An Integrative Approach for Improved Assessment of Cardiovascular Safety Data.

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h-1, relative standard error (%RSE) within parentheses] were 9.45 (15), 30.7 (7.8), 3.8 (13), and 0.115 (1.7) for QT, HR, total peripheral resistance, and SV, respectively. Potencies (nM, %RSE within parentheses) were IC 50 = 475 (11), IC 50 = 4.01 (5.4), EC 50 = 50.6 (93), and IC 50 = 47.8 (16), and efficacies (%RSE within parentheses) were I max = 0.944 (1.7), Imax = 1.00 (1.3), E max = 0.195 (9.9), and Imax = 0.745 (4.6) for ivabradine, sildenafil, dofetilide, and pimobendan. Hill parameters were estimated with good precision and below unity, indicating a shallow concentration-response relationship. An equilibrium concentration-biomarker response relationship was predicted and displayed graphically. This analysis demonstrates the utility of a model-based approach integrating data from different studies and compounds for refined preclinical safety margin assessment. SIGNIFICANCE STATEMENT: A model-based approach was proposed utilizing biomarker data on heart rate, blood pressure, and QT-interval. A pharmacodynamic model was developed to improve assessment of high-resolution telemetric cardiovascular safety data driven by different drugs (ivabradine, sildenafil, dofetilide, and pimobondan), wherein system- (turnover rates) and drug-specific parameters (e.g., potencies and efficacies) were sought. The model-predicted equilibrium concentration-biomarker response relationships and was used for safety assessment (predictions of 20% effective concentration, for example) of heart rate, blood pressure, and QT-interval.

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.

[Generic medicinal products: if you know them, you do not avoid them]. / I medicinali equivalenti: se li conosci non li eviti...

Although equivalent (generic) medicinal products have been introduced in the Italian market since decades, Italy is still among the latest for prescription of equivalent medicinal products. Several reasons may explain this behavior such as a scant familiarity with equivalent medicinal products, a general skepticism toward "not branded-named" medications and an "indolent laziness" both by specialists and general practitioners. Yet, the wider use of the generic drug could: (i) save economical resources for the National and Regional Health Services and allow to allocate them in clinical research and development of new therapies; (ii) reduce the economic burden for the patients by saving the brand drug-related co-payments, especially if they are on polytherapy. Moreover, given that current resources for our health system are limited, preferring drug with expired patent should be an "ethical" issue and a mandatory duty. The purpose of this brief review is to propose a concise but exhaustive analysis on equivalent medicinal products, in order to clarify still existing doubts and to remove remaining cultural obstacles to their use, if any, in the field of clinical cardiology.

Nanomedicine applied to cardiovascular diseases: latest developments.

Cardiovascular diseases are a major cause of disability and they are currently responsible for a significant number of deaths in a large percentage of the world population. A large number of therapeutic options have been developed for the management of cardiovascular diseases. However, they are insufficient to stop or significantly reduce the progression of these diseases, and may produce unpleasant side effects. In this situation, the need arises to continue exploring new technologies and strategies in order to overcome the disadvantages and limitations of conventional therapeutic options. Thus, treatment of cardiovascular diseases has become one of the major focuses of scientific and technological development in recent times. More specifically, there have been important advances in the area of nanotechnology and the controlled release of drugs, destined to circumvent many limitations of conventional therapies for the treatment of diseases such as hyperlipidemia, hypertension, myocardial infarction, stroke and thrombosis.

Pharmacogenomic Challenges in Cardiovascular Diseases: Examples of Drugs and Considerations for Future Integration in Clinical Practice.

INTRODUCTION: Even if cardiovascular disease (CVD) drugs are supported by high level proofs, the results of CVD treatment present great disparities: there are still patients dying with supposed optimal treatment, patients facing adverse events and CVD remains the primary cause of death in the world. Pharmacogenomics is the basis of personalisation of the treatment able to allow higher medication success rates. In this review, we will present detailed examples of CVD drugs to highlight the complexity of this challenging field and we will discuss novel concepts that should be considered for a fastest integration of pharmacogenomics in clinical practice of CVD. Areas Covered: The complexity of pharmacogenetics and pharmacogenomics of CVD drugs are presented though examples of medications such as statins, with a focus on their effectiveness and adverse effects. Expert Opinion: The application of personalised medicine in the CVD medical practice requires the study of human genome with regard to drugs pharmacokinetics, pharmacodynamics, interactions and tolerance profile. The existing state -of-the-art of CVD drugs gives hopes for a future revolution in the drug development that will maximise cardiovascular patients benefit while decreasing their risks for adverse effects. Article Highlights Box: • Coronary heart disease (CHD) remains the first cause of death worldwide. • Cardiovascular treatment has a significant percentage of insufficient efficacy, poor tolerance and compliance. • Predicting the response to therapy while diminishing the side effects is the basis of personalised medicine; pharmacogenomics is leading towards this direction. • The response to CVD therapy and side effects are in the heart of CVD pharmacogenomics and significant progress has been noted. • The application of pharmacogenomics in the CVD medical practice is facing many methodological, technical, ethical, behavioral and financial issues, while cost-effectiveness is the main prerequisite. • The consideration of gene × gene × environment interactions and the inclusion of "omics" data in pharmacogenomic studies of CVD drugs will facilitate the generation of reliable results and will promote tailored treatments and new strategies of drug research and development.

Future translational applications from the contemporary genomics era: a scientific statement from the American Heart Association.

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.

Incorporating exposure-response modeling into the assessment of QTc interval: A potential alternative to the thorough QT study.

ICH E14 mandates that a thorough QTc study (TQT) is conducted as part of the clinical drug development program to provide an accurate and precise estimate of a drug's effect on the QTc. In the April issue of CPT, Darpo et al. report the results of a study which validated an alternative approach to evaluating the effect of a drug on QTc using exposure-response modeling in phase I which has the potential to make the TQT study obsolete.

Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

How useful are medication patient information leaflets to older adults? A content, readability and layout analysis.

BACKGROUND: Patient information leaflets (PILs) are the most important information source for older patients to effectively manage their drug therapy. OBJECTIVE: The objective of this study is to evaluate the appropriateness of current available PILs for use by older adults. METHODS: The content of the PILs were assessed by checking the availability of information relevant to older patients including pharmacokinetics, safety and dose instructions. The layout of the PILs was evaluated using criteria derived from the relevant regulatory guidelines on the design of PILs. The Gunning Fog Index was used to determine the readability of the PILs to older adults. RESULTS: Total of 48 PILs were analysed involving 25 drug substances for the treatment of cardiovascular disease and type 2 diabetes. One out of the 48 PILs contained information on pharmacokinetic changes in older patients and only 15 % of the PILs specified the age of the older person. Thirty-one percent of the PILs provided nonspecific warnings to the older population, while only 15 % included specific side effects that could occur in the older generation. Text font sizes of the PILs were generally too small for older adults to read, with only 9 % of the PILs used type size 12 or over. The readability of 63 % of the PILs had a score above 12, which is considered difficult for older people to understand. CONCLUSION: Currently available medication PILs are inappropriate for use by older adults to manage their medications effectively, which could adversely affect patient safety and adherence to drug therapy.

Stable angina pectoris: the medical management of symptomatic myocardial ischemia.

Coronary artery disease (CAD) remains an important cause of morbidity and mortality and is a serious public health problem. Over the last 4 decades there have been dramatic advances in the both the prevention and treatment of CAD. The management of CAD was revolutionized by the development of effective surgical and percutaneous revascularization techniques. In this review we discuss the importance of the medical management of symptomatic, stable angina. Medical management approaches to both the treatment and prevention of symptomatic myocardial ischemia are summarized. In Canada, organic nitrates, ß-adrenergic blocking agents, and calcium channel antagonists have been available for the therapy of angina for more than 25 years. All 3 classes are of proven benefit in the improvement of symptoms and exercise capacity in patients with stable angina. Although there is no clear first choice within these classes of anti-anginal agents, the presence of prior or concurrent conditions (for example, prior myocardial infarction and/or hypertension) plays an important role in the choice of anti-anginal class in individual patients. For some patients, combinations of different anti-anginal agents can be effective; however it is recommended that this approach be individualized. Although not currently available in Canada, other classes of anti-anginal agents have been developed; their mechanism of action and clinical efficacy is discussed. Patients with stable angina have an excellent prognosis. Patients in this category who obtain relief from symptomatic myocardial ischemia may do well without invasive intervention.

Cardio-renal syndrome: an entity cardiologists and nephrologists should be dealing with collegially.

Heart failure may lead to acute kidney injury and vice versa. Chronic kidney disease may affect the clinical outcome in terms of cardiovascular morbidity and mortality while chronic heart failure may cause CKD. All these disorders contribute to the composite definition of cardio-renal syndromes. Renal impairment in HF patients has been increasingly recognized as an independent risk factor for morbidity and mortality; however, the most important clinical trials in HF tend to exclude patients with significant renal dysfunction. The mechanisms whereby renal insufficiency worsens the outcome in HF are not known, and several pathways could contribute to the "vicious heart/kidney circle." Traditionally, renal impairment has been attributed to the renal hypoperfusion due to reduced cardiac output and decreased systemic pressure. The hypovolemia leads to sympathetic activity, increased renin-angiotensin-aldosterone pathways and arginine-vasopressin release. All these mechanisms cause fluid and sodium retention, peripheral vasoconstriction and an increased congestion as well as cardiac workload. Therapy addressed to improve renal dysfunction, reduce neurohormonal activation and ameliorate renal blood flow could lead to a reduction in mortality and hospitalization in patients with cardio-renal syndrome.

Pediatric cardiovascular drug development and research: integration of modeling and simulation as one future direction.

The integration of the needs of children into the legal drug development process since 1997 in the United States and since 2007 in the European Union has improved health and stimulated innovative approaches in the design of clinical trials and will benefit both current and future populations. According to the US Food and Drug Administration, to date, 394 pediatric labels together with safer medicines and better dosing practices have provided a sound basis for the safer and more effective use of drugs in a pediatric population. This may be measurable with fewer medication errors and perhaps shorter hospital stays in the future. Although relevant data have been generated by clinical trials in pediatric populations, challenges, such as nonefficacy and safety issues, have arisen. Heterogeneity in the physiological maturation and growth processes and differences in the etiology and pathogenesis of disease in patients from birth to 18 years of age may explain these results. The use of cutting-edge technology, such as modeling and simulation of "in silico" pediatric populations, may allow the integration of data from previous trials and experiments into the design of future clinical trials and allow exploration in other areas that have the potential to enhance the outcome of clinical trials in children.

Nanocarrier for the enhanced bioavailability of a cardiovascular agent: in vitro, pharmacodynamic, pharmacokinetic and stability assessment.

The goals of the current study were to develop and characterize a nanoemulsion of ezetimibe, evaluate its stability, lipid lowering and pharmacokinetic profile. Solubility of the drug was estimated in various oils and surfactants. Existence of nanoemulsion region was confirmed by plotting phase diagrams. Various thermodynamic stability and dispersibility tests were performed on the formulations chosen from phase diagram. Percentage transmittance, refractive index, viscosity, droplet size and zeta potential of the optimized formulations were determined. Dialysis bag method was employed to study the release rate. The formulation selected for bioavailability estimation contained Capryol 90 (10%, v/v), Crempophor EL (11.25%, v/v), Transcutol(®) P (33.75%, v/v), and double distilled water (45%, v/v). The release rate from the nanoemulsion was highly significant (p<0.001) in contrast to the drug suspension. The level of total cholesterol in the group receiving nanoemulsion CF1 was found to be highly significant (p<0.001) in comparison to the group receiving drug suspension. Bioavailability studies in rats revealed superior absorption of ezetimibe from nanoemulsion as compared to the marketed formulation and drug suspension. The shelf life of the nanoemulsion was estimated to be 18.53 months. The present study corroborated nanoemulsion to be a promising choice to improve the bioavailability of ezetimibe.

Gender aspects in cardiovascular pharmacology.

The influence of biological sex on pharmacokinetics and pharmacodynamics has been previously described for each step of the metabolic cascade of pharmaceuticals. Women and men display differences in distribution, metabolism, and excretion of drugs for several biologic reasons. Estrogens are relevant in these processes, but cannot be regarded as the only responsible mechanism. Sex differences in the incidence of adverse drug reactions and pharmacotoxicity have also been reported for several classes of drugs and specifically for several cardiovascular preparations. Given the high incidence of cardiovascular conditions and thus the broad use of these drugs in the general population, these reports have to be considered of relevance to public health. Nonetheless, increased knowledge has not translated into the development and implementation of gender-specific pharmacologic guidelines which appear as the only effective strategy to minimize the incidence of sex-specific side effects and adverse drug reactions. In the present review, we analyze the basic aspects of sex-specific pharmacodynamics and present several examples of gender dimorphism in cardiovascular drugs. We also suggest measures to analyze and possibly improve current therapeutic strategies.

Missing steps in the STAIR case: a Translational Medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke.

The continued failure in approving new drugs for treatment of acute stroke has been recently set back by the failure of the NXY-059 (Stroke-Acute Ischemic NXY Treatment (SAINT) II) trial. The disappointment was heightened by the latter study being viewed as a most promising compound for stroke drug development program based on the preclinical data. Since the SAINT I/II development program included many of the STAIR (Stroke Therapy Academic Industry Round table) guidelines, yet have still failed to achieve the expected efficacy, there is a clear need to continue and analyze the path forward for stroke drug discovery. To this end, this review calls for a consortium approach including academia, government (FDA/NIH), and pharmaceutical industry partnerships to define this path. It is also imperative that more attention is given to the evolving discipline of Translational Medicine. A key issue in this respect is the need to devote more attention to the characteristics of the drug candidate nature-target interaction, and its relationship to pharmacodynamic treatment end points. It is equally important that efforts are spent to prove that phenotypic outcomes are linked to the purported mechanism of action of the compound. Development of technologies that allows a better assessment of these parameters, especially in in vivo models are paramount. Finally, rational patient selection and new outcome scales tailored in an adaptive design model must be evaluated.

Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy.

Dexrazoxane (Cardioxane, Zinecard, a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines. As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer, regardless of whether the drug is given before the first dose of anthracycline or the administration is delayed until cumulative doxorubicin dose is > or =300 mg/m2. The drug also appears to offer cardioprotection irrespective of pre-existing cardiac risk factors. Importantly, the antitumour efficacy of anthracyclines is unlikely to be altered by dexrazoxane use, although the drug has not been shown to improve progression-free and overall patient survival. At present, the cardioprotective efficacy of dexrazoxane in patients with childhood malignancies is supported by limited data. The drug is generally well tolerated and has a tolerability profile similar to that of placebo in cancer patients undergoing anthracycline-based chemotherapy, with the exception of a higher incidence of severe leukopenia (78% vs 68%; p < 0.01). Dexrazoxane is the only cardioprotective agent with proven efficacy in cancer patients receiving anthracycline chemotherapy and is a valuable option for the prevention of cardiotoxicity in this patient population.

Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure.

OBJECTIVE: To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). DATA SOURCES: English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. DATA SYNTHESIS: Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. CONCLUSIONS: The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.

[Rationale for the pharmacologic treatment of cardiovascular diseases]. / Bases racionais para a terapêutica farmacológica das doenças cardiovasculares.

In what concerns the appropriate usage of drugs in the treatment of cardiovascular diseases, this paper provides a set of concepts and guidelines to aid the clinician in the choice of drug, the appropriate dose, the form of administration and the assessment of results. Therefore, the concepts of pharmacokinetics and pharmacodynamics which condition the administration regimen are also presented, as well as the notions of bioavailability, halflife and clearance in the light of the theory of the two compartments, quoting examples in the various pharmacologic groups currently used in cardiology. The main forms of administration and the respective indications are analysed and the concepts of tolerance, hypersensitivity and intolerance to a drug are also discussed. The importance of the major clinical trials in the assessment of the effects of drugs is supported, which consubstantiates the clinical decision based on scientific evidence. The notions of the efficacy and benefit of a treatment are presented, with examples of some recent clinical trials. The paper ends with a reference to the drug surveillance and cost-benefit studies.

Pharmacokinetic optimisation of drug therapy in elderly patients.

With increasing age, there are a number of physiological changes that affect the handling of drugs in the human body. Increases in body fat percentage as well as decreases in lean body mass, hepatic metabolism and renal elimination capacity are of particular clinical significance. It is important to take these changes into account when choosing drug therapy for older patients in order to minimise adverse effects and maximise potential benefits. This is particularly important when prescribing drugs with a narrow therapeutic index such as digoxin, theophylline, phenytoin, lidocaine (lignocaine) or warfarin. When available, monitoring of plasma concentrations can assist in the optimisation of drug dosage.