122 results on '"Kratz JM"'
Search Results
2. Pick your poison: hERG-blocking alkaloids in the emetic herbal drug ipecac
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Kratz, JM, additional, Mair, CE, additional, Oettl, SK, additional, Saxena, P, additional, Scheel, O, additional, Schuster, D, additional, Hering, S, additional, and Rollinger, JM, additional
- Published
- 2016
- Full Text
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3. The 'Lotus Leave Diet' – A life-threatening experience? hERG channel blocking aporphine alkaloids from Nelumbo nucifera Gaertn
- Author
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Grienke, U, primary, Mair, CE, additional, Saxena, P, additional, Kratz, JM, additional, Baburin, I, additional, Schuster, D, additional, Hering, S, additional, and Rollinger, JM, additional
- Published
- 2014
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4. Pharmacophore-based identification of novel hERG channel blockers of natural origin - Development of a virtual screening workflow and experimental validation
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Kratz, JM, primary, Edtbauer, M, additional, Mair, CE, additional, Hering, S, additional, Schuster, D, additional, and Rollinger, JM, additional
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- 2013
- Full Text
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5. Use of a combined right ventricular ejection fraction-oximetry catheter system for coronary bypass surgery
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Alpert Cc, B. H. Dorman, Marilyn Ford, Francis G. Spinale, and Kratz Jm
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Male ,medicine.medical_specialty ,Cardiac output ,medicine.medical_treatment ,Thermodilution ,Critical Care and Intensive Care Medicine ,law.invention ,Coronary artery bypass surgery ,Electrocardiography ,law ,Internal medicine ,medicine.artery ,Cardiopulmonary bypass ,medicine ,Humans ,Oximetry ,Coronary Artery Bypass ,Aged ,Ejection fraction ,medicine.diagnostic_test ,business.industry ,Pulmonary artery catheter ,Hemodynamics ,Stroke Volume ,Pulse oximetry ,Bypass surgery ,Anesthesia ,Catheterization, Swan-Ganz ,Pulmonary artery ,Cardiology ,Ventricular Function, Right ,Female ,business - Abstract
OBJECTIVE To evaluate the reproducibility and accuracy of a new pulmonary artery catheter system that provides both right ventricular ejection fraction and continuous venous oxygen saturation monitoring. DESIGN Criterion standard study. SETTING University medical center. PATIENTS A consecutive sample of ten patients undergoing elective coronary artery bypass surgery provided informed consent for the study. Exclusion criteria included emergency surgery or clinically important preoperative tricuspid regurgitation as assessed by echocardiography. None of the patient sample was excluded. MEASUREMENTS Catheter-derived mixed venous and arterial oximetry data were compared with simultaneous values obtained using conventional laboratory cooximetry methods. Measurements were performed before cardiopulmonary bypass and intermittently up to 48 hrs after cardiopulmonary bypass. The variability of cardiac output and computed right ventricular ejection fraction was also assessed concurrently with the oximetry analysis. RESULTS A significant correlation was observed for mixed venous oxygen saturation between catheter-derived and laboratory cooximetry data (r2 = .81, p < .01). Similarly, arterial oxygen saturation values obtained from pulse oximetry and laboratory values were significantly related (r2 = .81, p < .01). The coefficient of variation for each set of five repeated measurements for cardiac output was 8%, and for computed right ventricular ejection fraction, it was 16%. CONCLUSIONS The combined catheter system provides the means to monitor both mixed venous oxygen saturation and right ventricular ejection fraction. These data provide a reliable and detailed assessment of cardiopulmonary function that should prove beneficial in the critical care setting.
- Published
- 1992
6. GENERAL ANESTHESIA VS. INTRAVENOUS SEDATION FOR THE PLACEMENT OF THE AUTOMATIC IMPLANTABLE CARDIOVERTER/DEFIBRILLATOR
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Mark L. Pinosky, Kratz Jm, Raymond C. Roy, Francis G. Spinale, Richard L. Fishman, Scott Reeves, B. H. Dorman, and Calvert C. Alpert
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Anesthesiology and Pain Medicine ,business.industry ,medicine.medical_treatment ,Anesthesia ,Medicine ,Intravenous sedation ,business ,Implantable cardioverter-defibrillator - Published
- 1995
7. Identification of Patients at Risk for Excessive Blood Loss During Coronary Artery Bypass Surgery
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Bailey Mk, Francis G. Spinale, B. H. Dorman, Kratz Jm, and Raymond C. Roy
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medicine.medical_specialty ,Blood Loss, Surgical ,Activated clotting time ,law.invention ,Coronary artery bypass surgery ,Risk Factors ,law ,Internal medicine ,Coagulation testing ,Cardiopulmonary bypass ,Humans ,Medicine ,Coronary Artery Bypass ,education ,Blood Coagulation ,Aged ,Blood coagulation test ,Prothrombin time ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Middle Aged ,Thromboelastography ,Thrombelastography ,Anesthesiology and Pain Medicine ,Evaluation Studies as Topic ,Anesthesia ,Cardiology ,Coagulation screen ,Blood Coagulation Tests ,business - Abstract
In light of the potential morbidity associated with transfusion of blood products, a reliable preoperative screening test to identify cardiothoracic surgical patients who are at potential risk for increased intraoperative blood loss would be useful. Accordingly, we examined the efficacy of a variety of coagulation tests to predict intraoperative blood loss in 60 patients presenting for coronary artery bypass surgery (CABG). A complete coagulation screen, activated clotting time (ACT), and thromboelastograph (TEG) were performed before surgery. Intraoperative blood loss was determined by weighing sponges and measuring the quantity of blood in suction canisters. The duration of cardiopulmonary bypass was 100 +/- 4 min, and total surgery time was 5.0 +/- 0.1 h. Total crystalloid and colloid requirements were 5.5 +/- 0.2 and 1.4 +/- 0.1 L. Forty-eight percent of the patients required blood with an average requirement of 2.5 +/- 0.5 units. Total intraoperative blood loss averaged 1590 +/- 95 mL with a range from 640 to 3928 mL. Using multiple linear regression, all coagulation and TEG variables were used to model perioperative blood loss. Results showed that all components of the TEG failed to predict blood loss (r0.25, P0.78). However, three components of the routine coagulation assay, including bleeding time, prothrombin time, and platelet count could be modeled to predict perioperative blood loss (r = 0.75, P0.05). Although TEG has been shown to have potential in identifying postcardiopulmonary bypass coagulopathies, these results suggest that it does not appear to be useful in determining the coagulation status of CABG patients preoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1993
8. Demystifying In Vivo Bioluminescence Imaging of a Chagas Disease Mouse Model for Drug Efficacy Studies.
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da Silva AC, Kratz JM, Morgado PGM, Freitas-Junior LH, and Moraes CB
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- Animals, Mice, Luciferases genetics, Luciferases metabolism, Trypanocidal Agents pharmacology, Trypanocidal Agents therapeutic use, Chagas Disease diagnostic imaging, Luminescent Measurements methods, Disease Models, Animal, Trypanosoma cruzi drug effects
- Abstract
To control and decrease the public health impact of human protozoan diseases such as Chagas disease, leishmaniasis, and human African trypanosomiasis, expediting the development of new drugs and vaccines is necessary. However, this process is filled with difficulties such as highly complex parasite biology and disease pathogenesis and, as typical for neglected tropical diseases, comparatively limited funding for research and development. Thus, in vitro and in vivo study models that can sufficiently reproduce infection and disease key features while providing rational use of resources are essential for progressing research for these conditions. One example is the in vivo bioluminescence imaging (BLI) mouse model for Chagas disease, which provides highly sensitive detection of long wavelength light generated by Trypanosoma cruzi parasites expressing luciferase. Despite this technique becoming the standard approach for drug efficacy in vivo studies, research groups might still struggle to implement it due to a lack of proper practical training on equipment handling and application of quality control procedures, even when suitable BLI equipment is readily available. Considering this scenario, this protocol aims to guide from planning experiments to data acquisition and analysis, with details that facilitate the implementation of protocols in research groups with little or no experience with BLI, either for Chagas disease or for other infectious disease mouse models.
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- 2024
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9. Synthesis and Anti- Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives.
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Slafer BW, Dessoy MA, de Oliveira RG, Mollo MC, Lee E, Matheeussen A, Maes L, Caljon G, Ferreira LLG, Krogh R, Andricopulo AD, Cruz LR, Mowbray CE, Kratz JM, and Dias LC
- Abstract
Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi , hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1-9 displayed good potency (EC
50 T. cruzi amastigote <1 μM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32-64 μM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)- Published
- 2024
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10. Design, synthesis, and lead optimization of piperazinyl-pyrimidine analogues as potent small molecules targeting the viral capping machinery of Chikungunya virus.
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Battisti V, Moesslacher J, Abdelnabi R, Leyssen P, Rosales Rosas AL, Langendries L, Aufy M, Studenik C, Kratz JM, Rollinger JM, Puerstinger G, Neyts J, Delang L, Urban E, and Langer T
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- Humans, Caco-2 Cells, Antiviral Agents chemistry, Pyrimidines pharmacology, Virus Replication, Chikungunya virus, Chikungunya Fever drug therapy
- Abstract
The worldwide re-emerge of the Chikungunya virus (CHIKV), the high morbidity associated with it, and the lack of an available vaccine or antiviral treatment make the development of a potent CHIKV-inhibitor highly desirable. Therefore, an extensive lead optimization was performed based on the previously reported CHVB compound 1b and the reported synthesis route was optimized - improving the overall yield in remarkably shorter synthesis and work-up time. Hundred analogues were designed, synthesized, and investigated for their antiviral activity, physiochemistry, and toxicological profile. An extensive structure-activity relationship study (SAR) was performed, which focused mainly on the combination of scaffold changes and revealed the key chemical features for potent anti-CHIKV inhibition. Further, a thorough ADMET investigation of the compounds was carried out: the compounds were screened for their aqueous solubility, lipophilicity, their toxicity in CaCo-2 cells, and possible hERG channel interactions. Additionally, 55 analogues were assessed for their metabolic stability in human liver microsomes (HLMs), leading to a structure-metabolism relationship study (SMR). The compounds showed an excellent safety profile, favourable physicochemical characteristics, and the required metabolic stability. A cross-resistance study confirmed the viral capping machinery (nsP1) to be the viral target of these compounds. This study identified 31b and 34 as potent, safe, and stable lead compounds for further development as selective CHIKV inhibitors. Finally, the collected insight led to a successful scaffold hop (64b) for future antiviral research studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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11. Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease.
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de Oliveira Rezende Júnior C, Martinez PDG, Ferreira RAA, Koovits PJ, Miranda Soares B, Ferreira LLG, Michelan-Duarte S, Chelucci RC, Andricopulo AD, Matheeussen A, Van Pelt N, Caljon G, Maes L, Campbell S, Kratz JM, Mowbray CE, and Dias LC
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- Animals, Structure-Activity Relationship, Mammals, Trypanocidal Agents chemistry, Chagas Disease drug therapy, Trypanosoma cruzi
- Abstract
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luiz Carlos Dias reports financial support was provided by Fundação de Amparo a Pesquisa do Estado de São Paulo - Fapesp., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
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12. Effects of Lipophilicity and Structural Features on the Antiherpes Activity of Digitalis Cardenolides and Derivatives.
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de Pádua RM, Kratz JM, Munkert J, Bertol JW, Rigotto C, Schuster D, Maltarollo VG, Kreis W, Simões CMO, and Braga FC
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- Cardenolides pharmacology, 1-Octanol, Rhamnose, Retrospective Studies, Plant Extracts chemistry, Antiviral Agents pharmacology, Glycosides, Lactones, Aldehydes, Water, Digitalis chemistry
- Abstract
There is growing interest in exploring Digitalis cardenolides as potential antiviral agents. Hence, we herein investigated the influence of structural features and lipophilicity on the antiherpes activity of 65 natural and semisynthetic cardenolides assayed in vitro against HSV-1. The presence of an α,β-unsaturated lactone ring at C-17, a β-hydroxy group at C-14 and C-3β-OR substituents were considered essential requirements for this biological activity. Glycosides were more active than their genins, especially monoglycosides containing a rhamnose residue. The activity enhanced in derivatives bearing an aldehyde group at C-19 instead of a methyl group, whereas inserting a C-5β-OH improved the antiherpes effect significantly. The cardenolides lipophilicity was accessed by measuring experimentally their log P values (n-octanol-water partition coefficient) and disclosed a range of lipophilicity (log P 0.75±0.25) associated with the optimal antiherpes activity. In silico studies were carried out and resulted in the establishment of two predictive models potentially useful to identify and/or optimize novel antiherpes cardenolides. The effectiveness of the models was confirmed by retrospective analysis of the studied compounds. This is the first SAR study addressing the antiherpes activity of cardenolides. The developed computational models were able to predict the active cardenolides and their log P values., (© 2022 The Authors. Chemistry & Biodiversity published by Wiley-VHCA AG, Zurich, Switzerland.)
- Published
- 2022
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13. The translational challenge in Chagas disease drug development.
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Kratz JM, Gonçalves KR, Romera LM, Moraes CB, Bittencourt-Cunha P, Schenkman S, Chatelain E, and Sosa-Estani S
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- Drug Development, Drug Discovery, Humans, Neglected Diseases drug therapy, Chagas Disease drug therapy, Chagas Disease parasitology, Trypanocidal Agents pharmacology, Trypanocidal Agents therapeutic use, Trypanosoma cruzi
- Abstract
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development for Chagas disease has historically been hampered by the complexity of the disease, critical knowledge gaps, and lack of coordinated R&D efforts. This review covers some of the translational challenges associated with the progression of new chemical entities from preclinical to clinical phases of development, and discusses how recent technological advances might allow the research community to answer key questions relevant to the disease and to overcome hurdles in R&D for Chagas disease.
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- 2022
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14. Chagas Disease Drug Discovery in Latin America-A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021.
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de Oliveira RG, Cruz LR, Mollo MC, Dias LC, and Kratz JM
- Abstract
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi that endangers almost 70 million people worldwide. The only two drugs that are currently approved for its treatment, benznidazole and nifurtimox, have controversial efficacy in adults and restricting safety issues, leaving thousands of patients without a suitable treatment. The neglect of Chagas disease is further illustrated by the lack of a robust and diverse drug discovery and development portfolio of new chemical entities, and it is of paramount importance to build a strong research and development network for antichagasic drugs. Focusing on drug discovery programs led by scientists based in Latin America, the main endemic region for this disease, we discuss herein what has been published in the last decade in terms of identification of new antiparasitic drugs to treat Chagas disease, shining a spotlight on the origin, chemical diversity, level of characterization of hits, and strategies used for optimization of lead compounds. Finally, we identify strengths and weaknesses in these drug discovery campaigns and highlight the importance of multidisciplinary collaboration and knowledge sharing., Competing Interests: Author JK is an employee of the company Drugs for Neglected Diseases Initiative (DNDi) Latin America. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Oliveira, Cruz, Mollo, Dias and Kratz.)
- Published
- 2021
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15. 2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.
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Ferreira RAA, Junior COR, Martinez PDG, Koovits PJ, Soares BM, Ferreira LLG, Michelan-Duarte S, Chelucci RC, Andricopulo AD, Galuppo MK, Uliana SRB, Matheeussen A, Caljon G, Maes L, Campbell S, Kratz JM, Mowbray CE, and Dias LC
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- Animals, Antiprotozoal Agents pharmacology, Benzimidazoles chemistry, Disease Models, Animal, Female, Humans, Mice, Mice, Inbred BALB C, Microsomes, Liver, Benzimidazoles pharmacology, Drug Discovery, Leishmania infantum drug effects, Leishmaniasis drug therapy
- Abstract
Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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16. Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.
- Author
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Koovits PJ, Dessoy MA, Matheeussen A, Maes L, Caljon G, Ferreira LLG, Chelucci RC, Michelan-Duarte S, Andricopulo AD, Campbell S, Kratz JM, Mowbray CE, and Dias LC
- Abstract
A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29 . Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)
- Published
- 2020
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17. Structure-activity relationship of 4-azaindole-2-piperidine derivatives as agents against Trypanosoma cruzi.
- Author
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Koovits PJ, Dessoy MA, Matheeussen A, Maes L, Caljon G, Mowbray CE, Kratz JM, and Dias LC
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- Animals, Humans, Piperidines pharmacology, Structure-Activity Relationship, Chagas Disease drug therapy, Piperidines therapeutic use, Trypanosoma cruzi drug effects
- Abstract
The structure-activity relationship of a 4-Azaindole-2-piperidine compound selected from GlaxoSmithKline's recently disclosed open-resource "Chagas box" and possessing moderate activity against Trypanosoma cruzi, the parasite responsible for Chagas disease, is presented. Despite considerable medicinal chemistry efforts, a suitably potent and metabolically stable compound could not be identified to advance the series into in vivo studies. This research should be of interest to those in the area of neglected diseases and in particular anti-kinetoplastid drug discovery., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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18. Drug discovery for chagas disease: A viewpoint.
- Author
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Kratz JM
- Subjects
- Chagas Disease parasitology, Humans, Trypanosoma cruzi drug effects, Chagas Disease drug therapy, Drug Discovery, Nifurtimox therapeutic use, Nitroimidazoles therapeutic use, Trypanocidal Agents therapeutic use
- Abstract
Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. It is a significant public health problem, affecting millions of people worldwide. And although it was described 110 years ago, only two old nitroheterocyclic drugs, benznidazole and nifurtimox, are currently available for the treatment of Chagas disease and both have several limitations. Besides the clear unmet medical need, many challenges preclude the development of new treatments, some of them related to a lack of understanding of the pathophysiology of the disease and parasite-host interactions. New knowledge and tools are becoming available, but the number of new chemical entities progressing through the preclinical pipeline is inadequate. Therefore, it is still uncertain whether safe, effective and accessible new drugs will be available in the near future. The Chagas disease research community must commit to even greater collaboration to ensure that patients eventually benefit from better treatments., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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19. Chemical Constituents and Pharmacology properties of Aristolochia triangularis: a south brazilian highly-consumed botanical with multiple bioactivities.
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Oliveira SQ, Kratz JM, Chaves VC, Guimarães TR, Costa DTM, Dimitrakoudi S, Vontzalidou A, Bordignon SAL, Simionato CP, Steindel M, Reginatto FH, Simões CMO, and Schenkel EP
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- Anti-Bacterial Agents pharmacology, Antifungal Agents pharmacology, Antiprotozoal Agents pharmacology, Antiviral Agents pharmacology, Aristolochic Acids chemistry, Brazil, Chemical Fractionation, Chromatography, High Pressure Liquid methods, Humans, Phytochemicals pharmacology, Plant Extracts pharmacology, Aristolochia chemistry, Phytochemicals chemistry
- Abstract
Aristolochia triangularis Cham., is one of the most frequently used medicinal plant in Southern Brazil. Preparations containing the leaves and/or stems are traditionally used as anti-inflammatory, diuretic, as well as antidote against snakebites. This study screened A. triangularis extracts, fractions and isolated compounds for different bioactivities. A weak antiproliferative activity against human lung cancer cell line (A549) was observed only for chloroform fraction obtained from stems (CFstems - CC50: 2.93 µg/mL). Also, a moderate antimicrobial activity against Staphylococcus aureus was detected just for chloroform fraction obtained from leaves (CFleaves -13-16 mm inhibition zone). Additionally, two semi-purified fractions (CFstems-4 and CFleaves-4) selectively inhibited HSV-1 replication (IC50 values of 0.40 and 2.61 µg/mL, respectively), while only CFleaves showed promising results against Leishmania amazonensis. Fractionation of extracts resulted in the isolation of one neolignan (-) cubebin and one lignan (+) galbacin. However, these compounds are not responsible for the in vitro bioactivities herein detected. The presence of aristolochic acid I and aristolochic acid II in the crude ethanol extract of stems (CEEstems) and leaves (CEEleaves) was also investigated. The HPLC analysis of these extracts did not display any peak with retention time or UV spectra comparable to aristolochic acids I and II.
- Published
- 2019
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20. Thirty-year experience with a bileaflet mechanical valve prosthesis.
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Johnson S, Stroud MR, Kratz JM, Bradley SM, Crawford FA Jr, and Ikonomidis JS
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- Adolescent, Adult, Aged, Aged, 80 and over, Aortic Valve surgery, Female, Humans, Male, Middle Aged, Mitral Valve surgery, Postoperative Complications epidemiology, Postoperative Complications etiology, Proportional Hazards Models, Reoperation, Risk Factors, Survival Analysis, Young Adult, Heart Valve Prosthesis adverse effects, Heart Valve Prosthesis Implantation adverse effects, Heart Valve Prosthesis Implantation mortality
- Abstract
Background: The objective was to evaluate the long-term outcomes of the St Jude Medical (Saint Paul, Minn) mechanical valve prosthesis implantation., Methods: Since 1979, every patient receiving this prosthesis has been followed annually., Results: From January 1979 to December 2014, 1023 patients were accrued. Patients' ages ranged from 18 to 85 years. Aortic valve replacement was performed in 584 patients, and mitral valve replacement was performed in 439 patients. Follow-up was 95% complete. Operative mortality was 3% (17/584, aortic valve replacement) and 4% (18/439, mitral valve replacement). In patients undergoing aortic valve replacement, late actuarial survival was 62% ± 2%, 32% ± 2%, and 14% ± 3% at 10, 20, and 30 years, respectively. Thirty-year freedom from reoperation, thromboembolism, valve thrombosis, bleeding, and endocarditis was 92% ± 2%, 79% ± 3%, 96% ± 1%, 56% ± 5%, and 92% ± 2%, respectively. In patients undergoing mitral valve replacement, late actuarial survival was 64% ± 3%, 28% ± 3%, and 14% ± 3% at 10, 20, and 30 years, respectively. Thirty-year freedom from reoperation, thromboembolism, valve thrombosis, bleeding, and endocarditis was 85% ± 5%, 55% ± 6%, 99% ± 1%, 57% ± 6%, and 95% ± 2%, respectively. The incidence of bleeding was 2.5% and 2.0% per patient-year for aortic valve replacement and mitral valve replacement, respectively. The incidence of thromboembolism was 1.6% and 2.9% per patient-year for aortic valve replacement and mitral valve replacement, respectively., Conclusions: Annual follow-up of all of our patients receiving a St Jude Medical mechanical valves prosthesis has allowed better identification valve-related issues and events. After 3 decades of observation with close follow-up, the St Jude Medical mechanical valve continues to be a reliable prosthesis., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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21. Clinical and pharmacological profile of benznidazole for treatment of Chagas disease.
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Kratz JM, Garcia Bournissen F, Forsyth CJ, and Sosa-Estani S
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- Animals, Chagas Disease epidemiology, Chagas Disease parasitology, Drug Resistance, Humans, Neglected Diseases drug therapy, Neglected Diseases epidemiology, Neglected Diseases parasitology, Nitroimidazoles adverse effects, Nitroimidazoles pharmacology, Public Health, Trypanocidal Agents adverse effects, Trypanocidal Agents pharmacology, Chagas Disease drug therapy, Nitroimidazoles therapeutic use, Trypanocidal Agents therapeutic use
- Abstract
Introduction: Chagas disease (CD) is one of the most neglected public health problems in the Americas, where <1% of the estimated 6 million people with the infection have been diagnosed and treated. The goal of treatment is to eliminate the parasite, decrease the probability of cardiomyopathy and other complications during the chronic stage of infection, and interrupt the cycle of disease transmission by preventing congenital infection. Currently, only benznidazole (BZN) and nifurtimox are recognized by the World Health Organization as effective drugs for treatment of CD. In this paper, we provide an overview of the clinical pharmacology of BZN. Areas covered: This review covers the historical background, chemistry, mechanism of action, pharmacokinetics, preclinical research, resistance, clinical research, toxicology, adverse effects, and current regulatory status of BZN. Expert commentary: Ongoing investigations aim to optimize BZN therapy by adjusting the current standard regimen or by combining BZN with new chemical entities. These studies are assessing alternatives that improve safety while maintaining or increasing the efficacy of BZN. Timely diagnosis and antitrypanosomal treatment are critical components of programs to eliminate CD as a public health problem, and can dramatically reduce the heavy burden of morbidity and mortality caused by the disease.
- Published
- 2018
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22. In Silico Workflow for the Discovery of Natural Products Activating the G Protein-Coupled Bile Acid Receptor 1.
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Kirchweger B, Kratz JM, Ladurner A, Grienke U, Langer T, Dirsch VM, and Rollinger JM
- Abstract
The G protein-coupled bile acid receptor (GPBAR1) has been recognized as a promising new target for the treatment of diverse diseases, including obesity, type 2 diabetes, fatty liver disease and atherosclerosis. The identification of novel and potent GPBAR1 agonists is highly relevant, as these diseases are on the rise and pharmacological unmet therapeutic needs are pervasive. Therefore, the aim of this study was to develop a proficient workflow for the in silico prediction of GPBAR1 activating compounds, primarily from natural sources. A protocol was set up, starting with a comprehensive collection of structural information of known ligands. This information was used to generate ligand-based pharmacophore models in LigandScout 4.08 Advanced. After theoretical validation, the two most promising models, namely BAMS22 and TTM8, were employed as queries for the virtual screening of natural product and synthetic small molecule databases. Virtual hits were progressed to shape matching experiments and physicochemical clustering. Out of 33 diverse virtual hits subjected to experimental testing using a reporter gene-based assay, two natural products, farnesiferol B ( 27 ) and microlobidene ( 28 ), were confirmed as GPBAR1 activators reaching more than 50% receptor activation at 20 μM with EC
50 s of 13.53 μM and 13.88 μM, respectively. This activity is comparable to that of the endogenous ligand lithocholic acid ( 1 ). Seven further virtual hits showed activity reaching at least 15% receptor activation either at 5 or 20 μM, including new scaffolds from natural and synthetic origin.- Published
- 2018
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23. Natural products modulating the hERG channel: heartaches and hope.
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Kratz JM, Grienke U, Scheel O, Mann SA, and Rollinger JM
- Subjects
- Drug Discovery, Humans, Molecular Structure, Myocytes, Cardiac physiology, Plants, Medicinal chemistry, Alkaloids chemistry, Alkaloids isolation & purification, Alkaloids pharmacology, Arrhythmias, Cardiac physiopathology, Biological Products chemistry, Biological Products isolation & purification, Biological Products pharmacology, Ether-A-Go-Go Potassium Channels drug effects, Ether-A-Go-Go Potassium Channels genetics, Heart physiology
- Abstract
Covering: 1996-December 2016The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity. Moreover, as a result of its notorious ligand promiscuity, this ion channel has emerged as an important antitarget in early drug discovery and development. Surprisingly, the hERG channel blocking profile of natural compounds present in frequently consumed botanicals (i.e. dietary supplements, spices, and herbal medicinal products) is not routinely assessed. This comprehensive review will address these issues and provide a critical compilation of hERG channel data for isolated natural products and extracts over the past two decades (1996-2016). In addition, the review will provide (i) a solid basis for the molecular understanding of the physiological functions of the hERG channel, (ii) the translational potential of in vitro/in vivo results to cardiotoxicity in humans, (iii) approaches for the identification of hERG channel blockers from natural sources, (iv) future perspectives for cardiac safety guidelines and their applications within phytopharmaceuticals and dietary supplements, and (v) novel applications of hERG channel modulation (e.g. as a drug target).
- Published
- 2017
- Full Text
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24. Solid dispersions enhance solubility, dissolution, and permeability of thalidomide.
- Author
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Barea SA, Mattos CB, Cruz AC, Chaves VC, Pereira RN, Simões CM, Kratz JM, and Koester LS
- Subjects
- Chemistry, Pharmaceutical, Drug Carriers administration & dosage, Permeability drug effects, Solubility, Thalidomide administration & dosage, X-Ray Diffraction, Drug Carriers chemistry, Drug Carriers metabolism, Membranes, Artificial, Thalidomide chemistry, Thalidomide metabolism
- Abstract
Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire
® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor® TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2-3x the equilibrium solubility) for a least 4 h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.- Published
- 2017
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25. Pharmacokinetics of Saquinavir Mesylate from Oral Self-Emulsifying Lipid-Based Delivery Systems.
- Author
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Caon T, Kratz JM, Kuminek G, Heller M, Micke GA, de Araujo BV, Koester LS, and Simões CM
- Subjects
- Administration, Intravenous, Administration, Oral, Animals, Biological Availability, Dogs, Emulsions, Lipids chemistry, Lipids pharmacokinetics, Male, Models, Biological, Saquinavir blood, Saquinavir chemistry, Drug Delivery Systems methods, Saquinavir administration & dosage, Saquinavir pharmacokinetics
- Abstract
Background and Objectives: Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly soluble drugs, compartmental pharmacokinetic analyses have not been extensively explored. The oral pharmacokinetics of commercial liquid formulation and a developed semisolid system containing saquinavir mesylate (SQVM) were compared in Beagle dogs. A compartmental analysis after intravenous bolus administration of this drug (1 mg/kg) was also performed., Method: Pharmacokinetic profiles were analyzed using both non-compartmental and compartmental approaches. Plasma concentration of the drug was determined by high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS)., Results: The disposition curve of SQVM given intravenously was better described by a three-compartment model. In contrast, plasma profiles obtained following the oral administration were fitted to a two-compartment model with lag time due to the fact that the distribution phase was masked by the absorption phase in these formulations., Conclusion: The proposed semisolid lipid system was found to be a promising formulation for commercial purposes given the similarity of SQVM absorption rate to that from the commercial liquid formulation.
- Published
- 2017
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26. Enzymatic synthesis of ascorbyl ester derived from linoleic acid.
- Author
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Balen M, Gomes GR, Kratz JM, Simões CM, Valério A, and de Oliveira D
- Subjects
- Ascorbic Acid chemical synthesis, Ascorbic Acid chemistry, Enzymes, Immobilized, Fungal Proteins, Linoleic Acids chemistry, Ascorbic Acid analogs & derivatives, Linoleic Acids chemical synthesis, Lipase chemistry
- Abstract
Antioxidants are substances that defend cells against damage, kidnapping and destroying free radicals. They have been largely used in the food industry due the possibility to control the oxidation process, aimed to increase shelf life. Thus, esterification reaction to obtain ascorbyl linoleate catalyzed by Novozym 435 lipase assisted by ultrasound bath was investigated. In this work, molecular sieve (4 Å) was added to the reaction medium to remove the water formed during the esterification reaction to improve the process performance. According to the results, ascorbyl linoleate production up to 90 % was reached after 1 h of reaction time carried out using ultrasound bath, 1:9 molar ratio of substrates L-ascorbic acid to linoleic acid, 20 mL of tert-butanol as organic solvent, 5 wt% of Novozym 435 lipase, 10 wt% of molecular sieve at 70 °C.
- Published
- 2017
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27. Strychnos pseudoquina A. St. Hil.: a Brazilian medicinal plant with promising in vitro antiherpes activity.
- Author
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Boff L, Silva IT, Argenta DF, Farias LM, Alvarenga LF, Pádua RM, Braga FC, Leite JP, Kratz JM, and Simões CM
- Subjects
- Animals, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacology, Antiviral Agents chemistry, Biflavonoids chemistry, Brazil, Cell Line, Chemokine CCL2 metabolism, Chlorocebus aethiops, Cytokines metabolism, Herpesvirus 1, Human physiology, Humans, Plant Extracts chemistry, Plant Extracts pharmacology, Plants, Medicinal chemistry, Quercetin chemistry, Quercetin pharmacology, Vero Cells, Antiviral Agents pharmacology, Biflavonoids pharmacology, Herpesvirus 1, Human drug effects, Quercetin analogs & derivatives, Strychnos chemistry
- Abstract
Aims: To investigate the anti-HSV and anti-inflammatory effects of a standardized ethyl acetate extract (SEAE) prepared with the stem bark of Strychnos pseudoquina, along with two isolated compounds: quercetin 3-O-methyl ether (3MQ) and strychnobiflavone (SBF)., Methods and Results: The mechanisms of action were evaluated by different methodological strategies. SEAE and SBF affected the early stages of viral infection and reduced HSV-1 protein expression. Both flavonoids elicited a concentration-dependent inhibition of monocyte chemoattractant protein-1 (MCP-1), whereas 3MQ reduced the chemokine release more significantly than SBF. Conversely, both compounds stimulated the production of the cytokines TNF-α and IL-1-β in LPS-stimulated cells, especially at the intermediate and the highest tested concentrations., Conclusions: SEAE and SBF interfered with various steps of HSV replication cycle, mainly adsorption, postadsorption and penetration, as well as with β and γ viral proteins expression; moreover, a direct inactivation of viral particles was observed. Besides, both flavonoids inhibited MCP-1 selectively, a feature that may be beneficial for the development of new anti-HSV agents., Significance and Impact of the Study: The results indicated that the samples present anti-HSV and anti-inflammatory activities, at different levels, which is an interesting feature since cold and genital sores are accompanied by an inflammation process., (© 2016 The Society for Applied Microbiology.)
- Published
- 2016
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28. hERG Channel Blocking Ipecac Alkaloids Identified by Combined In Silico - In Vitro Screening.
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Kratz JM, Mair CE, Oettl SK, Saxena P, Scheel O, Schuster D, Hering S, and Rollinger JM
- Subjects
- Alkaloids chemistry, Alkaloids isolation & purification, Animals, Computer Simulation, Humans, Ipecac chemistry, Molecular Structure, Xenopus laevis, Alkaloids pharmacology, Cephaelis chemistry, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ipecac pharmacology
- Abstract
Human ether-a-go-go-related gene channel blocking is associated with QT interval prolongation and increased risk of potentially fatal arrhythmias. As natural products keep increasing in popularity, there is an urgent need for studies assessing human ether-a-go-go-related gene channel-related cardiotoxic risks. We selected 49 plant species based on the results of a pharmacophore-based virtual screening campaign, in parallel with a literature data survey concerning highly consumed herbal medicines with reported cardiac liabilities. Lead-like enhanced extracts were prepared, an initial in vitro screening was performed at 100 µg/mL by voltage clamp on Xenopus oocytes, and five human ether-a-go-go-related gene channel blocking extracts were identified. In accordance to the six virtually predicted alkaloids, the root extract of Carapichea ipecacuanha inhibited human ether-a-go-go-related gene channel currents by 32.5 %. A phytochemical workflow resulted in the isolation and identification of five out of the six virtually predicted alkaloids. All isolates blocked human ether-a-go-go-related gene channel currents to different extents. The major ipecac constituents emetine (1) and cephaeline (2) showed IC50 values of 21.4 and 5.3 µM, respectively, measured by whole-cell patch clamp in HEK293 cells. This is the first report on human ether-a-go-go-related gene channel blockers from C. ipecacuanha. Its roots and rhizomes are used to produce different pharmacopeial ipecac preparations that are mainly used as emetics for poisoning treatment. Our findings raise further questions regarding the safety and over-the-counter appropriateness of these herbal products., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2016
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29. Pharmacokinetics of hERG Channel Blocking Voacangine in Wistar Rats Applying a Validated LC-ESI-MS/MS Method.
- Author
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Mair CE, de Miranda Silva C, Grienke U, Kratz JM, Carreño F, Zimmermann ES, de Araújo BV, Dalla Costa T, and Rollinger JM
- Subjects
- Animals, Humans, Ibogaine chemistry, Ibogaine pharmacokinetics, Ibogaine pharmacology, Male, Molecular Structure, Rats, Rats, Wistar, Tandem Mass Spectrometry methods, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ibogaine analogs & derivatives, Voacanga chemistry
- Abstract
Herbal preparations from Voacanga africana are used in West and Central African folk medicine and are also becoming increasingly popular as a legal high in Europe. Recently, the main alkaloid voacangine was found to be a potent human ether-à-go-go-related gene channel blocker in vitro. Blockage of this channel might imply possible cardiotoxicity. Therefore, the aim of this study was to characterise voacangine in vivo to assess its pharmacokinetics and to estimate if further studies to investigate its cardiotoxic risk are required. Male Wistar rats received different doses of voacangine as a pure compound and as a hydro-ethanolic extract of V. africana root bark with a quantified amount of 9.71 % voacangine. For the obtained data, a simultaneous population pharmacokinetics model was successfully developed, comprising a two-compartment model for i. v. dosing and a one-compartmental model with two first-order absorption rates for oral dosing. The absolute bioavailability of voacangine was determined to be 11-13 %. Model analysis showed significant differences in the first absorption rate constant for voacangine administered as a pure compound and voacangine from the extract of V. africana. Taking into account the obtained low bioavailability of voacangine, its cardiotoxic risk might be neglectable in healthy consumers, but may have a serious impact in light of drug/drug interactions and impaired health conditions., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2016
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30. Anti-inflammatory Effect and Toxicology Analysis of Oral Delivery Quercetin Nanosized Emulsion in Rats.
- Author
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Hädrich G, Vaz GR, Maidana M, Kratz JM, Loch-Neckel G, Favarin DC, Rogerio Ade P, da Silva FM Jr, Muccillo-Baisch AL, and Dora CL
- Subjects
- Animals, Anti-Inflammatory Agents pharmacokinetics, Anti-Inflammatory Agents toxicity, Antioxidants administration & dosage, Antioxidants pharmacokinetics, Antioxidants therapeutic use, Antioxidants toxicity, Caco-2 Cells, Edema drug therapy, Edema pathology, Humans, Lipid Peroxidation drug effects, Liver drug effects, Male, NF-kappa B analysis, NF-kappa B antagonists & inhibitors, Quercetin pharmacokinetics, Quercetin toxicity, Rats, Rats, Wistar, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents therapeutic use, Drug Carriers chemistry, Emulsions chemistry, Lipids chemistry, Quercetin administration & dosage, Quercetin therapeutic use
- Abstract
Purpose: This study evaluates the advantage of the quercetin encapsulation in nanosized emulsion (QU-NE) administered orally in rats in order to demonstrate its anti-oedematous and antioxidant effects as well as its toxicity., Methods: The nanocarriers were prepared using the hot solvent diffusion with the phase inversion temperature methods. The nanocarriers physicochemical properties were then investigated. The anti-edematous activity was tested using paw edema in rats. In addition, NF-kB expression in subcutaneous tissue of the paws was accessed by immunohistochemistry while the lipid peroxidation was analyzed in the liver by malondialdehyde reaction with thiobarbituric acid. Hematological, renal and hepatic toxicity as well as the genetic damage were also evaluated., Results: The results demonstrated that QU-NE exhibited pronounced anti-oedematous property comparable to drug diclofenac. This effect was associated with NF-κB pathway inhibition. The lipid peroxidation was also only reduced in rats treated with QU-NE. Besides this, no genetic damage, hematological, renal or hepatic toxicities were observed after administration of QU-NE., Conclusions: These results suggest that quercetin nanosized emulsion exhibits anti-oedematous and antioxidant properties and does not demonstrate toxic effects. This indicates that it has a potential application in the treatment of inflammatory diseases.
- Published
- 2016
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31. Rosmarinic Acid--Pharmaceutical and Clinical Aspects.
- Author
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Amoah SK, Sandjo LP, Kratz JM, and Biavatti MW
- Subjects
- Animals, Cinnamates pharmacokinetics, Cinnamates pharmacology, Depsides pharmacokinetics, Depsides pharmacology, Humans, Rosmarinic Acid, Cinnamates chemistry, Cinnamates therapeutic use, Depsides chemistry, Depsides therapeutic use
- Abstract
The biosynthesis and biotechnological production of Rosmarinic acid, a phenolic ester that is widespread in the plant kingdom, has been widely investigated. This compound has shown many remarkable biological and pharmacological activities, which have led to its pharmaceutical and analytical development, as well as clinical studies, which are summarized and analyzed here for the first time. This review compiles data from the Pubmed, Scopus, Scifinder, Web Of Science, and Science Direct databases published between 1990 and 2015, restricting the search to works with the keywords "Rosmarinic acid" in the title. The initial search identified more than 800 articles; after an initial screening and removal of duplicate works, the search was further refined, resulting in approximately 300 articles that were scrutinized and comprise this review. The articles were organized to describe extraction and isolation, analytical methods, pharmaceutical development, and biological and pharmacological activities [divided into nonclinical (in vitro, in vivo) and clinical studies], pharmacokinetic studies, and stability studies., (Georg Thieme Verlag KG Stuttgart · New York.)
- Published
- 2016
- Full Text
- View/download PDF
32. Inclusion complexes of hydrochlorothiazide and β-cyclodextrin: Physicochemical characteristics, in vitro and in vivo studies.
- Author
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Mendes C, Buttchevitz A, Kruger JH, Kratz JM, Simões CM, de Oliveira Benedet P, Oliveira PR, and Silva MA
- Subjects
- Animals, Caco-2 Cells, Calorimetry, Differential Scanning, Chemistry, Pharmaceutical, Chromatography, High Pressure Liquid, Drug Stability, Female, Freeze Drying, Hot Temperature, Humans, Intestinal Absorption, Powder Diffraction, Rats, Wistar, Solubility, Spectroscopy, Fourier Transform Infrared, X-Ray Diffraction, Diuretics administration & dosage, Diuretics chemistry, Diuretics pharmacology, Hydrochlorothiazide administration & dosage, Hydrochlorothiazide chemistry, Hydrochlorothiazide pharmacology, beta-Cyclodextrins administration & dosage, beta-Cyclodextrins chemistry, beta-Cyclodextrins pharmacology
- Abstract
Hydrochlorothiazide is a thiazide diuretic widely used in clinics to treat arterial hypertension. It is a class IV drug according to the Biopharmaceutical Classification System, that is, it presents low solubility and low permeability and, consequently, low absorption in the gastrointestinal tract. As a strategy to improve stability and biopharmaceutical properties of hydrochlorothiazide, the use of cyclodextrins to produce inclusion complexes, applying different methods, was investigated. In the phase solubility studies, β-cyclodextrin was identified as the cyclodextrin which provided the most promising results in terms of the solubilization of the drug. The thermal analysis verified the interaction between hydrochlorothiazide and β-cyclodextrin, indicating the formation of inclusion complexes, and the thermal stability varied according to the preparation technique. The physicochemical characterization showed that in the inclusion complexes obtained by co-evaporation, kneading followed by freeze-drying and kneading followed by spray-drying the hydrochlorothiazide complexation mostly occurred with different degrees of amorphization and the drug solubility was improved. These three inclusion complexes presented better in vitro characteristics and the inclusion complex obtained by kneading followed by freeze-drying increased the in vivo diuretic activity of the drug accompanied by significant effects on natriuresis, kaliuresis and chloriuresis. The inclusion complex formation was effective in improving the biopharmaceutical properties of hydrochlorothiazide and protecting the drug from hydrolysis. This paper describes an important alternative approach to the development of liquid pharmaceutical formulations to pediatric administration, a real need of the current pharmaceutical market., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2016
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33. Synergistic Antiproliferative Effects of a New Cucurbitacin B Derivative and Chemotherapy Drugs on Lung Cancer Cell Line A549.
- Author
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Marostica LL, Silva IT, Kratz JM, Persich L, Geller FC, Lang KL, Caro MS, Durán FJ, Schenkel EP, and Simões CM
- Subjects
- Actins metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Camptothecin analogs & derivatives, Camptothecin pharmacology, Camptothecin therapeutic use, Cell Line, Tumor, Cell Movement drug effects, Cisplatin pharmacology, Cisplatin therapeutic use, G2 Phase Cell Cycle Checkpoints drug effects, Humans, Inhibitor of Apoptosis Proteins metabolism, Irinotecan, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, M Phase Cell Cycle Checkpoints drug effects, Paclitaxel pharmacology, Paclitaxel therapeutic use, Reactive Oxygen Species metabolism, Survivin, Triterpenes chemistry, Triterpenes therapeutic use, Tumor Suppressor Protein p53 metabolism, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Drug Synergism, Triterpenes pharmacology
- Abstract
Nonsmall cell lung cancer (NSCLC) represents an important cause of mortality worldwide due to its aggressiveness and growing resistance to currently available therapy. Cucurbitacins have emerged as novel potential anticancer agents showing strong antiproliferative effects and can be promising candidates for combined treatments with clinically used anticancer agents. This study investigates the synergistic antiproliferative effects of a new semisynthetic derivative of cucurbitacin B (DACE) with three chemotherapy drugs: cisplatin (CIS), irinotecan (IRI), and paclitaxel (PAC) on A549 cells. The most effective combinations were selected for studies of the mechanism of action. Using an in silico tool, DACE seems to act by a different mechanism of action when compared with that of different classes of drugs already used in clinical settings. DACE also showed potent synergic effects with drugs, and the most potent combinations induced G2/M cell cycle arrest by modulating survivin and p53 expression, disruption of F-actin cytoskeleton, and cell death by apoptosis. These treatments completely inhibited the clonogenic potential and did not reduce the proliferation of nontumoral lung cells (MRC-5). DACE also showed relevant antimigratory and anti-invasive effects, and combined treatments modulated cell migration signaling pathways evolved with metastasis progression. The effects of DACE associated with drugs was potentiated by the oxidant agent l-buthionine-sulfoximine (BSO), and attenuated by N-acetilcysteine (NAC), an antioxidant agent. The antiproliferative effects induced by combined treatments were attenuated by a pan-caspase inhibitor, indicating that the effects of these treatments are dependent on caspase activity. Our data highlight the therapeutic potential of DACE used in combination with known chemotherapy drugs and offer important insights for the development of more effective and selective therapies against lung cancer.
- Published
- 2015
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34. Ball-milled solid dispersions of BCS Class IV drugs: Impact on the dissolution rate and intestinal permeability of acyclovir.
- Author
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Nart V, França MT, Anzilaggo D, Riekes MK, Kratz JM, de Campos CE, Simões CM, and Stulzer HK
- Subjects
- Caco-2 Cells, Drug Carriers pharmacokinetics, Drug Carriers pharmacology, Gastrointestinal Absorption, Humans, Permeability, Acyclovir chemistry, Acyclovir pharmacokinetics, Drug Carriers chemistry, Models, Biological
- Abstract
Acyclovir, an analog of 2'-deoxyguanosine, is one of the most important drugs in the current approved antiviral treatment. However, it's biopharmaceutical properties, contribute to acyclovir's poor oral bioavailability, which restricts the clinical use of the drug. In this view, the aim of this work was to improve the dissolution rate and intestinal permeability of acyclovir through the development of ball milling solid dispersions with the hydrophilic carriers Pluronic F68®, hydroxypropylmethyl cellulose K100M® and chitosan. Solid dispersions were obtained and completely characterized through different solid state techniques. The solid state data demonstrated a decrease in the crystallinity (amorphous phase and defects) and the presence of hydrogen bonds for SD HPMC and SD CTS. The enhancement of dissolution rates was observed for all SDs developed. In addition, no detrimental effects over the in vitro antiviral activity were detected. The solid dispersions with Pluronic F68® significantly improved the intestinal permeability of acyclovir across Caco-2 cells. In summary, the SDs developed in this study could be considered as potential systems for solid dosage forms containing acyclovir with superior biopharmaceutical properties., (Copyright © 2015 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
35. Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.
- Author
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Fransson R, Nordvall G, Bylund J, Carlsson-Jonsson A, Kratz JM, Svensson R, Artursson P, Hallberg M, and Sandström A
- Abstract
The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.
- Published
- 2014
- Full Text
- View/download PDF
36. Experimentally validated HERG pharmacophore models as cardiotoxicity prediction tools.
- Author
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Kratz JM, Schuster D, Edtbauer M, Saxena P, Mair CE, Kirchebner J, Matuszczak B, Baburin I, Hering S, and Rollinger JM
- Subjects
- Binding Sites, Cardiotonic Agents pharmacology, Drug Design, Drug Evaluation, Preclinical, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels genetics, Gene Expression, HEK293 Cells, High-Throughput Screening Assays, Humans, Ligands, Membrane Potentials drug effects, Molecular Conformation, Molecular Dynamics Simulation, Patch-Clamp Techniques, Potassium Channel Blockers pharmacology, Protein Binding, Recombinant Proteins chemistry, Recombinant Proteins genetics, Small Molecule Libraries pharmacology, Structure-Activity Relationship, User-Computer Interface, Cardiotonic Agents chemistry, Ether-A-Go-Go Potassium Channels chemistry, Potassium Channel Blockers chemistry, Small Molecule Libraries chemistry
- Abstract
The goal of this study was to design, experimentally validate, and apply a virtual screening workflow to identify novel hERG channel blockers. The hERG channel is an important antitarget in drug development since cardiotoxic risks remain as a major cause of attrition. A ligand-based pharmacophore model collection was developed and theoretically validated. The seven most complementary and suitable models were used for virtual screening of in-house and commercially available compound libraries. From the hit lists, 50 compounds were selected for experimental validation through bioactivity assessment using patch clamp techniques. Twenty compounds inhibited hERG channels expressed in HEK 293 cells with IC50 values ranging from 0.13 to 2.77 μM, attesting to the suitability of the models as cardiotoxicity prediction tools in a preclinical stage.
- Published
- 2014
- Full Text
- View/download PDF
37. Antiherpetic mechanism of a sulfated derivative of Agaricus brasiliensis fruiting bodies polysaccharide.
- Author
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Cardozo FT, Camelini CM, Leal PC, Kratz JM, Nunes RJ, Mendonça MM, and Simões CM
- Subjects
- Acyclovir pharmacology, Animals, Brazil, Chlorocebus aethiops, Drug Synergism, Polysaccharides chemistry, Vero Cells, Viral Plaque Assay, beta-Glucans chemistry, beta-Glucans isolation & purification, Agaricus chemistry, Antiviral Agents chemistry, Antiviral Agents pharmacology, Fruiting Bodies, Fungal chemistry, Herpesvirus 1, Human drug effects, Herpesvirus 2, Human drug effects, Polysaccharides pharmacology, beta-Glucans pharmacology
- Abstract
Objective: To study the anti-herpes simplex virus (HSV) activity of a (1→6)-(1→3)-β-D-glucan isolated from Agaricus brasiliensis fruiting bodies (FR) as well as its chemically sulfated derivative (FR-S)., Methods: The antiherpetic activity and mechanism of action was studied by viral plaque assay applying different methodological strategies., Results: Although FR presented no in vitro antiherpetic action at 1 mg/ml, FR-S displayed promising anti-HSV-1 and anti-HSV-2 activities in both simultaneous and postinfection treatments, resulting in selectivity indices (CC₅₀/EC₅₀) higher than 393. FR-S had no virucidal effect, but significantly suppressed HSV-1 (EC₅₀ = 0.32 µg/ml) and HSV-2 (EC₅₀ = 0.10 µg/ml) adsorption. FR-S was less effective on adsorption inhibition of mutant virus strains devoid of gC (HSV-1 gC⁻39 and HSV-2 gCneg1), indicating a possible interaction with this glycoprotein. The reduction of viral adsorption upon cell pretreatment with FR-S also suggests its interaction with cellular components. FR-S inhibited HSV-1 (EC₅₀ = 8.39 µg/ml) and HSV-2 (EC₅₀ = 2.86 µg/ml) penetration more efficiently than heparin. FR-S reduced HSV-1 and HSV-2 cell-to-cell spread. A synergic effect between FR-S and acyclovir was also detected., Conclusions: FR-S displays an interesting mechanism of antiviral action and represents a promising candidate for the treatment and/or prevention of herpetic infections, to be used as a single therapeutic agent or in combination with acyclovir., (© 2014 S. Karger AG, Basel.)
- Published
- 2014
- Full Text
- View/download PDF
38. Constrained H-Phe-Phe-NH2 analogues with high affinity to the substance P 1-7 binding site and with improved metabolic stability and cell permeability.
- Author
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Fransson R, Sköld C, Kratz JM, Svensson R, Artursson P, Nyberg F, Hallberg M, and Sandström A
- Subjects
- Binding Sites, Drug Stability, Humans, Models, Molecular, Peptide Fragments chemistry, Permeability, Protein Binding, Protein Conformation, Substance P chemistry, Dipeptides chemistry, Dipeptides metabolism, Peptide Fragments metabolism, Substance P metabolism
- Abstract
We recently reported the discovery of H-Phe-Phe-NH2 as a small and high affinity ligand for the substance P 1-7 (SP(1-7), H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP(1-7) mimetics, the dipeptide was chosen as a lead compound. Herein the structure-activity relationship (SAR) of a set of modified H-Phe-Phe-NH2 analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C-terminal of H-Phe-Phe-NH2 resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability.
- Published
- 2013
- Full Text
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39. Apicoaortic conduits: indications, complications, and imaging techniques.
- Author
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Nance JW, Barraza JM, Henzler T, McMaster WG, Kratz JM, and Schoepf UJ
- Subjects
- Blood Vessel Prosthesis Implantation, Cardiac Catheterization, Cardiopulmonary Bypass, Humans, Postoperative Complications diagnosis, Ventricular Outflow Obstruction congenital, Aorta, Thoracic surgery, Cardiac Surgical Procedures methods, Diagnostic Imaging, Ventricular Outflow Obstruction surgery
- Abstract
Left ventricular apex to descending aorta conduits may be used as a last resort treatment of severe left ventricular outflow tract obstruction in cases in which alternative therapies are contraindicated. Although this technique is rarely used in current practice for congenital cases, its use in the elderly population is increasing, largely due to the expansion of this patient cohort and associated comorbidities precluding aortic valve replacement, the most common of which are a severely calcified "porcelain" aorta and/or previous coronary artery bypass grafts preventing aortic root manipulation. Diagnostic imaging is essential in the presurgical workup and subsequent follow-up of these patients, as complications of the procedure are potentially life threatening and are not rare. Several imaging modalities may be used, each with advantages and disadvantages. Both anatomic and functional assessments play a role in the comprehensive evaluation of both presurgical and postsurgical patients.
- Published
- 2012
- Full Text
- View/download PDF
40. Preparation, characterization, and in vitro intestinal permeability evaluation of thalidomide-hydroxypropyl-β-cyclodextrin complexes.
- Author
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Kratz JM, Teixeira MR, Ferronato K, Teixeira HF, Koester LS, and Simões CM
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Caco-2 Cells, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Intestinal Absorption drug effects, Permeability drug effects, Solubility drug effects, Thalidomide pharmacology, X-Ray Diffraction, beta-Cyclodextrins pharmacology, Intestinal Absorption physiology, Thalidomide chemical synthesis, Thalidomide metabolism, beta-Cyclodextrins chemical synthesis, beta-Cyclodextrins metabolism
- Abstract
Thalidomide is emerging as a therapeutic agent with renewed clinical importance, presenting anti-inflammatory, immunomodulatory, and antineoplasic properties. In this work, we studied the complexation of thalidomide with cyclodextrins as a strategy to circumvent the poor aqueous solubility of the drug. Thalidomide-hydroxypropyl-β-cyclodextrin complexes were obtained by kneading method and were characterized by differential scanning calorimetry, powder X-ray diffractometry, and scanning electronic microscopy. The aqueous solubility and in vitro dissolution of thalidomide were significantly improved through the complexation. Physicochemical analysis of the complexes in solid state revealed a decreased crystallinity of the complexed drug in comparison with free thalidomide. Thalidomide was able to dissociate from the complexes and permeates across intestinal epithelial Caco-2 cells with a favorable high permeability profile equivalent to that of the free drug. In summary, the present results suggest that thalidomide-hydroxypropyl-β-cyclodextrin complexes could be regarded as a promising strategy for improving the gastrointestinal absorption of thalidomide.
- Published
- 2012
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41. Early postoperative outcomes and blood product utilization in adult cardiac surgery: the post-aprotinin era.
- Author
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DeSantis SM, Toole JM, Kratz JM, Uber WE, Wheat MJ, Stroud MR, Ikonomidis JS, and Spinale FG
- Subjects
- Acute Kidney Injury epidemiology, Aged, Contraindications, Female, Humans, Lysine analogs & derivatives, Male, Middle Aged, Postoperative Hemorrhage epidemiology, Postoperative Period, Respiratory Insufficiency epidemiology, Retrospective Studies, Risk Factors, Treatment Outcome, Aprotinin therapeutic use, Cardiac Surgical Procedures methods, Coronary Artery Bypass methods, Erythrocytes, Heart Valve Prosthesis, Hemostatics therapeutic use, Plasma
- Abstract
Background: Aprotinin was a commonly used pharmacological agent for homeostasis in cardiac surgery but was discontinued, resulting in the extensive use of lysine analogues. This study tested the hypothesis that early postoperative adverse events and blood product utilization would affected in this post-aprotinin era., Methods and Results: Adult patients (n=781) undergoing coronary artery bypass, valve replacement, or both from November 1, 2005, to October 31, 2008, at a single institution were included. Multiple logistic regression modeling and propensity scoring were performed on 29 preoperative and intraoperative variables in patients receiving aprotinin (n=325) or lysine analogues (n=456). The propensity-adjusted relative risk (RR) for the intraoperative use of packed red blood cells (RR, 0.75; 95% confidence interval [CI], 0.57 to 0.99), fresh frozen plasma (RR, 0.37; 95% CI, 0.21 to 0.64), and cryoprecipitate (RR:0.06; 95% CI, 0.02 to 0.22) were lower in the aprotinin versus lysine analog group (all P<0.05). The risk for mortality (RR, 0.53; 95% CI, 0.16 to 1.79) and neurological events (RR, 0.87; 95% CI, 0.35 to 2.18) remained similar between groups, whereas a trend for reduced risk for renal dysfunction was observed in the aprotinin group., Conclusions: In the post-aprotinin era, with the exclusive use of lysine analogues, the relative risk of early postoperative outcomes such as mortality and renal dysfunction have not improved, but the risk for the intraoperative use of blood products has increased. Thus, improvements in early postoperative outcomes have not been realized with the discontinued use of aprotinin, but rather increased blood product use has occurred with the attendant costs and risks inherent with this strategy.
- Published
- 2011
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42. Apicoaortic Conduits, an innovative solution to difficult aortic stenosis: the MUSC Experience.
- Author
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Nance JW Jr, Kratz JM, Ikonomidis JS, Toole JM, Barraza JM, McMaster WG, and Schoepf UJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Angiography, Child, Child, Preschool, Echocardiography, Female, Follow-Up Studies, Humans, Infant, Male, Middle Aged, Severity of Illness Index, South Carolina, Tomography, X-Ray Computed, Treatment Outcome, Young Adult, Aorta, Thoracic surgery, Aortic Valve Stenosis surgery, Blood Vessel Prosthesis Implantation methods, Heart Valve Prosthesis Implantation methods, Hospitals, University
- Published
- 2011
43. An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay.
- Author
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Kratz JM, Teixeira MR, Koester LS, and Simões CM
- Subjects
- Acyclovir pharmacokinetics, Carbamazepine pharmacokinetics, Humans, Hydrochlorothiazide pharmacokinetics, Propranolol pharmacokinetics, Ultraviolet Rays, Verapamil pharmacokinetics, Vinblastine pharmacokinetics, Caco-2 Cells metabolism, Cell Membrane Permeability physiology, Chromatography, High Pressure Liquid methods, Intestinal Mucosa metabolism, Pharmaceutical Preparations metabolism
- Abstract
The Caco-2 cell line has been used as a model to predict the in vitro permeability of the human intestinal barrier. The predictive potential of the assay relies on an appropriate in-house validation of the method. The objective of the present study was to develop a single HPLC-UV method for the identification and quantitation of marker drugs and to determine the suitability of the Caco-2 cell permeability assay. A simple chromatographic method was developed for the simultaneous determination of both passively (propranolol, carbamazepine, acyclovir, and hydrochlorothiazide) and actively transported drugs (vinblastine and verapamil). Separation was achieved on a C18 column with step-gradient elution (acetonitrile and aqueous solution of ammonium acetate, pH 3.0) at a flow rate of 1.0 mL/min and UV detection at 275 nm during the total run time of 35 min. The method was validated and found to be specific, linear, precise, and accurate. This chromatographic system can be readily used on a routine basis and its utilization can be extended to other permeability models. The results obtained in the Caco-2 bi-directional transport experiments confirmed the validity of the assay, given that high and low permeability profiles were identified, and P-glycoprotein functionality was established.
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- 2011
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44. Combined carotid endarterectomy and coronary artery bypass grafting versus coronary artery bypass grafting alone: a retrospective review of outcomes at our institution.
- Author
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Dick AM, Brothers T, Robison JG, Elliott BM, Kratz JM, Toole JM, Crumbley AJ, and Crawford FA Jr
- Subjects
- Aged, Carotid Stenosis complications, Carotid Stenosis mortality, Coronary Artery Disease complications, Coronary Artery Disease mortality, Female, Humans, Male, Middle Aged, Myocardial Infarction etiology, Odds Ratio, Propensity Score, Retrospective Studies, Risk Assessment, Risk Factors, Severity of Illness Index, South Carolina, Stroke etiology, Time Factors, Treatment Outcome, Carotid Stenosis surgery, Coronary Artery Bypass adverse effects, Coronary Artery Bypass mortality, Coronary Artery Disease surgery, Endarterectomy, Carotid adverse effects, Endarterectomy, Carotid mortality
- Abstract
Background: It remains controversial whether patients with concomitant carotid and coronary disease should undergo operative repair separately or in combination., Methods: Patients with documented cerebrovascular disease undergoing coronary artery bypass grafting (CABG) alone were matched by propensity scoring with patients undergoing combined carotid endarterectomy (CEA)/CABG procedures and compared for the occurrence of stroke, myocardial infarction (MI), and mortality., Results: Of the 4943 patients undergoing CABG, 908 had known cerebrovascular disease. Among these, 134 underwent concomitant CEA, and these were propensity matched with 134 patients undergoing CABG only. No differences were observed in the perioperative risks of stroke (4% vs 3%, odds ratio [OR] 1.5, 95% confidence interval [CI] 0.4-5.5), MI (0.7% vs 0.7%, not significant [NS]), or combined cardiovascular events (6% vs 10%, OR 0.5, 95% CI [0.2-1.3]), although mortality (1% vs 8%, OR 0.2, 95% CI [0.04-0.8] was higher with CABG only., Discussion: Addition of CEA to CABG did not significantly alter the risk of perioperative stroke relative to propensity-matched patients undergoing CABG alone.
- Published
- 2011
- Full Text
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45. Pacemaker and internal cardioverter defibrillator lead extraction: a safe and effective surgical approach.
- Author
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Kratz JM and Toole JM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Bacterial Infections etiology, Child, Child, Preschool, Defibrillators, Implantable microbiology, Female, Humans, Male, Middle Aged, Pacemaker, Artificial microbiology, Retrospective Studies, Defibrillators, Implantable adverse effects, Device Removal methods, Pacemaker, Artificial adverse effects
- Abstract
Background: Need for pacemaker or internal cardioverter defibrillator lead removal is increasing. Removal can be dangerous, difficult, or unsuccessful., Methods: We retrospectively reviewed our results and the techniques we used in 365 patients from 1992 through 2009 for successful complete removal of leads and complications. Various techniques of extraction were analyzed for effectiveness and complications. The eras before (1992 to 1999) and after the availability of laser sheath extraction (2000 to 2009) are compared., Results: Of 365 patients who underwent transvenous lead extraction, of which 235 were infected, and 130 had lead removal for noninfectious indication. Staphylococcus aureus was the infecting organism in 40%, and coagulase-negative Staphylococcus occurred in 33%. One-half of the organisms were methicillin resistant. Preimplant risk factors for infection included more than one device implant procedure in 105 (47%), preimplant Coumadin therapy (Bristol-Myers Squibb, Princeton, NJ) in 74 (31%), and hemodialysis in 9 (4%). Laser extraction became available in 2000. The era with the availability of laser extraction was associated with a better complete extraction rate (93% vs 89.55%) a lower bleeding rate (1.9% vs 3.1%), and complete extraction without the additional use of femoral workstation extraction tools. Mortality was 1.1%. No death was due to device removal. All deaths were the result of severe preoperative and continuing postextraction sepsis., Conclusions: A lead extraction protocol that included procedures done in an operating room environment allowing rapid, open intervention for bleeding, a varied choice of extraction tools, arterial line monitoring, transesophageal echocardiography, general anesthesia, and an experienced team yielded complete extraction in more than 90% of patients, with a low complication rate and no procedurally related deaths., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
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46. Twenty-five year experience with the St. Jude medical mechanical valve prosthesis.
- Author
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Toole JM, Stroud MR, Kratz JM, Crumbley AJ 3rd, Bradley SM, Crawford FA Jr, and Ikonomidis JS
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Cohort Studies, Confidence Intervals, Female, Follow-Up Studies, Heart Valve Diseases surgery, Humans, Male, Middle Aged, Multivariate Analysis, Odds Ratio, Postoperative Complications mortality, Probability, Proportional Hazards Models, Prospective Studies, Prosthesis Design, Prosthesis Failure, Risk Assessment, Survival Analysis, Time Factors, Treatment Outcome, Young Adult, Aortic Valve surgery, Bioprosthesis, Heart Valve Prosthesis, Heart Valve Prosthesis Implantation methods, Heart Valve Prosthesis Implantation mortality, Mitral Valve surgery
- Abstract
Background: We evaluated all adult St. Jude mechanical valve recipients at our institution since the initial implant in January 1979 and now present our 25-year experience., Methods: Nine hundred forty-five valve recipients were followed prospectively at 12-month intervals from January 1979 to December 2007., Results: Operative mortality was 3% in the aortic valve recipients and 5% in the mitral valve recipients. Follow-up was 95% complete. Among aortic valve recipients, late actuarial survival was 81% +/- 2%, 59% +/- 2%, 41% +/- 3%, 28% +/- 3%, and 17% +/- 4% at 5, 10, 15, 20, and 25 years, respectively. Twenty-five-year freedom from reoperation, thromboembolism, bleeding, and endocarditis was 90% +/- 2%, 69% +/- 5%, 67% +/- 3%, and 9% 3 +/- 2% respectively. Among mitral valve recipients late actuarial survival was 84% +/- 2%, 63% +/- 3%, 44% +/- 3%, 31% +/- 3%, and 23% +/- 4% at 5, 10, 15, 20, and 25 years, respectively. Twenty-five-year freedom from reoperation, thromboembolism, bleeding and endocarditis was 81% +/- 10%, 52% +/- 8%, 64% +/- 6%, and 97% +/- 1%. Freedom from valve-related mortality and morbidity at 25 years was 26% +/- 7% and 29% +/- 6% for aortic and mitral valve replacement, respectively. Freedom from valve-related mortality was 66% +/- 8% and 87% +/- 3% for aortic and mitral valve replacement, respectively., Conclusions: These results compare favorably with those for other mechanical prostheses. After two and a half decades of observation with close follow-up, the St. Jude mechanical valve continues to be a reliable prosthesis., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
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47. Pharmacokinetic study of a carbamazepine nanoemulsion in beagle dogs.
- Author
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Kuminek G, Kratz JM, Ribeiro R, Kelmann RG, de Araújo BV, Teixeira HF, Simões CM, and Koester LS
- Subjects
- 2-Hydroxypropyl-beta-cyclodextrin, Animals, Anticonvulsants administration & dosage, Carbamazepine administration & dosage, Cross-Over Studies, Dogs, Emulsions, Female, Injections, Intravenous, Nanoparticles, Random Allocation, Anticonvulsants pharmacokinetics, Carbamazepine pharmacokinetics, Excipients chemistry, beta-Cyclodextrins chemistry
- Abstract
This work describes the pharmacokinetics of a novel carbamazepine nanoemulsion. The plasma concentration profiles were determined in beagle dogs after i.v. bolus administration of a 5 mg/kg carbamazepine nanoemulsion and compared to the corresponding carbamazepine/hydroxypropyl-beta-cyclodextrin complex solution. Both formulations showed similar pharmacokinetic profiles and could represent valuable formulations in case of emergencies, when a rapid action in the central nervous system is desirable.
- Published
- 2009
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48. Anti-HSV-1 and anti-HIV-1 activity of gallic acid and pentyl gallate.
- Author
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Kratz JM, Andrighetti-Fröhner CR, Kolling DJ, Leal PC, Cirne-Santos CC, Yunes RA, Nunes RJ, Trybala E, Bergström T, Frugulhetti IC, Barardi CR, and Simões CM
- Subjects
- Animals, Anti-HIV Agents pharmacology, Cattle, Chlorocebus aethiops, Humans, Leukocytes, Mononuclear drug effects, Vero Cells, Virus Replication drug effects, Antiviral Agents pharmacology, Gallic Acid analogs & derivatives, Gallic Acid pharmacology, HIV-1 drug effects, Herpesvirus 1, Human drug effects
- Abstract
The synthetic n-alkyl esters of gallic acid (GA), also known as gallates, especially propyl, octyl and dodecyl gallates, are widely employed as antioxidants by food and pharmaceutical industries. The inhibitory effects of GA and 15 gallates on Herpes Simplex Virus type 1 (HSV-1) and Human Immunodeficiency Virus (HIV-1) replication were investigated here. After a preliminary screening of these compounds, GA and pentyl gallate (PG) seemed to be the most active compounds against HSV-1 replication and their mode of action was characterized through a set of assays, which attempted to localize the step of the viral multiplication cycle where impairment occurred. The detected anti-HSV-1 activity was mediated by the inhibition of virus attachment to and penetration into cells, and by virucidal properties. Furthermore, an anti-HIV-1 activity was also found, to different degrees. In summary, our results suggest that both compounds could be regarded as promising candidates for the development of topical anti-HSV-1 agents, and further studies concerning the anti-HIV-1 activity of this group of molecules are merited.
- Published
- 2008
- Full Text
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49. Removal of embedded central venous catheters.
- Author
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Lesher AP, Kratz JM, and Smith CD
- Subjects
- Adolescent, Catheterization, Central Venous methods, Child, Cohort Studies, Device Removal instrumentation, Equipment Failure, Equipment Safety, Female, Follow-Up Studies, Humans, Long-Term Care, Male, Retrospective Studies, Risk Assessment, Treatment Outcome, Catheterization, Central Venous adverse effects, Catheters, Indwelling adverse effects, Device Removal methods, Equipment Design
- Abstract
Background/purpose: Long-term central venous access devices (CVAD) play an integral role in the management of children who require nutritional support, chemotherapy, blood drawing, and transfusion of blood products. Infrequently, the CVAD may be difficult or impossible to remove with traction., Patient Population: Four patients, with ages ranging from 6 to 13 years, had 4 CVAD in place for 431, 730, 2232, and 3285 days which could not be removed by manual traction and local exploration., Results: With the use of technology developed for removal of embedded transvenous pacemaker catheters, each CVAD was successfully dislodged using a lead locking device (n = 3) or a lead locking device and an excimer laser (n = 1). There were no complications of the procedure in our series., Conclusions: There is no consensus on optimal management of embedded CVADs. In this small series, devices used routinely to remove embedded transvenous pacemaker wires were used to extract 4 embedded CVADs without complication; however, use of this technology in pediatric surgical patients is controversial because a small percentage of adult cases have resulted in tamponade or hemothorax, potentially resulting in death. Selection of patients and use of the technology in the appropriate setting are important considerations in weighing the risks vs the benefits of extracting such catheters or leaving them in place.
- Published
- 2008
- Full Text
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50. Use of recombinant activated factor VII concentrate to control postoperative hemorrhage in complex cardiovascular surgery.
- Author
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Bowman LJ, Uber WE, Stroud MR, Christiansen LR, Lazarchick J, Crumbley AJ 3rd, Kratz JM, Toole JM, Crawford FA Jr, and Ikonomidis JS
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury mortality, Adult, Aged, Aortic Diseases blood, Blood Coagulation Tests, Cohort Studies, Dose-Response Relationship, Drug, Factor VIIa adverse effects, Female, Heart Diseases blood, Hospital Mortality, Humans, Intensive Care Units, Male, Middle Aged, Pneumonia chemically induced, Pneumonia mortality, Postoperative Hemorrhage blood, Postoperative Hemorrhage mortality, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Reoperation, Retrospective Studies, Risk Factors, Thrombosis chemically induced, Thrombosis mortality, Aortic Diseases surgery, Factor VIIa administration & dosage, Heart Diseases surgery, Heart Transplantation, Postoperative Hemorrhage prevention & control
- Abstract
Background: Complex cardiovascular surgery often results in postoperative hemorrhage. Excessive blood product use may cause systemic thrombosis, end-organ dysfunction, and edema preventing chest closure. Recombinant activated factor VII (rFVIIa) concentrate may decrease hemorrhage where other treatment measures failed. We reviewed our experience with rFVIIa after complex cardiovascular surgery., Methods: A retrospective review evaluating 846 complex cardiovascular surgery patients of whom 36 received rFVIIa between January 1, 2001, and December 31, 2006, was performed. Efficacy and safety data were collected for the entire cohort in addition to delayed sternal closure requirements, reoperation, and operative mortality in the patient cohort temporally separated into two groups (pre-rFVIIa era, 2001 to 2003, 1 patient received rFVIIa; rFVIIa era, 2004 to 2006, 35 patients received rFVIIa)., Results: A total of 36 patients received 41 rFVIIa doses with an in-hospital survival of 91.7%. Hemorrhage was controlled in 83.3% of patients, with 1 dose sufficient in 75.0%. There was a significant decrease (p < 0.005) in all blood product requirements post-rFVIIa compared with pre-rFVIIa administration. In the intensive care unit (n = 6), rFVIIa significantly reduced chest tube output (p = 0.028) and prevented reexploration for bleeding in 5 patients. The requirement for delayed sternal closure was significantly higher in the pre-rFVIIa era versus the rFVIIa era (p = 0.011). The incidence of thrombosis in all patients receiving rFVIIa was 11.1%. In the rFVIIa era, a higher incidence of postoperative renal failure (p = 0.005) and pneumonia (p < 0.002) was detected in patients receiving rFVIIa., Conclusions: Recombinant activated factor VII appears to be effective in patients with refractory coagulopathy undergoing high-risk cardiovascular surgery.
- Published
- 2008
- Full Text
- View/download PDF
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