Current Pharmaceutical Design - Volume 17, Issue 11, 2011

In the past decades attention has been focused on gender differences in the access to health care resources and therapies but little emphasis has been put on the understanding of the basic mechanisms of gender differences and different action of cardiovascular drugs. The basic mechanisms underlying cell death and apoptosis which affect the way organs and systems respond to injury differ in the two sexes. It is known that estrogens improve endothelial repair after vascular injury but the gender differences in apoptosis and repair are not well understood. Malorni et al. discuss the basic mechanisms related to gender differences in apoptosis and cell death suggesting that these differences may explain, at least in part, those seen in physiology and in disease states. It is well known that men and women differ in the onset of cardiovascular diseases but that they level off later in life, it is also known that sex hormones have cardiovascular effect but little is known on their sex specific effect. In this issue Vitale et al detail the sex specific effect of sex hormones explaining why the same hormone may have different effect in the two sexes according to the underlying levels of the other sex hormones. Men and women have a different susceptibility to cardiovascular disease a different presentation and response to treatment and Banach, Anker, Kaski and Mercuro report on the gender differences in the treatment of cardiovascular diseases, heart failure and prevention. Most drugs have a different pharmacokinetic and pharmacodynamic properties in men, women. Furthermore, the effect of drugs may differ considerably between the two sexes and between adults and elderly. Several cardiovascular drugs have been approved for use in both sexes when there was evidence of effect only or predominantly in one of the two sexes. For example, statins have been approved for use in primary prevention of cardiovascular disease when the scientific evidence was gathered only in men (WOSCOPS), in some EU member states aspirin is approved for primary prevention of cardiovascular disease when its role in women is lacking, several anti-hypertensive drugs (especially first and second generation) have been approved and have indication for treatment of hypertension with similar dosages for the two sexes without a clear evidence of specific benefit in women. The Value study has shown that Valsartan is effective in men and much less in women and this evidence has also been reported for other cardiovascular drugs. Scientific guidelines only recently have started to highlight the differences between young and adults while only seldom take into account the gender differences or the lack of evidence for the effectiveness of some drugs in one of the two sexes. More recently the Regulatory Agencies have become more cautious on the possible gender difference in the effectiveness and safety of drugs. However, a gap still exists in recognizing the gender differences in the effectiveness and safety and in giving specific marketing authorizations according to the sex specific effect of the drugs. On ethical grounds drug companies should be more cautious in assessing the effectiveness of drugs according to age and sex. However, realistically this does not happen because of the interest to market the same drug for the wider range of users. It becomes evident that there is a need to develop gender specific guidelines for the scientific and regulatory evaluation of drugs and gender specific approvals when this is needed. Franconi et al. will discuss the issues related to the gender differences in cardiovascular pharmacology. There is still much needed to understand and solve the gender bias in cardiovascular medicine. However, this can be solved only using a scientifically correct and rigorous approach. Cardiovascular drugs should be developed according to their specific effect, the development should include patients of both sexes recruited according to the expected effect of the drugs in each sex. For most drugs unequal numbers of men and women will be required to show efficacy.

It has become apparent over the past few decades that several factors can determine lethal or sublethal alterations of cardiovascular system cell function such as inflammatory reaction products, peptides and hormones. In turn, the loss of cellular components from the blood vessels wall and the heart tissue contributes to the development of cardiovascular diseases (CVD). Hence, in the recent years, the efforts of several research groups have specifically been devoted to deeply investigate the implication of the main forms of cell injury, necrosis, apoptosis and autophagy, in the development of cardiac and blood vessel alterations associated with human diseases. Furthermore, several lines of evidence demonstrate that CVD clearly display significant gender differences in terms of onset, progression and outcome. Cardiovascular cells contain functional estrogen and androgen receptors and are targets for sex hormone action, which can influence many physiological and pathological processes, including vascular and myocardial cell homeostasis. However, hormones are important but not unique actors in this issue, further genetic and epigenetic determinants being involved. This review focuses on recent studies on the effects of gender differences, including sex hormones, on cardiac and vascular cell injury and death and their influence in determining atherosclerosis, heart failure and other main human CVD.

The clinical presentation of heart disease is different between men and women and this distinction is pivotal for a correct diagnosis and an adequate treatment. However, the definition of symptoms classically associated with heart disease is mainly based on the characteristics of those reported in men. Chest pain or chest discomfort in women are therefore often regarded as “atypical” and these symptoms tend to be misdiagnosed and under- treated. Further, women are less likely to receive appropriate invasive and non invasive investigations. They are less likely to refer for medical help and tend to present late in the process of the cardiovascular disease, with delays in the start of effective treatment. Therefore, a gender-specific assessment of cardiovascular risk is strongly advised for patients presenting with symptoms suggestive of heart disease.

Ischemic heart disease (IHD) is a leading cause of mortality and morbidity in most developed countries. Many studies revealed gender differences in the presentation, prevalence, and clinical outcomes of IHD. Compared with females, ST-segment elevation myocardial infarction is more often diagnosed in men. They also have a higher prevalence of IHD. These findings indicate that gender may have an important influence on IHD. Appropriate prevention, rapid diagnosis, and optimal treatment may essentially improve the care of all patients. It is therefore necessary to take into account gender differences in the features of IHD between males and females.

Heart failure (HF) represents a growing health issue with significant morbidity, expense, and mortality in western world. Despite a similar prevalence between gender our knowledge about this disease mostly come from studies perfomed in men. Instead, until now women have been under-represented in HF trials and this limits our knowledge of HF in women to extrapolation of findings from men. However according to the available data women with HF differ from men regarding pathophysiology, clinical presentation and prognosis. Women with HF often present at an older age, have a better systolic function, suffer from more comorbidities, have an higher rate of hospital admissions and have a better age-adjusted survival compared to men. Moreover pharmacodynamic specificities related to gender have been described. Taken together these gender-related differences can affect response to several kinds of treatments and the general clinical approach to the patient by the physician. The understanding of these differences may improve the clinicalmanagement of HF and possible new gender-specific diagnostic and therapeutic options may be developed. To this aim, it remains mandatory. to increase the number of female patients with HF enrolled in clinical trials.

For many years, the majority of the observational and epidemiological studies assessing coronary artery disease patients, national and international clinical guidelines, registries and randomized trials have focused almost exclusively on men whereas women were usually excluded in most series. This underrepresentation of women in the medical literature in this field has resulted in few data being available regarding the clinical course of the condition, its management and clinical outcomes in this specific population, despite the relatively high prevalence of ischemic heart disease in women. The situation has changed -at least partially- in the past few years with publications focusing on this issue and reporting the existence of inequalities between genders regarding the diagnosis and treatment of coronary heart disease. This article will briefly review gender differences in the clinical presentation, diagnostic strategies and prognosis of coronary heart disease.

Gender differences in biological substrates of disease determine different clinical manifestations of CV disease with important implications for prevention, diagnosis and therapy in the two sexes. In women, the activity of sex hormones reduces the influence of CV risk factors during the reproductive age, and delays the onset of CHD of 2 decades compared to men. However, women as men suffer from CV events, and in women mortality from all CV causes and have a greater than the sum of the others 7 causes of death together. Women are more likely than men to die of a first myocardial infarction a probability of developing heart failure or a second infarction than their male counterparts. The levels of lipid components vary in different ages of life and in the two genders. TC and LDL increase in men between 35 and 50 years of age. On the contrary LDL levels do not change significantly in fertile women in which they have a lower predictive value for CHD than in men, HDL levels are higher in premenopausal women than in men of the same all age and their role in predicting CHD is considerably higher in women. High triglycerides and Lp(a) are more important as a risk factor in women than in men. Because of the greater incidence of cardiovascular diseases in men until the early 80s, information about the importance of risk factors associated with an increased risk of cardiovascular events has been gathered mainly in men and transferred to women. Most studies on lipid-lowering therapy did not have the adequate statistical power to show significant reductions in CV events in women. Regarding the indications for use of statins in daily practice, current data suggest that in secondary prevention statins are equally effective in both genders while in primary prevention the CV benefits from lipid-lowering therapy in women are less clear than in men and therefore should be used according to the degree of risk calculated from the available score systems.

Women tend to develop hypertension later as they transition into menopause, and during and after menopause the development of hypertension in women is independent of age and body mass index (BMI) but is related to menopause itself. One of the mechanisms of hypertension development in postmenopausal women is believed to be the lack of estrogen leading to vasoconstriction due to both reninangiotensin- aldosterone (RAA)-sensitive and sodium-sensitive pathways. Nowadays, we have many medications of antihypertensive therapy, including angiotensin converting enzyme (ACE) and inhibitor and angiotensin receptor blocker (ARB) in addition to diuretics, beta-blockers, calcium channel blockers. The present review summarizes gender differences in the effects of ARB on blood pressure lowering and cardiovascular outcomes from the published reports of large-scaled, randomized clinical trials and its substudy on sexspecific difference. Many antihypertensive drugs have been developed, and the benefit of blood pressure lowering therapy for the prevention of cardiovascular disease would be expected not only in men but also in women as indicated in the large-scaled clinical studies with ARB.

Cardiovascular diseases differ between men and women as do outcomes after therapeutic interventions. Management of these diseases, however, is generally guided by evidence from trials conducted predominantly in men, with few studies focused on women alone. Our goal is to review the sex/gender differences in cardiovascular therapies, which show many areas of uncertainty regarding women due to their small enrolment in clinical trials; thus, in some cases, firm conclusions about efficacy in women are difficult to obtain. Nevertheless, female gender appears to suffer from more adverse drug effects (ADE) than the male gender. For example, women are significantly more likely to experience drug-induced QT-prolongation and torsade de pointes arrhythmia and many other types of ADE. The major sex-specific differences present in pharmacokinetics, especially for the major drug metabolizing enzymes, the cytochromes P450 family, but also for phase II reactions such as glucuronidation, are discussed. Pharmacodynamic mechanisms underlying sex/gender differences are not clearly elucidated yet; however, this highlights the need for more studies focusing on women in order to optimize sex/gender-specific therapy and, therefore, improve clinical outcomes in women with cardiovascular diseases.

Bioconjugation, a novel technique is usually exploited to improve the biopharmaceutical aspects of a bioactive as well as afford its spatial and temporal distribution. The strategy enlightens newer vistas for delivery of drugs, peptides, enzymes, and oligonucleotides. Site specific delivery may be obtained by tailoring the conjugates as an inactive prodrug and designing polymer drug linkages susceptible to cleavage by specific enzymes or pH. These prodrugs substantially change the mechanisms of cellular entry, pharmacokinetic disposition and ultimately target the drug. The conjugate vehicles are being exploited for targeting pharmacological agents to visceral tissues viz brain, colon etc. These biomaterials are bringing into play, novel drug delivery systems for selectively and specifically ferrying drugs to the desired organ. Noteworthy contributions reported with bioconjugated nanoparticles for biosensing and bioimaging incorporate cell staining, DNA detection, separation and recombination relevance in DNA protection. Only recently, these tailor-made polymers have also gained impetuous for enzyme therapy, gene therapy, insulin therapy, cancer therapy and management of AIDS with the interception of minimal side effects. The present review exhaustively provides an insight to the polymer bioconjugates and their implications for targeted delivery. The article also discusses the therapeutic aspects of these conjugates and that these may serve as fascinating tools for drug delivery.