RESUMO
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.
Assuntos
Doença de Chagas , Inibidores da Topoisomerase II , Triazóis , Trypanosoma , Tripanossomíase Africana , Animais , Humanos , Camundongos , Doença de Chagas/tratamento farmacológico , Microscopia Crioeletrônica , DNA Topoisomerases Tipo II/metabolismo , Trypanosoma/efeitos dos fármacos , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/uso terapêutico , Triazóis/química , Triazóis/farmacologia , Triazóis/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Avaliação Pré-Clínica de MedicamentosRESUMO
BACKGROUND: Early-stage breast cancer patients treated with chemotherapy risk the development of metabolic disease and weight gain, which can result in increased morbidity and reduced quality of life in survivorship. We aimed to analyze changes within the gastrointestinal microbiome of early-stage breast cancer patients treated with and without chemotherapy to investigate a potential relationship between dysbiosis, a systemic inflammatory response, and resultant anthropomorphic changes. METHODS: We undertook an a priori analysis of serially collected stool and plasma samples from 40 patients with early-stage breast cancer who underwent adjuvant endocrine therapy only, adjuvant chemotherapy only, or both. Gut microbiota were assessed by metagenomic comparison of stool samples following deep sequencing. Inflammatory biomarkers were evaluated by proteomic analysis of plasma and measurement of fecal calprotectin. Body composition was investigated by dual-energy X-ray absorptiometry to determine biomass indices. RESULTS: As opposed to treatment with endocrine therapy only, chemotherapy resulted in statistically and clinically significant weight gain and an increase in the android to gynoid ratio of fat distribution. Patients treated with chemotherapy gained an average of 0.15% total mass per month, as opposed to a significantly different loss of 0.19% in those patients who received endocrine-only therapy. Concurrently, a twofold increase in fecal calprotectin occurred after chemotherapy that is indicative of interferon-dependent inflammation and evidence of colonic inflammation. These anthropomorphic and inflammatory changes occurred in concert with a chemotherapy-dependent effect on the gut microbiome as evidenced by a reduction in both the abundance and variety of microbial species. CONCLUSIONS: We confirm the association of chemotherapy treatment with weight gain and potential deleterious anthropometric changes and suggest that alterations of bacterial flora may contribute to these phenomena through the induction of systemic inflammation. Consequently, the gut microbiome may be a future target for intervention in preventing chemotherapy-dependent anthropometric changes.
Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Estudos Prospectivos , Disbiose/induzido quimicamente , Qualidade de Vida , Proteômica , Inflamação/induzido quimicamente , Aumento de Peso , Fezes/química , Fezes/microbiologia , Antineoplásicos/efeitos adversos , Complexo Antígeno L1 Leucocitário/análise , Complexo Antígeno L1 Leucocitário/uso terapêuticoRESUMO
Plant-parasitic cyst nematodes use a stylet to deliver effector proteins produced in oesophageal gland cells into root cells to cause disease in plants. These effectors are deployed to modulate plant defence responses and developmental programmes for the formation of a specialized feeding site called a syncytium. The Hg2D01 effector gene, coding for a novel 185-amino-acid secreted protein, was previously shown to be up-regulated in the dorsal gland of parasitic juveniles of the soybean cyst nematode Heterodera glycines, but its function has remained unknown. Genome analyses revealed that Hg2D01 belongs to a highly diversified effector gene family in the genomes of H. glycines and the sugar beet cyst nematode Heterodera schachtii. For functional studies using the model Arabidopsis thaliana-H. schachtii pathosystem, we cloned the orthologous Hs2D01 sequence from H. schachtii. We demonstrate that Hs2D01 is a cytoplasmic effector that interacts with the intracellular kinase domain of HAESA (HAE), a cell surface-associated leucine-rich repeat (LRR) receptor-like kinase (RLK) involved in signalling the activation of cell wall-remodelling enzymes important for cell separation during abscission and lateral root emergence. Furthermore, we show that AtHAE is expressed in the syncytium and, therefore, could serve as a viable host target for Hs2D01. Infective juveniles effectively penetrated the roots of HAE and HAESA-LIKE2 (HSL2) double mutant plants; however, fewer nematodes developed on the roots, consistent with a role for this receptor family in nematode infection. Taken together, our results suggest that the Hs2D01-AtHAE interaction may play an important role in sugar beet cyst nematode parasitism.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Beta vulgaris , Cistos , Tylenchoidea , Animais , Arabidopsis/metabolismo , Beta vulgaris/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Tylenchoidea/genética , Tylenchoidea/metabolismo , Açúcares/metabolismo , Raízes de Plantas/parasitologia , Doenças das Plantas/genética , Regulação da Expressão Gênica de Plantas , Proteínas Serina-Treonina QuinasesRESUMO
AIMS: To explore the impact of incorporating a faster cardiac magnetic resonance (CMR) imaging protocol in a low-middle-income country (LMIC) and using the result to guide chelation in transfusion-dependent patients. METHODS AND RESULTS: A prospective UK-India collaborative cohort study was conducted in two cities in India. Two visits 13 months apart included clinical assessment and chelation therapy recommendations based on rapid CMR results. Participants were recruited by the local patient advocate charity, who organized the patient medical camps. The average scanning time was 11.3 ± 2.5 min at the baseline and 9.8 ± 2.4 min (P < 0.001) at follow-up. The baseline visit was attended by 103 patients (mean age 25 years) and 83% attended the second assessment. At baseline, 29% had a cardiac T2* < 20 ms, which represents significant iron loading, and 12% had left ventricular ejection fraction <60%, the accepted lower limit in this population. Only 3% were free of liver iron (T2* ≥ 17 ms). At 13 months, more patients were taking intensified dual chelation therapy (43% vs. 55%, P = 0.002). In those with cardiac siderosis (baseline T2* < 20 ms), there was an improvement in T2*-10.9 ± 5.9 to 13.5 ± 8.7 ms, P = 0.005-and fewer were classified as having clinically important cardiac iron loading (T2* < 20 ms, 24% vs. 16%, P < 0.001). This is the first illustration in an LMIC that incorporating CMR results into patient management plans can improve cardiac iron loading. CONCLUSION: For thalassaemia patients in an LMIC, a simplified CMR protocol linked to therapeutic recommendation via the patient camp model led to enhanced chelation therapy and a reduction in cardiac iron in 1 year.
Assuntos
Talassemia , Talassemia beta , Adulto , Terapia por Quelação/métodos , Estudos de Coortes , Humanos , Ferro , Imageamento por Ressonância Magnética , Estudos Prospectivos , Volume Sistólico , Talassemia/terapia , Função Ventricular Esquerda , Talassemia beta/patologia , Talassemia beta/terapiaRESUMO
OBJECTIVE: This study compared the effects of 90â¯s of manual compressive therapy (MCT) on latent myofascial trigger points (LTPs) for 3 sessions per week for 4 weeks to determine changes in individual pressure pain threshold (PPT). A total of 30 (15 males, 15 females; ageâ¯=â¯22⯱â¯4â¯y/o, heightâ¯=â¯175⯱â¯18â¯cm, weightâ¯=â¯162.5⯱â¯57.5â¯kg) symptomatic subjects with LTPs volunteered for the study. METHODS: PPT was measured at baseline and pre- and post-treatment for all 12 sessions with a pressure algometer across the 4-week treatment time frame. The MCT was applied to the control group on their LTP at pressure intended to provide a sham condition (1/10 on verbalized analog scale (VAS)). Two experimental groups had MCT applied either directly on the LTP (d-TP) or in close-proximity to their LTP (cp-TP) at moderate pressure (7/10 on VAS). RESULTS: There was a significant increase in PPT from the first through twelfth treatment sessions (pâ¯<â¯0.001, partial η2â¯=â¯0.914). A significant increase in PPTs between treatment groups was acutely observed from pre- to post-therapy tests (pâ¯=â¯0.001, partial η2â¯=â¯0.146). The differences between pre- versus post-treatment PPT measures indicated significant differences (d-TP vs. control, pâ¯<â¯0.001; cp-TP vs. control, pâ¯=â¯0.007). No differences were observed between experimental groups (pâ¯=â¯0.215). CONCLUSIONS: PPT continued to increase after several weeks of MCT when applied directly on or within 2.5â¯cm of an identified LTP compared to control.
Assuntos
Manipulações Musculoesqueléticas/métodos , Síndromes da Dor Miofascial/terapia , Limiar da Dor/fisiologia , Pontos-Gatilho/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Dinamômetro de Força Muscular , Adulto JovemRESUMO
Neuropathic pain afflicts millions of individuals and represents a major health problem for which there is limited effective and safe therapy. Emerging literature links altered sphingolipid metabolism to nociceptive processing. However, the neuropharmacology of sphingolipid signaling in the central nervous system in the context of chronic pain remains largely unexplored and controversial. We now provide evidence that sphingosine-1-phosphate (S1P) generated in the dorsal horn of the spinal cord in response to nerve injury drives neuropathic pain by selectively activating the S1P receptor subtype 1 (S1PR1) in astrocytes. Accordingly, genetic and pharmacological inhibition of S1PR1 with multiple antagonists in distinct chemical classes, but not agonists, attenuated and even reversed neuropathic pain in rodents of both sexes and in two models of traumatic nerve injury. These S1PR1 antagonists retained their ability to inhibit neuropathic pain during sustained drug administration, and their effects were independent of endogenous opioid circuits. Moreover, mice with astrocyte-specific knockout of S1pr1 did not develop neuropathic pain following nerve injury, thereby identifying astrocytes as the primary cellular substrate of S1PR1 activity. On a molecular level, the beneficial reductions in neuropathic pain resulting from S1PR1 inhibition were driven by interleukin 10 (IL-10), a potent neuroprotective and anti-inflammatory cytokine. Collectively, our results provide fundamental neurobiological insights that identify the cellular and molecular mechanisms engaged by the S1PR1 axis in neuropathic pain and establish S1PR1 as a target for therapeutic intervention with S1PR1 antagonists as a class of nonnarcotic analgesics.
Assuntos
Astrócitos/metabolismo , Neuralgia/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Sulfonas/uso terapêutico , Triazóis/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Interleucina-10/metabolismo , Masculino , Camundongos , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Ratos Sprague-Dawley , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Sulfonas/farmacologia , Triazóis/farmacologiaRESUMO
OBJECTIVE: In Arabidopsis, the abscission of floral organs is regulated by two related receptor-like protein kinases, HAESA and HAESA-like 2 (HAE/HSL2). Signaling by HAE/HSL2 leads to expression of genes encoding secreted cell wall remodeling and hydrolase enzymes. hae hsl2 mutants fail to induce expression of these genes and retain floral organs indefinitely. Mutants in the gene NEVERSHED (NEV) also fail to abscise floral organs and phenotypically resemble hae hsl2. NEV encodes an ADP-ribosylation factor GTPase-activating protein that localizes to the trans-Golgi network and early endosome. nev displays altered Golgi morphology and aberrations in vesicular trafficking. The mechanism by which nev fails to abscise is presently unknown. It has been hypothesized that nev fails to activate HAE/HSL2 signaling. In this study we use RNA-Sequencing to test this hypothesis. RESULTS: We show that the transcriptional alterations in hae hsl2 and nev are highly divergent. hae hsl2 displays a clear reduction in expression of genes associated with cell wall remodeling and pectin degradation, while nev displays vast transcriptional changes associated with response to pathogens. These results suggest that the mechanism of the defect between hae hsl2 and nev are distinct.
Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Parede Celular/metabolismo , Flores/genética , Regulação da Expressão Gênica de Plantas/genética , Pectinas/metabolismo , Transcriptoma/genética , Proteínas Ativadoras de GTPase , Mutação , Proteínas Serina-Treonina QuinasesRESUMO
Condensins play a unique role in orchestrating the global folding of the chromosome, an essential cellular process, and contribute to human disease and bacterial pathogenicity. As such, they represent an attractive and as yet untapped target for diverse therapeutic interventions. We describe here the discovery of small molecule inhibitors of the Escherichia coli condensin MukBEF. Pilot screening of a small diversity set revealed five compounds that inhibit the MukBEF pathway, two of which, Michellamine B and NSC260594, affected MukB directly. Computer-assisted docking suggested plausible binding sites for the two compounds in the hinge and head domains of MukB, and both binding sites were experimentally validated using mutational analysis and inspection of NSC260594 analogs. These results outline a strategy for the discovery of condensin inhibitors, identify druggable binding sites on the protein, and describe two small molecule inhibitors of condensins.
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas de Escherichia coli/antagonistas & inibidores , Escherichia coli/efeitos dos fármacos , Proteínas Repressoras/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Sítios de Ligação , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Isoquinolinas/química , Isoquinolinas/farmacologia , Simulação de Acoplamento Molecular , Naftalenos/química , Naftalenos/farmacologia , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Excess nitrogen and phosphorus ("nutrients") loadings continue to affect ecosystem function and human health across the U.S. Our ability to connect atmospheric inputs of nutrients to aquatic end points remains limited due to uncoupled air and water quality monitoring. Where connections exist, the information provides insights about source apportionment, trends, risk to sensitive ecosystems, and efficacy of pollution reduction efforts. We examine several issues driving the need for better integrated monitoring, including: coastal eutrophication, urban hotspots of deposition, a shift from oxidized to reduced nitrogen deposition, and the disappearance of pristine lakes. Successful coordination requires consistent data reporting; collocating deposition and water quality monitoring; improving phosphorus deposition measurements; and filling coverage gaps in urban corridors, agricultural areas, undeveloped watersheds, and coastal zones.
Assuntos
Ecossistema , Qualidade da Água , Monitoramento Ambiental , Eutrofização , Humanos , Nitrogênio , Nutrientes , Fósforo , ÁguaRESUMO
The complement system is an elegantly regulated biochemical cascade formed by the collective molecular recognition properties and proteolytic activities of more than two dozen membrane-bound or serum proteins. Complement plays diverse roles in human physiology, such as acting as a sentry against invading microorganisms, priming of the adaptive immune response, and removal of immune complexes. However, dysregulation of complement can serve as a trigger for a wide range of human diseases, which include autoimmune, inflammatory, and degenerative conditions. Despite several potential advantages of modulating complement with small-molecule inhibitors, small-molecule drugs are highly underrepresented in the current complement-directed therapeutics pipeline. In this study, we have employed a cheminformatics drug discovery approach based on the extensive structural and functional knowledge available for the central proteolytic fragment of the cascade, C3b. Using parallel in silico screening methodologies, we identified 45 small molecules that putatively bind C3b near ligand-guided functional hot spots. Surface plasmon resonance experiments resulted in the validation of seven dose-dependent C3b-binding compounds. Competition-based biochemical assays demonstrated the ability of several C3b-binding compounds to interfere with binding of the original C3b ligand that guided their discovery. In vitro assays of complement function identified a single complement inhibitory compound, termed cmp-5, and mechanistic studies of the cmp-5 inhibitory mode revealed it acts at the level of C5 activation. This study has led to the identification of a promising new class of C3b-binding small-molecule complement inhibitors and, to our knowledge, provides the first demonstration of cheminformatics-based, complement-directed drug discovery.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Complemento C3b/metabolismo , Inativadores do Complemento/isolamento & purificação , Biologia Computacional , Imunossupressores/isolamento & purificação , Doenças Neurodegenerativas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas , Ativação do Complemento , Complemento C3b/química , Inativadores do Complemento/uso terapêutico , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunossupressores/uso terapêutico , Ligação Proteica , Proteólise , Ressonância de Plasmônio de SuperfícieRESUMO
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.
Assuntos
Antituberculosos/farmacologia , Indóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Antituberculosos/toxicidade , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana Múltipla/genética , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/toxicidade , Injeções Intravenosas , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Ratos , Ratos Wistar , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologiaRESUMO
New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.
Assuntos
Trifosfato de Adenosina/biossíntese , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/farmacologia , Piridinas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Complexo III da Cadeia de Transporte de Elétrons/genética , Imidazóis/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Piperidinas/farmacocinética , Piridinas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in ß-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.
Assuntos
American Heart Association , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Talassemia beta/complicações , Talassemia beta/tratamento farmacológico , Consenso , Insuficiência Cardíaca/fisiopatologia , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/tratamento farmacológico , Estados UnidosRESUMO
BACKGROUND: The ongoing nature of iron loss in patients receiving hemodialysis makes it difficult to maintain adequate iron stores without supplementation. The effects of ferumoxytol on iron indices have been measured 35 days after baseline, but no study has assessed indices at earlier points in time. OBJECTIVE: To evaluate the time to transferrin saturation (TSAT) and ferritin stabilization, the point at which TSAT and serum ferritin levels can be accurately measured during a 13-treatment period following a loading dose of ferumoxytol. METHODS: Ferumoxytol was administered according to the package insert to 15 adults undergoing hemodialysis. Vital signs were recorded before treatment, 30 and 60 minutes after receiving ferumoxytol, and at the end of treatment to monitor for adverse reactions and hemodynamic instability. Monitoring continued for a 13-treatment period (30 days) after drug administration. Blood was collected throughout the study to measure TSAT, ferritin, hemoglobin (Hb), and C-reactive protein (CRP). RESULTS: TSAT values at 14, 21, and 28 days after drug administration were not significantly different from those at 7 days, signifying that TSAT values stabilized by day 7. Serum ferritin values at day 14 were significantly lower than those 7 days after drug administration (p = 0.028). Although serum ferritin values at days 21 and 28 tended to decrease relative to values at day 14, the differences were not statistically significant. Therefore, it appears that serum ferritin stabilized by day 14 after drug administration. Mean (SD) Hb values at screening and at end of the study were 11.7 (1.0) g/dL and 12.0 (0.9) g/dL, respectively (p = NS). CRP also did not change significantly throughout the study period. CONCLUSIONS: Dialysis patients achieve stable iron indices quickly. TSAT stabilized by day 7 and ferritin stabilized 14 days after a loading dose of ferumoxytol 1 g. Adverse effects were minimal and did not necessitate discontinuation of ferumoxytol.
Assuntos
Anemia/prevenção & controle , Óxido Ferroso-Férrico/administração & dosagem , Hematínicos/administração & dosagem , Diálise Renal , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Ferro , Masculino , Pessoa de Meia-Idade , Transferrina/metabolismoRESUMO
The World Health Organization has recommended the integrated model of care as the current best practice of care, and, in recent years, it has been gaining popularity worldwide in various settings. However, there have been very few reports on applications of this model to the care of patients with gastrointestinal problems and no reports in the case of inflammatory bowel disease (IBD). However, several IBD centres worldwide have been using the model as part of their standard care. This discussion paper aims to bring together these units' shared experiences with a range of integrated models of care in order to identify common features and provide recommendations on aspirational care for IBD patients.
Assuntos
Prestação Integrada de Cuidados de Saúde/normas , Doenças Inflamatórias Intestinais/terapia , Padrão de Cuidado , Gerenciamento Clínico , Saúde Global , Humanos , Doenças Inflamatórias Intestinais/psicologiaRESUMO
OBJECTIVE: To determine the prevalence of complementary and alternative medicine (CAM) use over time in a population-based cohort of patients with inflammatory bowel disease (IBD). METHODS: The Manitoba IBD Cohort Study is a longitudinal, population-based study of multiple determinants of health outcomes in an IBD cohort. Participants completed semi-annual surveys, and annual in-person interviews. Enquiries about the use of 12 types of CAM service providers and 13 CAM products, based on items from a national survey, were included at months 0, 12, 30 and 54. RESULTS: Overall, 74% of respondents used a CAM service or product in the 4.5-year period, with approximately 40% using some type of CAM at each time point, and 14% using CAM consistently at every time point. There was a trend for women to use CAM more than men; there was no difference in CAM use between patients with Crohn's disease and those with ulcerative colitis. The most often used CAM services (on average) were massage therapy (30%) and chiropractic (14%), physiotherapy (4%), acupuncture (3.5%) and naturopathy/homeopathy (3.5%). A wide range of CAM products were used, with Lactobacillus acidophilus (8%), fish and other oils (5.5%), glucosamine (4%) and chamomile (3.5%) as the most common. On average, only 18% of consumers used CAM for their IBD, so the majority chose it for other problems. There were no differences in psychological variables between CAM users and non-users. CONCLUSIONS: Those with IBD commonly try CAM, although very few use these approaches regularly over the years. CAM is not usually used by patients with IBD for disease management, but clinicians should be aware that many will test the services and products.
Assuntos
Terapias Complementares/estatística & dados numéricos , Doenças Inflamatórias Intestinais/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapias Complementares/métodos , Terapias Complementares/psicologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/psicologia , Estudos Longitudinais , Masculino , Manitoba/epidemiologia , Pessoa de Meia-Idade , Qualidade de Vida , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Adulto JovemRESUMO
PH-797804 ((aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS), first proposed by molecular modeling and subsequently confirmed by experiments. Due to steric constraints imposed by the pyridinone carbonyl group and the 6- and 6'-methyl substituents of PH-797804, rotation around the connecting bond of the pyridinone and the N-phenyl ring is restricted. Density functional theory predicts a remarkably high rotational energy barrier of >30â kcal mol(-1), corresponding to a half-life of more than one hundred years at room temperature. This gives rise to discrete conformational spaces for the N-phenylpyridinone group, and as a result, two atropic isomers that do not interconvert under ambient conditions. Molecular modeling studies predict that the two isomers should differ in their binding affinity for p38α kinase; whereas the atropic S (aS) isomer binds favorably, the opposite aR isomer incurs significant steric interference with p38α kinase. The two isomers were subsequently identified and separated by chiral chromatography. IC50 values from p38α kinase assays confirm that one atropisomer is >100-fold more potent than the other. It was ultimately confirmed by small-molecule X-ray diffraction that the more potent atropisomer, PH-797804, is the aS isomer of the racemic pair. Extensive pharmacological characterization supports that PH-797804 carries most activity both inâ vitro and inâ vivo, and it has a stability profile compatible with oral formulation and delivery options.
Assuntos
Benzamidas/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Artrite/tratamento farmacológico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Simulação por Computador , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Feminino , Lipopolissacarídeos/toxicidade , Masculino , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Piridonas/farmacologia , Piridonas/uso terapêutico , Teoria Quântica , Ratos , Receptores de Superfície Celular , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
Assuntos
Antimaláricos/farmacologia , Descoberta de Drogas , Imidazóis/farmacologia , Fígado/parasitologia , Malária/tratamento farmacológico , Piperazinas/farmacologia , Plasmodium/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Resistência a Medicamentos , Eritrócitos/parasitologia , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Imidazóis/uso terapêutico , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Plasmodium/citologia , Plasmodium/crescimento & desenvolvimento , Plasmodium/fisiologia , Plasmodium berghei/citologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/fisiologia , Plasmodium falciparum/citologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/fisiologia , Plasmodium yoelii/citologia , Plasmodium yoelii/efeitos dos fármacos , Plasmodium yoelii/crescimento & desenvolvimento , Plasmodium yoelii/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Distribuição Aleatória , Bibliotecas de Moléculas Pequenas , Esporozoítos/efeitos dos fármacos , Esporozoítos/crescimento & desenvolvimentoRESUMO
Right ventricular (RV) failure is one of the strongest predictors of mortality both in the presence of left ventricular decompensation and in the context of pulmonary vascular disease. Despite this, there is a limited understanding of the biochemical and mechanical characteristics of the pressure-overloaded RV at the level of the cardiac myocyte. To better understand this, we studied ventricular muscle obtained from neonatal calves that were subjected to hypobaric atmospheric conditions, which result in profound pulmonary hypertension. We found that RV pressure overload resulted in significant changes in the phosphorylation of key contractile proteins. Total phosphorylation of troponin I was decreased with pressure overload, predominantly reflecting changes at the putative PKA site at Ser(22/23). Similarly, both troponin T and myosin light chain 2 showed a significant decline in phosphorylation. Desmin was unchanged, and myosin-binding protein C (MyBP-C) phosphorylation was apparently increased. However, the apparent increase in MyBP-C phosphorylation was not due to phosphorylation but rather to an increase in MyBP-C total protein. Importantly, these findings were seen in all regions of the RV and were paralleled by reduced Ca(2+) sensitivity with preserved maximal Ca(2+) saturated developed force normalized to cross-sectional area in isolated skinned right ventricular myocyte fragments. No changes in total force or cooperativity were seen. Taken together, these results suggest that RV failure is mechanistically unique from left ventricular failure.
Assuntos
Citoesqueleto de Actina/metabolismo , Hipertensão Pulmonar/metabolismo , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Disfunção Ventricular Direita/metabolismo , Função Ventricular Direita , Animais , Animais Recém-Nascidos , Bovinos , Modelos Animais de Doenças , Acoplamento Excitação-Contração , Ventrículos do Coração/metabolismo , Hemodinâmica , Oxigenoterapia Hiperbárica , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Contração Miocárdica , Fosforilação , Índice de Gravidade de Doença , Disfunção Ventricular Direita/etiologia , Disfunção Ventricular Direita/fisiopatologia , Pressão VentricularRESUMO
Soluble oligomeric amyloid-beta (Abeta) species are toxic to many cell types and are a putative etiological factor in Alzheimer's disease. The NINDS-Custom Collection of 1040 drugs and biologically active compounds was robotically screened for inhibitors of Abeta oligomer formation with a single-site biotinylated Abeta(1-42) oligomer assembly assay. Several quinoline-like compounds were identified with IC(50)'s <10 microM, including the antiprotozoal clioquinol that has been reported to have effects on metal ion metabolism. The 2-OH, 4-OH, and 6-OH quinolines do not block Abeta oligomer formation up to a concentration of 100 microM. Analogs of clioquinol have shown activity in reducing Abeta levels and improving behavioral deficits in mouse models of Abeta pathology. The inhibitory effects of clioquinol and other 8-OH quinoline derivatives on oligomer formation in vitro are unrelated to their chelating activity. Crosslinking studies suggest that clioquinol acts at the stage of trimer formation. These preliminary data may suggest that 8-OH quinolines have the potential for suppressing Abeta oligomer formation which should be considered when assessing the effects of these compounds in animal models and clinical trials.