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PubMed2005

New insights in the treatment of dyslipidemia: a focus on cardiovascular event reduction and the anti-atherosclerotic effects of atorvastatin.

The identification and treatment of dyslipidemia is a critical component of ongoing efforts to reduce the incidence of atherosclerotic disease in both men and women. Several recent large-scale atorvastatin trials provide a plethora of information that expands the current body of literature describing the pathophysiology of cardiovascular disease and the prevention of acute cardiovascular events. These trials demonstrate the benefit of statin therapy in a broad variety of patient populations, explore the clinical efficacy of more intensive statin regimens, and suggest that the pleiotropic effects of statins may contribute to cardiovascular endpoint reduction. In addition, these studies have challenged whether current guidelines for low-density lipoprotein cholesterol levels provide optimal risk reduction for cardiovascular events. Additional studies with atorvastatin are underway to further explore the extent to which statins can provide cardiovascular benefits.

Anticholesteremic Agents↗

PubMed2005

Lipoprotein(a) and atherosclerosis: new perspectives on the mechanism of action of an enigmatic lipoprotein.

Although elevated plasma concentrations of lipoprotein(a) (Lp(a)) have been identified as a risk factor for coronary heart disease, the pathophysiologic and physiologic roles of Lp(a) continue to elude basic researchers and clinicians alike. Lp(a) is a challenging lipoprotein to study because it has a complex structure consisting of a low-density lipoprotein-like moiety to which is covalently attached the unique glycoprotein apolipoprotein(a) (apo(a)). Apo(a) contains multiply repeated kringle domains that are similar to a sequence found in the fibrinolytic proenzyme plasminogen; differing numbers of kringle sequences in apo(a) give rise to Lp(a) isoform size heterogeneity. In addition to elevated plasma concentrations of Lp(a), apo(a) isoform size has been identified as a risk factor for coronary heart disease, although studies addressing this relationship have been limited. The similarity of Lp(a) to low-density lipoprotein and plasminogen provides an enticing link between the processes of atherosclerosis and thrombosis, although a clear demonstration of this association in vivo has not been provided. Clearly, Lp(a) is a risk factor for both atherothrombotic and purely thrombotic events; a plethora of mechanisms to explain these clinical findings has been provided by both in vitro studies as well as animal models for Lp(a).

Animals↗

PubMed2000

Transgenic and knockout mice to study the renin-angiotensin system and other interacting vasoactive pathways.

Essential hypertension is an insidious disease in which the afflicted person risks disability and death from myocardial infarction and stroke. Many factors contribute to the development of essential hypertension, including environment, diet, daily stress, and genetics. Although several single gene disorders causing high blood pressure have been identified, the genetics of essential hypertension are much more complicated. The current hypothesis is that a combination of genetic variations in multiple genes may predispose a person to hypertension. Both overexpression and gene inactivation ("knockout") have proven useful tools to evaluate the genetics of essential hypertension and to identify pathways regulating blood pressure. Molecular and physiologic evaluations of transgenic and knockout mice carried out over the past 5 years have provided a plethora of information about the mechanisms of blood pressure regulation and the development and maintenance of hypertension. This review focuses on the newer mouse models that have been developed to investigate hypertension with an emphasis on vascular and renal mechanisms, contributed by the renin-angiotensin system, and other pathways intersecting with the renin-angiotensin system.

Angiotensin II↗

PubMed2004

Molecular diagnosis in lymphoma.

The evolution of our ability to diagnose and classify lymphomas in an increasingly refined manner has paralleled the development of novel technologic approaches, with contemporary practice dependent upon the harnessing of a plethora of data that include microscopic, immunophenotypic, and genetic information. Although each of these components is currently indispensable, there is a purported progressive improvement in biologic objectivity as one maneuvers through these respective technologies. Accordingly, and in particular given the rapid pace at which key insights into lymphoma biology are emerging with microarray and other cutting-edge technologies, the role of molecular genetic testing is assuming even greater relevance. The ability to diagnose and classify lymphomas more accurately, precisely, and rationally by incorporating molecular data ought to lead to the development of more appropriate directed therapies.

Antigens, Neoplasm↗

PubMed2005

Novel kinase inhibitors in renal cell carcinoma: progressive development of static agents.

The rapidly expanding knowledge regarding neoplastic diseases is providing a plethora of new targets for drug discovery and development as exemplified by recent data in renal cell carcinoma. The initial experience with molecularly "targeted" agents has demonstrated that development of the newer non-cytotoxic agents will provide unique challenges requiring modification of many traditional drug development concepts and methods. We discuss recently reported data from a few renal cell carcinoma trials with putative cytostatic agents and highlight issues that need to be addressed for efficient development of cytostatic agents during various phases of clinical development.

Angiogenesis Inhibitors↗

PubMed2003

Opioids: a review.

Recent discoveries in opioid pharmacology help explain the enormous variability in clinical responses to these powerful analgesics. Although there is only one m opioid receptor gene, splice variants of that gene's expression result in a panoply of different functioning receptors. Other sources of variable response include polymorphisms in the m opioid receptor regulatory region, and pharmacokinetic differences because of cytochrome P-450 mono-oxygenase heterogeneity. Analgesic tolerance is likely the key phenomenon limiting the benefit of opioids. A plethora of intracellular pathways affects this. Among them are the N-methyl-D-aspartate receptor, protein kinase C gamma activity, nitric oxide synthase, and GM1 ganglioside content of the neuronal membrane. Clinical studies undercut the routine use of meperidine in most settings. Other studies have shown better ways to diminish opioid side effects.

Analgesics, Opioid↗

PubMed2000

Probing for genes in seronegative spondyloarthropathy.

Seronegative spondyloarthropathies are a group of disorders characterized by inflammation of the spine, sacroiliac joints, and peripheral arthritis along with various characteristic extra-articular features. Their pathogenesis and immunogenetics have not yet been fully elucidated. Ankylosing Spondylitis (AS) is probably the best studied of these disease. It has now been 27 years since the association of human leukocyte antigen (HLA) B27 and AS has been demonstrated. Since then, a plethora of association studies and linkage studies unequivocally demonstrate that genetic determinants within or near the major histocompatible complex (MHC) are critical to the etiology of AS. Surprisingly though, the total MHC contribution to AS has been estimated at only 30%. In this review, we highlight the genetic basis of AS as the prototypical chronic axial arthritis, and discuss the rationale and approach in searching for non-HLA linked genes.

Diseases in Twins↗

PubMed2001

Neuropsychiatric lupus.

Neuropsychiatric (NP) manifestations of systemic lupus erythematosus (SLE) have been recognized for more than 100 years but continue to pose a diagnostic and therapeutic challenge for rheumatologists and other physicians involved in the care of SLE patients. NP-SLE includes a plethora of clinical manifestations and the reported prevalence has varied widely between 14% and 75%. The recent introduction of a standard nomenclature, case definitions, and diagnostic criteria for 19 NP-SLE syndromes should facilitate a more consistent approach to the classification of patients and to the execution of large multicenter clinical studies. The etiology of NP-SLE is likely multifactorial and includes microangiopathy, autoantibody production, and the intrathecal production of proinflammatory cytokines. Newer imaging modalities of brain structure and function provide novel ways of understanding pathogenic mechanisms. The use of standardized neuropsychometric techniques to evaluate cognitive function has identified a high prevalence of cognitive impairment in SLE patients. The management of patients with NP-SLE includes symptomatic and immunosuppressive therapies, evidence for which is largely limited to uncontrolled clinical trials and anecdotal experience. Multicenter initiatives are required to address important issues on prognosis and management.

Cognition Disorders↗

PubMed2004

Prostatitis: the cost of disease and therapies to patients and society.

Prostatitis is an elusive clinical phenomenon that has become a synonymous term to describe a plethora of lower urinary tract symptoms in men including urinary problems, sexual dysfunction, and pelvic pain. Although symptom presentation has been standardized, an accurate, consistent clinical diagnosis continues to be elusive at best. As a result, recurrence is common, quality of life is compromised, and the patients and society feel the cost of this disease.

Anti-Bacterial Agents↗

PubMed2004

Minimally invasive therapies for prostatitis.

A plethora of reports describe a number of promising new minimally invasive treatment modalities available to patients with chronic prostatitis. This article reviews these studies, with most evaluating treatments using heat or intraprostatic injection. The results are difficult to compare because of the inconsistencies in study design, modalities of treatment, and outcome measures. Standard criteria for assessing symptom severity in chronic prostatitis recently have been developed and prospective clinical trials are underway to evaluate minimally invasive therapies for this debilitating condition. Until definitive data from these trials are available, minimally invasive therapies most likely will continue to be empirical and not a standard of care.

Anti-Bacterial Agents↗

PubMed2006

Novel kinase inhibitors in renal cell carcinoma: progressive development of static agents.

Journal Article↗

PubMed2001

New millennium, new slings.

The etiology of stress incontinence is not completely understood. In the past, bladder neck suspensions were performed to correct anatomic abnormalities of the bladder neck and urethral hypermobility. This procedure was attractive because of its simplicity, low morbidity, and excellent early success rate. With time, the successes seen with bladder neck suspensions have not proven to be durable, and alternative surgical procedures have been developed. Until recently, the indications for bladder neck suspension were types I and II stress incontinence; slings were reserved for type III incontinence. However, slings have been shown to be as effective as and more durable than bladder neck suspensions for treatment of all types of stress incontinence; therefore, their popularity has spread. The success of distal urethral slings suggests that it is not necessary to correct anatomic hypermobility to correct stress incontinence. A plethora of new procedures and materials has emerged, leading to an increased need for well-controlled, objective outcome studies in order to understand the impact of these surgeries on our patients.

Biocompatible Materials↗

PubMed2006

Safety of biologics in inflammatory bowel disease.

Various biologic agents have been evaluated in patients with inflammatory bowel disease (eg, Crohn's disease ) and ulcerative colitis (UC). At present, only one, infliximab (humanized monoclonal anti-tumor necrosis factor-alpha antibody), is approved by the US Food and Drug Administration for induction and maintenance treatment in patients with active moderate to severe and/or fistulizing CD who are refractory to conventional therapy. Two recent trials, Active Ulcerative Colitis Trial (ACT) 1 and ACT 2, observed high efficacy of infliximab in inducting and maintaining clinical remission, mucosal healing, and corticosteroid-sparing effects in patients with moderate to severe UC. A plethora of randomized, double-blind, controlled and open-label, uncontrolled studies on large and small numbers of patients has assessed efficacy and safety of various biologic agents of potential use in treatment of inflammatory bowel disease. With respect to safety of biologic agents used for treatment, the most accurate data are available only in the case of infliximab. This is due to the fact that infliximab was evaluated in many more trials than any other biologic agent. Moreover, postmarketing experience also provides very valuable information about any side effects occurring during treatment with this agent.

Journal Article↗

PubMed2005

Rosacea: the battle goes on.

Rosacea presents an enigma to patients and physicians alike. Although new insights and a plethora of therapies provide hope, the underlying etiology remains unknown. This assures a certain amount of frustration as available treatments temporize rather than cure the disease. This article examines the current state of knowledge regarding this fascinating entity.

Anti-Infective Agents↗

PubMed1991

A randomized controlled trial of allopurinol in coronary bypass surgery.

A plethora of experimental evidence indicates that allopurinol reduces the formation of cytotoxic free radicals during myocardial ischemia and reperfusion. The purpose of this study was to evaluate the effect of allopurinol on cardiac performance and early mortality after coronary bypass surgery. Allopurinol (n = 89) or placebo (n = 80) was administered to 169 patients before surgery. Randomization produced groups evenly matched for surgical risk factors. Hospital mortality rate in the placebo group was 14 of 80 (18%) in the allopurinol group 4 of 89 (4%), p = 0.014. Cardiac performance, scored by cardiac index and the need for ionotropic or mechanical support, was significantly better in the allopurinol group. More nonfatal complications occurred in the allopurinol group. When either a complication or death is termed an event, the proportion of events was equal in the two groups. No side effects were identified. We now administer allopurinol to all patients who are undergoing bypass surgery unless specifically contraindicated.

Adult↗

PubMed1989

Magnetic resonance imaging and the future of cardiac imaging.

Within the last 5 years, technology for cardiac imaging has improved spectacularly. The choices now include ultrasound with Doppler, single-photon emission computed tomography and positron emission tomography, cine computed tomography, biplane and digital subtraction angiography and magnetic resonance imaging (MRI). MRI is the most expensive noninvasive option, but also provides the best information on chamber size, wall motion, valvular function and great vessel blood flow. It is multiplanar and multiparametric; thus, nearly any clinical problem except detailed coronary anatomy can be addressed, but the very plethora of technical details is daunting. With contrast agents as indicators, relative tissue perfusion of any organ appears achievable, including regional perfusion of the myocardial wall. As patient acceptance is high, MRI may become a major cardiac imaging tool and occupy the central position between office ultrasound and invasive angiography.

Cardiovascular Diseases↗

PubMed1990

Secondary prevention of acute myocardial infarction with beta-blocking agents and calcium antagonists.

The discovery that beta blockers possess clinically useful hypotensive, antianginal and antiarrhythmic properties has attracted the interest of clinicians, researchers and the pharmaceutical community alike. In addition, minor differences in a variety of ancillary properties have led to speculation that specific classes of drugs might have advantages over other classes. The enthusiasm that greeted reports from the first small trials, which showed that beta blockers reduced the postmyocardial infarction mortality rate, attracted the commercial support necessary to evaluate different beta blockers in this clinical setting. The plethora of beta blockers that subsequently became available for study led to considerable improvement in both the design and implementation of large clinical trials. Despite apparent discrepancies in the results of various trials, meta-analysis indicates that most, if not all, beta blockers reduce postinfarction mortality. However, because meta-analysis cannot recommend a particular drug or specific dose for use in an individual patient, clinical practice must be based on the results of individual trials, not on the conclusions of meta-analysis. The clinical utility of beta blockers in the secondary prevention of myocardial infarction, coupled with experimental evidence that calcium antagonists reduce infarct size, led to a series of large studies designed to establish whether calcium antagonists have any effect on reducing mortality in patients with myocardial infarction. Lessons learned from the beta-blocker trials permitted a more rapid evaluation of the efficacy of calcium antagonists in this setting. It is clear that, unlike beta blockers, calcium antagonists are not effective in the secondary prevention of myocardial infarction.

Adrenergic beta-Antagonists↗

PubMed1993

Bone mass, nutrition, and other lifestyle factors.

Since the proceedings of the last Consensus Conference on Osteoporosis were published as a supplement to The American Journal of Medicine in November 1991, there has been a plethora of well-documented studies reported in the literature. This article will address some of the issues concerning the relation between bone mass and nutrition raised in those studies.

Adolescent↗