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1.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(3. Vyp. 2): 49-53, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32307430

RESUMO

AIM: To evaluate the efficacy of including cytoflavin in rehabilitation measures in the early recovery period of patients with ischemic stroke. MATERIAL AND METHODS: Results of rehabilitation measures of 100 patients (50 women and 50 men, aged 18 to 85 years) in the early recovery period of ischemic stroke were analyzed. Psychological testing included NIHSS, MMSE, Rankin scale, Rivermead mobility index, exercise tolerance test. Depending on the rehabilitation scheme, patients were divided into the main group (n=50), who received a verticalization course and cytoflavin (intravenously, drip 20.0 ml in 250.0 ml 5% glucose for 14 days). The control group (n=50) included patients who received standard treatment. RESULTS AND CONCLUSION: Inclusion of cytoflavin in the rehabilitation scheme for patients with ischemic stroke increased the effectiveness of treatment, which was manifested by a decrease in the severity of neurological disorders assessed with NIHSS by 17.6% in the main group versus 10.8% in the control group (p<0.05) and recovery of cognitive functions assessed with MMSE by 5.8% versus 1.6%, respectively (p<0.05). In addition, there was a positive dynamics in the restoration of blood pressure (by 37.1% in the main group versus 30.6% in the control group (p<0.05)).


Assuntos
Isquemia Encefálica/terapia , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Cognição/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Mononucleotídeo de Flavina/administração & dosagem , Mononucleotídeo de Flavina/farmacologia , Mononucleotídeo de Flavina/uso terapêutico , Humanos , Inosina Difosfato/administração & dosagem , Inosina Difosfato/farmacologia , Inosina Difosfato/uso terapêutico , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Acidente Vascular Cerebral/metabolismo , Succinatos/administração & dosagem , Succinatos/farmacologia , Succinatos/uso terapêutico , Resultado do Tratamento , Adulto Jovem
2.
Toxicol Lett ; 324: 95-103, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32017979

RESUMO

Sulfur mustard (SM) is a toxicant and chemical warfare agent with strong vesicant properties. The mechanisms behind SM-induced toxicity are not fully understood and no antidote or effective therapy against SM exists. Both, the risk of SM release in asymmetric conflicts or terrorist attacks and the usage of SM-derived nitrogen mustards as cancer chemotherapeutics, render the mechanisms of mustard-induced toxicity a highly relevant research subject. Herein, we review a central role of the abundant cellular molecule nicotinamide adenine dinucleotide (NAD+) in molecular mechanisms underlying SM toxicity. We also discuss the potential beneficial effects of NAD+ precursors in counteracting SM-induced damage.


Assuntos
Substâncias para a Guerra Química/toxicidade , Gás de Mostarda/toxicidade , NAD/fisiologia , Animais , Suplementos Nutricionais , Humanos , NAD/administração & dosagem , Niacinamida/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerases/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Sirtuínas/antagonistas & inibidores
3.
Gynecol Oncol ; 156(2): 301-307, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31870556

RESUMO

OBJECTIVE: To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior. METHODS: Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events. RESULTS: Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation. CONCLUSIONS: Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Niacinamida/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/enzimologia , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinoxalinas/administração & dosagem , Sulfonamidas/administração & dosagem , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Adulto Jovem
4.
N Engl J Med ; 381(24): 2315-2326, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31826340

RESUMO

BACKGROUND: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. METHODS: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. RESULTS: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. CONCLUSIONS: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Niacinamida/análogos & derivados , Pirazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/farmacocinética
5.
Clín. investig. arterioscler. (Ed. impr.) ; 31(6): 251-260, nov.-dic. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-185150

RESUMO

Introduction: High Density Lipoproteins (HDL) are dysfunctional in hypercholesterolemia patients. The hypothesis was tested that nicotinamide (NAM) administration will influence HDL metabolism and reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT) in a murine model of hypercholesterolemia. Methods: Apolipoprotein E-deficient (KOE) mice were challenged with a high-fat diet for 4 weeks. The effect of different doses of NAM on cholesterol metabolism, and the ability of HDL to promote m-RCT was assessed. Results: The administration of NAM to KOE mice produced an increase (∼1.5-fold; P < 0.05) in the plasma levels of cholesterol, which was mainly accounted for by the non-HDL fraction. NAM produced a [3H]-cholesterol plasma accumulation (∼1.5-fold) in the m-RCT setting. As revealed by kinetic analysis, the latter was mainly explained by an impaired clearance of circulating non-HDL (∼0.8-fold). The relative content of [3H]-tracer was lowered in the livers (∼0.6-fold) and feces (> 0.5-fold) of NAM-treated mice. This finding was accompanied by a significant (or trend close to significance) up-regulation of the relative gene expression of Abcg5 and Abcg8 in the liver (Abcg5: 2.9-fold; P < 0.05; Abcg8: 2.4-fold; P = 0.06) and small intestine (Abcg5: 2.1-fold; P = 0.15; Abcg8: 1.9-fold; P < 0.05) of high-dose, NAM-treated mice. Conclusion: The data from this study show that the administration of NAM to KOE mice impaired m-RCT in vivo. This finding was partly due to a defective hepatic clearance of plasma non-HDL


No dispnible


Assuntos
Animais , Camundongos , Apolipoproteínas E/deficiência , Niacinamida/administração & dosagem , Colesterol/análise , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/tratamento farmacológico , Apolipoproteínas E/administração & dosagem , Niacinamida/metabolismo , Colesterol/metabolismo , Gorduras na Dieta , Expressão Gênica , HDL-Colesterol
6.
World J Gastroenterol ; 25(38): 5800-5813, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636473

RESUMO

BACKGROUND: Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing. AIM: To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms. METHODS: We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot. RESULTS: SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (P < 0.01), histological score (P < 0.001), inflammatory cytokine levels (P < 0.01), and apoptotic cell rate (P < 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice. CONCLUSION: SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.


Assuntos
Apoptose , Colite Ulcerativa/patologia , Estresse do Retículo Endoplasmático , Mucosa Intestinal/patologia , Sirtuína 1/metabolismo , Animais , Células CACO-2 , Caspase 12/metabolismo , Técnicas de Cocultura , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Humanos , Mucosa Intestinal/citologia , Macrófagos , Camundongos , Niacinamida/administração & dosagem , Sirtuína 1/antagonistas & inibidores , Fator de Transcrição CHOP/metabolismo
7.
Khirurgiia (Mosk) ; (5): 57-63, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31169820

RESUMO

AIM: To study the effectiveness of intraoperative administration of Cytoflavine for the prevention of ischemic brain injury during cerebral aneurysm (CA) clipping with temporary occlusion of the leading artery under general anesthesia. MATERIAL AND METHODS: The prospective cohort single-center study included 40 patients with CA ( the main group - 27 patients with intraoperative administration of cytoflavine; the comparison group -13 patients without use of cytoflavine), who underwent aneurism clipping with temporary occlusion of the afferent artery. We assesed the intraoperative state of the brain, the time of awakening and extubation of patients after surgery, neurological deficit and local ischemic changes in the area of surgery according to the CT of the brain in the early postoperative period, resuscitation bed-day and the relationship of these indicators with the duration of temporary occlusion of the afferent artery in the selected groups of patients. RESULTS: In intergroup comparison, patients of the main group treated with intraoperative cytoflavin showed a reduction in the time of awakening (p=0.013) and the time of extubation (p=0.01) both with temporary occlusion of the afferent artery and in patients without temporary occlusion (p<0.05). The duration of resuscitation bed-day decreased in the main group of patients receiving intraoperatively cytoflavine (p=0.01), as well as in patients in the comparison group without temporary occlusion (p<0.05). CONCLUSION: Temporary occlusion of the afferent artery with short intervals of vessel occlusion in combination with intraoperative intravenous administration of cytoflavine expands the tolerability to artery occlusion in patients operated in the 'cold' period, reduces the possibility of neurological deficit, reduces the recovery period and resuscitation bed-day after surgical clipping CA.


Assuntos
Lesões Encefálicas/prevenção & controle , Isquemia Encefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Mononucleotídeo de Flavina/administração & dosagem , Inosina Difosfato/administração & dosagem , Aneurisma Intracraniano/fisiopatologia , Fármacos Neuroprotetores/administração & dosagem , Procedimentos Neurocirúrgicos/efeitos adversos , Niacinamida/administração & dosagem , Succinatos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/cirurgia , Lesões Encefálicas/etiologia , Lesões Encefálicas/fisiopatologia , Lesões Encefálicas/cirurgia , Isquemia Encefálica/etiologia , Isquemia Encefálica/cirurgia , Combinação de Medicamentos , Mononucleotídeo de Flavina/farmacologia , Humanos , Inosina Difosfato/farmacologia , Aneurisma Intracraniano/complicações , Aneurisma Intracraniano/cirurgia , Cuidados Intraoperatórios , Fármacos Neuroprotetores/farmacologia , Procedimentos Neurocirúrgicos/métodos , Niacinamida/farmacologia , Estudos Prospectivos , Succinatos/farmacologia , Técnicas de Sutura
8.
Eur J Pharm Sci ; 135: 32-37, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31077749

RESUMO

To prepare the way for using the isotopically labelled SABRE hyperpolarized 4,6-d2-nicotinamide as an MRI agent in humans we have performed an in-vivo study to measure its pharmacokinetics in the plasma of healthy rats after intravenous and oral administration. Male Han Wistar rats were dosed with either 4,6-d2-nicotinamide or the corresponding control, non-labelled nicotinamide, and plasma samples were obtained at eight time points for up to 24 h after administration. Pharmacokinetic parameters were determined from agent concentration-versus-time data for both 4,6-d2-nicotinamide and nicotinamide. 4,6-d2-Nicotinamide proved to be well tolerated regardless of route of administration at the concentrations used (20, 80 and 120 mg/kg). Pharmacokinetic parameters were similar after oral and intravenous administration and similar to those obtained for nicotinamide. Analysis of nicotinamide plasma concentrations after dosing 4,6-d2-nicotinamide intravenously demonstrates a reversible exchange of endogenous nicotinamide by this labelled agent over the time-course of our assays. Supported by a large body of evidence for the safety of nicotinamide when dosed orally in humans, we conclude that 4,6-d2-nicotinamide can also be safely administered intravenously, which will provide significant benefit when using this agent for planned imaging studies in humans.


Assuntos
Niacinamida/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Deutério , Relação Dose-Resposta a Droga , Infusões Intravenosas , Masculino , Niacinamida/administração & dosagem , Niacinamida/sangue , Ratos , Espectrometria de Massas em Tandem/métodos
9.
J Am Soc Nephrol ; 30(6): 1096-1108, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31085679

RESUMO

BACKGROUND: Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS: To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS: Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS: LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Lantânio/administração & dosagem , Niacinamida/administração & dosagem , Fosfatos/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Método Duplo-Cego , Feminino , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Insuficiência Renal Crônica/sangue , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
10.
Drugs ; 79(8): 855-862, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062264

RESUMO

BACKGROUND: Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients. METHODS: Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits. RESULTS: One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels. CONCLUSION: In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.


Assuntos
Endotoxemia/tratamento farmacológico , Endotoxinas/sangue , Niacinamida/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Sevelamer/administração & dosagem , Idoso , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Hiperfosfatemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fosfatos/sangue , Diálise Renal , Ácido Úrico/sangue
11.
J Drugs Dermatol ; 18(5): 454-459, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141852

RESUMO

Background: Stubborn dyschromia such as melasma and post-inflammatory hyperpigmentation (PIH) are leading causes for cosmetic consultation. Topical treatment is challenging, using a range of modalities, to stop, hinder, and/or prevent steps in the pigment production process. Tranexamic acid (TXA), a potent plasmin inhibitor, is proposed to control pigmentation by inhibiting the release of inflammatory mediators involved in triggering melanogenesis. TXA has been recently introduced as a topical therapy aimed at reducing pigmentation in melasma. Methods: In a 12-week clinical study, a novel, topical facial serum containing 3% TXA, 1% kojic acid, and 5% niacinamide was evaluated for its effectiveness in treating melasma, PIH, and hyperpigmentation in Brazilian female subjects with Fitzpatrick skin types I-IV. Efficacy evaluations were performed at pre-treatment baseline, weeks 2, 4, 8, and 12, and included expert clinical grading, bio-instrumental measurements, and self-assessment questionnaires. Cutaneous tolerability was also evaluated by assessing subjective and objective irritation of the treatment area. Results: A significant improvement in the appearance of PIH, hyperpigmentation, melasma, skin texture, and skin tone homogeneity was observed beginning at week 2 and continued through week 12. Melanin index, as measured by Mexameter®, demonstrated a significant decrease by week 12 as compared to both pre-treatment baseline and control. Conclusions: The findings suggest that the test product is an effective and well-tolerated treatment option for addressing hyperpigmentary conditions, including melasma. Additional in vitro data suggests that TXA may act by mediating the inhibition of PGE2-stimulated human epidermal melanocytes. J Drugs Dermatol. 2019;18(5):454-459.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Dermatoses Faciais/tratamento farmacológico , Hiperpigmentação/tratamento farmacológico , Administração Cutânea , Adulto , Fármacos Dermatológicos/administração & dosagem , Dermatoses Faciais/patologia , Feminino , Humanos , Hiperpigmentação/patologia , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Pironas/administração & dosagem , Pironas/uso terapêutico , Inquéritos e Questionários , Ácido Tranexâmico/administração & dosagem , Ácido Tranexâmico/uso terapêutico , Resultado do Tratamento
12.
J Drugs Dermatol ; 18(5): 477-479, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141858

RESUMO

Here, we present a case of arsenic-induced Bowen's disease treated with a regimen consisting of topical 5-fluouracil and oral nicotinamide. The use of this therapy modality resulted in near complete resolution of all of the patient's lesions except for those on her palms, soles, and scalp. Excellent wound care and treatment adherence were major factors contributing to the success of this treatment option. Our results ultimately provide an alternative approach to treating multiple arsenical keratoses in patients who are limited to a drug plan involving 5-FU and oral nicotinamide and who are able to be rigorously compliant with application of medication and wound care. J Drugs Dermatol. 2019;18(5):477-479.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Arsênico/efeitos adversos , Doença de Bowen/diagnóstico , Fluoruracila/uso terapêutico , Neoplasias Cutâneas/diagnóstico , Poluentes da Água/efeitos adversos , Administração Cutânea , Administração Oral , Antimetabólitos Antineoplásicos/administração & dosagem , Doença de Bowen/induzido quimicamente , Doença de Bowen/tratamento farmacológico , Diagnóstico Diferencial , Quimioterapia Combinada , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Abastecimento de Água
13.
J Biol Chem ; 294(23): 9295-9307, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-30948509

RESUMO

Interest in pharmacological agents capable of increasing cellular NAD+ concentrations has stimulated investigations of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). NR and NMN require large dosages for effect. Herein, we describe synthesis of dihydronicotinamide riboside (NRH) and the discovery that NRH is a potent NAD+ concentration-enhancing agent, which acts within as little as 1 h after administration to mammalian cells to increase NAD+ concentrations by 2.5-10-fold over control values. Comparisons with NR and NMN show that in every instance, NRH provides greater NAD+ increases at equivalent concentrations. NRH also provides substantial NAD+ increases in tissues when administered by intraperitoneal injection to C57BL/6J mice. NRH substantially increases NAD+/NADH ratio in cultured cells and in liver and no induction of apoptotic markers or significant increases in lactate levels in cells. Cells treated with NRH are resistant to cell death caused by NAD+-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate. Studies to identify its biochemical mechanism of action showed that it does not inhibit NAD+ consumption, suggesting that it acts as a biochemical precursor to NAD+ Cell lysates possess an ATP-dependent kinase activity that efficiently converts NRH to the compound NMNH, but independent of Nrk1 or Nrk2. These studies identify a putative new metabolic pathway to NAD+ and a potent pharmacologic agent for NAD+ concentration enhancement in cells and tissues.


Assuntos
Apoptose/efeitos dos fármacos , NAD/metabolismo , Niacinamida/análogos & derivados , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Humanos , Peróxido de Hidrogênio/farmacologia , Injeções Intraperitoneais , Ácido Láctico/metabolismo , Fígado/metabolismo , Masculino , Metanossulfonato de Metila/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , NAD/análise , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Niacinamida/administração & dosagem , Niacinamida/síntese química , Niacinamida/farmacologia
14.
Mol Biol Rep ; 46(4): 3701-3711, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006095

RESUMO

Nowadays, medicinal plants have been widely used everywhere to provide essential care for many disorders including diabetes. Recent reports assumed that the antidiabetic activities of pomegranate aril juice (PAJ) may be ascribed to its punicalagin (PCG). Therefore, the present study evaluated and compared the antidiabetic activities of PAJ and its PCG, and monitored some mechanisms of their actions in streptozotocin-nicotinamide (STZ-NA) type 2 diabetic rats. STZ-NA diabetic rats were given, orally/daily, PAJ (100 or 300 mg/kg body weight, containing 2.6 and 7.8 mg of PCG/kg body weight, respectively), pure PCG (2.6 or 7.8 mg/kg body weight), or distilled water (vehicle) for 6 weeks. PAJ (especially at the high dose) alleviated significantly (P < 0.05-0.001) most signs of type 2 diabetes including body-weight loss, insulin resistance (IR) and hyperglycemia through decreasing serum tumor necrosis factor-α concentration and the expression of hepatic c-Jun N-terminal kinase, and increasing the skeletal muscle weight and the expression of hepatic insulin receptor substrate-1 in STZ-NA diabetic rats. Also, it decreased significantly (P < 0.001) the oxidative liver injury in STZ-NA diabetic rats through decreasing the hepatic lipid peroxidation and nitric oxide production, and improving the hepatic antioxidant defense system. Although the low dose of PCG induced some modulation in STZ-NA diabetic rats, the high dose of PCG did not show any valuable antidiabetic activity, but induced many side effects. In conclusion, PAJ was safer and more effective than pure PCG in alleviating IR and oxidative liver injury in STZ-NA diabetic rats.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Taninos Hidrolisáveis/administração & dosagem , Taninos Hidrolisáveis/uso terapêutico , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/patologia , Niacinamida/administração & dosagem , Estreptozocina/administração & dosagem , Animais , Antioxidantes/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Taninos Hidrolisáveis/metabolismo , Hiperglicemia/tratamento farmacológico , Proteínas Substratos do Receptor de Insulina/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Músculo Esquelético/efeitos dos fármacos , Niacinamida/metabolismo , Óxido Nítrico/metabolismo , Ratos , Estreptozocina/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos
15.
Int J Pharm ; 564: 180-187, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30981873

RESUMO

Intravesical mucoadhesive self-emulsifying drug delivery system (SEDDS) have been developed via synthesis and incorporation of S-protected chitosan CS-MNA into SEDDS. N-acetyl cysteine-6-mercaptonicotinamide (NAC-6-MNA) was synthetized via disulphide exchange reaction between N-acetyl cysteine and 6-mercaptonicotinamide dimer. NAC-6-MNA was attached to chitosan (CS) via carbodiimide mediated amide bond formation. The S-protected chitosan (CS-MNA) and chitosan (CS) were complexed with sodium dodecyl sulfate (CS-SDS and CS-MNA-SDS) and incorporated in SEDDS at a concentration of 1% (m/m). SEDDS, SEDDS-CS-SDS and SEDDS-CS-MNA-SDS were characterized regarding size and zeta potential. 6-MNA release from SEDDS-CS-MNA-SDS in presence of glutathione was evaluated. Mucoadhesive properties of these novel formulations were assessed via rheology measurements and residence time evaluation on porcine bladder. Cytotoxicity of formulations was determined on porcine bladder. S-protected chitosan displayed 465.42 ±â€¯75.64 µmol of NAC-6-MNA per gram of polymer. SEDDS and SEDDS-CS-SDS and SEDDS-CS-MNA-SDS displayed a size of 22.5 ±â€¯0.9, 37.4 ±â€¯0.1 and 98.5 ±â€¯5.7 nm at a concentration of 20% (m/v) in simulated urine pH 6.2, and a zeta potential of -5.1 ±â€¯0.2, -1.6 ±â€¯0.1 and -1.4 ±â€¯0.2 mV at a concentration of 1% (m/v) in water at pH 6, respectively. 80% of MNA was released from SEDDS-CS-MNA-SDS in presence of glutathione. Viscosity of SEDDS-CS-SDS/mucus and SEDDS-CS-MNA-SDS/mucus was 6- and 18-fold higher than SEDDS/mucus after 90 min incubation. 2.6%, 5.8% and 14% of SEDDS, SEDDS-CS-SDS and SEDDS-CS-MNA-SDS remained on bladder mucosa within 120 min, respectively. No pronounced bladder cytotoxicity was observed in presence of 0.5% (m/v) formulations. According to these results, SEDDS-CS-MNA-SDS might be a promising carrier for intravesical drug administration.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Niacinamida/química , Adesividade , Administração Intravesical , Animais , Sobrevivência Celular/efeitos dos fármacos , Quitosana/administração & dosagem , Emulsões , Membrana Mucosa/química , Muco , Niacinamida/administração & dosagem , Dodecilsulfato de Sódio/administração & dosagem , Dodecilsulfato de Sódio/química , Suínos , Bexiga Urinária/química , Bexiga Urinária/efeitos dos fármacos
16.
Daru ; 27(1): 525-531, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903555

RESUMO

BACKGROUND: The major adverse effect associated with systemic administration of Fluconazole (FLZ), is hepatic toxicity. FLZ is most commonly used antifungal drug in treatment of invasive fungal infections. METHODS: FLZ toxicity was challenged by individual and in combination of three vitamins (B1, B2 B3). Animals were divided nine groups with six animals in each group. FLZ, at a dose of 50 mg/kg b.w, was orally administered for 90 days in experimental animals. Vitamins as individual or in combination was administered concomitantly to challenge or alleviate the toxicity of FLZ. They were sacrificed at the end of protocol for biochemical and histopathology analysis. Focus was made to observe the role of these micro nutrient's (vitamins) on liver for alteration in of pathological and physiological effects by FLZ in the Wistar albino rats. RESULTS: Combination of vitamin B1 + B2 + B3 in FLZ induced toxicity was able to restore the level of alkaline phosphatase (ALP) near to normal but with high level of ALP in B1 Control group. Aspartate aminotransferase (AST) was restored to normal in FLZ + B1, FLZ + B2 and FLZ + B1 + B2 + B3 groups and vice versa in FLZ + B3 group animals. Further the level of alanine aminotransferase (ALT) was restored to normal in FLZ + B3 animals. There were no significant changes found in total bilirubin (TBI), and direct bilirubin (DBI) as compare to normal control. Histopathological studies on animals' studies validated the serological results in normalizing the cellular architecture of liver. CONCLUSIONS: Restoration of altered biochemical parameters and cellular architecture of hepatocytes by different combination of these vitamins proves the chemo preventive potential of these micro nutrients' in FLZ toxicity. Graphical abstract Vitamin B combination attenuates fluconazole toxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fluconazol/toxicidade , Niacinamida/administração & dosagem , Riboflavina/administração & dosagem , Tiamina/administração & dosagem , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar
17.
Oncol Rep ; 41(4): 2482-2490, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30816494

RESUMO

Motesanib (AMG 706) is a small organic molecule that acts as a multi­targeted tyrosine kinase inhibitor of VEGF, PDGF and stem cell factor receptor. It exhibits a potent antitumor effect in vitro and in vivo. To investigate the anticancer effect and possible mechanisms of motesanib in cisplatin­resistant human bladder cancer cells (T24R2), T24R2 cells were treated with motesanib (50 µM) with or without cisplatin (2.5 µg/ml). Cell growth was assessed by the Cell Counting Kit­8 and clonogenic assays. Cell cycle progression and apoptotic cell death were examined using flow cytometry. The expression levels of apoptosis­ and survival­related proteins were determined by western blot analysis. In combination with cisplatin, motesanib exhibited synergistic inhibition on T24R2 cell growth. Treatment using motesanib in combination with cisplatin markedly induced apoptosis and promoted cell cycle arrest in the S phase. It also increased the expression of apoptosis­related genes including caspases, poly(ADP­ribose) polymerase and cytochrome c, whereas it decreased the expression of survival­related genes including p­PI3K and p­Akt. In conclusion, combination treatment with motesanib and cisplatin revealed a synergistically enhanced anticancer effect on cisplatin­resistant human bladder cancer cells, accompanied with induced apoptosis and cell cycle arrest. Thus, the multikinase inhibitor motesanib could be developed as possible therapeutic agent for bladder cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/farmacologia , Niacinamida/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Indóis/uso terapêutico , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/patologia
18.
AAPS PharmSciTech ; 20(3): 115, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771018

RESUMO

Naringenin exerts anti-inflammatory, hypolipidemic, and hepatoprotective effects; however, it shows low oral bioavailability because of poor water solubility. In this work, cocrystals of naringenin were formed to address these issues. Using the solution crystallization method, various naringenin cocrystals were prepared with different cocrystal coformers, including naringenin-nicotinamide, naringenin-isonicotinamide, naringenin-caffeine, naringenin-betaine, and naringenin-L-proline. The formation of these cocrystals was assayed by using DSC, XRD, and FT-IR spectroscopy. The stoichiometric ratio of naringenin and the CCFs in the corresponding cocrystals was investigated by NMR. The solubility of naringenin, as well as its dissolution rate, was markedly improved by forming cocrystals. The oral bioavailability of naringenin administered as naringenin-L-proline and naringenin-betaine cocrystals was achieved significantly greater than that of pure naringenin (p < 0.05). In particular, the Cmax of naringenin-L-proline and naringenin-betaine cocrystals were 2.00-fold and 3.35-fold higher, and the AUC of naringenin-L-proline and naringenin-betaine cocrystals were 2.39-fold and 4.91-fold, respectively, higher than pure naringenin in rats. With the naringenin-betaine cocrystals for oral delivery, the drug distribution in the liver was significantly increased compared to pure naringenin. Accordingly, the naringenin-betaine cocrystals showed improved anti-hyperlipidemia effects on the C57 BL/6J PNPLA3 I148M transgenic mouse hyperlipidemia model. Collectively, cocrystal formation is a promising way to increase the bioavailability of naringenin for treating hyperlipidemia.


Assuntos
Flavanonas/farmacologia , Flavanonas/farmacocinética , Hipolipemiantes/farmacologia , Hipolipemiantes/farmacocinética , Animais , Betaína/química , Disponibilidade Biológica , Cafeína/química , Varredura Diferencial de Calorimetria , Cristalização , Flavanonas/química , Hipolipemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Niacinamida/administração & dosagem , Prolina/química , Ratos , Ratos Sprague-Dawley , Soluções , Espectroscopia de Infravermelho com Transformada de Fourier
19.
J Eur Acad Dermatol Venereol ; 33(7): 1261-1267, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30801825

RESUMO

The incidence of non-melanoma skin cancer (NMSC) is dramatically increasing worldwide, despite the increased use of improved sunscreens. In 2014, the Surgeon General estimated that 2.2-5.0 million people were treated annually for NMSC. As the number of newly diagnosed skin cancers continues to rise, there is a need for additional preventative measures beyond sunscreens. Several newer topical products that focus on boosting DNA repair, modulating DNA transcription, decreasing inflammation and selectively targeting precancerous cells may play an important role in future skin cancer prevention.


Assuntos
Carcinoma Basocelular/prevenção & controle , Carcinoma de Células Escamosas/prevenção & controle , Enzimas Reparadoras do DNA/administração & dosagem , Neoplasias Cutâneas/prevenção & controle , Administração Cutânea , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Humanos , Niacinamida/administração & dosagem , Polifenóis/administração & dosagem , Retinoides/administração & dosagem , Protetores Solares/uso terapêutico , Complexo Vitamínico B/administração & dosagem
20.
J Pharm Biomed Anal ; 166: 244-251, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30665192

RESUMO

Motesanib is a potent angiokinase inhibitor, has shown potential therapeutic effects against various cancers. An accurate, reproducible, rapid, specific, sensitive, and valid ultraperformance liquid chromatography-tandem mass spectrometry method was established to quantify motesanib in rat plasma. Motesanib and linifanib (used as an internal standard; IS) were extracted from plasma by liquid-liquid extraction using tert-butyl methyl ether as extracting agent. Chromatographic separation was performed on Acquity™ UPLC BEH™ C18 column (100 mm × 2.1 mm i.d., 1.7 µm; Waters Corp., USA) using a mobile phase comprising of 0.1% formic acid acetonitrile: ammonium acetate (90:10 v/v) eluted at a flow rate of 0.25 mL/min. The electrospray ionization in the positive-mode was used for sample ionization. In the multiple reaction monitoring mode, motesanib and the IS were quantified using precursor-to-product ion transitions of m/z 374.03 → 212.02 and m/z 376.05 → 251.05, respectively. The ranges of the calibration curves were 5.0-1000.0 ng/mL with coefficient of determination of ≥0.998. The method was validated by following recently implemented USFDA guideline for bioanalytical method validation. The lower limit of quantification was 5.0 ng/mL, whereas the intra-day and inter-day accuracies of quality controls (QCs) samples were ranged between 88.91% to 95.65% and 90.20% to 102.17%, respectively. In addition, the linearity, recovery, precision, and stability parameters were found to be within the acceptable range. The method was applied successfully to in vitro microsomal metabolic stability and preliminary oral pharmacokinetic studies in rats. The applied UPLC/MS/MS method was found to be adequately sensitive and therefore suitable for application in routine motesanib pharmacokinetic studies.


Assuntos
Antineoplásicos/sangue , Indóis/sangue , Niacinamida/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Administração Oral , Animais , Antineoplásicos/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Indóis/farmacocinética , Limite de Detecção , Extração Líquido-Líquido , Masculino , Niacinamida/sangue , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Ratos Wistar , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
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