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The realization of sustainable and cheap Mg-S batteries depends on significant improvements in cycling stability. Building on the immense research on cathode optimization from Li-S batteries, for the first time a beneficial role of MXenes for Mg-S batteries is reported. Through a facile, low-temperature vacuum-filtration technique, several novel current collector- and binder-free cathode films were developed, with either dipenthamethylene thiuram tetrasulfide (PMTT) or S8 nanoparticles as the source of redox-active sulfur. The importance of combining MXene with a high surface area co-host material, such as carbon nanotubes, was demonstrated. A positive effect of MXenes on the average voltage and reduced self-discharge was also discovered. Ascribed to the rich polar surface chemistry of Ti3 C2 Tx MXene, an almost doubling of the discharge capacity (530 vs. 290â mA h g-1 ) was achieved by using MXene as a polysulfide-confining interlayer, obtaining a capacity retention of 83 % after 25 cycles.
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Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.
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Acetilcolina/metabolismo , Cuerpo Estriado , Trastornos de Alimentación y de la Ingestión de Alimentos/metabolismo , Ácido Glutámico/metabolismo , Interneuronas/metabolismo , Adulto , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Donepezilo/farmacología , Conducta Alimentaria/efectos de los fármacos , Trastornos de Alimentación y de la Ingestión de Alimentos/tratamiento farmacológico , Trastornos de Alimentación y de la Ingestión de Alimentos/genética , Trastornos de Alimentación y de la Ingestión de Alimentos/fisiopatología , Femenino , Humanos , Levodopa/farmacología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteínas de Transporte Vesicular de Acetilcolina/genética , Proteínas de Transporte Vesicular de Acetilcolina/metabolismoRESUMEN
BACKGROUND & AIMS: Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. METHODS: We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. RESULTS: Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.
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5-Hidroxitriptófano/administración & dosificación , Estreñimiento/tratamiento farmacológico , Depresión/tratamiento farmacológico , Tracto Gastrointestinal/fisiopatología , Serotonina/metabolismo , Animales , Estreñimiento/etiología , Estreñimiento/fisiopatología , Preparaciones de Acción Retardada/administración & dosificación , Depresión/complicaciones , Depresión/genética , Depresión/fisiopatología , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/efectos de los fármacos , Sistema Nervioso Entérico/fisiopatología , Femenino , Motilidad Gastrointestinal/efectos de los fármacos , Motilidad Gastrointestinal/fisiología , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/inervación , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Resultado del Tratamiento , Triptófano Hidroxilasa/genética , Triptófano Hidroxilasa/metabolismoRESUMEN
5-hydroxytryptophan (5-HTP) has shown therapeutic promise in a range of human CNS disorders. But native 5-HTP immediate release (IR) is poorly druggable, as rapid absorption causes rapid onset of adverse events, and rapid elimination causes fluctuating exposure. Recently, we reported that 5-HTP delivered as slow-release (SR) in mice augmented the brain pro-serotonergic effect of selective serotonin reuptake inhibitors (SSRIs), without the usual adverse events associated with 5-HTP IR. However, our previous study entailed translational limitations, in terms of route, dose, and duration. Here we modeled oral 5-HTP SR in mice by administering 5-HTP via the food. We modeled oral SSRI treatment via fluoxetine in the water, in a regimen recapitulating clinical pharmacokinetics and pharmacodynamics. 5-HTP SR produced plasma 5-HTP levels well within the range enhancing brain 5-HT function in humans. 5-HTP SR robustly increased brain 5-HT synthesis and levels. When administered with an SSRI, 5-HTP SR enhanced 5-HT-sensitive behaviors and neurotrophic mRNA expression. 5-HTP SR's pro-serotonergic effects were stronger in mice with endogenous brain 5-HT deficiency. In a comprehensive screen, 5-HTP SR was devoid of overt toxicological effects. The present preclinical data, appreciated in the context of published 5-HTP clinical data, suggest that 5-HTP SR could represent a new therapeutic approach to the plethora of CNS disorders potentially treatable with a pro-serotonergic drug. 5-HTP SR might in particular be therapeutically relevant when brain 5-HT deficiency is pathogenic and as an adjunctive augmentation therapy to SSRI therapy.
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5-Hidroxitriptófano/farmacología , 5-Hidroxitriptófano/administración & dosificación , 5-Hidroxitriptófano/análisis , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Química Encefálica , Femenino , Fluoxetina/farmacología , Masculino , Ratones Transgénicos , Prueba de Estudio Conceptual , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Importance: Phase 3 trials have not compared oral semaglutide, a glucagon-like peptide 1 receptor agonist, with other classes of glucose-lowering therapy. Objective: To compare efficacy and assess long-term adverse event profiles of once-daily oral semaglutide vs sitagliptin, 100 mg added on to metformin with or without sulfonylurea, in patients with type 2 diabetes. Design, Setting, and Participants: Randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Of 2463 patients screened, 1864 adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea were randomized. Interventions: Patients were randomized to receive once-daily oral semaglutide, 3 mg (n = 466), 7 mg (n = 466), or 14 mg (n = 465), or sitagliptin, 100 mg (n = 467). Semaglutide was initiated at 3 mg/d and escalated every 4 weeks, first to 7 mg/d then to 14 mg/d, until the randomized dosage was achieved. Main Outcomes and Measures: The primary end point was change in glycated hemoglobin (HbA1c), and the key secondary end point was change in body weight, both from baseline to week 26. Both were assessed at weeks 52 and 78 as additional secondary end points. End points were tested for noninferiority with respect to HbA1c (noninferiority margin, 0.3%) prior to testing for superiority of HbA1c and body weight. Results: Among 1864 patients randomized (mean age, 58 [SD, 10] years; mean baseline HbA1c, 8.3% [SD, 0.9%]; mean body mass index, 32.5 [SD, 6.4]; n=879 [47.2%] women), 1758 (94.3%) completed the trial and 298 prematurely discontinued treatment (16.7% for semaglutide, 3 mg/d; 15.0% for semaglutide, 7 mg/d; 19.1% for semaglutide, 14 mg/d; and 13.1% for sitagliptin). Semaglutide, 7 and 14 mg/d, compared with sitagliptin, significantly reduced HbA1c (differences, -0.3% [95% CI, -0.4% to -0.1%] and -0.5% [95% CI, -0.6% to -0.4%], respectively; P < .001 for both) and body weight (differences, -1.6 kg [95% CI, -2.0 to -1.1 kg] and -2.5 kg [95% CI, -3.0 to -2.0 kg], respectively; P < .001 for both) from baseline to week 26. Noninferiority of semaglutide, 3 mg/d, with respect to HbA1c was not demonstrated. Week 78 reductions in both end points were statistically significantly greater with semaglutide, 14 mg/d, vs sitagliptin. Conclusions and Relevance: Among adults with type 2 diabetes uncontrolled with metformin with or without sulfonylurea, oral semaglutide, 7 mg/d and 14 mg/d, compared with sitagliptin, resulted in significantly greater reductions in HbA1c over 26 weeks, but there was no significant benefit with the 3-mg/d dosage. Further research is needed to assess effectiveness in a clinical setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02607865.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón/agonistas , Péptidos Similares al Glucagón/administración & dosificación , Hipoglucemiantes/administración & dosificación , Fosfato de Sitagliptina/administración & dosificación , Administración Oral , Adulto , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Péptidos Similares al Glucagón/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Fosfato de Sitagliptina/efectos adversos , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
INTRODUCTION: Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for the once-weekly treatment of type 2 diabetes. The objective of this 16-week, double-blind, single-center thorough QT study was to confirm that semaglutide treatment does not prolong cardiac repolarization versus placebo. Prolongation of the QT interval is a biomarker for ventricular tachyarrhythmia. METHODS: In a parallel design, 168 healthy subjects were randomized to the treatment or placebo arms, of whom 166 were treated with subcutaneous semaglutide (N = 83; escalated to a supratherapeutic dose of 1.5 mg) or placebo (N = 83). The subjects (60% males) had a mean age of 38.2 years and body mass index of 25.1 kg/m2. To assess QT assay sensitivity, subjects in the placebo group received a single 400 mg moxifloxacin dose as positive control, and placebo in a crossover fashion. The primary endpoint was the time-matched change from baseline in QT interval corrected individually for heart rate (ΔQTcI), calculated from 11 electrocardiogram recordings from 0 to 48 h after the last 1.5 mg dose. Similar assessments were made for the therapeutic 0.5 and 1.0 mg semaglutide dose levels. RESULTS: No QTcI prolongation occurred with any semaglutide dose; the upper limits of two-sided 90% confidence intervals of the placebo-subtracted ΔQTcI were < 10 ms at all doses and time points. Exposure-response analysis showed no dependence of QTcI on semaglutide concentration. QT assay sensitivity was confirmed. The semaglutide safety profile was similar to that of other GLP-1 receptor agonists. CONCLUSION: Based on investigations of QT/QTc, no concern with regard to ventricular arrhythmias was raised as semaglutide did not prolong the cardiac repolarization duration in healthy subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT 02064348. FUNDING: Novo Nordisk.
RESUMEN
Synaptic cell adhesion molecules represent important targets for neuronal activity-dependent proteolysis. Postsynaptic neuroligins (NLs) form trans-synaptic complexes with presynaptic neurexins (NXs). Both NXs and NLs are cleaved from the cell surface by metalloproteases in an activity-dependent manner, releasing a soluble extracellular fragment and membrane-tethered C-terminal fragment. The cleavage of NL1 depresses synaptic transmission, but the mechanism by which this occurs is unknown. Metabotropic glutamate receptor 2 (mGluR2) are located primarily at the periphery of presynaptic terminals, where they inhibit the formation of cyclic adenosine monophosphate (cAMP) and consequently suppress the release of glutamate and decrease synaptic transmission. In the present study, we found that the soluble ectodomain of NL1 binds to and activates mGluR2 in both neurons and heterologous cells, resulting in a decrease in cAMP formation. In a slice preparation from the hippocampus of mice, NL1 inhibited the release of glutamate from mossy fibers that project to CA3 pyramidal neurons. The presynaptic effect of NL1 was abolished in the presence of a selective antagonist for mGluR2. Thus, our data suggest that the soluble extracellular domain of NL1 functionally interacts with mGluR2 and thereby decreases synaptic strength.
RESUMEN
AIMS/HYPOTHESIS: Semaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed. METHODS: In this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18-64 years) participants with type 2 diabetes (eligibility: HbA1c of 6.5-9.0% (47.5-74.9 mmol/mol); BMI 20.0-35.0 kg/m2; and treatment with diet and exercise and/or metformin monotherapy with a dose unchanged in the 30 days prior to screening) were randomised (1:1) to once-weekly s.c. semaglutide 1.0 mg (0.25, 0.5, 1.0 mg escalated) or placebo for 12 weeks. Co-primary endpoints were changes from baseline to end of treatment in the first (AUC0-10 min) and second (AUC10-120 min) insulin secretion phases, as measured by the IVGTT. An arginine stimulation test (AST) and a 24 h meal stimulation test were also conducted. A graded glucose infusion test (GGIT) assessed insulin secretion rate (ISR) in treated participants and a group of untreated healthy participants. Safety endpoints were also assessed. RESULTS: In total, 37 participants received semaglutide and 38 received placebo. Following IVGTT, for insulin, both AUC0-10min and AUC10-120min were significantly increased with semaglutide (estimated treatment ratio [95% CI] 3.02 [2.53, 3.60] and 2.10 [1.86, 2.37], respectively; p < 0.0001). The 24 h meal test showed reduced fasting, postprandial and overall (AUC0-24h) glucose and glucagon responses with semaglutide (p < 0.0001). The AST showed that maximal insulin capacity increased following semaglutide treatment. During GGIT, semaglutide significantly increased ISR to levels similar to those in healthy participants. Semaglutide was well tolerated. CONCLUSIONS/INTERPRETATION: Twelve weeks of once-weekly treatment with semaglutide significantly improved beta cell function and glycaemic control in participants with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02212067 FUNDING: The study was funded by Novo Nordisk A/S.
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Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptidos Similares al Glucagón/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Adolescente , Adulto , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Metformina/administración & dosificación , Metformina/uso terapéutico , Persona de Mediana Edad , Embarazo , Adulto JovenRESUMEN
BACKGROUND: The pharmacokinetics and tolerability of semaglutide, a once-weekly human glucagon-like peptide-1 analog in development for the treatment of type 2 diabetes mellitus, were investigated in subjects with/without renal impairment (RI). METHODS: Fifty-six subjects, categorized into renal function groups [normal, mild, moderate, severe, and end-stage renal disease (ESRD)], received a single subcutaneous dose of semaglutide 0.5 mg. Semaglutide plasma concentrations were assessed ≤480 h post-dose; the primary endpoint was the area under the plasma concentration-time curve from time zero to infinity. RESULTS: Semaglutide exposure in subjects with mild/moderate RI and ESRD was similar to that in subjects with normal renal function. In subjects with severe RI, the mean exposure of semaglutide was 22% higher than in subjects with normal renal function, and the 95% confidence interval (1.02-1.47) for the ratio exceeded the pre-specified limits (0.70-1.43). When adjusted for differences in sex, age, and body weight between the groups, all comparisons were within the pre-specified clinically relevant limits. Across RI groups there was no relationship between creatinine clearance (CLCR) and semaglutide exposure, or between CLCR and semaglutide maximum plasma drug concentration (C max). Hemodialysis did not appear to affect the pharmacokinetics of semaglutide. No appreciable changes in safety parameters or vital signs and no serious adverse events were noted. One subject with severe RI reported two major hypoglycemic events. CONCLUSION: When adjusted for differences in sex, age, and body weight, semaglutide exposure was similar between subjects with RI and subjects with normal renal function. Semaglutide (0.5 mg) was well-tolerated. Dose adjustment may not be warranted for subjects with RI. CLINICALTRIALS. GOV IDENTIFIER: NCT00833716.
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Péptido 1 Similar al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/efectos adversos , Péptidos Similares al Glucagón/farmacocinética , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Insuficiencia Renal/complicaciones , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/sangre , Humanos , Hipoglucemiantes/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Renal/sangre , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Semaglutide is a glucagon-like peptide-1 analogue in development for the once-weekly treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (metformin, warfarin, atorvastatin and digoxin) was evaluated in healthy subjects. METHODS: Subjects received metformin (500 mg twice daily for 3.5 days), warfarin (25 mg, single dose), atorvastatin (40 mg, single dose) or digoxin (0.5 mg, single dose) before and with subcutaneous semaglutide treatment at steady state (1.0 mg). Lack of drug-drug interaction was concluded if the 90% confidence intervals for the area under the plasma concentration-time curve ratio before and with semaglutide were within a pre-specified interval (0.80-1.25). RESULTS: Overall, metformin, warfarin, atorvastatin and digoxin pharmacokinetics were not affected to a clinically relevant degree with semaglutide co-administration. Estimated area under the plasma concentration-time curve ratios for all concomitant medications before and with semaglutide treatment were within the pre-specified interval. In addition, semaglutide did not affect maximum plasma concentration of concomitant medications to a relevant degree. Furthermore, no clinically relevant change in international normalised ratio response to warfarin was observed with semaglutide co-administration. Most adverse events with semaglutide treatment were mild or moderate. Adverse events with semaglutide and co-administered medication were comparable to those reported during treatment with semaglutide alone, and were mostly gastrointestinal related. CONCLUSIONS: No clinically significant pharmacokinetic or pharmacodynamic interactions were identified and no new safety issues observed with combined treatment with semaglutide. This suggests that no dose adjustments should be required when semaglutide is administered concomitantly with these medications.
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Atorvastatina/farmacocinética , Digoxina/farmacocinética , Péptidos Similares al Glucagón/farmacología , Metformina/farmacocinética , Warfarina/farmacocinética , Adolescente , Adulto , Atorvastatina/administración & dosificación , Atorvastatina/sangre , Estudios Cruzados , Digoxina/sangre , Interacciones Farmacológicas , Quimioterapia Combinada/efectos adversos , Femenino , Péptidos Similares al Glucagón/administración & dosificación , Péptidos Similares al Glucagón/análogos & derivados , Voluntarios Sanos , Humanos , Hipoglucemiantes/farmacología , Masculino , Metformina/administración & dosificación , Metformina/sangre , Persona de Mediana Edad , Warfarina/administración & dosificación , Warfarina/sangre , Adulto JovenRESUMEN
BACKGROUND: Due to population aging, an increasing number of elderly patients with diabetes use insulin. It is therefore important to investigate the characteristics of new insulins in this population. Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with faster absorption. This study investigated the pharmacological properties of faster aspart in elderly subjects with type 1 diabetes mellitus (T1DM). METHODS: In a randomised, double-blind, two-period crossover trial, 30 elderly (≥65 years) and 37 younger adults (18-35 years) with T1DM received single subcutaneous faster aspart or IAsp dosing (0.2 U/kg) and underwent an euglycaemic clamp (target 5.5 mmol/L) for up to 12 h. RESULTS: The pharmacokinetic and pharmacodynamic time profiles were left-shifted for faster aspart versus IAsp. In each age group, onset of appearance occurred approximately twice as fast (~3 min earlier) and early exposure (area under the concentration-time curve [AUC] for serum IAsp from time zero to 30 min [AUCIAsp,0-30 min]) was greater (by 86% in elderly and 67% in younger adults) for faster aspart than for IAsp. Likewise, onset of action occurred 10 min faster in the elderly and 9 min faster in younger adults, and early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 30 min [AUCGIR,0-30 min]) was greater (by 109%) for faster aspart than for IAsp in both age groups. Total exposure (AUCIAsp,0-t) and the maximum concentration (C max) for faster aspart were greater (by 30 and 28%, respectively) in elderly than in younger adults. No age group differences were seen for the total (AUCGIR,0-t) or maximum (GIRmax) glucose-lowering effect. CONCLUSION: This study demonstrated that the ultra-fast pharmacological properties of faster aspart are similar in elderly subjects and younger adults with T1DM. ClinicalTrials.gov Identifier: NCT02003677.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Insulina Aspart/farmacocinética , Insulina Aspart/uso terapéutico , Adolescente , Adulto , Anciano , Envejecimiento/sangre , Envejecimiento/efectos de los fármacos , Glucemia/análisis , Química Farmacéutica , Estudios Cruzados , Diabetes Mellitus Tipo 1/sangre , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Insulina Aspart/administración & dosificación , Insulina Aspart/química , Insulina de Acción Corta/administración & dosificación , Insulina de Acción Corta/química , Insulina de Acción Corta/farmacocinética , Insulina de Acción Corta/uso terapéutico , Masculino , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Absorption of current rapid-acting insulins is too slow for patients with diabetes mellitus to achieve optimal postprandial glucose control. Faster-acting insulin aspart (faster aspart) is insulin aspart in a new formulation with faster early absorption. We compared the pharmacokinetic/pharmacodynamic properties of faster aspart and insulin aspart across a clinically relevant dose range. METHODS: In this randomised, double-blind, crossover trial, 46 subjects with type 1 diabetes mellitus received single subcutaneous doses of faster aspart and insulin aspart at 0.1, 0.2 (repeated three times to estimate within-subject variability) and 0.4 U/kg in a euglycaemic clamp setting (target 5.5 mmol/L). RESULTS: Consistently for the three doses, faster aspart demonstrated faster onset and greater early absorption and glucose-lowering effect versus insulin aspart. Across all three doses, onset of appearance occurred approximately twice as fast (approximately 5 min earlier) and early insulin exposure (AUCIAsp,0-30min) was approximately 1.5- to 2-fold greater for faster aspart versus insulin aspart. Likewise, onset of action occurred approximately 5 min faster and early glucose-lowering effect (AUCGIR,0-30min) was approximately 1.5- to 2-fold larger for faster aspart versus insulin aspart. Relative bioavailability was approximately 100% and total glucose-lowering effect was similar for faster aspart versus insulin aspart. Dose-concentration and dose-response relationships were comparable between faster aspart and insulin aspart. Within-subject variability in glucose-lowering effect was low for faster aspart (coefficient of variation approximately 20%) and not significantly different from insulin aspart. CONCLUSION: The faster onset and greater early insulin exposure and glucose-lowering effect with faster aspart versus insulin aspart are preserved across a broad range of doses and consistently observed from day to day. CLINICALTRIALS. GOV IDENTIFIER: NCT02033239.
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Diabetes Mellitus Tipo 1/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinética , Insulina Aspart/farmacología , Insulina Aspart/farmacocinética , Adulto , Glucemia/efectos de los fármacos , Estudios Cruzados , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Insulina Aspart/administración & dosificación , Insulina Aspart/sangre , Masculino , Persona de Mediana EdadRESUMEN
Serotonin transporter (SERT) inhibitors treat depression by elevating brain extracellular 5-hydroxytryptamine (5-HTExt). However, only one-third of patients respond adequately. Treatment-resistant depression (TRD) is a major unmet need. Interestingly, elevating 5-HTExt beyond what is achieved by a SERT inhibitor appears to treat TRD. Adjunctive administration of 5-hydroxytryptophan (5-HTP) safely elevates 5-HTExt beyond the SERT inhibitor effect in humans; however, 5-HTP cannot be a clinically viable drug because of its poor pharmacokinetics. A slow-release (SR) delivery mode would be predicted to overcome the pharmacokinetic limitations of 5-HTP, substantially enhancing the pharmacological action and transforming 5-HTP into a clinically viable drug. Animal studies bear out this prediction. Thus, adjunct 5-HTP SR could be an important new treatment for TRD. Here, we review the clinical and preclinical evidence for this treatment.
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5-Hidroxitriptófano/administración & dosificación , Antidepresivos de Segunda Generación/administración & dosificación , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , 5-Hidroxitriptófano/farmacocinética , 5-Hidroxitriptófano/farmacología , Animales , Antidepresivos de Segunda Generación/farmacocinética , Antidepresivos de Segunda Generación/farmacología , Preparaciones de Acción Retardada , Trastorno Depresivo Resistente al Tratamiento/fisiopatología , Humanos , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HTExt) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HTExt beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HTExt beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HTExt elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HTExt elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HTExt beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HTExt spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HTExt beyond the SSRI effect and represent a novel treatment for TRD.
Asunto(s)
5-Hidroxitriptófano/farmacología , Encéfalo/efectos de los fármacos , Fluoxetina/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Serotonina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Femenino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacosRESUMEN
OBJECTIVES: Since population-based data on prognostic factors affecting survival in patients with breast cancer with bone metastasis (BM) are currently limited, we conducted this nationwide retrospective cohort study to examine the prognostic role of disease stage at breast cancer diagnosis and length of BM-free interval (BMFI). SETTING: Denmark. PARTICIPANTS: 2427 women with a breast cancer diagnosis between 1997 and 2011 in the Danish Cancer Registry and a concurrent or subsequent BM diagnosis in the Danish National Registry of Patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Survival (crude) based on Kaplan-Meier method and mortality risk (crude and adjusted for age, year of diagnosis, estrogen receptor status and comorbidity) based on Cox proportional hazards regression analyses by stage of disease at breast cancer diagnosis and by length of BMFI (time from breast cancer to BM diagnosis), following patients from BM diagnosis until death, emigration or until 31 December 2012, whichever came first. RESULTS: Survival decreased with more advanced stage of disease at the time of breast cancer diagnosis; risk of mortality during the first year following a BM diagnosis was over two times higher for those presenting with metastatic versus localised disease (adjusted HR=2.12 (95% CI 1.71 to 2.62)). With respect to length of BMFI, survival was highest in women with a BMFI <1â year (ie, in those who presented with BM at the time of breast cancer diagnosis or were diagnosed within 1â year). However, among patients with a BMFI ≥1â year, survival increased with longer BMFI (1-year survival: 39.9% (95% CI 36.3% to 43.6%) for BMFI 1 to <3â years and 52.6% (95% CI 47.4% to 57.6%) for BMFI ≥5â years). This pattern was also observed in multivariate analyses. CONCLUSIONS: Stage of disease at breast cancer diagnosis and length of BMFI appear to be important prognostic factors for survival following BM.
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Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/terapia , Dinamarca , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study was to investigate how prostate cancer treatment varies by level of comorbidity among men with localized prostate cancer. MATERIALS AND METHODS: A nationwide cohort study was conducted of all patients younger than 75 years of age with incident localized prostate cancer registered in the Danish Cancer Registry from 1 October 2003 to 31 December 2010. Number and percentages were tabulated, and the prevalence ratios were calculated of patients treated with radical prostatectomy or radiotherapy during the first year after prostate cancer diagnosis according to comorbidity level at the time of prostate cancer diagnosis. RESULTS: The study included 9643 patients, of whom 79% (7576) had no comorbidity, 10% (979) had a Charlson comorbidity index score of 1, 8% (779) had a Charlson score of 2, and 3% (309) had a Charlson score of 3 or more. The cumulative 1 year incidences of prostatectomies were 41%, 23% and 13% among those with Charlson scores of 0, 1-2 and ≥ 3, respectively. This corresponded to 1 year prevalence ratios of 0.60 [95% confidence interval (CI) 0.54-0.67] and 0.33 (95% CI 0.25-0.44) for patients with Charlson scores of 1-2 and ≥ 3, respectively, compared with patients with Charlson 0. The cumulative 1 year incidence of radiotherapy did not differ much by Charlson score. The 1 year prevalence ratios of radiotherapy were 1.27 (95% CI, 1.12-1.45) and 1.10 (95% CI 0.94-1.28) for patients with Charlson scores of 1 and ≥ 2, respectively, compared with patients with Charlson 0. CONCLUSION: The results show that patients with comorbidity were treated less aggressively for their localized prostate cancer than patients without comorbidity.
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Próstata/patología , Prostatectomía/estadística & datos numéricos , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/terapia , Adulto , Anciano , Estudios de Cohortes , Comorbilidad , Dinamarca , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Pronóstico , Próstata/cirugía , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Sistema de Registros , Medición de Riesgo , Espera VigilanteRESUMEN
PURPOSE: The aim of this study was to quantify the effect of the look back period on the misclassification of new users of antibiotics and asthma medications. METHODS: We included all children born in Denmark from 1995 through 2006 and all prescriptions of antibiotics and asthma medication from 1995 through 2011. The study period was 2007 through 2011. True new users redeemed their first prescription in the study period whereas prior users redeemed their first prescription before the study period. Look-back periods ranged from 30 days up to 12 years prior to the study period, and we defined new users as those without a prescription in the look-back period. The relative misclassification (RM) was estimated as the number of defined new users divided by the number of true new users. RESULTS: For antibiotics, the RM decreased from 4.75 for look-back periods of 30 days to 2.36 for 2 years and 1.33 for 5 years. For asthma medication, the RM decreased from 2.53 for look-back periods of 30 days to 1.48 for 2 years and 1.20 for 5 years. Older age, male gender, and absence of treatment-related diagnoses were associated with higher RM. CONCLUSIONS: Studies applying the new user design are strongly dependent on the available information on prescriptions. For drug classes with intermittent use such as asthma medications, even a 2-year look-back period produced severe misclassification. Excluding children with a prior treatment-related diagnosis can reduce the level of misclassification.
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Antiasmáticos/administración & dosificación , Antibacterianos/administración & dosificación , Revisión de la Utilización de Medicamentos/estadística & datos numéricos , Farmacoepidemiología/métodos , Niño , Preescolar , Estudios de Cohortes , Dinamarca , Femenino , Humanos , Masculino , Farmacoepidemiología/estadística & datos numéricos , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND AND STUDY AIMS: Self-expanding metal stents (SEMS) used as a bridge to surgery for obstructive colorectal cancer (CRC) have fallen under suspicion for inducing tumor dissemination, and thereby increasing recurrence risk and long-term mortality. The aim of this study was to compare overall mortality and CRC recurrence in patients receiving preoperative SEMS vs. patients undergoing urgent resection. PATIENTS AND METHODS: This was a Danish, nationwide, population-based cohort study (2005â-â2010). For patients with CRC who survived the first 30 days after resection, the long-term survival in terms of mortality rate ratios was assessed using Cox regression with adjustment for important covariates. For patients with Dukes' Aâ-âC disease only, recurrence risk was similarly assessed using incidence rate ratios. RESULTS: The 5-year survival was 49â% among 581 patients with preoperative SEMS and 40â% among 3333 patients undergoing urgent resection, corresponding to an adjusted mortality rate ratio of 0.98 (95â% confidence interval [CI] 0.90 to 1.07). For patients with Dukes' stage Aâ-âC disease, the 5-year recurrence risk was 39â% among 286 patients after preoperative SEMS and 30â% among 1627 patients after urgent resection, corresponding to an adjusted incidence rate ratio of 1.12 (95â%CI 0.99 to 1.28). CONCLUSIONS: Long-term mortality associated with the use of SEMS as a bridge to surgery was comparable to that of urgent resection. SEMS use may be associated with an increased CRC recurrence risk.