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1.
Diabetes Obes Metab ; 22(11): 2133-2140, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32627316

RESUMO

AIM: To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS). MATERIALS AND METHODS: Individuals aged 12 years and older with BBS received once-daily setmelanotide. The dose was titrated every 2 weeks to establish the individual therapeutic dose (≤3 mg); treatment continued for an additional 10 weeks. Participants who lost 5 kg or more (or ≥5% of body weight if <100 kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes. RESULTS: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12 months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points. CONCLUSIONS: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.


Assuntos
Síndrome de Bardet-Biedl , Receptor Tipo 4 de Melanocortina , Síndrome de Bardet-Biedl/tratamento farmacológico , Síndrome de Bardet-Biedl/epidemiologia , Humanos , Obesidade/complicações , Obesidade/tratamento farmacológico , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
2.
Inorg Chem ; 59(2): 980-983, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31909612

RESUMO

A rotorlike supramolecular crystal, {[K(18-crown-6)]PbI3}∞, is composed of a linear [PbI3]∞ chain acting as a stator and [K(18-crown-6)]+ cations fastened to the [PbI3]∞ chain and K-I bond like rotators and axes, respectively. A reversible breaking-symmetry phase transition occurs at ∼305 K. Variable-temperature 1H NMR spectra and dielectrics were used for the dynamic analysis of [K(18-crown-6)]+ cations in the crystal.

3.
Inorg Chem ; 56(16): 9525-9534, 2017 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-28783354

RESUMO

In this study, we used the facile solvent evaporation method to achieve the inorganic-organic hybrid crystals of [triethylpropylammonium][PbI3], which have been characterized by elemental analysis, IR spectroscopy, thermogravimetric analysis, and differential scanning calorimetry as well as single-crystal X-ray structure analysis. The hybrid solid crystallizes in the monoclinic space group P21/c at room temperature and is composed of one-dimensional [PbI3]∞ chains, where the neighboring PbI6 coordination octahedra connect together via the face-sharing mode and the organic cations fall in the spaces between [PbI3]∞ chains. The hybrid exhibits a dielectric phase transition with a critical temperature of ca. 432 K, dielectric relaxation at frequencies below 107 Hz, and single-ion conducting behavior, the conductivity of which increases rapidly from 9.43 × 10-10 S cm-1 at 383 K to 4.47 × 10-5 S cm-1 at 473 K. The variable-temperature single-crystal and powder X-ray diffraction analyses revealed that the dielectric phase transition is related to the disorder-to-order transformation of cations in the lattice. The electric modulus and impedance spectral analyses further disclosed that the dielectric relaxation arises from the ionic displacement polarization and molecular dipole orientation of cations. The single-ion conductance is due to the migration of cations that fall in the spaces of rigid inorganic [PbI3]∞ chains. The phase transition gives rise to this hybrid showing switchable ion-conducting nature around the critical temperature of the phase transition. Besides the fascinating functionalities mentioned above, the hybrid also exhibits a thermochromic luminescence feature originating from the electron transition between the valence and conduction bands of the inorganic [PbI3]∞ chain.

4.
Lancet ; 385(9981): 1949-56, 2015 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-25931244

RESUMO

BACKGROUND: Treatment of complicated urinary-tract infections is challenging due to rising antimicrobial resistance. We assessed the efficacy and safety of ceftolozane-tazobactam, a novel antibacterial with Gram-negative activity, in the treatment of patients with complicated lower-urinary-tract infections or pyelonephritis. METHODS: ASPECT-cUTI was a randomised, double-blind, double-dummy, non-inferiority trial done in 209 centres in 25 countries. Between July, 2011, and September, 2013, hospital inpatients aged 18 years or older who had pyuria and a diagnosis of a complicated lower-urinary-tract infection or pyelonephritis were randomly assigned in a 1:1 ratio to receive intravenous 1·5 g ceftolozane-tazobactam every 8 h or intravenous high-dose (750 mg) levofloxacin once daily for 7 days. The randomisation schedule was computer generated in blocks of four and stratified by study site. The next allocation was obtained by the study site pharmacist via an interactive voice-response system. The primary endpoint was a composite of microbiological eradication and clinical cure 5-9 days after treatment in the microbiological modified intention-to-treat (MITT) population, with a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, numbers NCT01345929 and NCT01345955. FINDINGS: Of 1083 patients enrolled, 800 (73·9%), of whom 656 (82·0%) had pyelonephritis, were included in the microbiological MITT population. Ceftolozane-tazobactam was non-inferior to levofloxacin for composite cure (306 [76·9%] of 398 vs 275 [68·4%] of 402, 95% CI 2·3-14·6) and, as the lower bound of the two-sided 95% CI around the treatment difference was positive and greater than zero, superiority was indicated. Adverse event profiles were similar in the two treatment groups and were mainly non-serious. INTERPRETATION: Treatment with ceftolozane-tazobactam led to better responses than high-dose levofloxacin in patients with complicated lower-urinary-tract infections or pyelonephritis. FUNDING: Cubist Pharmaceuticals.


Assuntos
Anti-Infecciosos Urinários/administração & dosagem , Cefalosporinas/administração & dosagem , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Levofloxacino/administração & dosagem , Ácido Penicilânico/análogos & derivados , Infecções Urinárias/tratamento farmacológico , Adulto , Idoso , Anti-Infecciosos Urinários/efeitos adversos , Cefalosporinas/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Infusões Intravenosas , Levofloxacino/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/efeitos adversos , Pielonefrite/tratamento farmacológico , Tazobactam , Resultado do Tratamento , Adulto Jovem
5.
Clin Infect Dis ; 60(10): 1462-71, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25670823

RESUMO

BACKGROUND: Increasing antimicrobial resistance among pathogens causing complicated intra-abdominal infections (cIAIs) supports the development of new antimicrobials. Ceftolozane/tazobactam, a novel antimicrobial therapy, is active against multidrug-resistant Pseudomonas aeruginosa and most extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. METHODS: ASPECT-cIAI (Assessment of the Safety Profile and Efficacy of Ceftolozane/Tazobactam in Complicated Intra-abdominal Infections) was a prospective, randomized, double-blind trial. Hospitalized patients with cIAI received either ceftolozane/tazobactam (1.5 g) plus metronidazole (500 mg) every 8 hours or meropenem (1 g) every 8 hours intravenously for 4-14 days. The prospectively defined objectives were to demonstrate statistical noninferiority in clinical cure rates at the test-of-cure visit (24-32 days from start of therapy) in the microbiological intent-to-treat (primary) and microbiologically evaluable (secondary) populations using a noninferiority margin of 10%. Microbiological outcomes and safety were also evaluated. RESULTS: Ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in the primary (83.0% [323/389] vs 87.3% [364/417]; weighted difference, -4.2%; 95% confidence interval [CI], -8.91 to .54) and secondary (94.2% [259/275] vs 94.7% [304/321]; weighted difference, -1.0%; 95% CI, -4.52 to 2.59) endpoints, meeting the prespecified noninferiority margin. In patients with ESBL-producing Enterobacteriaceae, clinical cure rates were 95.8% (23/24) and 88.5% (23/26) in the ceftolozane/tazobactam plus metronidazole and meropenem groups, respectively, and 100% (13/13) and 72.7% (8/11) in patients with CTX-M-14/15 ESBLs. The frequency of adverse events (AEs) was similar in both treatment groups (44.0% vs 42.7%); the most common AEs in either group were nausea and diarrhea. CONCLUSIONS: Treatment with ceftolozane/tazobactam plus metronidazole was noninferior to meropenem in adult patients with cIAI, including infections caused by multidrug-resistant pathogens. CLINICAL TRIALS REGISTRATION: NCT01445665 and NCT01445678.


Assuntos
Antibacterianos/administração & dosagem , Infecções Bacterianas/tratamento farmacológico , Cefalosporinas/administração & dosagem , Farmacorresistência Bacteriana Múltipla , Infecções Intra-Abdominais/tratamento farmacológico , Metronidazol/administração & dosagem , Ácido Penicilânico/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/microbiologia , Método Duplo-Cego , Quimioterapia Combinada/métodos , Feminino , Humanos , Infecções Intra-Abdominais/microbiologia , Masculino , Pessoa de Meia-Idade , Ácido Penicilânico/administração & dosagem , Estudos Prospectivos , Tazobactam , Resultado do Tratamento , Adulto Jovem
6.
J Affect Disord ; 359: 394-402, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38806066

RESUMO

BACKGROUND: Both depression and constipation are universal disorders that seriously affect quality of life. But the phenotypic relationship and causality between depression and constipation are still unclear. METHODS: We first assessed phenotypic relationships by logistic regression analysis using large-scale data extracted from the National Health and Nutrition Examination Survey (N = 11,585). We then evaluated causality by bidirectional two-sample mendelian randomization (MR) analysis using Genome-wide association study (GWAS) data (depression: N = 807,553; constipation: N = 377,277). To investigate whether depression severity affects the causal relationship between depression and constipation, we conducted a further MR study on GWAS data of major depression (N = 480,359). RESULTS: About 11.31 % of the participants in the constipation group suffered from depression, which was significantly higher than the normal bowel group (6.09 %). The observational study showed a positive correlation between depression and constipation (OR = 1.968, 95%CI = 1.530-2.532). Besides, the risk of constipation was higher in participants with severe depression (OR = 2.294, 95%CI = 1.538-3.422) than in participants with mild depression (OR = 1.549, 95%CI = 1.242-1.932). Bidirectional MR analysis revealed an obviously causal effect of depression on constipation, but no causal effect of constipation on depression. In addition, the MR analysis also revealed a causal relationship between major depression and constipation. LIMITATION: The exact mechanism by which depression affects constipation is still unclear. CONCLUSION: This study reveals a positive correlation between depression and constipation and the causal effect of depression on constipation. Clinicians should keep the risk of constipation in mind when treating patients with depression.


Assuntos
Constipação Intestinal , Depressão , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Constipação Intestinal/epidemiologia , Constipação Intestinal/genética , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Depressão/epidemiologia , Depressão/genética , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/epidemiologia , Inquéritos Nutricionais , Idoso
7.
Dalton Trans ; 53(6): 2687-2695, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38226466

RESUMO

The supramolecular crystals, Mn(15-crown-5)(MnCl4)(DMF), (1; 15-crown-5 = 1,4,7,10,13-pentaoxacyclopentadecane), were synthesized via a self-assembly strategy under ambient conditions. Comprehensive characterization of the crystals involved microanalysis for C, H, and N elements, thermogravimetric (TG) analysis, differential scanning calorimetry (DSC) and single-crystal X-ray diffraction techniques. The results reveal that 1 undergoes a two-step thermotropic and isostructural phase transition at around 217 K and 351 K upon heating. All three phases belong to the same space group (P212121) with analogous cell parameters. These two phase transitions primarily involve the thermally activated ring rotational dynamics of the 15-crown-5 molecule, with only the transition at ca. 351 K being associated with a dielectric anomaly. 1 exhibits intense luminescence with a peak at ∼600 nm and a high quantum yield of 68%. The mechanisms underlying this intense luminescence are likely linked to low-symmetry ligand fields. Additionally, 1 displays phase transition-induced luminescence enhancement behavior, and the possible mechanism is further discussed.

8.
Lancet Diabetes Endocrinol ; 12(6): 380-389, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697184

RESUMO

BACKGROUND: Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. METHODS: This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 3·0 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04725240) and is complete. FINDINGS: Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m2 (SD 6·5). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<0·0001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69-98%; p<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68-100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<0·0001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (NCT03651765), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of -26% (SD 12) from index trial baseline. INTERPRETATION: These findings support setmelanotide as a novel effective treatment of hypothalamic obesity. FUNDING: Rhythm Pharmaceuticals.


Assuntos
Doenças Hipotalâmicas , Obesidade , alfa-MSH , Humanos , Masculino , Feminino , Adulto , Adolescente , Obesidade/tratamento farmacológico , Adulto Jovem , Doenças Hipotalâmicas/tratamento farmacológico , Criança , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico , alfa-MSH/administração & dosagem , Receptor Tipo 4 de Melanocortina/agonistas , Resultado do Tratamento , Índice de Massa Corporal
9.
J Cancer ; 14(3): 417-433, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36860927

RESUMO

Normal somatic cells inevitably experience replicative stress and senescence during proliferation. Somatic cell carcinogenesis can be prevented in part by limiting the reproduction of damaged or old cells and removing them from the cell cycle [1, 2]. However, Cancer cells must overcome the issues of replication pressure and senescence as well as preserve telomere length in order to achieve immortality, in contrast to normal somatic cells [1, 2]. Although telomerase accounts for the bulk of telomere lengthening methods in human cancer cells, there is a non-negligible portion of telomere lengthening pathways that depend on alternative lengthening of telomeres (ALT) [3]. For the selection of novel possible therapeutic targets for ALT-related disorders, a thorough understanding of the molecular biology of these diseases is crucial [4]. The roles of ALT, typical ALT tumor cell traits, the pathophysiology and molecular mechanisms of ALT tumor disorders, such as adrenocortical carcinoma (ACC), are all summarized in this work. Additionally, this research compiles as many of its hypothetically viable but unproven treatment targets as it can (ALT-associated PML bodies (APB), etc.). This review is intended to contribute as much as possible to the development of research, while also trying to provide a partial information for prospective investigations on ALT pathways and associated diseases.

10.
Heliyon ; 9(12): e22686, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38213600

RESUMO

In this present age, innovation has become inextricably tied to both long-term economic growth and environmentally sound development. In this context, the impact that environmentally focused technological advancements or innovations have on environmental quality is of the utmost importance. Therefore, the main goal of the present study is to determine how Green innovation (GI) affects environmental degradation in the BRICS countries from 1992 to 2021. The ecological footprint (EFT) is an indicator used in the study to measure environmental degradation. The study divides the components that contribute to the explanation into two categories: the GI threshold variable and the independent variables RE, GDP, and population (POP). Additionally, this study investigates the indirect impact of RE, GDP, and POP through the threshold effect of GI. The stochastic impacts of the explanatory factors are explored using sophisticated panel data estimation methods and a panel threshold model. According to the findings of the study, an improvement in environmental quality occurs when the threshold level of GI is achieved, which indicates that innovation in the form of a lower EFT is responsible for the improvement. In light of the findings, recommendations for policymakers and stakeholders in BRICS countries are to promote RE and drive GI.

11.
Dalton Trans ; 52(46): 17407-17415, 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-37946582

RESUMO

It is necessary to take full account of the activity, selectivity, dynamic performance, economic benefits, and environmental impact of the catalysts in the overall water splitting of electrocatalysis for the reasonable design of electrocatalysts. Designing nanostructures of catalysts and optimizing defect engineering are considered environmentally friendly and cost-effective electrocatalyst synthesis strategies. Herein, we report that metal cations regulate the microstructure of sea-urchin-like MnO2 and act as dopants to cause the lattice expansion of MnO2, resulting in crystal surface defects. The valence unsaturated Mn4+/Mn3+ greatly promotes the electrocatalytic oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). The optimal Al-MnO2 showed that the overpotential is 390 and 170 mV in the process of catalyzing OER and HER, respectively, at a current density of 10 mA cm-2. It is exciting to note that after 5000 cycles of Al-MnO2 within the kinetic potential range of OER and HER, its performance remained almost unchanged. This work provides a simple, efficient, and environmentally friendly route for the design of efficient integrated water-splitting electrocatalysts.

12.
ACS Appl Mater Interfaces ; 15(12): 15533-15544, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36920420

RESUMO

The rational design of highly efficient and stable electrocatalysts for the oxygen evolution reaction (OER) is an urgent need but remains challenging for various sustainable energy systems. How to adjust the atomic structure and electronic structure of the active center is a key bottleneck problem. Accelerating the electron transfer process and the deep self-reconstruction of active sites could be a cost-effective strategy toward electrocatalytic OER catalyst development. Here, a crystalline-amorphous (c-a) coupled Ni3S2/NiPx electrocatalyst self-supported on nickel foam with an intimate interface was developed via a feasible solvothermal-electrochemistry method. The coupling interface of the crystalline structure with high conductivity and amorphous structure with numerous potential active sites could regulate the electronic structure and optimize the adsorption/desorption of O-containing species, ultimately resulting in high OER catalytic performance. The obtained Ni3S2/NiPx/NF presents a low OER overpotential of 265 mV to obtain 10 mA·cm-2 and a small Tafel slope of 51.6 mV·dec-1. Also, the catalyst with the coupled interface exhibited significantly enhanced long-term stability compared to the other two catalysts, with <5% decay in OER activity over 20 h of continuous operation, while that of Ni3S2/NF and NiPx/NF decreased by about 30 and 50%, respectively. This study provides inspiration for other energy conversion reactions in optimizing the performance of catalysts by coupling crystalline-amorphous structures.

13.
Anal Chem ; 84(14): 5959-67, 2012 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-22816779

RESUMO

Liquid chromatography tandem mass spectrometry (LC-MS/MS) has been shown to be a viable tool for preclinical pharmacokinetic (PK) analysis of monoclonal antibody (mAb) therapeutics. This work describes free and total PK assays for the mAb PF-00547,659 in serum of ulcerative colitis patients in a First-In-Human study [Vermeire, S. et al. Gut2011, 60 (8), 1068-1075]. The assay to measure free PF-00547,659 used immuno-enrichment with a biotinylated anti-idiotypic antibody and streptavidin magnetic beads. The total assay used enrichment by protein G magnetic beads. Following elution of PF-00547,659 from the beads, addition of an extended sequence stable isotope labeled peptide and trypsin digestion, a proteotypic peptide derived from the CDR region of the light chain of PF-00547,659 was quantified by LC-MS/MS. The free assay had a calibration range from 7.03 ng/mL to 450 ng/mL. The assay was precise and accurate with interbatch imprecision <16.5%, and interbatch inaccuracy <13.7% at all concentrations investigated during assay qualification. Results from LC-MS/MS methodologies are compared with historical immunoassay data originally acquired during the course of the clinical study. PK parameter estimates were highly correlated between the two analytical approaches. This work provides precedence that immunoaffinity LC-MS/MS can effectively be used to measure the serum concentrations of mAb therapeutics in clinical studies.


Assuntos
Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Cromatografia Líquida/métodos , Mucoproteínas/imunologia , Espectrometria de Massas em Tandem/métodos , Anticorpos Monoclonais/imunologia , Humanos , Imunoensaio
14.
Adv Sci (Weinh) ; 9(5): e2104278, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34962091

RESUMO

Transforming carbon dots (CDs) fluorescent materials into smart materials with complex functions is a topic of great interest to nanoscience. However, designing CDs with regulating fluorescence/phosphorescence that can be visually monitored with the environment changes in real-time remains a challenge. Here, a very simple strategy, one-step solvent-free catalytic assistant strategy, which is low cost, facile, environment-friendly, and high throughput, is put forward. Hydrogen bond is used to manipulate nanostructure of CDs, and the obtained carbon dots (M-CDs) show a series of attractive properties including matrix-free room-temperature phosphorescence, time-dependent fluorescence, and near-infrared emissive characteristics. Different from the traditional aggregation caused quenching or aggregation-induced emission fluorescent materials, M-CDs exhibit unprecedented and unique dispersion induced redshift fluorescence phenomenon, promoting the studies of fluorescence from static to dynamic. The causes of this phenomenon are further analyzed in detail. As a kind of intelligent fluorescent materials, this new designed CDs greatly enrich the basic recognition of CDs by illustrating the relationship between redshift fluorescence behaviors and the dispersion states, and may provide with an opportunity for solid-state fluorescent materials, anti-counterfeiting, cellular imaging, and hopefully many others.


Assuntos
Carbono , Pontos Quânticos , Carbono/química , Fluorescência , Pontos Quânticos/química
15.
Dalton Trans ; 51(39): 15158-15165, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36149368

RESUMO

The supramolecular lead iodide perovskite crystals, {[NH4(18-crown-6)]PbI3}∞ (1), (18-crown-6 = 1,4,7,10,13,16-hexaoxacyclooctadecane), was successfully achieved by a facile solvent evaporation strategy using a DMF solution containing equal molar quantities of PbI2, NH4I and 18-crown-6. The supramolecular perovskite was characterized by microanalysis for C, H and N elements, thermogravimetric (TG) analysis, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and single crystal X-ray diffraction techniques. DSC measurements demonstrated that 1 experiences a two-step thermotropic phase transition around 333 K and 383 K, respectively. The phase transition is relevant to the disorder-order transformation of the 18-crown-6 molecule at ∼333 K, while both breaking-symmetry and ordered-disordered transformation of the 18-crown-6 molecule occurred at ∼383 K. In addition, the sharp change of the PbI6 coordination octahedron distortion degree plays a synergistic role in the two-step phase transition. The dielectric relaxation occurs above 243 K in 1 and is mainly attributed to the displacement of the NH4+ ions relative to the ring of the 18-crown-6 molecule and {PbI3}∞ chain induced by an AC electrical field.

16.
Lancet Diabetes Endocrinol ; 10(12): 859-868, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36356613

RESUMO

BACKGROUND: Impaired cilial signalling in the melanocortin-4 receptor (MC4R) pathway might contribute to obesity in patients with Bardet-Biedl syndrome and Alström syndrome, rare genetic diseases associated with hyperphagia and early-onset severe obesity. We aimed to evaluate the effect of setmelanotide on bodyweight in these patients. METHODS: This multicentre, randomised, 14-week double-blind, placebo-controlled, phase 3 trial followed by a 52-week open-label period, was performed at 12 sites (hospitals, clinics, and universities) in the USA, Canada, the UK, France, and Spain. Patients aged 6 years or older were included if they had a clinical diagnosis of Bardet-Biedl syndrome or Alström syndrome and obesity (defined as BMI >97th percentile for age and sex for those aged 6-15 years and ≥30 kg/m2 for those aged ≥16 years). Patients were randomly assigned (1:1) using a numerical randomisation code to receive up to 3·0 mg of subcutaneous setmelanotide or placebo once per day during the 14-week double-blind period, followed by open-label setmelanotide for 52 weeks. The primary endpoint, measured in the full analysis set, was the proportion of patients aged 12 years or older who reached at least a 10% reduction in bodyweight from baseline after 52 weeks of setmelanotide treatment. This study is registered with ClinicalTrials.gov, NCT03746522. FINDINGS: Between Dec 10, 2018, and Nov 25, 2019, 38 patients were enrolled and randomly assigned to receive setmelanotide (n=19) or placebo (n=19; 16 with Bardet-Biedl syndrome and three with Alström syndrome in each group). In terms of the primary endpoint, 32·3% (95% CI 16·7 to 51·4; p=0·0006) of patients aged 12 years or older with Bardet-Biedl syndrome reached at least a 10% reduction in bodyweight after 52 weeks of setmelanotide. The most commonly reported treatment-emergent adverse events were skin hyperpigmentation (23 [61%] of 38) and injection site erythema (18 [48%]). Two patients had four serious adverse events (blindness, anaphylactic reaction, and suicidal ideation); none were considered related to setmelanotide treatment. INTERPRETATION: Setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome; however, these results were inconclusive in patients with Alström syndrome. These results support the use of setmelanotide and provided the necessary evidence for approval of this drug as the first treatment for obesity in patients with Bardet-Biedl syndrome. FUNDING: Rhythm Pharmaceuticals.


Assuntos
Síndrome de Alstrom , Síndrome de Bardet-Biedl , Humanos , Receptor Tipo 4 de Melanocortina , Resultado do Tratamento , Obesidade/complicações , Obesidade/tratamento farmacológico
17.
Contemp Clin Trials Commun ; 22: 100780, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34013094

RESUMO

BACKGROUND: A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier: NCT03746522). METHODS: It was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m2 (in those aged ≥16 years) or a weight >97th percentile (in those aged 6-15 years) are included. Participants are initially randomized in a 1:1 ratio to receive setmelanotide or placebo for 14 weeks (period 1). Following period 1, all participants receive 38 weeks of open-label treatment with setmelanotide (period 2). In each treatment period, setmelanotide is administered at 3 mg once a day following completion of dose escalation. The primary endpoint is the proportion of participants aged ≥12 years achieving a clinically meaningful reduction from baseline (≥10%) in body weight after ~52 weeks (eg, following period 2). Safety and tolerability are assessed by frequency of adverse events. CONCLUSIONS: This pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome. SUBMISSION CATEGORY: Study Design, Statistical Design, Study Protocols.

18.
Lancet Diabetes Endocrinol ; 8(12): 960-970, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33137293

RESUMO

BACKGROUND: The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. METHODS: These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. FINDINGS: Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. INTERPRETATION: Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. FUNDING: Rhythm Pharmaceuticals.


Assuntos
Insuficiência Adrenal/complicações , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Pró-Opiomelanocortina/deficiência , Receptor Tipo 4 de Melanocortina/agonistas , Receptores para Leptina/deficiência , alfa-MSH/análogos & derivados , Adolescente , Adulto , Criança , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Obesidade/complicações , Obesidade/etiologia , Obesidade/patologia , Prognóstico , Adulto Jovem , alfa-MSH/uso terapêutico
19.
Pediatr Infect Dis J ; 28(3): 177-81, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19209092

RESUMO

BACKGROUND: The pentavalent rotavirus vaccine (PRV), RotaTeq, can be concomitantly administered with most routine childhood vaccines. This study evaluated the immunogenicity and reactogenicity of PRV when used concomitantly with a hexavalent vaccine containing diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b. METHODS: Healthy infants (N = 403) received hexavalent vaccine concomitantly with either PRV or placebo at 2, 3, and 4 months of age. Antibody responses were measured immediately before and 42 +/- 3 days after vaccination. Parents/legal guardians recorded all adverse events for 14 days after vaccination. RESULTS: Seroprotective titers for hepatitis B (hepatitis B surface antigen > or =10 mIU/mL) were achieved by 97.8% of subjects in both vaccine treatment groups. Seroprotective titers to H. influenzae type b (polyribosylribitol phosphate > or =0.15 microg/mL) were achieved by 91.4% of subjects receiving both vaccines and 95.1% of subjects receiving only hexavalent vaccine. Seroprotective titers to diphtheria, tetanus, and poliovirus were also comparable between the vaccine treatment groups, as were geometric mean antibody titers to the pertussis antigens. Among PRV recipients, 92% had a > or =3-fold rise in serum antirotavirus immunoglobulin A levels. Concomitant administration was well tolerated. The incidence of adverse events was similar for both groups, with no statistically significant increases in fever, vomiting, diarrhea, or irritability. CONCLUSIONS: In this study, concomitant administration of PRV with hexavalent vaccine was well tolerated and the immune responses to the antigens of the hexavalent vaccine were noninferior when compared with those of the control group. In addition, PRV was immunogenic when administered concomitantly with hexavalent vaccine.


Assuntos
Anticorpos Antivirais/sangue , Gastroenterite , Infecções por Rotavirus , Vacinas contra Rotavirus , Vacinas Combinadas , Anticorpos Antibacterianos/sangue , Cápsulas Bacterianas/administração & dosagem , Cápsulas Bacterianas/efeitos adversos , Cápsulas Bacterianas/imunologia , Vacinas contra Difteria, Tétano e Coqueluche Acelular/administração & dosagem , Vacinas contra Difteria, Tétano e Coqueluche Acelular/efeitos adversos , Vacinas contra Difteria, Tétano e Coqueluche Acelular/imunologia , Relação Dose-Resposta Imunológica , Método Duplo-Cego , Feminino , Gastroenterite/imunologia , Gastroenterite/prevenção & controle , Gastroenterite/virologia , Vacinas Anti-Haemophilus/administração & dosagem , Vacinas Anti-Haemophilus/efeitos adversos , Vacinas Anti-Haemophilus/imunologia , Vacinas contra Hepatite B/administração & dosagem , Vacinas contra Hepatite B/efeitos adversos , Vacinas contra Hepatite B/imunologia , Humanos , Lactente , Masculino , Vacina Antipólio de Vírus Inativado/administração & dosagem , Vacina Antipólio de Vírus Inativado/efeitos adversos , Vacina Antipólio de Vírus Inativado/imunologia , Infecções por Rotavirus/imunologia , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia , Resultado do Tratamento , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/efeitos adversos , Vacinas Combinadas/imunologia
20.
Pediatr Infect Dis J ; 27(10): 874-80, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18756184

RESUMO

OBJECTIVES: The live oral pentavalent rotavirus vaccine (PRV) is well tolerated and highly efficacious against rotavirus gastroenteritis. This open-label, multicenter study evaluated the immunogenicity and safety of coadministering oral poliovirus vaccine (OPV) with PRV. METHODS: From 2005 to 2006, healthy 6- to 12-week-old Latin American infants were randomized to PRV and OPV concomitantly or PRV 2-4 weeks before OPV. Three doses of each vaccine were administered 8-10 weeks apart. Subjects did not receive OPV at birth. Routine licensed pediatric vaccines were allowed. Antibody responses to PRV and OPV were evaluated 42 days after the last dose of each vaccine. Adverse events were recorded for 14 days after each study visit. RESULTS: In the concomitant-use group (n = 372), more than 98% of subjects achieved serum-neutralizing antibody titer > or = 1:8 against poliovirus types 1, 2, and 3. The poliovirus seroprotection rate in the concomitant-use group was statistically noninferior to the staggered-use group (n = 363). The immunoglobulin A (IgA) antirotavirus geometric mean titer was 46% lower in the concomitant-use group than in the staggered-use group. However, concomitant use elicited a > or = 3-fold increase (from predose 1 to postdose 3) in serum antirotavirus IgA in 93% of subjects and achieved the definition of noninferiority. Both regimens were similarly well tolerated. CONCLUSIONS: PRV did not interfere with immune responses to OPV. Although coadministration with OPV reduced serum antirotavirus IgA geometric mean titer, seroresponse rates were high and consistent with those observed in previous studies showing high vaccine efficacy. These results support including PRV in vaccination schedules involving OPV.


Assuntos
Anticorpos Antivirais/sangue , Vacina Antipólio Oral , Poliovirus/imunologia , Vacinas contra Rotavirus , Rotavirus/imunologia , Administração Oral , Anticorpos Antivirais/imunologia , Feminino , Humanos , Esquemas de Imunização , Lactente , Intussuscepção/etiologia , Masculino , Testes de Neutralização , Vacina Antipólio Oral/administração & dosagem , Vacina Antipólio Oral/efeitos adversos , Vacina Antipólio Oral/imunologia , Vírus Reordenados/imunologia , Infecções por Rotavirus/prevenção & controle , Vacinas contra Rotavirus/administração & dosagem , Vacinas contra Rotavirus/efeitos adversos , Vacinas contra Rotavirus/imunologia
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