Low quality of some generic cardiovascular medicinal products represents a matter for growing concern.

AIMS: Generic medicinal products (GMPs) are low-priced copies of off-patent medicines that reduce healthcare costs and broaden access to healthcare. Thus, healthcare authorities, professionals, and providers recommend their use. In recent years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved hundreds of GMPs based on specific bioequivalent trials. The question is whether the brand name drugs and GMPs or the different GMPs similar in purity, efficacy, and safety. METHODS AND RESULTS: We have reviewed the progressive increasing recalls and warning letters of cardiovascular GMPs issued recently by the FDA/EMA. Both Agencies found numerous irregularities in the purity, safety, effectiveness, and current good manufacturing practices in some GMPs widely used in cardiovascular therapy. This evidence and the recent identification of nitrosamine impurities classified as probable human carcinogens in several angiotensin receptor blockers confirm that the presence of low-quality/substandard GMPs represents a serious public health problem with significant impact on national clinical and economic burden. CONCLUSION: A global strategy that unifies the efforts of all the stakeholders, including drug manufacturers, healthcare providers, governments, health professionals, patients, and judicial systems are needed to protect the drug chain supply and ensure that only high-quality GMPs are available for use.

Pharmacotherapy in Older Adults with Cardiovascular Disease: Report from an American College of Cardiology, American Geriatrics Society, and National Institute on Aging Workshop.

OBJECTIVES: To identify the top priority areas for research to optimize pharmacotherapy in older adults with cardiovascular disease (CVD). DESIGN: Consensus meeting. SETTING: Multidisciplinary workshop supported by the National Institute on Aging, the American College of Cardiology, and the American Geriatrics Society, February 6-7, 2017. PARTICIPANTS: Leaders in the Cardiology and Geriatrics communities, (officers in professional societies, journal editors, clinical trialists, Division chiefs), representatives from the NIA; National Heart, Lung, and Blood Institute; Food and Drug Administration; Centers for Medicare and Medicaid Services, Alliance for Academic Internal Medicine, Patient-Centered Outcomes Research Institute, Agency for Healthcare Research and Quality, pharmaceutical industry, and trainees and early career faculty with interests in geriatric cardiology. MEASUREMENTS: Summary of workshop proceedings and recommendations. RESULTS: To better align older adults' healthcare preferences with their care, research is needed to improve skills in patient engagement and communication. Similarly, to coordinate and meet the needs of older adults with multiple comorbidities encountering multiple healthcare providers and systems, systems and disciplines must be integrated. The lack of data from efficacy trials of CVD medications relevant to the majority of older adults creates uncertainty in determining the risks and benefits of many CVD therapies; thus, developing evidence-based guidelines for older adults with CVD is a top research priority. Polypharmacy and medication nonadherence lead to poor outcomes in older people, making research on appropriate prescribing and deprescribing to reduce polypharmacy and methods to improve adherence to beneficial therapies a priority. CONCLUSION: The needs and circumstances of older adults with CVD differ from those that the current medical system has been designed to meet. Optimizing pharmacotherapy in older adults will require new data from traditional and pragmatic research to determine optimal CVD therapy, reduce polypharmacy, increase adherence, and meet person-centered goals. Better integration of the multiple systems and disciplines involved in the care of older adults will be essential to implement and disseminate best practices. J Am Geriatr Soc 67:371-380, 2019.

Fighting fake medicines: First quality evaluation of cardiac drugs in Africa.

BACKGROUND: The growing menace of poor quality and falsified drugs constitutes a major hazard, compromising healthcare and patient outcomes. Efforts to assess drug standards worldwide have almost exclusively focused on anti-microbial drugs; with no study to date on cardiovascular drugs. Our study aims to assess quality of seven routinely used cardiovascular medications (anticoagulants, antihypertensives and statins) in ten Sub-Saharan African countries. METHODS: Drugs were prospectively collected using standardized methods between 2012 and 2014 from licensed (random pharmacies) and unlicensed (street-markets) places of sale in Africa. We developed a validated reversed-phase liquid chromatography with tandem mass spectrometry method to accurately quantify the active ingredient in a certified public laboratory. Three quality categories were defined based on the ratio of the measured to the expected dosage of the active ingredient: A (good quality): 95% to 105%, B (low quality): 85 to 94.99% or 105.01 to 115%, C (very low quality): <85% or >115%. RESULTS: All expected medicines (n=3468 samples) were collected in Benin, Burkina-Faso, Congo-Brazzaville, the Democratic Republic of Congo, Guinea, Côte d'Ivoire, Mauritania, Niger, Togo and Senegal. Out of the 1530 samples randomly tested, poor quality (types B and C) was identified in 249 (16.3%) samples. The prevalence of poor quality was significantly increased in certain specific drugs (amlodipine 29% and captopril 26%), in generic versions (23%) and in drugs produced in Asia (35%). The proportion of poor quality reached 50% when drugs produced in Asia were sold in street-markets. CONCLUSION: In this first study assessing the quality of cardiovascular drugs in Africa, we found a significant proportion of poor quality drugs. This requires continued monitoring strategies.

Establishment of one-step approach to detoxification of hypertoxic aconite based on the evaluation of alkaloids contents and quality.

Aconite is a valuable drug and also a toxic material, which can be used only after detoxification processing. Although traditional processing methods can achieve detoxification effect as desired, there are some obvious drawbacks, including a significant loss of alkaloids and poor quality consistency. It is thus necessary to develop a new detoxification approach. In the present study, we designed a novel one-step detoxification approach by quickly drying fresh-cut aconite particles. In order to evaluate the technical advantages, the contents of mesaconitine, aconitine, hypaconitine, benzoylmesaconine, benzoylaconine, benzoylhypaconine, neoline, fuziline, songorine, and talatisamine were determined using HPLC and UHPLC/Q-TOF-MS. Multivariate analysis methods, such as Clustering analysis and Principle component analysis, were applied to determine the quality differences between samples. Our results showed that traditional processes could reduce toxicity as desired, but also led to more than 85.2% alkaloids loss. However, our novel one-step method was capable of achieving virtually the same detoxification effect, with only an approximately 30% alkaloids loss. Cluster analysis and Principal component analysis analyses suggested that Shengfupian and the novel products were significantly different from various traditional products. Acute toxicity testing showed that the novel products achieved a good detoxification effect, with its maximum tolerated dose being equivalent to 20 times of adult dosage. And cardiac effect testing also showed that the activity of the novel products was stronger than that of traditional products. Moreover, particles specification greatly improved the quality consistency of the novel products, which was immensely superior to the traditional products. These results would help guide the rational optimization of aconite processing technologies, providing better drugs for clinical treatment.

Abdominal aortic aneurysm.

Abdominal aortic aneurysm refers to abdominal aortic dilation of 3.0 cm or greater. The main risk factors are age older than 65 years, male sex, and smoking history. Other risk factors include a family history of abdominal aortic aneurysm, coronary artery disease, hypertension, peripheral artery disease, and previous myocardial infarction. Diagnosis may be made by physical examination, an incidental finding on imaging, or ultrasonography. The U.S. Preventive Services Task Force released updated recommendations for abdominal aortic aneurysm screening in 2014. Men 65 to 75 years of age with a history of smoking should undergo one-time screening with ultrasonography based on evidence that screening will improve abdominal aortic aneurysm-related mortality in this population. Men in this age group without a history of smoking may benefit if they have other risk factors (e.g., family history of abdominal aortic aneurysm, other vascular aneurysms, coronary artery disease). There is inconclusive evidence to recommend screening for abdominal aortic aneurysm in women 65 to 75 years of age with a smoking history. Women without a smoking history should not undergo screening because the harms likely outweigh the benefits. Persons who have a stable abdominal aortic aneurysm should undergo regular surveillance or operative intervention depending on aneurysm size. Surgical intervention by open or endovascular repair is the primary option and is typically reserved for aneurysms 5.5 cm in diameter or greater. There are limited options for medical treatment beyond risk factor modification. Ruptured abdominal aortic aneurysm is a medical emergency presenting with hypotension, shooting abdominal or back pain, and a pulsatile abdominal mass. It is associated with high prehospitalization mortality. Emergent surgical intervention is indicated for a rupture but has a high operative mortality rate.

Competencias que actualmente se le exigen al anestesiólogo en anestesia cardiovascular / Current competences required by the anaesthesiologist in cardiovascular anaesthesia

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Comparative effectiveness research: drug-drug comparisons in heart failure.

Drug-drug CER is valuable when applied to the right question using the right methods in a relevant context. Being aware of limitations and strengths, and incorporating these insights into the interpretation of results is crucial. Rigorously performed drug-drug CER can help guide clinical practice and future research in HF.

Cardioprotective effect of HPLC standardized ethanolic extract of Terminalia pallida fruits against isoproterenol-induced myocardial infarction in albino rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia pallida is an evergreen endemic tree, mentioned in Ayurveda as the fruits of Terminalia pallida are excellent in cardioprotective property. Tribal people use Terminalia pallida fruit for the treatment of diabetes and this plant widely used in many other disorders. AIM OF STUDY: The present investigation was to evaluate the antioxidant, biochemical profile and histological studies of qualitatively standardized ethanolic extract of Terminalia pallida fruits (TpFE) against isoproterenol-induced myocardial infarction in rats. MATERIALS AND METHODS: TpFE was standardized by high performance liquid chromatography (HPLC) and mass spectroscopy (MS). Rats were pretreated orally with different doses of TpFE (100, 300, and 500mgkg(-1) body weight) and cardioprotective positive control gallic acid (GA) for 30 days prior to isoproterenol (ISO) induced myocardial infarction. The rats were sacrificed, hearts were collected and homogenized for biochemical analysis. The effects on total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C), high density lipoprotein cholesterol (HDL-C), lipid peroxidation (LPO) marker, malondialdehyde (MDA), creatine kinase (CK), lactate dehydrogenase (LDH), alanine transaminase (ALT), aspartate transaminase (AST), catalase (CAT), glutathione peroxidase (GPx), sodium potassium (Na(+)/K(+)), calcium (Ca(2+)) and magnesium (Mg(2+)) adenosine triphosphatases (ATPases) were estimated in heart tissue homogenate. RESULTS: Rats administered with ISO showed a significant increase in TC, TG, LDL-C, VLDL-C, and MDA and a significant decrease in HDL-C, cardiac marker enzymes - CK, LDH, ALT and AST. ISO significantly reduced antioxidants - CAT, GPx, and membrane bound enzymes - Na(+)/K(+), Ca(2+) and Mg(2+) ATPases. Pretreatment with TpFE (100, 300, and 500mgkg(-1) bw) and GA (15mgkg(-1) bw) for a period of 30 days significantly inhibited the effects of ISO. Moreover, biochemical findings were supported by histopathological observations. CONCLUSION: The present study provide evidence for the first time, that TpFE pretreatment ameliorated myocardial injury in ISO-induced myocardial infarcted rats and exhibited cardioprotective activity.

Analysis on outcome of 5284 patients with coronary artery disease: the role of integrative medicine.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) has a history of thousands of years and has made great contributions to the health and well-being of the people. Integrative medicine (IM) treatment, combing TCM and conventional medicine, has been the most representative characteristic for coronary artery disease (CAD) patients in China, especially those in IM hospitals. However, the secondary prevention status of CAD and the potential benefit of IM therapy in improving CAD prognosis remains unclear. MATERIALS AND METHODS: By means of a unified clinical and research information platform, we collected clinical information of hospitalized patients with CAD in cardiovascular department of 9 IM hospitals in Beijing and Tianjin from January 2003 to September 2006. The primary endpoints were major adverse cardiac events (MACEs) which include all-cause death in hospital and during one-year follow-up, acute myocardial infarction (AMI), percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG). The diagnostic and therapeutic status of CAD patients was evaluated based on the latest available clinical guidelines. Meanwhile, a logistic stepwise regression analysis was also used to identify independent prognostic factors. RESULTS: 5284 hospitalized patients with CAD were registered. The top five TCM patterns were in turn blood stasis 79.3%, Qi deficiency 56.5%, phlegm-turbidness 41.1%, Yin deficiency 24.8%, Yang deficiency 11.3%. The standard-reaching rate of CAD patients with hyperlipidemia was 85.6% for total cholesterol, 31.2% for triglyceride, 21.4% for low-density lipoprotein cholesterol, 52.5% for high-density lipoprotein cholesterol, while it was 61.9% and 80.9% in systolic and diastolic blood pressure of CAD with hypertension respectively. The top five commonly used herbs by functions were Qi-tonifying agents 89.25%, blood-activating agents 86.04%, Qi-regulating agents 77.60%, heat-clearing agents 67.50%, dampness-draining agents 65.95%. The herbs commonly used were Salvia miltiorrhiza Bunge 63.10%, Poria 59.99%, Raidx Astragali 49.67%, Radix Paeoniae Rubra 48.71%, peach seed 47.32%, angelica 46.82%, Radix Ligustici Chuanxiong 46.36%, safflower 45.40%, Pinellia 45.30%, glycyrrhiza 41.36%. 90 patients (1.7%) died in hospital, and the overall incidence of endpoints was 6.1% (322/5284). The logistic stepwise regress analysis showed that AMI (OR, 5.62, 95% CI=2.56-12.33), heart failure (OR, 2.68, 95% CI=1.67-4.29), age≥60 years (OR, 2.01, 95% CI=1.22-3.30), and medication of phosphodiesterase inhibitors (OR, 1.67, 95% CI=1.15-2.42) were independent risk factors for in-hospital mortality and one-year follow-up MACEs, while statins (OR, 0.23, 95% CI=0.06-0.91) and IM therapy (OR, 0.69, 95% CI=0.49-0.97) were protective factors. CONCLUSION: There was still certain gap between the usage of conventional medicine and clinical guideline in IM hospitals of China. Integrative Medicine might have potential benefit for CAD patients in reducing MACEs. However, the scheme of IM intervention and the mechanism of action are still needed to be further determined.

Discontinued drugs in 2006: cardiovascular drugs translational medicine perspective.

This perspective on discontinued cardiovascular drugs is the first in a series of papers on drugs dropped from clinical development in 2006. The compounds described in this perspective have been removed from development in various stages and for different reasons. This paper hereby provides a translational medicine perspective on these compounds based on information available through the Pharmaprojects pipeline database. In particular, potential gaps in the pipeline, due to a lack of biomarkers and translational medicine perspectives are emphasized.

The problem of polypharmacy in heart failure.

Improvements in the medical therapy for chronic heart failure have led to a dramatic decrease in the morbidity and mortality of patients with heart failure over the past two decades. This improvement has been gained at the expense of an increasing number of potent drugs that heart failure patients have to take chronically. Because heart failure forms the end-stage of different cardiovascular diseases and their predisposing risk factors, patients need drug treatment not only for heart failure itself but also for related conditions. Even more, because most heart failure patients are elderly, a number of unrelated, noncardiovascular diseases become apparent, which further increase the number of pharmaceutical substances with which heart failure patients are treated. The resulting polypharmacy leads to problems including economic burden, patient compliance, and most importantly, partly unpredictable drug interactions. This article reviews the existing data concerning some of these problems, to provide an aid for choosing the appropriate drugs in heart failure patients and minimizing the patient's risk.

Development of cardiovascular drugs: the U.S. regulatory milieu from the perspective of a participating nonregulator.

The Food and Drug Administration (FDA) is responsible for assuring that drugs, devices, and biologicals available in the U.S. are effective and acceptably safe for their intended uses. Both law and regulation define the procedures to be followed by the FDA in judging the effectiveness and safety of therapies. The FDA comprises a cadre of highly skilled public servants who receive and evaluate all data collected by the manufacturer during therapy, not just the portion that reaches publication. To assist in reaching final conclusions about approvability, the FDA can empanel legally constituted advisory committees and external consultants when the need is perceived for additional specific scientific/technical expertise and substantial experience in clinical practice. Evidentiary standards for marketing approval of drugs, biologicals, and devices generally require direct demonstration of clinical benefit, rather than inferences drawn from "surrogate" pharmacologic/device-mediated effects, sufficient exposure to enable a reasonable assessment of countervailing risk, consideration of specific design elements in the pivotal clinical trials (including prespecified hypotheses [implicitly incorporated in "primary end points"], rigorous plans for statistical analyses, and so on), and assessment of persistence of effectiveness and associated stability of safety over time. Finally, sufficient information must be available so that practitioners can receive written instructions for use (the label) adequate to support the likelihood that recipients of the therapy will receive the expected benefits within the envelope of the stated risks. This article will discuss and expand on these issues, with examples.