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1.
Nature ; 633(8030): 654-661, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39261724

RESUMEN

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.


Asunto(s)
Anticuerpos Monoclonales , Presión Sanguínea , Receptores del Factor Natriurético Atrial , Vasoconstricción , Venas , Adulto , Animales , Perros , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven , Regulación Alostérica/efectos de los fármacos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Diuresis/efectos de los fármacos , Voluntarios Sanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Hemodinámica/efectos de los fármacos , Macaca fascicularis , Músculo Liso Vascular/efectos de los fármacos , Natriuresis/efectos de los fármacos , Receptores del Factor Natriurético Atrial/metabolismo , Receptores del Factor Natriurético Atrial/agonistas , Receptores del Factor Natriurético Atrial/genética , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Venas/efectos de los fármacos , Venas/fisiología
2.
Annu Rev Pharmacol Toxicol ; 61: 655-677, 2021 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-32976736

RESUMEN

Chronic pain treatment remains a sore challenge, and in our aging society, the number of patients reporting inadequate pain relief continues to grow. Current treatment options all have their drawbacks, including limited efficacy and the propensity of abuse and addiction; the latter is exemplified by the ongoing opioid crisis. Extensive research in the last few decades has focused on mechanisms underlying chronic pain states, thereby producing attractive opportunities for novel, effective and safe pharmaceutical interventions. Members of the transient receptor potential (TRP) ion channel family represent innovative targets to tackle pain sensation at the root. Three TRP channels, TRPV1, TRPM3, and TRPA1, are of particular interest, as they were identified as sensors of chemical- and heat-induced pain in nociceptor neurons. This review summarizes the knowledge regarding TRP channel-based pain therapies, including the bumpy road of the clinical development of TRPV1 antagonists, the current status of TRPA1 antagonists, and the future potential of targeting TRPM3.


Asunto(s)
Dolor Crónico , Canales de Potencial de Receptor Transitorio , Humanos , Neuronas , Nocicepción
3.
N Engl J Med ; 384(19): 1824-1835, 2021 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-33440088

RESUMEN

BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule. RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 212 to 354), regardless of vaccine dose or age group, and reached 96% by day 57 with a further increase in titers (GMT, 288 to 488) in cohort 1a. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 15, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3. CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).


Asunto(s)
Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Inmunogenicidad Vacunal , SARS-CoV-2/inmunología , Ad26COVS1 , Adolescente , Adulto , Anticuerpos Neutralizantes/sangre , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Estudios de Cohortes , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
4.
Microvasc Res ; 152: 104654, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38215901

RESUMEN

BACKGROUND: Quantification of the vasodilation after topical application of capsaicin or cinnamaldehyde is often implemented to indirectly assess Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) or Ankyrin 1 (TRPA1) functionality respectively. This method has been well-established on the human forearm. However, to enable TRP functionality assessments in distal peripheral neuropathy, the vascular response upon TRP activation on dorsal finger skin was characterized. METHODS: Two doses of cinnamaldehyde (3 % and 10 % v/v) and capsaicin (300 µg and 1000 µg) were topically applied (20 µL) on the skin of the mid three proximal phalanges in 17 healthy men. The dose-response, and inter-hand and inter-period reproducibility of the dermal blood flow (DBF) increase was assessed using Laser Speckle Contrast Imaging (LSCI) during 60 min post-application. Linear mixed models explored dose-driven differences, whereas the intra-class correlation coefficient (ICC) estimated the reproducibility of the vascular response. RESULTS: Both doses of cinnamaldehyde and capsaicin induced a robust, dose-dependent increase in DBF. The vascular response to cinnamaldehyde 10 % on finger skin, expressed as area under the curve, correlated well over time (ICC = 0.66) and excellently between hands (ICC = 0.87). Similarly, the response to capsaicin 1000 µg correlated moderately over time (ICC = 0.50) and well between hands (ICC = 0.73). CONCLUSION: The vascular response upon topical cinnamaldehyde and capsaicin application on finger skin is an alternative approach for measurements on forearm skin. Thereby, it is a promising vascular read-out to investigate the pathophysiology, and TRP involvement in particular, of specific peripheral neuropathic pain syndromes.


Asunto(s)
Acroleína/análogos & derivados , Canales de Potencial de Receptor Transitorio , Masculino , Humanos , Capsaicina/farmacología , Reproducibilidad de los Resultados , Nervios Periféricos , Canales Catiónicos TRPV
5.
Br J Clin Pharmacol ; 90(10): 2638-2651, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38953404

RESUMEN

AIMS: Cerebral hypometabolism occurs years prior to a diagnosis of neurodegenerative diseases and coincides with reduced cerebral perfusion and declining noradrenergic transmission from the locus coeruleus. In pre-clinical models, ß-adrenoceptor (ß-AR) agonists increase cerebrocortical glucose metabolism, and may have therapeutic potential for neurodegenerative diseases. This study investigated the safety and effects on regional cerebral blood flow (rCBF) of the oral, brain-penetrant ß2-AR agonist, clenbuterol, in healthy volunteers (HV) and patients with mild cognitive impairment (MCI) or Parkinson's disease (PD). METHODS: This study evaluated the safety and effects on cerebral activity of the oral, brain-penetrant, ß2-AR agonist clenbuterol (20-160 µg) in healthy volunteers and patients with MCI or PD. Regional CBF, which is tightly coupled to glucose metabolism, was measured by arterial spin labelling MRI in 32 subjects (25 HV and 8 MCI or PD) across five cohorts. In some cohorts, low doses of nadolol (1-5 mg), a ß-AR antagonist with minimal brain penetration, were administered with clenbuterol to control peripheral ß2-AR responses. RESULTS: Significant, dose-dependent increases in rCBF were seen in multiple brain regions, including hippocampus, amygdala and thalamus, following the administration of clenbuterol to HVs (mean changes from baseline in hippocampal rCBF of -1.7%, 7.3%, 22.9%, 28.4% 3 h after 20, 40, 80 and 160 µg clenbuterol, respectively). In patients with MCI or PD, increases in rCBF following 80 µg clenbuterol were observed both without and with 5 mg nadolol (in hippocampus, 18.6%/13.7% without/with nadolol). Clenbuterol was safe and well-tolerated in all subjects; known side effects of ß2-agonists, including increased heart rate and tremor, were mild in intensity and were blocked by low-dose nadolol. CONCLUSIONS: The effects of clenbuterol on rCBF were evident both in the absence and presence of low-dose nadolol, suggesting central nervous system (CNS) involvement. Concomitant inhibition of the peripheral effects of clenbuterol by nadolol confirms that meaningful ß2-AR antagonism in the periphery was achieved without interrupting the central effects of clenbuterol on rCBF.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Circulación Cerebrovascular , Clenbuterol , Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Clenbuterol/administración & dosificación , Clenbuterol/farmacología , Clenbuterol/efectos adversos , Masculino , Femenino , Anciano , Circulación Cerebrovascular/efectos de los fármacos , Persona de Mediana Edad , Disfunción Cognitiva/inducido químicamente , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Imagen por Resonancia Magnética , Relación Dosis-Respuesta a Droga , Nadolol/farmacología , Nadolol/administración & dosificación , Nadolol/efectos adversos , Voluntarios Sanos , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Adulto Joven
6.
Skin Pharmacol Physiol ; 36(2): 87-97, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36623479

RESUMEN

INTRODUCTION: Skin prick tests have a long history as diagnostic and pharmacodynamic biomarker. Besides visual assessments of the wheal and flare, objective blood flow measurements using laser Doppler imaging (LDI) and laser speckle contrast imaging (LSCI) have been reported. In light of these advancements, an up-to-date characterization of the histamine-evoked response is worthwhile. METHODS: A single-centre study was completed in healthy males. Two parameters were addressed: (1) dermal blood flow (DBF) within a 7.65-mm ring encircling the skin prick site (DBFring), and (2) surface area of the flare (AREAflare). First, the dose response was assessed using placebo (0.9% sodium chloride) or histamine (histamine dihydrochloride 1, 3, or 10 mg/mL) skin pricks on the volar surface of subjects' (n = 12) forearm. The DBFring was measured by LDI, and the AREAflare by LDI and by ruler. Secondly, the inter-arm and inter-period reproducibility of the DBFring and AREAflare, as evoked by histamine (10 mg/mL) and measured by LDI and LSCI, was examined (n = 14). Lastly, the effect of aprepitant (125 mg), ketotifen (1 mg), and a single (5 mg) and fourfold (20 mg) dose of desloratadine and levocetirizine on the histamine-induced (10 mg/mL) DBFring and AREAflare was evaluated with LSCI (n = 13 or 12). RESULTS: All three histamine doses induced a time-dependent vasodilation. Ruler recordings did not conclusively correlate with LDI assessments of the AREAflare. The DBFring and AREAflare were reasonably reproducible when measured by using LDI or LSCI, with negligible bias between arms and study periods and poor to moderate within-subject reproducibility (0.23 ≤ ICC ≤ 0.71). While the fourfold dose of desloratadine (p = 0.0041) and the single and fourfold dose of levocetirizine (p < 0.0001) managed to reduce the AREAflare, only the fourfold dose of levocetirizine (p = 0.0052) reduced the DBFring. CONCLUSION: Caution is warranted when translating years of clinical experience with histamine skin prick tests to objective recordings of the associated changes in skin perfusion. Ruler and LDI assessments of the AREAflare do not consistently correlate, and the reproducibility and histamine dependency of the measurements are not obvious. While 10 mg/mL histamine may be a good choice for qualitative diagnostic evaluations, a lower dose may be better suited to use as a quantitative biomarker.


Asunto(s)
Histamina , Piel , Humanos , Masculino , Biomarcadores , Histamina/farmacología , Reproducibilidad de los Resultados
7.
J Allergy Clin Immunol ; 149(1): 189-199, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34126156

RESUMEN

BACKGROUND: The efficacy of an allergen-specific IgG cocktail to treat cat allergy suggests that allergen-specific IgG may be a major protective mechanism elicited by allergen immunotherapy. OBJECTIVES: Extending these findings, we tested a Bet v 1-specific antibody cocktail in birch-allergic subjects. METHODS: This was a phase 1, randomized, double-blind, study with 2 parts. Part A administered ascending doses of the Bet v 1-specific antibody cocktail REGN5713/14/15 (150-900 mg) in 32 healthy adults. Part B administered a single subcutaneous 900-mg dose or placebo in 64 birch-allergic subjects. Total nasal symptom score response to titrated birch extract nasal allergen challenge and skin prick test (SPT) with birch and alder allergen were assessed at screening and days 8, 29, 57, and 113 (SPT only); basophil activation tests (n = 26) were conducted. RESULTS: Single-dose REGN5713/14/15 significantly reduced total nasal symptom score following birch nasal allergen challenge relative to baseline. Differences in total nasal symptom score areas under the curve (0-1 hour) for subjects treated with REGN5713/14/15 versus those given placebo (day 8: -1.17, P = .001; day 29: -1.18, P = .001; day 57: -0.85, P = .024) and titration SPT with birch difference in area under the curve of mean wheal diameters for subjects treated with REGN5713/14/15 versus placebo (all P < .001) were sustained for ≥2 months; similar results were observed with alder SPT. REGN5713/14/15 was well tolerated. Basophil responsiveness to birch-related allergens was significantly decreased in subjects treated with REGN5713/14/15 versus those given placebo on days 8, 57, and 113 (all P < .01). CONCLUSIONS: Single-dose REGN5713/14/15 was well tolerated and provided a rapid (1 week) and durable (2 months) reduction in allergic symptoms after birch allergen nasal allergen challenge, potentially offering a new paradigm for the treatment of birch allergy symptoms.


Asunto(s)
Alérgenos/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Plantas/inmunología , Inmunoglobulina G/uso terapéutico , Rinitis Alérgica Estacional/terapia , Adulto , Basófilos/inmunología , Betula/inmunología , Desensibilización Inmunológica , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rinitis Alérgica Estacional/inmunología , Adulto Joven
8.
Br J Clin Pharmacol ; 88(4): 1785-1794, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34558102

RESUMEN

AIMS: In search of noninvasive biomarkers to assess the pharmacodynamic effects of portal pressure-lowering drugs, the reproducibility of flow measurements in the superior mesenteric artery was evaluated using Doppler ultrasound. METHODS: A reproducibility study was conducted in 15 healthy male volunteers (18-50 y). Eight ultrasound measurements were performed for each subject: 2 observers each conducted 2 measurements during 2 separate visits. The following flow parameters were captured: peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), volume flow (VF) and vessel diameter. Reproducibility was assessed by the intraclass correlation coefficient. RESULTS: Results are presented as intraclass correlation coefficient [95% confidence interval]. The flow parameters PSV, EDV, PI and VF correlated excellently within observer during visit 1 (0.888 [0.748-0.953], 0.910 [0.793-0.962], 0.844 [0.656-0.933] and 0.916 [0.857-0.951], respectively) and visit 2 (0.925 [0.829-0.968], 0.942 [0.863-0.976], 0.883 [0.719-0.954] and 0.915 [0.855-0.951], respectively). Measurements conducted during 2 separate visits by 1 observer correlated well to excellently for PSV, EDV, PI and VF (0.756 [0.552-0.875], 0.836 [0.694-0.916], 0.807 [0.631-0.904] and 0.839 [0.783-0.882], respectively). Measurements conducted by 2 distinct observers correlated well to excellently for PSV, EDV and VF during visit 1 (0.813 [0.584-0.922], 0.884 [0.597-0.945] and 0.786 [0.575-0.899], respectively) and visit 2 (0.779 [0.498-0.912], 0.861 [0.672-0.945], 0.810 [0.553-0.926], respectively). Vessel diameter measurements were poorly reproducible. CONCLUSION: Doppler ultrasound is a reproducible method for flow measurements in the superior mesenteric artery in a standardized group of healthy volunteers. Therefore, it is a promising technique to assess pharmacodynamic effects of splanchnic vasoactive compounds in early clinical drug development.


Asunto(s)
Ultrasonografía Doppler , Velocidad del Flujo Sanguíneo , Humanos , Masculino , Valores de Referencia , Reproducibilidad de los Resultados , Ultrasonografía , Ultrasonografía Doppler/métodos
9.
Eur J Nucl Med Mol Imaging ; 48(2): 596-611, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32638097

RESUMEN

PURPOSE: Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that modulates intracellular transport and protein quality control. Inhibition of HDAC6 deacetylase activity has shown beneficial effects in disease models, including Alzheimer's disease and amyotrophic lateral sclerosis. This first-in-human positron emission tomography (PET) study evaluated the brain binding of [18F]EKZ-001 ([18F]Bavarostat), a radiotracer selective for HDAC6, in healthy adult subjects. METHODS: Biodistribution and radiation dosimetry studies were performed in four healthy subjects (2M/2F, 23.5 ± 2.4 years) using sequential whole-body PET/CT. The most appropriate kinetic model to quantify brain uptake was determined in 12 healthy subjects (6M/6F, 57.6 ± 3.7 years) from 120-min dynamic PET/MR scans using a radiometabolite-corrected arterial plasma input function. Four subjects underwent retest scans (2M/2F, 57.3 ± 5.6 years) with a 1-day interscan interval to determine test-retest variability (TRV). Regional volume of distribution (VT) was calculated using one-tissue and two-tissue compartment models (1-2TCM) and Logan graphical analysis (LGA), with time-stability assessed. VT differences between males and females were evaluated using volume of interest and whole-brain voxel-wise approaches. RESULTS: The effective dose was 39.1 ± 7.0 µSv/MBq. Based on the Akaike information criterion, 2TCM was the preferred model compared to 1TCM. Regional LGA VT were in agreement with 2TCM VT, however demonstrated a lower absolute TRV of 7.7 ± 4.9%. Regional VT values were relatively homogeneous with highest values in the hippocampus and entorhinal cortex. Reduction of acquisition time was achieved with a 0 to 60-min scan followed by a 90 to 120-min scan. Males demonstrated significantly higher VT than females in the majority of cortical and subcortical brain regions. No relevant radiotracer related adverse events were reported. CONCLUSION: [18F]EKZ-001 is safe and appropriate for quantifying HDAC6 expression in the human brain with Logan graphical analysis as the preferred quantitative approach. Males showed higher HDAC6 expression across the brain compared to females.


Asunto(s)
Encéfalo/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Femenino , Histona Desacetilasa 6 , Humanos , Masculino , Tomografía de Emisión de Positrones , Distribución Tisular , Tomografía Computarizada por Rayos X , Adulto Joven
11.
Microvasc Res ; 129: 103965, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31812705

RESUMEN

A comparison was made between the established laser Doppler imaging (LDI) technique and the more recently developed laser speckle contrast imaging (LSCI) method to measure changes in capsaicin- and cinnamaldehyde-induced dermal blood flow (DBF) as an indicator of TRPV1 and TRPA1 activation, respectively. METHODS: Capsaicin (1000 µg/20 µl) and cinnamaldehyde (10%) solutions were applied on the forearm of 16 healthy male volunteers, alongside their corresponding vehicle solutions. Pre challenge and 10, 20, 30, 40 and 60 min post challenge application, changes in DBF were assessed with the LSCI technique, followed by LDI. The area under the curve from 0 to 60 min (AUC0-60) post capsaicin and cinnamaldehyde application was calculated as a summary measure of the response. Correlation between the LDI and LSCI instrument was assessed using a simple linear regression analysis. Sample size calculations (SSC) were performed for future studies using either the LDI or LSCI technique. RESULTS: Higher arbitrary perfusion values were obtained with LDI compared to LSCI, yet a complete discrimination between the challenge and vehicle responses was achieved with both techniques. A strong degree of correlation was observed between LDI and LSCI measurements of the capsaicin- (R = 0.84 at Tmax and R = 0.92 for AUC0-60) and cinnamaldehyde-induced (R = 0.78 at Tmax and R = 0.81 for AUC0-60) increase in DBF. SSC revealed that LSCI requires considerably less subjects to obtain a power of 80% (about 15 versus 27 subjects in case of capsaicin and 7 versus 13 for cinnamaladehyde). CONCLUSIONS: The LSCI technique was identified as the preferred method to capture capsaicin- and cinnamaldehyde-induced changes in DBF. Besides its reduced variability, the shorter scan time provides a major advantage, allowing real-time DBF measurements.


Asunto(s)
Acroleína/análogos & derivados , Capsaicina/administración & dosificación , Flujometría por Láser-Doppler , Microcirculación/efectos de los fármacos , Imagen de Perfusión , Fármacos del Sistema Sensorial/administración & dosificación , Piel/irrigación sanguínea , Canal Catiónico TRPA1/agonistas , Canales Catiónicos TRPV/agonistas , Acroleína/administración & dosificación , Adolescente , Adulto , Biomarcadores/metabolismo , Velocidad del Flujo Sanguíneo , Antebrazo , Voluntarios Sanos , Humanos , Masculino , Valor Predictivo de las Pruebas , Flujo Sanguíneo Regional , Reproducibilidad de los Resultados , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPV/metabolismo , Factores de Tiempo , Adulto Joven
12.
Artículo en Inglés | MEDLINE | ID: mdl-30745392

RESUMEN

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.


Asunto(s)
Antivirales/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacocinética , Hepatitis C/tratamiento farmacológico , Adulto , Amidas , Antivirales/farmacología , Sulfato de Atazanavir/farmacocinética , Sulfato de Atazanavir/farmacología , Benzofuranos/farmacocinética , Benzofuranos/farmacología , Carbamatos , Ciclopropanos , Darunavir/farmacocinética , Darunavir/farmacología , Interacciones Farmacológicas , Femenino , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Voluntarios Sanos , Hepacivirus/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Lopinavir/farmacocinética , Lopinavir/farmacología , Masculino , Persona de Mediana Edad , Quinoxalinas/farmacocinética , Quinoxalinas/farmacología , Ritonavir/farmacocinética , Ritonavir/farmacología , Sulfonamidas , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto Joven
13.
Cephalalgia ; 39(1): 100-110, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-29783863

RESUMEN

OBJECTIVES: The aim of this study was to assess the effects of concomitant administration of erenumab and sumatriptan on resting blood pressure, pharmacokinetics, safety, and tolerability in healthy subjects. METHODS: In this phase 1, parallel-group, one-way crossover, double-blind, placebo-controlled study, healthy adult subjects were randomized (1:2) to receive either intravenous placebo and subcutaneous sumatriptan 12 mg (i.e. two 6-mg injections separated by 1 hour) or intravenous erenumab 140 mg and subcutaneous sumatriptan 12 mg. Blood pressure was measured pre-dose and at prespecified times post-dose. The primary endpoint was individual time-weighted averages of mean arterial pressure, measured from 0 hours to 2.5 hours after the first dose of sumatriptan. Pharmacokinetic parameters for sumatriptan were evaluated by calculating geometric mean ratios (erenumab and sumatriptan/placebo and sumatriptan). Adverse events and anti-erenumab antibodies were also evaluated. RESULTS: A total of 34 subjects were randomized and included in the analysis. Least squares mean (standard error) time-weighted averages of mean arterial pressure were 87.4 (1.0) mmHg for the placebo and sumatriptan group and 87.4 (1.2) mmHg for the erenumab and sumatriptan group. Mean difference in mean arterial pressure between groups was -0.04 mmHg (90% confidence interval: -2.2, 2.1). Geometric mean ratio estimates for maximum plasma concentration of sumatriptan was 0.95 (90% confidence interval: 0.82, 1.09), area under the plasma concentration-time curve (AUC) from time 0 to 6 hours was 0.98 (90% confidence interval: 0.93, 1.03), and AUC from time 0 to infinity was 1.00 (90% confidence interval: 0.96, 1.05). No clinically relevant safety findings for co-administration of sumatriptan and erenumab were identified. CONCLUSION: Co-administration of erenumab and sumatriptan had no additional effect on resting blood pressure or on pharmacokinetics of sumatriptan. Trial registration: ClinicalTrials.gov, NCT02741310.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Presión Sanguínea/efectos de los fármacos , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Sumatriptán/farmacología , Adulto , Estudios Cruzados , Método Doble Ciego , Quimioterapia Combinada , Femenino , Voluntarios Sanos , Humanos , Masculino , Trastornos Migrañosos/tratamiento farmacológico
14.
Drug Metab Dispos ; 46(11): 1507-1513, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30166405

RESUMEN

CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio [CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus (DMT) and 31-DMT, respectively; P < 0.001]. There was, however, no relationship between CYP3A4 activity and tacrolimus metabolite/parent ratios. Additional analyses in 16 healthy volunteers showed that dual pharmacological inhibition of CYP3A4 and P-glycoprotein using itraconazole resulted in increased tacrolimus metabolite/parent ratios (+65%, +112%, and 25% for 13-, 15-, and 31-DMT, respectively; P < 0.01). This finding was confirmed in a cohort of nine renal transplant recipients who underwent tacrolimus pharmacokinetic assessments before and during CYP3A4 inhibition (58% increase in overall metabolite/tacrolimus ratio; P = 0.017).


Asunto(s)
Citocromo P-450 CYP3A/genética , Riñón/metabolismo , Tacrolimus/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Genotipo , Voluntarios Sanos , Humanos , Inmunosupresores/metabolismo , Trasplante de Riñón/métodos , Masculino , Midazolam/metabolismo , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética
15.
Cephalalgia ; 37(12): 1164-1172, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27687880

RESUMEN

Background Migraine is much more common in females than in males, and occurrence is associated with changes in female sex hormones. Calcitonin gene-related peptide (CGRP) plays a key role in migraine, and variations in female sex hormones may affect CGRP sensitivity and/or production. Objectives Investigate repeatability, gender differences, influence of the menstrual cycle and of migraine on CGRP-dependent changes in dermal blood flow (DBF). Methods CGRP-dependent increases in DBF were assessed using laser Doppler perfusion imaging after topical application of 300 or 1000 µg capsaicin on the forearm of healthy subjects and migraine patients. Results In healthy males, DBF response did not vary over time and was comparable with DBF in male migraineurs. In healthy females, capsaicin-induced DBF responses to both doses of capsaicin were higher during menstruation compared to the late-secretory phase (p < 0.05); this menstrual cycle dependence was absent in female migraine patients. Compared to healthy subjects, female migraineurs displayed a higher DBF response both during menstruation and during the late-secretory phase (p < 0.05). Conclusions An increased capsaicin-induced, CGRP-mediated DBF response was observed during menstruation in healthy women, but in female migraine patients this increased response was not affected by the menstrual cycle.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Trastornos Migrañosos/fisiopatología , Piel/irrigación sanguínea , Adulto , Capsaicina/farmacología , Femenino , Humanos , Flujometría por Láser-Doppler , Masculino , Ciclo Menstrual , Trastornos Migrañosos/metabolismo , Fármacos del Sistema Sensorial/farmacología , Piel/efectos de los fármacos , Piel/metabolismo , Vasodilatación/efectos de los fármacos , Adulto Joven
16.
Br J Clin Pharmacol ; 83(3): 603-611, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27685892

RESUMEN

AIM: To develop a non-invasive, safe and reproducible target-engagement biomarker for future TRPA1 antagonists in healthy volunteers. METHODS: Dose finding (n = 11): 3%, 10%, and 30% cinnamaldehyde (CA) and placebo (= vehicle) was topically applied on the right forearm. One-way ANOVA with post-hoc Bonferroni was used to compare between doses. Reproducibility: 10% CA doses were topically applied during one visit on both arms (n = 10) or during two visits (n = 23) separated by a washout period of 7 days. CA-induced dermal blood flow (DBF) was assessed by laser Doppler imaging (LDI) at baseline and at 10, 20, 30, 40 and 50 min post-CA. Paired t-test was used to compare between arms or visits. Concordance correlation coefficient (CCC) was calculated to assess reproducibility. Data are expressed as percent change from baseline (mean ± 95% CI). RESULTS: All three doses increased DBF compared to vehicle at all time-points, with the maximum response at 10-20 min post-CA. Dose response was found when comparing AUC0-50min of 30% CA (51 364 ± 8475%*min) with 10% CA (32 239 ± 8034%*min, P = 0.03) and 3% CA (30 226 ± 11 958%*min, P = 0.015). 10% CA was chosen as an effective and safe dose. DBF response to 10% CA was found to be reproducible between arms (AUC0-50min , CCC = 0.91) and visits (AUC0-50min , CCC = 0.83). Based on sample size calculations, this model allows a change in CA-induced DBF of 30-50% to be detected between two independent groups of maximum 10-15 subjects with 80% power. CONCLUSIONS: Evaluation of CA-induced changes in DBF offers a safe, non-invasive and reproducible target-engagement biomarker in vivo in humans to evaluate TRPA1 antagonists.


Asunto(s)
Acroleína/análogos & derivados , Flujo Sanguíneo Regional/efectos de los fármacos , Acroleína/farmacología , Adolescente , Adulto , Biomarcadores , Relación Dosis-Respuesta a Droga , Femenino , Antebrazo/irrigación sanguínea , Humanos , Flujometría por Láser-Doppler , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Piel/irrigación sanguínea , Canal Catiónico TRPA1/agonistas , Adulto Joven
17.
Br J Clin Pharmacol ; 83(9): 1966-1975, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28429492

RESUMEN

AIMS: Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS: Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS: For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS: Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.


Asunto(s)
Peso Corporal , Ketorolaco Trometamina/farmacocinética , Periodo Posparto/sangre , Factores Sexuales , Adulto , Antiinflamatorios no Esteroideos/sangre , Antiinflamatorios no Esteroideos/farmacocinética , Femenino , Humanos , Ketorolaco Trometamina/sangre , Masculino , Metaanálisis como Asunto , Dinámicas no Lineales , Embarazo , Estereoisomerismo , Adulto Joven
18.
Pharm Res ; 34(9): 1784-1795, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28593473

RESUMEN

PURPOSE: Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. METHODS: Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated. RESULTS: Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87-91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF. CONCLUSIONS: Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.


Asunto(s)
Anticuerpos Monoclonales/sangre , Anticuerpos Monoclonales/farmacología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Capsaicina/farmacología , Trastornos Migrañosos/tratamiento farmacológico , Fármacos del Sistema Sensorial/farmacología , Piel/irrigación sanguínea , Adulto , Anticuerpos Monoclonales Humanizados , Femenino , Humanos , Masculino , Trastornos Migrañosos/fisiopatología , Modelos Biológicos , Adulto Joven
20.
Br J Clin Pharmacol ; 82(5): 1325-1332, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27367040

RESUMEN

AIMS: Roux-en-Y gastric bypass (RYGB) alters the anatomical structure of the gastrointestinal tract, which can result in alterations in drug disposition. The aim of the present study was to evaluate the oral disposition of two compounds belonging to the Biopharmaceutical Classification System Class II - fenofibrate (bile salt-dependent solubility) and posaconazole (gastric pH-dependent dissolution) - before and after RYGB in the same individuals. METHODS: A single-dose pharmacokinetic study with two model compounds - namely, 67 mg fenofibrate (Lipanthyl®) and 400 mg posaconazole (Noxafil®) - was performed in 12 volunteers pre- and post-RYGB. After oral administration, blood samples were collected at different time points up to 48 h after administration. Plasma concentrations were determined by high-performance liquid chromatography in order to calculate the area under the concentration-time curve up to 48 h (AUC0-48 h ), the peak plasma concentration (Cmax) and the time to reach peak concentration (Tmax ). RESULTS: After administration of fenofibrate, no relevant differences in AUC0-48 h , Cmax and Tmax between the pre- and postoperative setting were observed. The geometric mean of the ratio of AUC0-48 h post/pre-RYGB for fenofibrate was 1.10 [95% confidence interval (CI) 0.87, 1.40; P = 0.40]. For posaconazole, an important decrease in AUC0-48 h and Cmax following RYGB was shown; the geometric mean of the AUC0-48 h post/pre-RYGB ratio was 0.68 (95% CI 0.48, 0.96; P = 0.03) and the geometric mean of the Cmax pre/post-RYGB ratio was 0.60 (95% CI 0.39, 0.94; P = 0.03). The decreased exposure of posaconazole could be explained by the increased gastric pH and accelerated gastric emptying of fluids post-RYGB. No difference for Tmax was observed. CONCLUSIONS: The disposition of fenofibrate was not altered after RYGB, whereas the oral disposition of posaconazole was significantly decreased following RYGB.


Asunto(s)
Área Bajo la Curva , Fenofibrato/farmacocinética , Derivación Gástrica , Triazoles/farmacocinética , Administración Oral , Fenofibrato/administración & dosificación , Fenofibrato/sangre , Triazoles/administración & dosificación , Triazoles/sangre
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