Stress electrocardiography testing in coronary artery disease: Is it time for its swan song or to redefine its role in the modern era ?

Stress electrocardiography (sECG) or treadmill stress testing is a well validated noninvasive diagnostic modality available to clinicians at low cost yet providing valuable functional data for coronary artery disease (CAD) diagnostic and prognostic evaluation. With the advances in cardiac imaging in both functional and anatomic fronts and the existing limitations of sECG testing, this modality appears less favored worldwide as reflected in some recent guideline updates. We review the past present and future of sECG to provide a viewpoint on where it stands in CAD evaluation and if it will remain relevant as a diagnostic modality or be retired going forward. We also provide our perspectives on how sECG can co-exist with other modalities such as calcium scoring and discuss the role of such testing in the Indian population.

Development Of Hplc Method For Stress Testing Of Combination Of Two Drugs Using Design Of Experiment Concept

This study was conducted to develop, an High Performance Liquid Chromatography using photodiode array detector (HPLC-PDA) method to analyse the samples generated by the stress testing of antifilarial combination (albendazole and diethylcarbamazine citrate) in the solution state. The concept of Quality by Design (Design of Experiment, DoE) approach was used for the development. For the separation of the drugs and its degradation products (DPs), DoE was applied in two stages, i.e., primary parameter stage where factors having major effect were selected. This stage gives us CQA (Critical Quality Attribute) which along with minor factors affecting were varied to get the secondary design. For each of the stage a different design was selected; for primary stage IV optimal design (Response Surface Method) was selected whereas for secondary stage, Taguchi orthogonal array design was selected. The major primary parameters affecting the HPLC method as screened by preliminary studies were the buffer pH, organic modifier (methanol or acetonitrile), initial hold time (start of gradient) and gradient time. The primary stage was completed successfully. The results were compiled in form of resolution of peak from next peak and analysed by DoE. The process fixed the values for buffer pH (4.38), organic modifier (acetonitrile) and gradient time (30 min). The CQA from primary run was initial hold time. This parameter along with other parameters: initial and final concentration of organic modifier, buffer type (phosphate or acetate), buffer strength (mM) and oven temperature were further varied and samples withdrawn were analysed. The data of secondary design was compiled in the form of resolution (R), analysed by Design Expert and final value for secondary parameter for HPLC method were fixed. The resolution of the peaks for some secondary runs was sufficient reflecting some type of interaction between the drugs and/or degradation products.

LC and LC–MS/MS studies for the identification and characterization of degradation products of acebutolol / 药物分析学报

The aim of the present investigation was to demonstrate an approach involving use of liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC–MS) to separate, identify and characterize very small quantities of degradation products (DPs) of acebutolol without their isolation from the reaction mixtures. The drug was subjected to oxidative, hydrolytic, thermal and photolytic stress conditions as per International Conference on Harmonization (ICH) guideline Q1A(R2). Among all the stress conditions the drug was found to be labile in hydrolytic (acidic & basic) and photolytic stress conditions, while it was stable in water-induced hydrolysis, oxidative and thermal stress conditions. A total of four degradation products were formed. A C18 column was employed for the separation of all the DPs on a gradient mode by using high-performance liquid chromatography (HPLC). All the DPs were characterized with the help of their fragmentation pattern and the masses obtained upon LC–MS/MS and MSn analysis. All the hitherto unknown degradation products were identified as 1-(2-(2-hydroxy-3- (isopropylamino)propoxy)-5-(amino)phenyl)ethanone (DP-I), N-(4-(2-hydroxy-3-(isopropylamino) propoxy)-3-acetylphenyl)acrylamide (DP-II), 1-(2-(2-hydroxy-3-(isopropylamino)propoxy)-5-(hydroxymethylamino) phenyl)ethanone (DP-III) and 1-(6-(2-hydroxy-3-(isopropylamino)propoxy)-2,3-dihydro- 2-propylbenzo[d]oxazol-5-yl)ethanone (DP-IV). Finally the in-silico carcinogenicity and hepatotoxicity predictions of the drug and all the DPs were performed by using toxicity prediction softwares viz., TOPKAT, LAZAR and Discovery Studio ADMET. The results of in-silico toxicity studies revealed that acebutolol (0.967) and DP-I (0.986) were found to be carcinogenic, while acebutolol (0.490) and DP-IV (0.437) were found to be hepatotoxic.

LC-MS characterization of valsartan degradation products and comparison with LC-PDA

abstract Valsartan was submitted to forced degradation under acid hydrolysis condition as prescribed by the ICH. Degraded sample aliquots were separated via HPLC using a Hypersil ODS (C18) column (250 x 4.6 mm i.d., 5 µm). Either photodiode array (PDA) detection or mass spectrometry (MS) full scan monitoring of HPLC runs were used. HPLC-PDA failed to indicate Valsartan degradation under forced acid degradation, showing an insignificant peak area variation and that Valsartan apparently remained pure. HPLC-MS using electrospray ionization (ESI) and total ionic current (TIC) monitoring did not reveal any peak variation either, but inspection of the ESI mass spectra showed the appearance of m/z 306 and m/z 352 ions for the same retention time as that of Valsartan (m/z 436). These ions were identified as being protonated molecules of two co-eluting degradation products formed by hydrolysis. These assignments were confirmed by ESI-MS/MS with direct infusion of the degraded samples. The results showed that the use of selective HPLC-MS is essential for monitoring Valsartan degradation. Efficient HPLC separation coupled to selective and structural diagnostic MS monitoring seems therefore mandatory for comprehensive drug degradation studies, particularly for new drugs and formulations, and for method development.

resumo Valsartana (VAL) foi submetida à degradação forçada em meio ácido conforme procedimento descrito no ICH. Os produtos de degradação (PDs) foram monitorados ao longo do tempo de degradação pela técnica de Cromatografia Líquida (LC) utilizando uma coluna Hypersil ODS (C18) (250 x 4,6 mm d.i., 5 µm). A detecção foi feita com dois detectores: espectrofotométrico (PDA) e espectrometria de massas (MS) por corrente iônica total. Ambas as técnicas falharam na identificação dos PDs obtidos ao longo do monitoramento, mostrando insignificantes variações na área do pico e permanecendo com pureza de pico ao longo de toda a eluição. Somente depois da avaliação por íon extraído (XIC), foi possível observar o aumento do íon m/z 306 e m/z 352 exatamente no mesmo tempo de retenção do íon molecular (m/z 436). Estes resultados mostram um caso simples e didático em que somente o uso de um método seletivo de LC-MS pode ser utilizado para monitorar produtos de degradação. Neste trabalho, é apresentado um caso real em que a separação por LC deve ser acoplada a métodos seletivos obtidos por MS, especialmente no estudo de PDs para novos fármacos, formulações e no desenvolvimento de métodos.

Sildenafil Determination by Using UPLC in Different Italian Viagra Tablets.

The introduction of generics drugs has brought the need for more control of their quality and purity. In Italy from June 23, 2013 the Pfizer® has no longer the patent for the Viagra’s production and other industries produce equivalent products containing Sildenafil citrate. Study design: Thus, in this work, the chemical profiles of both Viagra Italian Pfizer® and 3 Italian commercial Sildenafil citrate tables (generic pharmaceutical manufacturers) for male erectile dysfunction were obtained by using UltraPerformanceLiquid Chromatography (UPLC). Methodology: UPLC methodology was successfully used for the assay of Sildenafil citrate in different products in Italy which are under the cover of alternative systems of medicine. Results: The results show that: i) the chromatographic profiles obtained from Italian Sildenafil citrate tablets are identical and not present other active pharmaceutical ingredients; ii) the commercial samples have a quantity of Sildenafil citrate comparable with the corresponding labelled amounts. Conclusion: The UPLC method can be used for determination of Sildenafil citrate tables marketed by generic pharmaceutical manufacturers in Italy.

Desenvolvimento de método indicativo de estabilidade para o antineoplásico cloridrato de doxorrubicina e avaliação da toxicidade in vitro de seus principais produtos de degradação / Stability indicating method development for the antineoplastic drug doxorubicin and in vitro toxicity evaluation of its main degradation products

Em julho de 2008, a ANVISA publicou um informe técnico esclarecendo um item importante da RE nº 1 (2005), que trata sobre os estudos de estabilidade de medicamentos. Este documento originou uma nova RDC de nº 58, publicada em dezembro de 2013, a qual estabelece limites para produtos de degradação em medicamentos. O objetivo do presente trabalho foi avaliar o comportamento do antineoplástico cloridrato de doxorrubicina frente a condições de decomposição (hidrólise ácida, básica, oxidação, temperatura e fotólise), a fim de se determinar suas principais vias de degradação e também elucidar as estruturas de seus principais produtos de degradação. Para isso foi desenvolvido e validado um método indicativo de estabilidade por HPLC-DAD-MS, o qual utiliza como fase estacionária uma coluna Luna C18(2) (150 mm x 3,0 mm, µm) com gradiente de fase móvel de tampão formiato de amônio 5 mmoles.L-1 pH 3 e metanol e fluxo de 0,3 mL.min-1. Ao longo do estudo foram encontrados diversos produtos de degradação, dentre eles a 7- deoxidehidrodoxorrubicinona, originada por hidrólise ácida e também o produto da degradação térmica de m/z 530, o qual foi encontrado nas análises do medicamento após expirado seu prazo de validade. Além disso, a avaliação da toxicidade in vitro de amostras contendo produtos de degradação de origem térmica indicou atividade citotóxica para células mononucleares

ANVISA has published in July 2008, a technical sheet expaining an important item of the RE No. 1 (2005), which describes drugs stability studies. This document originated a new RDC No. 58, published in December 2013, which sets thresholds for degradation products in pharmaceuticals. The aim of this study was to evaluate the behavior for the antineoplastic doxorubicin when exposed to stress conditions (acid and base hydrolysis, oxidaton, photolysis and temperature) in order to determine the major pathaways of degradation and also to elucidate the stuctures of their main degradation products. To this was developed and validated a target stability indicatinf method by HPLC-DAD-MS, with Luna C18 (2) (150 mm x 3.0 mm. 3 µm) column as stationary phase and a mobile phase gradient composed of ammonium formate buffer 5 mmoles.L-1 and pH 3 and metanol with flow of 0.3 ml min-1. Throughout the study many degradation products was discovered, among them 7- deoxydehydrodoxorubicinone, formed by acid hydrolysis and also the main product of termal decomposition of m/z 530, wich was found in the analyzes of the medicine after the expiry of its validity were found. Furthermore, evaluation of the in vitro toxicity of samples containing degradation products of thermal decomposition was found to be citotoxic for mononuclear cells

Silent Myocardial Ischemia in Master Marathon Runners.

Background: Silent myocardial ischemia is defined as objective documentation of myocardial ischemia in the absence of angina or anginal equivalents. There are a number of reports of exercise-related sudden deaths and myocardial infarctions in aerobically trained athletes suffering from exercise - induced silent myocardial ischemia. The most appropriate and used method to discover silent myocardial ischemia is the exercise stress testing. Case Reports: In this article the authors describe three emblematic cases of silent myocardial ischemia detected in master marathon runners during systematic prepartecipation screening. These marathon runners were asymptomatic but suffering from a severe coronary artery disease that only thanks to exercise treadmill stress test was detected and properly treated. Conclusions: Silent myocardial ischemia is not such a rare event in athletes, indeed quite the opposite. In fact, even though athletes are asymptomatic this does not exclude the possibility that they are suffering from severe coronary artery disease.

Development of forced degradation and stability indicating studies of drugs-A review / 药物分析学报

Forced degradation is a degradation of new drug substance and drug product at conditions more severe than accelerated conditions. It is required to demonstrate specificity of stability indicating methods and also provides an insight into degradation pathways and degradation products of the drug substance and helps in elucidation of the structure of the degradation products. Forced degradation studies show the chemical behavior of the molecule which in turn helps in the development of formulation and package. In addition, the regulatory guidance is very general and does not explain about the performance of forced degradation studies. Thus, this review discusses the current trends in performance of forced degradation studies by providing a strategy for conducting studies on degradation mechanisms and also describes the analytical methods helpful for development of stability indicating method.

Stress Testing and Imaging Protocols for Myocardial Perfusion Studies / 핵의학분자영상

Scince 201Tl was introduced as a myocardial perfusion imaging agent in the early 1970s, scintigraphic evaluation of myocardial perfusion for the diagnosis of coronary artery disease is a valuable noninvasive diagnostic imaging modality. Stress radionuclide myocardial perfusion imaging is widely accepted to have high diagnostic and prognostic use in the assessment of patients with known or suspected coronary artery disease. With wise use of this nonivasive imaging technique, more patients are referred for stress perfusion imaging. Until now various protocols for stress testing and myocardial imaging were developed and used in worldwide. This article presented various protocols of stress testing and myocardial imaging for clinical use.

Preliminary study of using atropine in patients with chronotropic incompetence and poor exercise capacity during treadmill stress testing / 中国基层医药

Objective To evaluate the usefulness of atropine in decreasing the number of tests with ineonclusire results in patients with a poor ehronotropic response or exercise capacity during treadmill stress testing(TET).Methods The study comprised 80 patients undergoing TET.In subjects experiencing fatigue at submaximal exercise,atropine was administered in doses of 0.5mg per minute until the test conclusion(positive test results or target heart rate aehieyed)or until a maxium dose of 2mg was administered and some exercise during no use atropine 64 patients control group compare observe.Results 80 patients reguired atropine(mean dose,1mg)during the study;proceeded to achieve their target heart rate(n=68,85%)or positive test results(n=45,56%)the mean increase in heart rate after atropine administration was(25±11)beats/min(range 5～54 beats/min).Atropine administration resulted in conclusive tests more often in subjects with poor chronotropic response than in subjects with poor exercise capacity was 56% vs not receiving atropine 22%(P＜0.01).Conclusion The use of atropine as adjunct to standard TET can help decrease the number of inconclusive teats.

Correlação entre o teste de caminhada de 6 minutos e as variáveis do teste ergométrico em pacientes com insuficiência cardíaca: estudo piloto / Correlation between six-minute walk test and exercise stress testing variables in patients with heart failure: a pilot study

Objetivo: Correlacionar a distância percorrida no teste de 6 minutos (TC6M) com as variáveis do testeergométrico (TE). Métodos: Foram estudados 21 pacientes, sendo 66%brancos, 62% homens, com média de idade de 60±11 anos, 38% diabéticos e com dislipidemia e 57% com hipertensãoarterial, com insuficiência cardíaca isquêmica (33%) e nãoisquêmica(67%), nas classes funcionais II (90%) e III (10%) da NYHA, com fração de ejeção = 0,35±0,058, utilizandoseo teste de caminhada de 6 minutos (TC6M) e o teste ergométrico (Bruce modificado). Foram excluídos ospacientes não otimizados com terapêutica medicamentosa,problemas ortopédicos, doença vascular periférica ou quaisquer limitações para esforço. Analisou-se no TC6Ma distância total percorrida, sendo o paciente submetido a 3 testes com intervalos de 20 minutos. Foi comparado o valor de distância média alcançada no TC6M com a distância percorrida no teste ergométrico; o consumo deoxigênio máximo (VO2) e o equivalente metabólico máximo (MET) do TE. Para a análise estatística foram utilizados: o teste do qui-quadrado, de Mann-Whitney e a correlação de Pearson. Resultados: Houve significativas correlações positivas entre a distância percorrida no TC6M e a distância percorrida no teste de esforço (p=0,0001; r=0,76); e entreo VO2 máximo (p=0,001; r=0,68) e o MET máximo (p=0,001; r=0,68) neste grupo de pacientes. Conclusão: O TC6M é um teste reprodutível, de fácil realização e de baixo custo que pode ser utilizado para a avaliação de pacientes com IC, podendo fornecer informações valiosas que normalmente são obtidassomente com o TE. O aumento da amostra poderá determinar o verdadeiro valor dessas informações.

Objective: To correlate the distance on Six-minute walk test (6-MWT) with parameters obtained during exercise stress testing (EST) with a Bruce-modified protocol. Methods: We studied 21 patients, of whom 66% were white, 62% male, age 60±11 years, 38% diabetic and with dyslipidemia and 57% with arterial hypertension, 33% with with ischemic and 67% with nonischemicHF, NYHA class II (90%) and III (10%), with ejection fraction= 0.35±0.058. We excluded patients with suboptimal therapy, orthopedic disability, peripheral vascular disease or unable to exercise. Patients weresubmitted to 6-MWT for three times, with a 20-minute interval, and mean distance value was considered forcomparisons with distance, maximal oxygen uptake (maxVO2) and maximal metabolic equivalent (MET) during EST. Chi-square, Mann-Whitney and Pearson’scorrelation tests were used. Results: We observed significant positive correlationsbetween mean distance on 6-MWT and EST distance (p=0.0001; r=0.76), EST maxVO2 (p=0.001; r=0.68) and EST MET (p=0.001; r=0.68). Conclusion: On heart failure patients, 6-MWT is a reproducible, low-cost and easily obtainable test that can provide valuable information, usually only available on EST. Future studies with larger samplesizes will validate the present study results.

Comparison of Silent Patients with Painful Patients in Patients with Coronary Artery Stenoses during Exercise Myocardial Perfusion Scintigraphy

BACKGROUND AND OBJECTIVES: The angiographic profiles and myocardial ischemic variables were compared between patients with and without chest pain during exercise myocardial perfusion scintigraphy in patients with coronary artery stenoses. MATERIALS AND METHODS: Study population were 102 consecutive patients who have significant luminal stenoses (> 50%) on coronary angiography. They underwent symptom-limited treadmill exercise test and myocardial perfusion single photon emission computed tomography (SPECT). Tc-99m methoxylisobutyl isonitrile (MIBI) was injected intravenously at rest and one minute before the termination of exercise. Tomographic images were acquired within 1 hour of tracer injection. Electrocardiographic variables, scintigraphic summed reversibility scores and angiographic profiles were compared between patients with and without chest pain during exercise. RESULTS: Silent ischemia was noted in 52/102 (51%) of the subjects. The summed reversibility score of myocardial SPECT was not significanlty different between patients with (6.0+/-4.2) and without (5.1+/-5.0) chest pain. The extent, vessel distribution and stenosis severity of coronary artery disease were not significantly different between two groups. ST segment depression was more prominent in patients with chest pain (1.51+/-1.49 mm) than without chest pain (0.5+/-1.1 mm) during exercise stress testing. CONCLUSION: The degree of coronary stenoses and scintigraphic myocardial ischemia was not different between patients with and without chest pain during exercise stress testing.

Teste ergométrico em idosos. Parâmetros clínicos, metabólicos, hemodinâmicos e eletrocardiográficos / Stress test in the elderly. Clinical, hemodynamic, metabolic and electrocardiographic variables

PURPOSE: To identify in the elderly adaptations imposed by exercise in both sexes. METHODS: 1528 stress tests were performed on subjects divided in: group I (GI) (90) between 65 to 75 years old, and group II (GII) more than 75 years old. Protocols applied were Bruce (72), and modified Naughton (28). Clinical, hemodynamic and electrocardiographic variables were estimated as recommended by the World Health Organization, and the metabolic variables in the adapted Naughton protocols by the American College of Sports Medicine standards. RESULTS: Analysis of GI and GII, respectively disclosed: 1) stress electrocardiogram (ECG): normal, 36 and 35; ST depression, 20 and 22; ST elevation, 6 and 1; ventricular ectopic beats, 11 and 14; supra ventricular ectopic beats, 5 and 6; 2) metabolic and hemodynamic variables: the double-product: 26636 (+/-1539) and 23133 (+/-3218) mmHg X bpm (p < 0.0001). Maximum oxygen uptake measured in METS: GI, men, 7.7 (+/-1.9), women 5.4 (+/-0.8) (p < 0.0001); GII, NS, curve of systolic blood pressure: GI, men, 8.4 +/- (0.5), women, 10.6 (+/-1.8) mmHg/Met (p = 0.03); GII- NS. Difference of diastolic blood pressure and heart rate during exercise were similar between the two groups; 3) chest pain was the main clinical variable. CONCLUSION: The more frequent indication for stress testing to evaluate chest pain in GI, did not correspond to a predominance of this symptom in this group, during exercise; in GI, in contrast to what is seen in the young, the curve of systolic blood pressure was greater in women; despite the greater prevalence of coronary artery disease in aged subjects, it was not observed significative differences between the two groups, to ischaemic ST depression.

Safety Profile of Adenosine Myocardial Perfusion Imaging

BACKGROUND: Myocardial perfusion scintigraphy with intravenous adenosine has proved efficacy for the diagonosis and risk stratification of coronary artery disease. To determine the safety of adenosine infusion in conjunction with radionuclide imaging, we evaluated prospectively 1,093 patients who underwent myocardial perfusion study. METHODS: Informations on safety and adverse events during and immediately after adenosine infusion were collected and statistical analysis was performed. RESULTS: The adverse events were reported in 730 patients (66.8%), but no death or myocardial infarction. There asverse events were well tolerated and no prolonged effect was noted. Chest pain occured in 223 patients(20.4%) and facial flushing and dyspnea were reported by 246 patients(22.5%) and 253 patients(23.1%), respectively. ECG changes, such as mild arrhythmia, ST depression and AV block were checked in 230 patients(21.0%). The infusion was prematurely terminated in 32 patients(2.9%), due to serve chest pain, serve brochospasm, or third degree AV block. Higher frequency of chest pain was reported in women compare to men(p<0.05), and ST segment depression was more frequent in patients with abnormal myocardial perfusion scitigraphic findings(p<0.05). CONCLUSION: These results demonstrate that intravenous infusion of adenosine is relatively safe, and myocardial perfusion scintigraphy with intravenous ademosine is feasible technique in the evaluation of the coronary artery disease patients unable to exercise.

Resposta cronotrópica e pressórica nas miocardiopatias em portadores de insuficiência cardíaca durante prova ergométrica. Correlação das variáveis espirométricas ao esforço / Chronotropic and Pressoric Response in Cardiomyopathy in Patients with Heart Failure During Stress Testing. Correlation of Spyroergometric Variables According to Effort

PURPOSE--To correlate the variables heart rate (HR), blood pressure (BP) and double product (DP) during the ergometric test with the variables oxygen consumption (VO2) and pulmonary ventilation (VE) of spiroergometry. METHODS--A study was carried out with 40 male patients suffering from cardiomyopathy with heart failure (functional class II-IV of NYHA)-of ischemic (IS), Chagas' disease (CH) and idiopathic (ID) etiology. These three groups were compared to a group of 10 normal individuals (N). The 4 groups were evaluated under 4 different conditions: rest (RES), anaerobic threshold (LA), power peak of exercise (P) and in the fourth minute recovery (REC). The investigation was carried out with the data obtained through spiroergometry (using a treadmill and spiroergometric equipment specific for the effort), as well as data related to HR, BP, DP, VO2 and VE. RESULTS--There were significant differences observed in the ergometric evaluate of the HR, BP and DP responses in the IS, CH and ID groups as compared with the N group. There were significant difference observed in the spirometric evaluation to the VO2 and VE efforts in the IS, CH and ID groups as compared with the N group. CONCLUSION--The HR, BP and DP variables studies, obtained by means of classic ergometry, unaided by direct methodology (spiroergometry) enabled them to infer valuable data for the control and evaluation of cardiomyopathies with IC, taking into consideration the low chronotropic and pressoric responses in the various phases of evaluation during this study, corresponding to the concomitant low performance of O2 consumption and pulmonary ventilation.

RESULTS OF TWENTY FOUR HOURS AMBULATORY MONITORING OF ELECTROCARDIOGRAM AND EXERCISE STRESS TESTING IN PVC SCHOOL CHILDREN WITHOUT ORGANIC HEART DISEASE / 体力科学

Twenty four hours ambulatory monitoring of electrocardiogram and exercise stress testing were performed in 60 children who were refered to our hospital because of isolated premature ventricular contractions (PVCs) .<BR>Complex ventricular ectopy was found in 28 out of 60 PVC children. Out of 28 subjects with complex ventricular ectopies 21 had PVCs originated from the right ventricle.<BR>Frequency of PVCs per day was high in primary ventricular tachycardia and low in ventricular tachycardia with organic heart disease and there was statistical significance (p<0.01) between these two groups.<BR>There was no characteristics in coupling interval, prematurity index and vulnerability index which could specify ventricular tachycardia, couplets PVCs and isolated PVC.<BR>VT rate in exercise stress testing was higher than that in twenty four hours ambulatory monitoring of electrocardiogram (Holter recording) . Both exercise stress testing and twenty four hours monitering of electrocardiogram should be done to control VT school children.