8 days in between. Auditory ERPs were recorded pre-dose and 2 h post-dose on days 1 (acute effect) and 5 (subacute and absolute superimposed effect). Descriptive statistics with one confirmatory statement on P300 latency demonstrated a significant shortening after acute, subacute, and superimposed administration of 40 mg ABIO-08/01. While ERP amplitudes showed only minor effects, low-resolution brain electromagnetic tomography (LORETA) demonstrated that ABIO-08/01 promotes more efficient information processing by reallocating perceptual and cognitive ERP resources. Thus, our ERP studies confirm early pharmacological findings in animals of a cognition-enhancing effect of ABIO-08/01, which is interesting in the context of the anxiolytic mode of action of the compound as its CNS effects are quite different from those of anxiolytic sedatives, such as benzodiazepines.