RESUMO
Designing effective drug nanocarriers that are easy to synthesize, robust, and nontoxic is a significant challenge in nanomedicine. Polyamine-multivalent molecule nanocomplexes are promising drug carriers due to their simple and all-aqueous manufacturing process. However, these systems can present issues of colloidal instability over time and cellular toxicity due to the cationic polymer. In this study, we finely modulate the formation parameters of poly(allylamine-tripolyphosphate) complexes to jointly optimize the robustness and safety. Polyallylamine was ionically assembled with tripolyphosphate anions to form liquid-like nanocomplexes with a size of around 200 nm and a zeta potential of -30 mV. We found that nanocomplexes exhibit tremendous long-term stability (9 months of storage) in colloidal dispersion and that they are suitable as protein-loading agents. Moreover, the formation of nanocomplexes induced by tripolyphosphate anions produces a switch-off in the toxicity of the system by altering the overall charge from positive to negative. In addition, we demonstrate that nanocomplexes can be internalized by bone-marrow-derived macrophage cells. Altogether, these nanocomplexes have attractive and promising properties as delivery nanoplatforms for potential therapies based on the immune system activation.
Assuntos
Alilamina , Polifosfatos , Portadores de Fármacos , PolímerosRESUMO
The interaction between polyamines and phosphate species is found in a wide range of biological and abiotic systems, yielding crucial consequences that range from the formation of supramolecular colloids to structure determination. In this work, the occurrence of phosphate-amino interactions is evidenced from changes in the electronic response of graphene field effect transistors (gFETs). First, the surface of the transistors is modified with poly(allylamine), and the effect of phosphate binding on the transfer characteristics is interpreted in terms of its impact on the surface charge density. The electronic response of the polyamine-functionalized gFETs is shown to be sensitive to the presence of different phosphate anions, such as orthophosphate, adenosine triphosphate, and tripolyphosphate, and a simple binding model is developed to explain the dependence of the shift of the Dirac point potential on the phosphate species concentration. Afterward, the impact of phosphate-amino interactions on the immobilization of enzymes to polyamine-modified graphene surfaces is investigated, and a decrease in the amount of anchored enzyme as the phosphate concentration increases is found. Finally, multilayer polyamine-urease biosensors are fabricated while increasing the phosphate concentration in the enzyme solution, and the sensing properties of the gFETs toward urea are evaluated. It is found that the presence of simple phosphate anions alters the nanoarchitecture of the polyelectrolyte-urease assemblies, with direct implications on urea sensing.
Assuntos
Alilamina , Técnicas Biossensoriais , Grafite , Trifosfato de Adenosina , Ânions , Grafite/química , Fosfatos , Poliaminas , Polieletrólitos , Transistores Eletrônicos , Ureia , Urease/químicaRESUMO
Salicylic acid (SA) is a phenolic phytohormone with critical roles in plant growth regulation and resistance to biotic and abiotic stress. Since low SA concentrations can modulate many plant biochemical responses, innovative analytical tools are required to deeply understand its activity and to control its exogenous application in modern agricultural systems. Herein, a NIR-activated composite based on NaYF4:Yb,Er@NaYF4 core@shell upconversion nanoparticles decorated with the poly(allylamine)-Cu(II) complex [UCNPs-PAAm-Cu(II)] was developed to sensitively determine the SA molecule in plant-derived samples. Accordingly, the PAAm-Cu(II) complex grafted on the UCNPs induces a strategic charge transfer band which triggers a quenching process through a resonance energy transfer (RET) mechanism. Such process is gradually deactivated upon the addition of SA and the consequent formation of the SA-Cu(II) complex, allowing a luminescence recovery in the 1-800 nM linear range. This mechanism is promoted by the strong stability of the SA-Cu(II) complex (log ß2-SA/Cu = 19.01) which is over twelve orders of magnitude stronger than the PAAm-Cu2+ counterpart. Furthermore, the equilibrium and kinetic studies on the involved mononuclear Cu2+ complexes formation permitted instantaneous analytical responses and excellent selectivity against other representative phytohormones and metallic cations. The reliability of this method was demonstrated by determining the SA content of some edible fruits and vegetables comprising apple, lemon, kiwi, tomato, and cucumber, whose concentrations ranged from 0.30 to 2.99 µg g-1, with percent recoveries between 94.6 to 102.3%. Thereby, the reported nanocomplex can help to understand the SA activity in plants with significant applications in crop yield improvement and food quality assessment.
Assuntos
Alilamina , Nanopartículas , Cobre , Cinética , Nanopartículas/química , Extratos Vegetais , Reguladores de Crescimento de Plantas , Reprodutibilidade dos Testes , Ácido SalicílicoRESUMO
Two practical and efficient approaches have been implemented as alternative procedures for the synthesis of naftifine and novel diversely substituted analogues 16 and 20 in good to excellent yields, mediated by Mannich-type reactions as the key step of the processes. In these approaches, the γ-aminoalcohols 15 and 19 were obtained as the key intermediates and their subsequent dehydration catalyzed either by Brønsted acids like H2SO4 and HCl or Lewis acid like AlCl3, respectively, led to naftifine, along with the target allylamines 16 and 20. The antifungal assay results showed that intermediates 18 (bearing both a ß-aminoketo- and N-methyl functionalities in their structures) and products 20 were the most active. Particularly, structures 18b, 18c, and the allylamine 20c showed the lowest MIC values, in the 0.5-7.8 µg/mL range, against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes. Interesting enough, compound 18b bearing a 4-Br as the substituent of the phenyl ring, also displayed high activity against Candida albicans and Cryptococcus neoformans with MIC80 = 7.8 µg/mL, being fungicide rather than fungistatic with a relevant MFC value = 15.6 µg/mL against C. neoformans.
Assuntos
Alilamina/análogos & derivados , Antifúngicos/síntese química , Antifúngicos/farmacologia , Técnicas de Química Sintética , Desenho de Fármacos , Alilamina/síntese química , Alilamina/química , Alilamina/farmacologia , Antifúngicos/química , Catálise , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
INTRODUCTION: Colesevelam HCl (colesevelam) is a bile acid sequestrant initially approved by the US Food and Drug Administration (FDA) in 2000 as an adjunct to diet and exercise to lower elevated low-density lipoprotein cholesterol (LDL-C) levels in adults with primary lipidemia, as monotherapy, or in combination with a statin. More recently, the drug was approved for use in adults with type 2 diabetes mellitus (T2DM) to improve glycemic control. Thus, colesevelam is currently the only single-agent monotherapy approved by the FDA to lower both LDL-C and glycated hemoglobin (A1c) levels in adults with T2DM and elevated LDL-C. Moreover, the formulation options for colesevelam have also expanded since its original approval. MATERIALS AND METHODS: A Medline search was conducted to provide evidence to support the efficacy and safety for the use of colesevelam tablets or oral suspension preparations when treating patients with lipidemia, T2DM, or both. No limitations were placed on publication date or any other parameter. RESULTS: Clinical studies have shown that colesevelam is efficacious in lowering LDL-C levels, improving the lipid profile, and improving glycemic control by reducing both A1c and fasting plasma glucose levels in T2DM. Equilibrium and kinetics data show that colesevelam is equivalent in its tablet and oral suspension formulation. CONCLUSION: Having 2 effective oral routes enhances convenience and improves compliance, both of which contribute to maximal therapeutic outcomes. These compliance benefits are due to the ease and flexibility of preparing the powder in various beverages and the pleasant taste from the inclusion of a low-calorie citrus flavoring.
Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Alilamina/administração & dosagem , Alilamina/efeitos adversos , Alilamina/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Glicemia , LDL-Colesterol/efeitos dos fármacos , Cloridrato de Colesevelam , Diabetes Mellitus Tipo 2/epidemiologia , Hemoglobinas Glicadas , Humanos , Hipercolesterolemia/epidemiologia , Lipídeos/sangue , Suspensões , ComprimidosRESUMO
We report the morphologic description of the bile acid sequestrants (BAS) colesevelam and colestipol, as well as the largest series of cholestyramine. Histologically similar medication resins from 4 institutions were prospectively collected over 1 year (26 specimens, 15 patients). Comorbidities included hyperlipidemia (4/15), hypertension (4/15), inflammatory bowel disease (4/15), coronary artery disease (3/15), diarrhea (7/15), hypothyroidism (2/15), and ischemic bowel (1/15). Sites of involvement included the esophagus (1/26), stomach (1/26), small intestine (1/26), ileocecal valve (1/26), and colorectum (22/26). Associated histologic diagnoses included normal (8/26), chronic mucosal injury (11/26), acute inflammation (9/26), erosion/ulceration (6/26), and cytomegalovirus (2/26). The BAS resins were histologically indistinguishable from each other; they were all eosinophilic on hematoxylin and eosin (H&E) and lacked internal "fish-scales." To validate these observations, respective medications were submitted for histologic processing; the processed medications were identical to those in the patient specimens. Rare, irregular "fracture" lines presented diagnostic pitfalls by mimicking the true "fish-scales" of Kayexalate and sevelamer. Clues to the correct identification of BAS include recognition that the "fracture" lines were subtle, irregular, and restricted to large fragments or thick sections, likely representing a processing artifact. Moreover, Kayexalate is violet on H&E and black on acid fast bacillus, and sevelamer characteristically displays a 2-tone color on H&E and is magenta on acid fast bacillus. An association with inflammatory injury was seen (15/26). We believe that the BAS are innocent bystanders in complicated patients, although we cannot exclude their ability to cause mucosal injury in specific settings.
Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/análise , Colestipol/análise , Fármacos Gastrointestinais/análise , Intestinos/química , Resinas de Troca Iônica/análise , Adulto , Idoso , Alilamina/efeitos adversos , Alilamina/análise , Anticolesterolemiantes/efeitos adversos , Biópsia , Resina de Colestiramina/análise , Cloridrato de Colesevelam , Colestipol/efeitos adversos , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Mucosa Intestinal/química , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Resinas de Troca Iônica/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Estados UnidosRESUMO
Chagas disease represents a relevant health problem in Central and South America. The first line of treatment is Nifurtimox and Benznidazole which have a great deal of disadvantages that demands the rapid generation of therapeutic alternatives. Based in our research on aza-thiaheterocycles as anti-Trypanosoma cruzi agents we identified pharmacophores that act through oxidative stress. Here, we describe the synthesis and the activity of new containing bioactive-heterocycles analogues of naftifine as potential T. cruzi membrane sterol biosynthesis inhibitors. Benzimidazole 1,3-dioxides (11 and 13) and quinoxaline 1,4-dioxides (22 and 23) displayed excellent parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated with the compounds showed that any of them are able to accumulate squalene suggesting that in the anti-T. cruzi mechanism of action is not involved the inhibition of sterol biosynthesis. Some derivatives were also tested as antifungal agents. The results obtained in the present work open potential therapeutic possibilities of new compounds for these infectious diseases.
Assuntos
Alilamina/análogos & derivados , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Alilamina/química , Alilamina/farmacologia , Alilamina/toxicidade , Animais , Linhagem Celular , Desenho de Fármacos , Fungos/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Testes de Sensibilidade Microbiana , Esqualeno/metabolismo , Tripanossomicidas/toxicidade , Trypanosoma cruzi/metabolismoRESUMO
OBJECTIVE: Evaluate the efficacy and safety of colesevelam hydrochloride in children with heterozygous familial hypercholesterolemia (heFH). STUDY DESIGN: This was a randomized, double-blind, 41-site study in 194 children aged 10 to 17 years (inclusive) with heFH (statin-naïve or on a stable statin regimen). After a 4-week stabilization period (period I), subjects were randomized 1:1:1 to placebo, colesevelam 1.875 g/d, or colesevelam 3.75 g/d for 8 weeks (period II). All then received open-label colesevelam 3.75 g/d for 18 weeks (period III), with follow-up 2 weeks later. The primary endpoint was percent change in low-density lipoprotein (LDL)-cholesterol from baseline to week 8. Secondary endpoints included percent change in other lipoprotein variables, including non-high-density lipoprotein (non-HDL)-cholesterol. Adverse events were also evaluated. RESULTS: At week 8, a significant difference from baseline in LDL-cholesterol was reported with colesevelam 1.875 g/d (-6.3%; P = .031) and colesevelam 3.75 g/d (-12.5%; P < .001) compared with placebo. Significant treatment effects were also reported for total cholesterol (-7.4%), non-HDL-cholesterol (-10.9%), HDL-cholesterol (+6.1%), apolipoprotein A-I (+6.9%), and apolipoprotein B (-8.3%) and a nonsignificant effect for triglycerides (+5.1%) with colesevelam 3.75 g/d compared with placebo at week 8. These treatment effects were maintained during period III. CONCLUSIONS: Colesevelam significantly lowered LDL-cholesterol levels in children with heFH.
Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adolescente , Alilamina/efeitos adversos , Alilamina/farmacologia , Alilamina/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Criança , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Cloridrato de Colesevelam , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , MasculinoRESUMO
BACKGROUND: Poor glycemic control is a risk factor for microvascular complications in patients with type 2 diabetes mellitus. Achieving glycemic control safely with insulin therapy can be challenging. METHODS: A prospective, 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted at 50 sites in the United States and 1 site in Mexico between August 12, 2004, and December 28, 2005. Subjects had type 2 diabetes mellitus that was not adequately controlled (glycated hemoglobin level, 7.5%-9.5%, inclusive) receiving insulin therapy alone or in combination with oral antidiabetes agents. In total 287 subjects (52% men; mean age, 57 years; with a mean baseline glycated hemoglobin level of 8.3%) were randomized: 147 to receive colesevelam hydrochloride, 3.75 g/d, and 140 to receive placebo. RESULTS: Using the least squares method, the mean (SE) change in glycated hemoglobin level from baseline to week 16 was -0.41% (0.07%) for the colesevelam-treated group and 0.09% (0.07%) for the placebo group (treatment difference, -0.50% [0.09%]; 95% confidence interval, -0.68% to -0.32%; P < .001). Consistent reductions in fasting plasma glucose and fructosamine levels, glycemic-control response rate, and lipid control measures were observed with colesevelam. As expected, the colesevelam-treated group had a 12.8% reduction in low-density lipoprotein cholesterol concentration relative to placebo (P < .001). Of recipients of colesevelam and placebo, respectively, 30 and 26 discontinued the study prematurely; 7 and 9 withdrew because of protocol-specified hyperglycemia, and 10 and 4 withdrew because of adverse events. Both treatments were generally well tolerated. CONCLUSIONS: Colesevelam treatment seems to be safe and effective for improving glycemic control and lipid management in patients with type 2 diabetes mellitus receiving insulin-based therapy, and it may provide a novel treatment for improving dual cardiovascular risk factors.
Assuntos
Alilamina/análogos & derivados , Anticolesterolemiantes/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Adolescente , Adulto , Idoso , Alilamina/uso terapêutico , LDL-Colesterol/sangue , Cloridrato de Colesevelam , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Masculino , México , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Estados UnidosRESUMO
As infecções fúngicas, cutâneas e subcutâneas, têm alta prevalência e caráter crônico, especialmente, em pacientes com alterações imunológicas, fazendo-se necessário o emprego de antifúngico em doses elevadas e por longos períodos. Recidivas e persistência dessas infecções podem ter como causa cepas resistentes a antifúngicos e a avaliação da eficácia das drogas empregadas na terapia, pode contribuir para o controle da infecção. A eficácia de um antifúngico pode ser avaliada por testes in vitro. O comitê norte-americano CLSI publicou em 2002 o método M38-A, diluição em meio líquido para alguns antifúngicos, considerado de referência para fungos filamentosos, porém há críticas quanto à preparação de inóculo e adequação do meio de cultura. Modificações na preparação do inóculo, para melhoria do método foram propostas pelo grupo europeu EUCAST. Entretanto, o método de referência emprega procedimentos complexos e sua aplicação em laboratórios clínicos é inviável. Outro método, de execução mais simples, recomendado pelo CLSI-M44-A (Method for Antifungal Disk Diffusion Susceptibility Testing of Yeast) tem como base o método de Kirby-Bauer, é indicado para rotina laboratorial, porém, restringe-se a avaliar a sensibilidade de leveduras ao fluconazol. Em micoses cutâneas e subcutâneas são empregadas drogas azólicas e alilaminas. Dentre estas, a terbinafina tem uso amplo sob distintas formulações, em medicina humana e veterinária. O objetivo deste trabalho foi investigar método de disco-difusão em dois meios de cultura ágar Mueller-Hinton (2% glicose + 0,5 µg azul de metileno) e ágar Yeast Morphological Agar)] para emprego em laboratórios clínicos, em testes de sensibilidade à terbinafina com isolados de fungos causadores de micoses cutâneas e subcutâneas. No mercado nacional, há discos contendo diversos antifúngicos, porém, não há para terbinafina. Neste estudo, foram avaliadas concentrações distintas de terbinafina (0,125-100µg) contra 10 isolados e mensurados...