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1.
Adv Chronic Kidney Dis ; 27(5): 434-441, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33308510

RESUMO

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Insuficiência Renal Crônica/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , /prevenção & controle , /uso terapêutico , Cloroquina/uso terapêutico , Creatinina/metabolismo , Citidina/análogos & derivados , Citidina/uso terapêutico , Dexametasona/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Hidroxicloroquina/uso terapêutico , Hidroxilaminas/uso terapêutico , Imunização Passiva , Interferons/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Lopinavir/uso terapêutico , Pirazinas/uso terapêutico , Eliminação Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico
2.
Expert Opin Investig Drugs ; 28(4): 311-322, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30879349

RESUMO

INTRODUCTION: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citidina/análogos & derivados , Neoplasias/tratamento farmacológico , Administração Oral , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Disponibilidade Biológica , Citidina/farmacocinética , Citidina/farmacologia , Citidina/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Humanos , Neoplasias/patologia , Seleção de Pacientes
3.
J Cosmet Dermatol ; 18(1): 278-285, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30291682

RESUMO

BACKGROUND: Melanocytes, which reside in the basal layer of the epidermis, produce the pigment melanin in cytoplasmic organelles known as melanosomes. Melanosomes are transferred to keratinocytes which provide the color in our skin. Recently, Diwakar et  al reported the crucial roles of protein glycosylation in both melanogenesis and melanosome transfer to keratinocytes, and each was inhibited by the nucleotide cytidine. OBJECTIVE: The main objective of this study was to determine the clinical effects of topical application of cytidine to the hyperpigmented regions of the face in a group of human volunteers. METHODS: A randomized, vehicle-controlled study was conducted for 12 weeks on healthy Korean female subjects. Cytidine was formulated into the lotion at concentrations of 2%, 3%, and 4% (w/w) and compared to the vehicle control formulation. The clinical outcomes were evaluated by performing visual assessment grading, measuring melanin index, skin brightness, and skin color parameters. In vitro skin penetration studies were conducted using Franz cell chambers for the 2% cytidine test formulation. RESULTS: The test group showed significant improvements in the visual assessment scores, melanin index, skin brightness, and skin color compared to the control group. Although significant dose-dependent improvements were seen in the clinical study, the in vitro Franz cell studies indicated that the clinical efficacy and potency of cytidine might be further enhanced by formulating a better topical delivery system, which will be the goal of our future studies. CONCLUSIONS: This randomized, double-blind, 12-week clinical study successfully demonstrated the efficacy of cytidine on skin depigmentation in a dose-dependent manner.


Assuntos
Citidina/uso terapêutico , Dermatoses Faciais/tratamento farmacológico , Hiperpigmentação/tratamento farmacológico , Preparações Clareadoras de Pele/uso terapêutico , Administração Cutânea , Adulto , Citidina/administração & dosagem , Citidina/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Permeabilidade , Preparações Clareadoras de Pele/administração & dosagem , Preparações Clareadoras de Pele/farmacocinética , Adulto Jovem
4.
Int J Mol Sci ; 18(10)2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29039788

RESUMO

Epigenetic inactivation of tumor suppressor genes (TSG) is a fundamental event in the pathogenesis of human cancer. This silencing is accomplished by aberrant chromatin modifications including DNA hypermethylation of the gene promoter. One of the most frequently hypermethylated TSG in human cancer is the Ras Association Domain Family 1A (RASSF1A) gene. Aberrant methylation of RASSF1A has been reported in melanoma, sarcoma and carcinoma of different tissues. RASSF1A hypermethylation has been correlated with tumor progression and poor prognosis. Reactivation of epigenetically silenced TSG has been suggested as a therapy in cancer treatment. In particular, natural compounds isolated from herbal extracts have been tested for their capacity to induce RASSF1A in cancer cells, through demethylation. Here, we review the treatment of cancer cells with natural supplements (e.g., methyl donors, vitamins and polyphenols) that have been utilized to revert or prevent the epigenetic silencing of RASSF1A. Moreover, we specify pathways that were involved in RASSF1A reactivation. Several of these compounds (e.g., reseveratol and curcumin) act by inhibiting the activity or expression of DNA methyltransferases and reactive RASSF1A in cancer. Thus natural compounds could serve as important agents in tumor prevention or cancer therapy. However, the exact epigenetic reactivation mechanism is still under investigation.


Assuntos
Produtos Biológicos/farmacologia , Metilação de DNA/efeitos dos fármacos , Genes Supressores de Tumor , Neoplasias/genética , Proteínas Supressoras de Tumor/genética , Animais , Citidina/farmacologia , Citidina/uso terapêutico , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Polifenóis/farmacologia , Vitaminas/farmacologia
5.
Biol Pharm Bull ; 40(8): 1320-1325, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28539527

RESUMO

The effects of zebularine, a DNA methyltransferase inhibitor, on the invasion activity as well as intracellular expression level of let-7b, tumor suppressor microRNA, were examined in three human colorectal cancer (CRC) cell lines: SW480, SW620, and oxaliplatin-resistant SW620 (SW620/OxR). Zebularine suppressed the invasion activity of SW620 and SW620/OxR cells. The intracellular expression level of let-7b was up-regulated by zebularine in SW620 and SW620/OxR cells. The overexpression of let-7b by the transfection of let-7b mimic suppressed invasion activity in SW620 and SW620/OxR cells. These results suggest that zebularine may inhibit invasion activity by up-regulating the intracellular expression level of let-7b in high-invasive CRC cells.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Citidina/análogos & derivados , Inibidores Enzimáticos/farmacologia , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/patologia , Citidina/farmacologia , Citidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/uso terapêutico , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Humanos , Invasividade Neoplásica/prevenção & controle , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina , Transfecção , Regulação para Cima
6.
Cancer Treat Rev ; 54: 10-23, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28189913

RESUMO

BACKGROUND: It is assumed that DNA methylation plays a key role in both tumour development and therapy resistance. Demethylating agents have been shown to be effective in the treatment of haematological malignancies. Based on encouraging preclinical results, demethylating agents may also be effective in solid tumours. This systematic review summarizes the evidence of the effect of demethylating agents on clinical response, methylation and the immune system in solid tumours. METHODS: We conducted a systematic literature search from 1949 to December 2016, according to the PRISMA guidelines. Studies which evaluated treatment with azacitidine, decitabine, guadecitabine, hydralazine, procaine, MG98 and/or zebularine in patients with solid tumours were included. Data on clinical response, effects on methylation and immune response were extracted. RESULTS: Fifty-eight studies were included: in 13 studies complete responses (CR) were observed, 35 studies showed partial responses (PR), 47 studies stable disease (SD) and all studies except two showed progressive disease (PD). Effects on global methylation were observed in 11/15 studies and demethylation/re-expression of tumour specific genes was seen in 15/17 studies. No clear correlation between (de)methylation and clinical response was observed. In 14 studies immune-related responses were reported, such as re-expression of cancer-testis antigens and upregulation of interferon genes. CONCLUSION: Demethylating agents are able to improve clinical outcome and alter methylation status in patients with solid tumours. Although beneficial effect has been shown in individual patients, overall response is limited. Further research on biomarker predicting therapy efficacy is indicated, particularly in earlier stage and highly methylated tumours.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Citidina/análogos & derivados , Citidina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina , Humanos , Hidralazina/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Metilação/efeitos dos fármacos , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/radioterapia , Procaína/uso terapêutico , Resultado do Tratamento
7.
Antimicrob Agents Chemother ; 60(3): 1907-11, 2015 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-26711754

RESUMO

Prolonged norovirus shedding may occur in certain patients, such as organ transplant recipients. We established a mouse model for persistent norovirus infection (using the mouse norovirus MNV.CR6 strain). The nucleoside viral polymerase inhibitor 2'-C-methylcytidine (2CMC), but not favipiravir (T-705), reduced viral shedding to undetectable levels. Viral rebound was observed after stopping treatment, which was again effectively controlled by treatment with 2CMC. No drug-resistant variants emerged.


Assuntos
Infecções por Caliciviridae/tratamento farmacológico , Citidina/análogos & derivados , Gastroenterite/tratamento farmacológico , Norovirus/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos , Amidas/uso terapêutico , Animais , Infecções por Caliciviridae/virologia , Citidina/uso terapêutico , Modelos Animais de Doenças , Fezes/virologia , Gastroenterite/virologia , Camundongos , Camundongos Knockout , Norovirus/crescimento & desenvolvimento , Pirazinas/uso terapêutico , Receptores de Interferon/genética , Transplantados
8.
Cochrane Database Syst Rev ; (9): CD011611, 2015 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-26415966

RESUMO

BACKGROUND: There is emerging evidence that glutamatergic system dysfunction might play an important role in the pathophysiology of bipolar depression. This review focuses on the use of glutamate receptor modulators for depression in bipolar disorder. OBJECTIVES: 1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder.2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing acute depression symptoms. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR, to 9 January 2015). This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We cross-checked reference lists of relevant papers and systematic reviews. We did not apply any restrictions to date, language or publication status. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing ketamine, memantine, or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes for this review were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. We contacted study authors for additional information. MAIN RESULTS: Five studies (329 participants) were included in this review. All included studies were placebo-controlled and two-armed, and the glutamate receptor modulators - ketamine (two trials), memantine (two trials), and cytidine (one trial) - were used as add-on drugs to mood stabilisers. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for memantine and cytidine (8 to 12 weeks, and 12 weeks, respectively). Three of the studies took place in the USA, one in Taiwan, and in one, the location was unclear. The majority (70.5%) of participants were from Taiwan. All participants had a primary diagnosis of bipolar disorder, according to the DSM-IV or DSM-IV-TR, and were in a current depressive phase. The severity of depression was at least moderate in all but one study.Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after the infusion for the primary outcome, response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; I² = 0%, 2 studies, 33 participants). This evidence was rated as low quality. The statistically significant difference disappeared at three days, but the mean estimate still favoured ketamine (OR 8.24, 95% CI 0.84 to 80.61; 2 studies, 33 participants; very low quality evidence). We found no difference in response between ketamine and placebo at one week (OR 4.00, 95% CI 0.33 to 48.66; P = 0.28, 1 study; 18 participants; very low quality evidence).There was no significant difference between memantine and placebo in response rate one week after treatment (OR 1.08, 95% CI 0.06 to 19.05; P = 0.96, 1 study, 29 participants), two weeks (OR 4.88, 95% CI 0.78 to 30.29; P = 0.09, 1 study, 29 participants), four weeks (OR 5.33, 95% CI 1.02 to 27.76; P = 0.05, 1 study, 29 participants), or at three months (OR, 1.66, 95% CI 0.69 to 4.03; P = 0.26, I² = 36%, 2 studies, 261 participants). These findings were based on very low quality evidence.There was no significant difference between cytidine and placebo in response rate at three months (OR, 1.13, 95% CI 0.30 to 4.24; P = 0.86, 1 study, 35 participants; very low quality evidence).For the secondary outcome of remission, no significant differences were found between ketamine and placebo, nor between memantine and placebo. For the secondary outcome of change scores from baseline on depression scales, ketamine was more effective than placebo at 24 hours (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005, 2 studies, 32 participants) but not at one or two weeks after treatment. There was no difference between memantine and placebo for this outcome.We found no significant differences in terms of adverse events between placebo and ketamine, memantine, or cytidine. There were no differences between ketamine and placebo, memantine and placebo, or cytidine and placebo in total dropouts. No data were available on dropouts due to adverse effects for ketamine or cytidine; but no difference was found between memantine and placebo. AUTHORS' CONCLUSIONS: Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did not show any better efficacy in terms of remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. Ketamine's psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.We did not find conclusive evidence on adverse events with ketamine. To draw more robust conclusions, further RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine and to study different methods of sustaining antidepressant response, such as repeated administrations. There was not enough evidence to draw meaningful conclusions for the remaining two glutamate receptor modulators (memantine and cytidine). This review is limited not only by completeness of evidence, but also by the low to very low quality of the available evidence.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Citidina/uso terapêutico , Depressão/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Memantina/uso terapêutico , Adulto , Transtorno Bipolar/psicologia , Depressão/psicologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Transl Stroke Res ; 6(4): 296-300, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25824538

RESUMO

5-Aza-deoxycytidine (5-aza-dC) confers neuroprotection in ischemic mice by inhibiting DNA methylation. Zebularine is another DNA methylation inhibitor, less toxic and more stable in aqueous solutions and, therefore more biologically suitable. We investigated Zebularine's effects on brain ischemia in a rat middle cerebral artery occlusion (MCAo) model in order to elucidate its therapeutic potential. Male Wistar wild-type (WT) rats were randomly allocated to three treatment groups, vehicle, Zebularine 100 µg, and Zebularine 500 µg. Saline (10 µL) or Zebularine (10 µL) was administered intracerebroventricularly 20 min before 45-min occlusion of the middle cerebral artery. Reperfusion was allowed after 45-min occlusion, and the rats were sacrificed at 24-h reperfusion. The brains were removed, sliced, and stained with 2% 2,3,5-triphenyltetrazolium chloride (TTC) before measuring infarct size. Zebularine (500 µg) reduced infarct volumes significantly (p < 0.05) by 61% from 20.7 ± 4.2% in the vehicle treated to 8.1 ± 1.6% in the Zebularine treated. Zebularine (100 µg) also reduced infarct volumes dramatically by 55 to 9.4 ± 1.2%. The mechanisms behind this neuroprotection is not yet known, but the results agree with previous studies and support the notion that Zebularine-induced inhibition of DNA methyltransferase ameliorates ischemic brain injury in rats.


Assuntos
Citidina/análogos & derivados , Inibidores Enzimáticos/uso terapêutico , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Análise de Variância , Animais , Infarto Encefálico/etiologia , Infarto Encefálico/prevenção & controle , Citidina/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Reperfusão
11.
J Med Chem ; 58(9): 3693-703, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25905540

RESUMO

A series of 4-substituted fluoronucleosides have been synthesized in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound exhibited a significantly improved toxicity profile. Administered orally, compound 1f was well-tolerated at a dose up to 3 g/kg and showed insignificant toxicity on white blood cells and a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day (5 days). In duck HBV (DHBV)-infected duck models, both the serum and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly reduced by the treatment of 1f at a dose of 1 mg/kg/day for 10 days. In addition, both the viral DNA levels had a lower degree of recovery after withdrawal of the test compound for 3 days.


Assuntos
Antivirais/química , Citidina/análogos & derivados , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B/tratamento farmacológico , Nucleosídeos/química , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Citidina/química , Citidina/farmacologia , Citidina/uso terapêutico , Replicação do DNA/efeitos dos fármacos , DNA Viral/metabolismo , Patos , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Contagem de Leucócitos , Camundongos , Modelos Moleculares , Testes de Mutagenicidade , Nucleosídeos/farmacologia , Nucleosídeos/uso terapêutico , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Testes de Toxicidade Aguda
12.
J Antimicrob Chemother ; 70(1): 190-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25228588

RESUMO

OBJECTIVES: Norovirus outbreaks of acute gastroenteritis are highly prevalent, extensive and can disturb the functioning of health institutions, leading to the closure of hospital wards and causing life-threatening infections in long-term care facilities. There is no vaccine available; hence there is a pressing need for antivirals for the treatment (in immunodeficient patients) and prophylaxis of norovirus infections. We explored in a mouse model whether an inhibitor of norovirus replication can prevent/reduce transmission of the virus. METHODS: We reported recently that the viral polymerase inhibitor 2'-C-methylcytidine (2CMC) efficiently protects against murine norovirus (MNV)-induced diarrhoea and mortality in mice. Here, we established an MNV-transmission model, determined the 50% infectious dose and assessed the ability of an antiviral molecule to prevent or reduce transmission of (murine) norovirus when given either to the infected (seeder) mice or to the uninfected (sentinel) mice. RESULTS: A robust norovirus transmission model was established using genogroup V (murine) norovirus in AG129 mice. The 50% infectious dose was determined to be ∼ 270 CCID50 (50% cell culture infectious dose). Treatment of infected mice with 2CMC reduced viral shedding and markedly reduced transmission to uninfected sentinels. Also, prophylactic treatment of sentinels with 2CMC resulted in protection against infection with MNV. CONCLUSIONS: These findings constitute an important first step towards developing an efficient prophylaxis for the control of norovirus outbreaks.


Assuntos
Antivirais/uso terapêutico , Infecções por Caliciviridae/prevenção & controle , Quimioprevenção/métodos , Citidina/análogos & derivados , Norovirus/efeitos dos fármacos , Animais , Citidina/uso terapêutico , Diarreia/prevenção & controle , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Análise de Sobrevida
13.
Anticancer Res ; 34(12): 6951-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25503121

RESUMO

RX-3117 (fluorocyclopentenylcytosine) is a cytidine analog and this class of drugs, including gemcitabine, has been widely used for the treatment of various types of cancers. However, there is no oral formulation of gemcitabine and drug resistance to gemcitabine is common. In this study, the efficacy of orally-administered RX-3117 was examined in 9 different human tumor xenograft models (colon, non-small cell lung, small cell lung, pancreatic, renal and cervical), grown subcutaneously in athymic nude mice. In the Colo 205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 30%, 25% and 0% tumor growth inhibition (TGI), respectively, whereas oral treatment with RX-3117 induced 100%, 78%, 62% and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. RX-3117 was also evaluated in a single primary low-passage human pancreatic Tumorgraft™CTG-0298 (TGI 76%), which is relatively resistant to gemcitabine (TGI 38%) and has a favorable RX-3117-activating enzyme profile. These studies demonstrated the therapeutic potential and anticancer efficacy of RX-3117.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Citidina/análogos & derivados , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular Tumoral , Citidina/administração & dosagem , Citidina/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Modelos Animais de Doenças , Feminino , Células HCT116 , Células HT29 , Humanos , Camundongos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
14.
BMC Vet Res ; 10: 290, 2014 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-25480665

RESUMO

BACKGROUND: The antimetabolite 6-thioguanine (6-TG) has been used to treat both human and canine lymphoid malignancies. 6-TG has been shown to be epigenetically active as a demethylating agent in a human lymphoma cell line, causing downregulation of DNA methyltransferase 1 (DNMT1) through ubiquitin-targeted degradation. Zebularine (Zeb), a similar cytidine analog, also has demethylating activity as well as oral bioavailability. The hypothesis of the present study was that 6-TG and Zeb would cause downregulation of DNMT1 and globally demethylate the genomic DNA of canine lymphoma cells. The secondary hypothesis was that these agents would cause a dose-dependent decrease in cell proliferation in canine lymphoma cells. Canine CLGL-90 malignant T cells and CLL 17-7 cells were incubated in modified RPMI media. They were treated with 6-TG, Zeb, or control media at biologically relevant concentrations. RESULTS: Following treatment with each agent, DNMT1 protein and global DNA methylation were significantly decreased. A dose-dependent decrease in cell survival was also observed, with apoptosis being the primary mode of cell death in the CLGL-90 cell line. CONCLUSIONS: These results confirm the demethylating action of 6-TG and Zeb in canine cells which is similar to that shown in human cell lines. Confirmation of this mechanism supports the clinical application of these compounds as demethylating drugs in veterinary patients.


Assuntos
Antineoplásicos/farmacologia , Citidina/análogos & derivados , DNA-Citosina Metilases/antagonistas & inibidores , Doenças do Cão/tratamento farmacológico , Linfoma/veterinária , Tioguanina/farmacologia , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citidina/farmacologia , Citidina/uso terapêutico , Cães , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/veterinária , Leucemia de Células T/tratamento farmacológico , Leucemia de Células T/veterinária , Linfoma/tratamento farmacológico , Tioguanina/uso terapêutico
15.
Expert Opin Pharmacother ; 15(16): 2361-72, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25256052

RESUMO

INTRODUCTION: Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance. AREAS COVERED: Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies. EXPERT OPINION: Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Complexos de Coordenação/uso terapêutico , Citidina/análogos & derivados , Citidina/uso terapêutico , Sistemas de Liberação de Medicamentos , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Humanos , Nanoestruturas , Compostos Organoplatínicos/uso terapêutico , Compostos de Platina/uso terapêutico , Pirimidinas/uso terapêutico , Timidina/análogos & derivados , Timidina/uso terapêutico
16.
PLoS One ; 9(3): e92305, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24676085

RESUMO

DNA methylation is an epigenetic phenomenon known to play an important role in the development and progression of human cancer. Enzyme responsible for this process is DNA methyltransferase 1 (DNMT1) that maintains an altered methylation pattern by copying it from parent to daughter DNA strands after replication. Aberrant methylation of the promoter regions of genes critical for normal cellular functions is potentially reversible. Therefore, inactivation of DNMT1 seems to be a valuable target for the development of cancer therapies. Currently, the most popular DNMT inhibitors (DNMTi) are cytidine analogues like 5-azacytidine, 5-aza-2'-deoxycytidine (decitabine) and pyrimidin-2-one ribonucleoside (zebularine). In colorectal cancer, epigenetic modifications play an essential role at each step of carcinogenesis. Therefore, we have addressed the hypothesis that DNA methyltransferase inhibitors may potentiate inhibitory effects of classical chemotherapeutic agents, such as oxaliplatin and 5-fluorouracil (5-FU), commonly used in colorectal cancer therapy. Here, our report shows that DNMTi can have positive interactions with standard chemotherapeutics in colorectal cancer treatment. Using pharmacological models for the drug-drug interaction analysis, we have revealed that the combination of decitabine with 5-FU or oxaliplatin shows the most attractive interaction (synergism), whereas the effect of zebularine in combinations with chemotherapeutics is moderate and may be depended on genetic/epigenetic background of a cell line or secondary drug used in combination. Our results suggest that DNMTi administered in combination with standard chemotherapeutics might improve the treatment of patients with colorectal cancers.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , DNA-Citosina Metilases/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Apoptose , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Citidina/análogos & derivados , Citidina/uso terapêutico , Dano ao DNA , Decitabina , Fluoruracila/uso terapêutico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina
17.
Invest New Drugs ; 32(1): 154-9, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23609829

RESUMO

BACKGROUND: TAS-106 was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III. METHODS: This was a single-center, open-label, phase I study to identify the maximum tolerated dose (MTD), pharmacokinetics, and biologic effects of the combination of TAS-106 and carboplatin, following a standard 3 + 3 design. This phase I trial was comprised of a regimen of a 60-min IV infusion of carboplatin on day 1 of each 21-day cycle followed by a 24-h infusion of TAS-106, also on day 1 of each cycle. RESULTS: 39 patients were treated (21 male, 18 female, median age 62 years, range 21-80 years). Median number of prior therapies was 4. Maximum Tolerated Dose (MTD) was 3 mg/m(2) TAS-106 with AU 4 carboplatin. Dose-limiting toxicities were neutropenia and thrombocytopenia, with and without growth factor support. While no patients achieved a complete or partial response, four patients had stable disease lasting ≥4 months, including one patient each with ovarian, non-small cell lung, basal cell and colorectal cancer. CONCLUSIONS: In summary, the combination of TAS-106 and carboplatin was well-tolerated, and further studies in non-small cell lung and ovarian cancer are warranted to assess the efficacy of this drug combination.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Citidina/análogos & derivados , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Citidina/administração & dosagem , Citidina/efeitos adversos , Citidina/farmacocinética , Citidina/uso terapêutico , Demografia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Sistema Nervoso/patologia , Adulto Jovem
18.
Transbound Emerg Dis ; 61(6): e89-91, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23480064

RESUMO

Recent European contingency plans envisage emergency vaccination as an animal-friendly control strategy for foot-and-mouth disease (FMD). Anti-viral drugs may be used as an alternative or complementary measure. We here demonstrate that the nucleoside analogue 2'-C-methylcytidine (2'CMC) protects severe combined immunodeficient (SCID) mice against lethal FMD virus infection. In brief, SCID mice were inoculated with serotype A FMD virus and treated for five consecutive days with 2'CMC. All 15 treated mice remained healthy until the end of the study at 14 days post-infection (dpi). At that time, viral RNA was no longer detected in 13 of 15 treated mice. All eight untreated mice suffered from an acute generalized disease and were euthanized for ethical reasons on average at 4 dpi. These results illustrate the potential of small molecules to control FMD.


Assuntos
Antivirais/uso terapêutico , Citidina/análogos & derivados , Vírus da Febre Aftosa/efeitos dos fármacos , Febre Aftosa/tratamento farmacológico , Animais , Citidina/uso terapêutico , Modelos Animais de Doenças , Febre Aftosa/virologia , Camundongos , Camundongos SCID , RNA Viral/análise
19.
Belo Horizonte; CCATES; 2014. tab.
Não convencional em Português | BRISA/RedTESA | ID: biblio-879200

RESUMO

TECNOLOGIAS: Medicamento Pregabalina e medicamento com Vitamina B12 associada à citidina e uridina (ETNA®). INDICAÇÃO: Tratamento da dor neuropática diabética. CARACTERIZAÇÃO DAS TECNOLOGIAS: A pregabalina é um anticonvulsivante indicado, entre outros, para o tratamento da dor neuropática em adultos. Seu mecanismo de ação é a redução do influxo de cálcio para regular a transmissão de mensagens excitatórias entre as células nervosas. O medicamento ETNA® é uma combinação de vitamina B12, e nucleotídeos uridina e citidina e é indicado para o tratamento de doenças dos nervos periféricos. PERGUNTA: As intervenções pregabalina e ETNA® são seguras, eficazes e custo-efetivas no tratamento da dor neuropática diabética, em relação às alternativas gabapentina e amitriptilina já disponíveis no SUS? BUSCA E ANÁLISE DE EVIDÊNCIAS CIENTÍFICAS: Foi realizada uma busca por revisões sistemáticas e estudos econômicos nas bases de dados The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS e Centre for Reviews and Dissemination (CRD). Foi realizada também busca manual na internet e nas referências dos estudos encontrados. Foram selecionadas avaliações de tecnologias em saúde (ATS) em sites de agências internacionais e na Rede Brasileira de Avaliação de Tecnologias em Saúde (REBRATS). Foram selecionados estudos publicados em inglês, português ou espanhol. RESUMO DOS RESULTADOS DOS ESTUDOS SELECIONADOS: Foram incluídos nove estudos: quatro revisões sistemáticas, um ensaio clínico e quatro estudos econômicos. As revisões sistemáticas que consideraram a eficácia e segurança da pregabalina avaliaram como desfechos a redução na intensidade da dor, a taxa de resposta ao tratamento (≥50% na redução da dor), a impressão do paciente em relação à melhora e eventos adversos. Essas revisões apresentaram resultados a favor da pregabalina, porém em relação ao placebo. O ensaio clínico que avaliou a eficácia e segurança do medicamento ETNA® mostrou resultados a favor dessa intervenção, porém comparado somente à vitamina B12. Os resultados de custo-efetividade para a pregabalina consideraram como medida de efetividade o número de dias sem dor ou com dor leve, o número de dias com 30% e 50% de redução de dor e QALY (Anos de Visa Ajustados por Qualidade) ganhos. Apenas um estudo de custo-efetividade não favoreceu a pregabalina. RECOMENDAÇÕES: O tratamento da dor neuropática diabética é contemplado pelo Protocolo Clínico e Diretrizes Terapêuticas da Dor Crônica, o qual recomenda o medicamento amitriptilina em monoterapia (primeira escolha) ou a associação desta com gabapentina, em caso de falha terapêutica da monoterapia. As evidências avaliadas neste PTC permitem recomendar (fracamente) a pregabalina em substituição à gabapentina apenas em casos de falha terapêutica dos esquemas citados anteriormente, uma vez que nenhum estudo incluiu comparações diretas entre pregabalina e amitriptilina ou gabapentina, não comprovando haver superioridade terapêutica da tecnologia em relação aos medicamentos já disponíveis no SUS. Quanto ao ETNA®, a recomendação é contra o seu uso devido à escassez de estudos com evidências de qualidade suficiente para garantir a eficácia e segurança terapêutica dessa intervenção e justificar o gasto.(AU)


TECHNOLOGIES: Pregabalin and vitamin B12 associated with uridine and cytidine (ETNA®) . INDICATION: Treatment of diabetic neuropathic pain. TECHNOLOGIES CHARACTERIZATION: Pregabalin is an anticonvulsant indicated for the treatment of neuropathic pain in adults. Its mechanism of action is the reduction of calcium influx to regulate transmission of excitatory messages between nerve cells. ETNA ® is a combination of vitamin B12, uridine and cytidine nucleotides and it is indicated for the treatment of peripheral nerves diseases. QUESTION: Are ETNA ® and pregabalin safe, effective and cost-effective options in the treatment of diabetic neuropathic pain, regarding the alternatives amitriptyline and gabapentin available at SUS? SEARCH AND ANALYSIS OF SCIENTIFIC EVIDENCE: a search for systematic reviews and economic studies was performed in the databases The Cochrane Library (via Bireme), Medline (via Pubmed), LILACS and Centre for Reviews and Dissemination (CRD). Manual search was also conducted on the internet and in the references of the studies found. Health Technology Assessments (HTA) have been selected in international agencies and in Brazilian Network for Health Technology Assessment (REBRATS). Studies published in English, Portuguese or Spanish were selected. SUMMARY OF RESULTS OF THE SELECTED STUDIES: Nine studies were included, four systematic reviews, one clinical trial and four economic studies. Systematic reviews considering efficacy and safety of pregabalin evaluated the following outcomes: reduction in pain intensity, treatment response rate (≥50% on pain reduction), the Patient Global Impression of Change and adverse events. These reviews showed results in favor of pregabalin compared to placebo. The ETNA® Clinical trial showed results in favor of the intervention but compared to vitamin B12 alone. The results of cost-effectiveness for pregabalin considered as a measure of effectiveness the number of days with no pain or mild pain, the number of days with 30% and 50% reduction in pain and QALY gains. Only one cost-effectiveness study has not favored pregabalin. RECOMMENDATIONS: The treatment for neuropathic pain is contemplated in the therapeutic guideline for chronic disease, which recommends the use of amitriptyline in monotherapy as first choice or its association with gabapentin in cases of therapeutic failure with the monotherapy. The evidences appraised here allow recommending (weakly) the use of pregabalin in replacement of gabapentin only in cases of therapeutic failure of the schemes mentioned above, since no study included direct comparisons between pregabalin and amitriptyline or gabapentin, making it impossible to support the therapeutic superiority of pregabalin compared to other drugs already used in Brazil. The recommendation is against ETNA® use due to lack of studies with sufficient evidence of quality to ensure the efficacy and safety of this intervention and justify the expense.(AU)


TECNOLOGÍAS: Pregabalina y vitamina B12 asociado a uridina y citidina (ETNA®). INDICACIÓN: Tratamiento de la neuropatía diabética. CARACTERIZACIÓN DE LAS TECNOLOGÍAS: La pregabalina es un anticonvulsivo indicado, entre otras cosas, para el tratamiento de la neuropatía diabética en adultos. Su mecanismo de acción es la reducción de la afluencia de calcio para regular la transmisión de mensajes excitatorios entre las células nerviosas. ETNA ® es una combinación de vitamina B12 y de nucleótidos de uridina y citidina y está indicado para el tratamiento de enfermedades de los nervios periféricos. PREGUNTA: ¿Las intervenciones pregabalina y ETNA ® son seguros, eficaces y coste-efectiva en el tratamiento de la neuropatía diabética, en comparación con las alternativas gabapentina y amitriptylina ya disponible en el SUS? BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: una búsqueda de revisiones sistemáticas y estudios económicos se realizó en las bases de datos de la Cochrane Library (vía Bireme), MEDLINE (vía PubMed), LILACS y Centre for Reviews and Dissemination (CRD). Búsqueda manual también se llevó a cabo. Comentarios de las tecnologías de la salud han sido seleccionadas en las agencias internacionales y en la Red Brasileña de Evaluación de Tecnologías Sanitarias (REBRATS). Se seleccionaron los estudios publicados en inglés, portugués o español. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Se incluyeron nueve estudios, cuatro revisiones sistemáticas, un ensayo clínico y cuatro estudios económicos. Revisiones sistemáticas de eficacia e seguridad de pregabalina encontraron como resultados la reducción de la intensidad del dolor, la tasa de respuesta al tratamiento, la impresión del paciente con respecto a la mejora y los eventos adversos. Estos exámenes mostraron resultados a favor de la pregabalina, pero en relación con el placebo. El ensayo clínico que evaluó la eficacia de la droga ETNA ® mostró resultados a favor de la intervención, pero en comparación con la vitamina B12 en monoterapia. Los resultados de coste-efectividad de pregabalina han considerado como una medida de efectividad el número de días sin dolor o dolor leve , el número de días con 30 % y 50% de reducción en el dolor y AVAC (años de vida ajustado por calidad) . Sólo un estudio de costo-efectividad no ha favorecido la pregabalina. RECOMENDACIONES: El tratamiento de la neuropatía diabética se contempla en las guías clínicas y terapéuticas del dolor crónico, que recomienda el uso de amitriptylina en monoterapia (primera elección) o asociado con la gabapentina, en caso de fracaso terapéutico con la monoterapia. Las evidencias evaluadas aquí permiten recomendar (débilmente) el uso de pregabalina en el reemplazo de la gabapentina sólo en casos de fracaso terapéutico de los sistemas antes mencionados, ya que ningún estudio incluyó comparaciones directas entre pregabalina y amitriptilina o gabapentina, no probando superioridad terapéutica de la pregabalina en comparación con otros fármacos ya utilizados en Brasil. En cuanto a ETNA, la recomendación es contra su uso debido a la falta de estudios con pruebas de calidad suficiente para garantizar la eficacia y seguridad de esta intervención y justificar el gasto.(AU)


Assuntos
Humanos , Amitriptilina/uso terapêutico , Citidina/uso terapêutico , Neuropatias Diabéticas/tratamento farmacológico , Dor , Pregabalina/uso terapêutico , Uridina/uso terapêutico , Vitamina B 12/uso terapêutico , Análise Custo-Benefício/economia , Avaliação em Saúde , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde
20.
Oncology ; 85(6): 356-63, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24335431

RESUMO

5-Fluorouracil, other fluorinated pyrimidines and their derivatives are frequently used in chemotherapy to treat different types of cancer. These agents are classified as metabolic antagonists that target the DNA synthesis phase of the cell cycle. Therefore, these agents are more effective in rapidly growing tumors than in more indolent cancers. In order to develop new drugs that interfere with both DNA and RNA synthesis, the metabolism of pyrimidines was investigated, and new compounds were developed by the molecular design method, which analyzes the biochemical properties of the compounds. The nucleoside 3'-C-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III, which occur throughout the cell cycle except for the M phase. This review article discusses the antitumor activity of TAS-106 as a single agent or in combination therapy with the focus on preclinical and clinical findings.


Assuntos
Antineoplásicos/farmacologia , Citidina/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Citidina/farmacologia , Citidina/uso terapêutico , Humanos
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