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1.
Vet Parasitol ; 273: 11-16, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31442887

RESUMO

Heartworm infection (also known as dirofilariosis due to Dirofilaria immitis) in dogs causes chronic pulmonary disease that, if left untreated, can lead to right-side congestive heart failure. Currently, the only registered drug for adulticide therapy in dogs with heartworm disease (HWD) is melarsomine dihydrochloride. The recent targeting of the bacterial endosymbiont Wolbachia, through antibiotic therapy of the infected host, has offered an interesting alternative for the treatment of HWD. Recent reports of the adulticide activity of an ivermectin/doxycycline combination protocol has lead the American Heartworm Society (AHS) to include in its guidelines that, in cases where arsenical therapy is not possible or is contraindicated, a monthly heartworm preventive along with doxycycline for a 4-week period might be considered. In the present study, 20 dogs with confirmed natural D. immitis infection were included following owner consent. Fourteen dogs were treated with a topical formulation containing 10% w/v imidacloprid and 2.5% w/v moxidectin (Advocate®, Advantage Multi®, Bayer), monthly for nine months, associated to doxycycline (10 mg/kg/BID) for the first 30 days. Six dogs were treated with melarsomine (Immiticide®, Merial) (2.5 mg/kg) at enrollment, followed one month later by two injections 24 h apart. The presence of circulating antigens and the number of microfilariae (mf) were evaluated at the moment of enrollment and then at 1, 2, 3, 4, 5, 6, 7, 8, 12, 18, 24 months post enrollment. Echocardiogram and radiographs were performed at month 0, 6, 12, 18, 24. Monthly moxidectin combined with 30 days of doxycycline eliminated circulating microfilariae within one month, thus breaking the transmission cycle very quickly. Furthermore, dogs treated with the combination protocol started to become negative for circulating antigens at 4 months from the beginning of treatment and all except one were antigen negative at 9 months. All dogs treated with melarsomine were antigen negative by 5 months from the beginning of the treatment. No dogs showed worsening of pulmonary patterns or criteria indicative of pulmonary hypertension 12 to 24 months after. For the criteria mf concentration, antigen concentration, radiography and echocardiography at 12, 18 and 24 months the non-inferiority for the moxidectin group could be proven for a non-inferiority margin of 15% for the rate difference. Dogs treated with moxidectin and doxycycline became negative for microfilariae and antigens sooner when compared to melarsomine in the present study and to dogs treated with doxycycline combined with ivermectin in studies previously published.


Assuntos
Dirofilariose/tratamento farmacológico , Doxiciclina/uso terapêutico , Macrolídeos/uso terapêutico , Neonicotinoides/uso terapêutico , Nitrocompostos/uso terapêutico , Animais , Antígenos de Helmintos/sangue , Arsenicais/uso terapêutico , Dirofilaria immitis , Doenças do Cão/tratamento farmacológico , Cães , Quimioterapia Combinada , Feminino , Filaricidas/uso terapêutico , Masculino , Fatores de Tempo , Resultado do Tratamento , Triazinas/uso terapêutico
2.
Expert Opin Pharmacother ; 20(16): 1935-1942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454277

RESUMO

Introduction: Despite recent progress, the prognosis of acute myeloid leukemia remains poor, mainly in older and in relapsed/refractory patients. Recently, a large number of novel agents have been developed thanks to a better understanding of its pathogenesis. Among these, the potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib (formerly AG-221), has demonstrated promising antileukemic activity by targeting IDH2 mutations. Area covered: This review describes the mechanisms of action, the pharmacodynamic and pharmacokinetic properties, the safety, and efficacy of enasidenib. Phase I/II/III clinical trials are also reported and discussed. Expert opinion: Enasidenib is a novel agent able to differentiate leukemic blasts in functional, maturating cells. This drug is characterized by oral bioavailability and good tolerability. As a monotherapy, it demonstrates clinical and laboratorial improvement, in 19.6% and 38.8% of cases respectively. Differentiation syndrome is the most relevant, potentially life-threatening side effect, which physicians must be aware of. The authors believe that the way forwards now is to explore the role of enasidenib as a chemoresistance revertant when associated with chemotherapy, as a 'bridge to transplant' or when associated other novel agents if we wish to maximize its use.


Assuntos
Aminopiridinas/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Triazinas/uso terapêutico , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Ensaios Clínicos como Assunto , Aprovação de Drogas , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Meia-Vida , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/metabolismo , Prognóstico , Resultado do Tratamento , Triazinas/efeitos adversos , Triazinas/farmacocinética
3.
Chem Asian J ; 14(22): 3962-3968, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31389664

RESUMO

Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity.


Assuntos
Adenina/análogos & derivados , Antivirais/química , Guanina/análogos & derivados , Febres Hemorrágicas Virais/tratamento farmacológico , Adenina/farmacologia , Adenina/uso terapêutico , Amidas/química , Amidas/metabolismo , Amidas/farmacologia , Amidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Pareamento de Bases , Ebolavirus/efeitos dos fármacos , Guanina/farmacologia , Guanina/uso terapêutico , Humanos , Nucleotídeos/química , Nucleotídeos/uso terapêutico , Ácidos Fosfóricos/química , Ácidos Fosfóricos/uso terapêutico , Pirazinas/química , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Triazinas/química , Triazinas/uso terapêutico
4.
Nursing ; 49(8): 24-32, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268951
5.
Best Pract Res Clin Haematol ; 32(2): 145-153, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31203996

RESUMO

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/uso terapêutico , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Ensaios Clínicos como Assunto , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridinas/uso terapêutico , Triazinas/uso terapêutico
6.
Drugs Today (Barc) ; 55(6): 359-366, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31250840

RESUMO

Baloxavir marboxil is a newly approved antiviral agent with activity against influenza via a novel mechanism of action of inhibition of cap-dependent endonuclease (CEN). The novel agent was approved in October of 2018 in the United States for the treatment of acute uncomplicated influenza A and B in patients aged 12 years or older. Baloxavir is given as a single weight-based dose of 40 mg orally once for patients weighing less than 80 kg and 80 mg orally once for those weighing 80 kg or more within 48 hours of symptom onset. In comparison with current therapy, baloxavir is as effective in decreasing time to symptom alleviation as the drug of choice, oseltamivir, and significantly reduces viral load 1 day after treatment compared with placebo and oseltamivir. In safety analyses baloxavir was well tolerated with only mild adverse events reported (nausea, headache, diarrhea, bronchitis, nasopharyngitis), thus providing a safe and reliable alternative option to current therapy for acute uncomplicated influenza. Further studies are being conducted to evaluate the use of baloxavir in additional patient populations including pediatric patients less than 12 years of age and patients who are at high risk of complications related to influenza.


Assuntos
Antivirais/uso terapêutico , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Diarreia , Humanos
8.
J Vet Cardiol ; 23: 96-103, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31174734

RESUMO

Four dogs, referred for management of heartworm (HW) disease, were found to have HWs entangled in their tricuspid valve apparatus. None of the dogs were actively hemolyzing or showed signs of acute cardiovascular collapse that would have necessitated emergency transvenous HW extraction, and surgery was not performed at time of presentation. The dogs received pimobendan and sildenafil within 24 h of identifying HW in the tricuspid valve apparatus, and the HW moved to the pulmonary arteries within 2 days in most cases (median 2 days, range 1-14 days). All dogs survived to discharge from the original hospital admission and were subsequently treated with adulticide (melarsomine) without complication. All dogs were HW antigen negative 6 months after their last melarsomine injection. Four dogs appeared to respond positively to medical management aimed at decreasing pulmonary arterial pressure and improving the right ventricular function, but movement of HW out of the heart for other reasons cannot be excluded. This therapeutic option is not advised when dogs with HW disease are presented for acute collapse, ongoing hemolysis, and hypotension as surgical extraction is still considered the best option in these cases. It remains unknown if medical management is a safe option for all dogs with intracardiac HW without clinical signs of caval syndrome. Controlled prospective studies are required to determine the efficacy and safety of this treatment regimen in comparison with surgical extraction.


Assuntos
Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Piridazinas/uso terapêutico , Citrato de Sildenafila/uso terapêutico , Animais , Antígenos de Helmintos/sangue , Arsenicais/uso terapêutico , Dirofilaria/imunologia , Cães , Feminino , Filaricidas/uso terapêutico , Masculino , Triazinas/uso terapêutico , Valva Tricúspide/parasitologia , Vasodilatadores/uso terapêutico
9.
Cancer Immunol Immunother ; 68(7): 1133-1141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31139925

RESUMO

Advanced oral squamous cell carcinomas (OSCC) have limited therapeutic options. Although immune therapies are emerging as a potentially effective alternative or adjunct to chemotherapies, the therapeutic efficacy of combination immune chemotherapies has yet to be determined. Using a 4-nitroquinolone-N-oxide (4NQO) orthotopic model of OSCC in immunocompetent mice, we evaluated the therapeutic efficacy of single- and combined-agent treatment with a poly-epitope tumor peptide vaccine, cisplatin and/or an A2AR inhibitor, ZM241385. The monotherapies or their combinations resulted in a partial inhibition of tumor growth and, in some cases, a significant but transient upregulation of systemic anti-tumor CD8+ T cell responses. These responses eroded in the face of expanding immunoregulatory cell populations at later stages of tumor progression. Our findings support the need for the further development of combinatorial therapeutic approaches that could more effectively silence dominant immune inhibitory pathways operating in OSCC and provide novel, more beneficial treatment options for this tumor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias Bucais/terapia , Neoplasias Experimentais/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Cisplatino/uso terapêutico , Terapia Combinada/métodos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do Tratamento , Triazinas/uso terapêutico , Triazóis/uso terapêutico , Vacinas de Subunidades/uso terapêutico
10.
Parasit Vectors ; 12(1): 272, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138327

RESUMO

BACKGROUND: Toltrazuril is frequently administered for the metaphylactic control of piglet cystoisosporosis. In a previous study, the efficacy of parenteral toltrazuril (45 mg/piglet, Group Forceris®) applied on the 2nd day of life (dol), and of oral toltrazuril (20 mg/kg of body weight, Group Baycox®) applied on the 4th dol was evaluated in an experimental model with Cystoisospora suis infection on the 3rd dol (late infection, LI). In a follow-up study, efficacy and safety were evaluated against infections with C. suis on the 1st dol (early infection, EI). Parameters included oocyst excretion and faecal consistency, body weight development, bacteriological examinations and animal health. RESULTS: All control piglets (n = 12) shed oocysts and had diarrhoea, while parasite excretion was completely suppressed in both treatment groups (n = 13 each) and diarrhoea was reduced to a single animal (Forceris® group), resulting in significant differences for these parameters between the treated groups and the controls without significant differences among the treatment groups. No treatment-related adverse events were noted. Body weight gain was reduced in the control group during the acute phase of infection, resulting in significantly lower body weight on the 15th dol. Sows and piglets shed high numbers of Escherichia coli. Clostridium perfringens type A was only detected in low amounts in pooled litter samples. In comparison to the LI study oocyst shedding was more intense in the control animals in EI, while diarrhea was more frequent in LI. In both infection models a high efficacy of toltrazuril in the control of parasitological and clinical outcomes of experimental C. suis infection could be demonstrated. Since in the LI study high numbers of Cl. perfringens type A were detected, it is hypothesized that colonization with these opportunistic pathogens has synergistic effects with C. suis and may explain variable clinical outcomes in untreated animals as well as the sporadic occurrence of diarrhea in toltrazuril-treated piglets. CONCLUSIONS: Parenteral and oral toltrazuril administered on the 2nd or 4th dol is safe and effective against experimental infections with C. suis on the 1st to 3rd dol. The clinical outcome of experimental infections seems influenced by bacterial coinfections.


Assuntos
Coccidiose/veterinária , Ferro/uso terapêutico , Sarcocystidae/efeitos dos fármacos , Doenças dos Suínos/tratamento farmacológico , Triazinas/uso terapêutico , Administração Oral , Animais , Animais Lactentes , Bactérias/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Coccidiose/tratamento farmacológico , Coinfecção , Modelos Animais de Doenças , Combinação de Medicamentos , Fezes/parasitologia , Feminino , Seguimentos , Injeções Intramusculares , Ferro/administração & dosagem , Oocistos/efeitos dos fármacos , Oocistos/isolamento & purificação , Distribuição Aleatória , Suínos , Doenças dos Suínos/parasitologia , Resultado do Tratamento , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Ganho de Peso
11.
J Parasitol ; 105(2): 371-378, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31033388

RESUMO

Sarcocystis neurona is a ubiquitous parasite in the eastern United States, which is the principal causative agent in the neurologic disorder equine protozoal myeloencephalitis (EPM). While much is known about this protozoa's life cycle in its natural host, the opossum (Didelphis virginiana), little is known of how it acts in the aberrant equine host, which displays a high incidence of exposure with a relatively low rate of morbidity. For this study, we employed the popular interferon gamma knockout mouse model to determine the potential for recrudescence of S. neurona infection after treatment with the anticoccidial drug diclazuril. Mice were infected with S. neurona merozoites, and 7-days post-infection (DPI) they were treated with diclazuril for 30 or 60 days or not treated at all. All infected non-treated mice developed neurologic signs consistent with S. neurona infection within 30 DPI. All diclazuril-treated infected mice remained clinically normal while on treatment but developed neurologic signs within 60 days of treatment cessation. Histological examination of cerebella from all infected mice demonstrated characteristic lesions of S. neurona infection, regardless of treatment status. Cerebellar samples collected from infected treated mice, displaying neurologic signs, produced viable S. neurona in culture. However, cerebellar samples collected from infected and neurologically normal mice at the end of a 30-day treatment period did not produce viable S. neurona in culture. Analysis of the humoral immune response in infected mice showed that during treatment IgM antibody production decreased, suggesting the organism was sequestered from immune surveillance. The cessation of treatment and subsequent development of neurologic disease resulted in increased IgM antibody production, suggesting recognition by the immune system at that time. Based on the study results the authors propose that diclazuril was able to inhibit the replication and migration of S. neurona but not fully eliminate the parasite, suggesting recrudescence of infection after treatment is possible.


Assuntos
Coccidiostáticos/uso terapêutico , Encefalomielite/parasitologia , Nitrilos/uso terapêutico , Sarcocystis/patogenicidade , Sarcocistose/parasitologia , Triazinas/uso terapêutico , Animais , Encéfalo/parasitologia , Cerebelo/parasitologia , Cerebelo/patologia , Coccidiostáticos/farmacologia , Encefalomielite/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Fezes/parasitologia , Feminino , Imunoglobulinas/sangue , Imuno-Histoquímica , Interferon gama/genética , Masculino , Camundongos , Camundongos Knockout , Nitrilos/farmacologia , Gambás/parasitologia , Recidiva , Sarcocystis/efeitos dos fármacos , Sarcocistose/tratamento farmacológico , Triazinas/farmacologia , Células Vero
12.
Vet Parasitol ; 267: 4-8, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30878083

RESUMO

The objective of present studies was to evaluate and compare the anticoccidial activity of triazine compounds in broiler chickens infected with E. tenella, E. necatrix, E. acervulina, E. maxima, and two field mixed Eimeria species. The anticoccidial efficacy was evaluated using the anticoccidial index (ACI). The results showed that Aminomizuril (AZL) and Ethanamizuril (EZL) were active metabolites of nitromezuril, which demonstrated excellent effectiveness against E. tenella, E. necatrix, E. acervulina, E. maxima, and the field Eimeria isolates in broiler chickens at a dosage of 10 mg/kg in feed. The anticoccidial activities of AZL and EZL at dose 10 mg/kg were roughly equivalent to the parent nitromezuril at a dosage of 3 mg/kg in feed. The decrease in metabolite anticoccidial activity is probably due to an increasing polarity of compounds in the metabolic processes. The sensitivity of two field Eimeria isolates to triazines EZL, diclazuril and toltrazuril was tested using 4 indices including anticoccidial index (ACI), percent of optimum anticoccidial activity (POAA), reduction of lesion scores (RLS) and relative oocysts production (ROP). Results showed that the sensitivity of EZL treatment against the two field Eimeria isolates were relatively superior to that of diclazuril and toltrazuril treatment. The field Eimeria isolates from Gansu Province was determined to be slightly, moderately and highly resistant to EZL, diclazuril and toltrazuril respectively. The field Eimeria isolates from Zhejiang Province was slightly, highly and slightly resistant to EZL, diclazuril and toltrazuril respectively. The results above indicated that the anticoccidial activity of metabolites was lower than that of the parent nitromezuril and there was partial cross-resistance among triazines EZL, diclazuril and toltrazuril. However the field Eimeria isolates had higher sensitive to EZL than the triazines diclazuril and toltrazuril. It was suggested that the site of C4 substituents of phenol of triazine anticoccidials may have important biological functions and the metabolite EZL would be a potential novel anticoccidial agent worthy of more attention.


Assuntos
Coccidiose/veterinária , Eimeria/efeitos dos fármacos , Doenças das Aves Domésticas/tratamento farmacológico , Triazinas/uso terapêutico , Animais , Galinhas/parasitologia , Coccidiose/tratamento farmacológico , Resistência a Medicamentos , Nitrilos/uso terapêutico , Oocistos/efeitos dos fármacos , Doenças das Aves Domésticas/parasitologia
13.
Medicine (Baltimore) ; 98(10): e14823, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30855507

RESUMO

RATIONALE: Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death worldwide. Its poor prognosis is due to the high invasiveness of the disease and limited efficacy of available treatments. PATIENT CONCERNS: We reported an HCC patient who developed lung metastases 1 year after HCC resection. Sorafenib was then initiated; however, disease progression was noted 3 months later. Sorafenib therapy was initially maintained due to lack of effective alternatives, but disease progression continued. DIAGNOSES: HCC patient with lung metastases, and pulmonary portal, and mediastinal lymph node metastases (stage IVB). INTERVENTIONS: Brivanib alaninate was used alone as second-line therapy. OUTCOMES: All metastases showed increased size on radiographic imaging approximately 3 months after brivanib alaninate was initiated. However, 2.5 months later, the lung metastases significantly decreased in size or disappeared. The pulmonary portal, and mediastinal lymph node metastases also significantly decreased in size. At 9.5 months after brivanib alaninate initiation, the pulmonary portal, and mediastinal lymph node metastases nearly disappeared, and the lung metastases continued to decrease in size. Alpha fetoprotein (AFP) level showed the same change pattern as the tumor-response observed on radiographic imaging. The total duration of brivanib alaninate treatment was 11 months, which was stopped due to repeated grade 2 thrombocytopenia. The other side effects were tolerable. Fifteen months after initiation of brivanib alaninate, the patient remained in very good condition without evidence of disease progression. LESSONS: Brivanib alaninate alone as second-line therapy showed excellent antitumor efficacy for an HCC patient with numerous lung and lymph node metastases. It may exert its antitumor effects in a delayed-onset fashion. We suggest that patients receive brivanib alaninate for a long duration to fully determine its efficacy.


Assuntos
Alanina/análogos & derivados , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Triazinas/uso terapêutico , Alanina/uso terapêutico , Carcinoma Hepatocelular/diagnóstico por imagem , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Retratamento , Falha de Tratamento
14.
Gastroenterology ; 156(6): 1849-1861.e13, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30711629

RESUMO

BACKGROUND & AIMS: Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. METHODS: We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3ß (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry. RESULTS: Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B. CONCLUSIONS: In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/enzimologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Neoplasias Hepáticas/enzimologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator 6 Associado a Receptor de TNF/metabolismo , Evasão Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Regulação para Baixo , Granzimas/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Masculino , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Fator 6 Associado a Receptor de TNF/imunologia , Triazinas/farmacologia , Triazinas/uso terapêutico , Ubiquitinação
16.
Rev Esp Quimioter ; 32(1): 1-5, 2019 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-30676002

RESUMO

Baloxavir marboxil (5-hydroxy-4-pyridone-3-carboxyl acid) is a new antiviral drug with special efficacy on influenza viruses that acts by inhibiting the cap-dependent endonuclease required for its replication. It is the first representative of the so-called inhibitors of influenza-like PB2. It has shown efficacy against influenza viruses A and B and most strains of animal origin (avian flu). Clinical trials conducted in healthy patients between 12 and 64 years without pathologies and not hospitalized (mild flu) have shown a reduction in the duration of symptoms similar to that obtained by oseltamivir. However, baloxavir is a much more potent inhibitor of viral replication than this drug. It has been shown as a safe and well tolerated drug. A single dose of 40-80 mg is administered the first 48 hours after onset of symptoms. In these trials, strains with moderate sensitivity (PA / I38T mutants) were detected in 2.2% of influenza A (H1N1) pdm09 and in 9.7% of influenza A (H3N2). Although these data could be a good drug to treat mild or moderate influenza, requiring trials in severe influenza and patients with chronic diseases to establish their true clinical utility.


Assuntos
Antivirais/uso terapêutico , Endonucleases/antagonistas & inibidores , Influenza Humana/tratamento farmacológico , Orthomyxoviridae/efeitos dos fármacos , Orthomyxoviridae/enzimologia , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Adolescente , Adulto , Antivirais/farmacologia , Criança , Feminino , Humanos , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Adulto Jovem
17.
Eur J Med Chem ; 165: 216-224, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30684798

RESUMO

INTRODUCTION: The redox characteristics of 1,2,4-benzotriazine-1,4-dioxides (BTDOs) make them potential radiosensitizing agents for hypoxic cells in solid human cancers. Tirapazamine (TPZ) is the most clinically tested BTDO radiosensitizer, despite its toxicity at effective doses. To date, no BTDOs have been developed as diagnostic markers of tissue hypoxia. HYPOTHESIS: TPZ analogues with appropriate reporting groups can act as potential radiosensitizers and hypoxia selective diagnostics. EXPERIMENTAL AND RESULTS: 3-Chloro-1,2,4-benzotriazine 1-oxide was substituted at the C3 position to afford 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1-oxide, which was oxidized to 3-(2-hydroxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (HO-EOE-TPZ) or converted to 3-(2-tosyloxyethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (Tos-EOE-TPZ). Tos-EOE-TPZ was intended for use as a synthon for preparing 3-(2-azidoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (N3-EOE-TPZ) and 3-(2-iodoethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxide (I-EOE-TPZ). The logP values (-0.69 to 0.61) for these molecules bracketed that of TPZ (-0.34). Cell line dependent cytotoxicities (IC50) in air were in the 10-100 µM range, with Hypoxia Cytotoxicity Ratios (HCR; IC50-air/IC50-hypoxia) of 5-10. LUMO calculations indicated that these molecules are in the optimal redox range for radiosensitization, offering cell-line-specific Relative Radiosensitization Ratios (RRSR; SER/OER) of 0.58-0.88, compared to TPZ (0.67-0.76). CONCLUSION: The LUMO, IC50, HCR and RRSR values of 3-(2-substituted ethoxyethyl)-amino-1,2,4-benzotriazine-1,4-dioxides are similar to the corresponding values for TPZ, supporting the conclusion that these TPZ analogues are potentially useful as hypoxia-activated radiosensitizers. Further studies into their biodistributions in animal models are being pursued to determine the in vivo potential in hypoxia management.


Assuntos
Hipóxia , Radiossensibilizantes/química , Tirapazamina/análogos & derivados , Triazinas/uso terapêutico , Animais , Biomarcadores , Humanos , Oxirredução , Óxidos , Relação Estrutura-Atividade , Tirapazamina/uso terapêutico , Triazinas/síntese química , Triazinas/química
18.
J Mol Model ; 25(1): 13, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30607513

RESUMO

The c-Met D1228V/H/N mutation clinically causes acquired resistance to type I tyrosine kinase inhibitors (TKIs), while maintaining sensitivity to type II TKIs in targeted gastric cancer therapy. The mutation is located in the activation loop (A-loop) region of the c-Met kinase domain, which substitutes the negatively charged residue Asp1228 with electroneutral amino acid Val, His, or Asn, thus electrostatically destabilizing the DFG-in conformation of A-loop and inducing its transition to DFG-out state. The transition is spontaneous in a dynamics point of view and the A-loop exhibits a large intrinsic disorder during the transitional dynamics course. In DFG-in conformation, the wild-type Asp1228 is surrounded by a number of positively charged residues within its first and second shells, which can also form a hydrogen-bonding network with its vicinal residues Phe1089, Lys1110, Asp1222, and Met1229 in the first shell. Type I and type II TKIs respond oppositely to the mutation; the former shows a generic resistance to the mutation, whereas the latter is generally sensitized by the mutation. Both types of TKIs do not directly interact with the mutation. Instead, the mutation-induced conformational change in A-loop reshapes kinase active site and then influences the site interactions with inhibitor ligands, thus conferring different selectivity to the type I and type II TKIs. Graphical abstract The molecular mechanism of D1228V/H/N mutation-induced inhibitor resistance and sensitivity in c-Met kinase is investigated. The mutation electrostatically destabilizes the DFG-in conformation of kinase A-loop and induces its spontaneous transition to DFG-out state, which reshapes kinase active site and influences the site interactions with inhibitor ligands.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Gástricas/tratamento farmacológico , Anilidas/química , Anilidas/metabolismo , Anilidas/uso terapêutico , Sítios de Ligação , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Terapia de Alvo Molecular/métodos , Ligação Proteica , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-met/química , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazinas/química , Pirazinas/metabolismo , Pirazinas/uso terapêutico , Piridinas/química , Piridinas/metabolismo , Piridinas/uso terapêutico , Eletricidade Estática , Triazinas/química , Triazinas/metabolismo , Triazinas/uso terapêutico
19.
PLoS One ; 14(1): e0210600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30645607

RESUMO

OBJECTIVE: The aims of this study were to identify the influencing factors such as gender, age, dose and combinations of other antiepileptic drugs (AEDs), especially in triple combinations on the pharmacokinetic of Lamotrigine (LTG) in epilepsy patients of Northwest Chinese Han population. METHODS: Data of the LTG concentration and clinical information were analyzed retrospectively from a therapeutic drug monitoring (TDM) database at the Clinical Pharmacy Laboratory of Xi'an Central Hospital between January 1, 2016 and January 1, 2018. The independent-sample t-test, one-way ANOVA analysis and Bonferroni and Tamhane T3 post-hoc test, the stepwise multivariate regression analysis were adopted by IBM SPSS, version 22.0. RESULTS: 226 serum samples met the inclusion criteria and were evaluated. The mean LTG serum concentration was 5.48±3.83 µg/mL. There were no gender differences (P = 0.64), and there were no significant effects by age on LTG serum concentration after age stratification (3-14 years old, 14-45 years old, 45-59 years old) (P = 0.05). Multiple regression analysis showed that the daily LTG dose and co-administration of other AEDs significantly affected LTG serum concentrations. Combination with enzyme-inducer AEDs, the mean steady-state LTG concentration could be decreased by 30.73% compared with LTG monotherapy. Among enzyme-inducer AEDs, particularly strong inducer Carbamazepine (CBZ) could decrease the mean LTG concentration by 53.65%, but weak inducer AEDs such as Oxcarbazepine (OXC) and Topiramate (TPM) had no effect, Valproic acid (VPA) could increase the mean LTG concentration by 93.95%, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination. CONCLUSIONS: There were no significant gender and age effects, but the LTG daily dose and co-administration of other AEDs significantly affected LTG serum concentration. Combination with enzyme-inducer AEDs, especially CBZ could significantly decrease LTG serum concentrations, VPA could significantly increase LTG serum concentrations, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination. In the clinical setting, these findings can help to estimate LTG concentrations and adjust dosage and evaluate adverse drug reactions.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Lamotrigina/uso terapêutico , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Carbamazepina/uso terapêutico , Criança , Pré-Escolar , China , Quimioterapia Combinada , Epilepsia/etnologia , Feminino , Humanos , Lamotrigina/sangue , Lamotrigina/farmacocinética , Masculino , Pessoa de Meia-Idade , Oxcarbazepina/uso terapêutico , Estudos Retrospectivos , Topiramato/uso terapêutico , Triazinas/uso terapêutico , Ácido Valproico/uso terapêutico , Adulto Jovem
20.
Cancer Biol Ther ; 20(1): 21-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30261145

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) progression and chemotherapy insensitivity have been associated with aberrant PI3K/mTOR/MEK signalling. However, cell death responses activated by inhibitors of these pathways can differ - contextually varying with tumour genetic background. Here, we demonstrate that combining the dual PI3K/mTOR inhibitor PF5212384 (PF384) and MEK inhibitor PD325901 (PD901) more effectively induces apoptosis compared with either agent alone, independent of KRAS mutational status in PDAC cell lines. Additionally, a non-caspase dependent decrease in cell viability upon PF384 treatment was observed, and may be attributed to autophagy and G0/G1 cell cycle arrest. Using reverse phase protein arrays, we identify key molecular events associated with the conversion of cytostatic responses (elicited by single inhibitor treatments) into a complete cell death response when PF384 and PD901 are combined. This response was also independent of KRAS mutation, occurring in both BxPC3 (KRAS wildtype) and MIA-PaCa-2 (KRASG12C mutated) cells. In both cell lines, Bim expression increased in response to PF384/PD901 treatment (by 60% and 48%, respectively), while siRNA-mediated silencing of Bim attenuated the apoptosis induced by combination treatment. In parallel, Mcl-1 levels decreased by 36% in BxPC3, and 30% in MIA-PaCa-2 cells. This is consistent with a functional role for Mcl-1, and siRNA-mediated silencing enhanced apoptosis in PF384/PD901-treated MIA-PaCa-2 cells, whilst Mcl-1 overexpression decreased apoptosis induction by 24%. Moreover, a novel role was identified for PDCD4 loss in driving the apoptotic response to PF384/PD901 in BxPC3 and MIA-PaCa-2 cell lines. Overall, our data indicates PF384/PD901 co-treatment activates the same apoptotic mechanism in wild-type or KRAS mutant PDAC cells.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Difenilamina/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Mutação , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Triazinas/farmacologia , Triazinas/uso terapêutico
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