Biff F. Palmer

New Indications for Treatment of Chronic Inflammation by TNF-α Blockade

The impressive anti-inflammatory effects of the tumor necrosis factor (TNF)&agr; blockers etanercept and infliximab have led to their use in multiple inflammatory diseases besides their original indication, rheumatoid arthritis (RA). The well-studied clinical effects of both agents in RA are the reduction of signs and symptoms of joint inflammation as well as the arrest of bone destruction. Infliximab has also been Food and Drug Administration-approved in the treatment of Crohn disease; etanercept is now FDA-approved for juvenile chronic arthritis and psoriatic arthritis. Favorable initial clinical trials have been reported in other rheumatic diseases, including ankylosing spondylitis and adult Still disease. In addition, TNF&agr; blockade is being studied in the treatment of uveitis, myelodysplastic syndromes, and graft-versus-host disease. Studies in sepsis and septic shock have identified small subsets of patients that may benefit from TNF&agr; blockade, but broader use in septic patients has not improved survival. The TNF&agr; blockers have had relatively infrequent serious side effects, especially compared with the immunosuppressive and cytotoxic agents otherwise employed to treat these diseases. Further studies of optimal dosing, combination with other therapies, and long-term benefits and side effects will emerge from future trials.

Dihydropyridine calcium channel antagonists in the management of hypertension.

Dihydropyridine calcium channel antagonists have been maligned in recent years because of concerns regarding their cardiovascular and overall safety profile. Specifically, it was widely publicised in the mid-1990s that these agents might increase the risk of myocardial infarction, gastrointestinal bleeding and cancer. Data linking these agents with increased cardiovascular risk were based on nonrandomised studies and implicated short-acting, immediate-release agents. These results were inappropriately extrapolated to longer-acting compounds, extended-release products, and to the non-dihydropyridine class. Fortunately, recent studies have vindicated the class from safety allegations. These studies are reviewed herein.Compared with both diuretics and contemporary agents, amlodipine decreases cardiovascular events to a similar or greater extent without evidence for increased coronary heart disease, gastrointestinal bleeding or cancer. Despite these data, initial concerns have had lasting repercussions, as the use of dihydropyridine calcium channel antagonists appears to lag behind what emerging data would support. Dihydropyridine calcium channel antagonists have several noteworthy attributes that merit consideration in the management of hypertension. The blood pressure response to this class of drugs is less contingent on patient factors such as age and race compared with other antihypertensive agents (e.g. ACE inhibitors). Dihydropyridine calcium channel antagonists may exert effects that protect against stroke that are independent of their blood pressure-lowering mechanism. Unlike diuretics and β-adrenoceptor anatagonists (β-blockers), dihydropyridine calcium channel antagonists are lipid neutral and do not disturb glucose homeostasis. Dihydropyridine calcium channel antagonists demonstrate a highly desirable profile when administered as part of combination therapy. Combinations of dihydropyridine calcium channel antagonists and ACE inhibitors or angiotensin receptor antagonists display additive efficacy and an enviable adverse-effect profile. Collectively, the cardiovascular benefit, metabolic neutrality and homogeneous blood pressure response illuminated in recent studies, and reviewed here, represent a reaffirmation of the benefit of long-acting dihydropyridine calcium channel antagonists and should serve to help reinforce the critical importance of these agents in the therapeutic armamentarium against cardiovascular disease.

In Vino Veritas: Alcohol and Heart Disease

Numerous epidemiological studies, numbering nearly 100, have documented an inverse association between alcohol consumption and vascular risk. The preponderance of evidence supports an independent beneficial effect of mild-to-moderate alcoholic beverage consumption on risk of coronary heart disease (CHD). However, it is important to remember that observational data cannot prove causation; unmeasured or incompletely controlled confounding factors cannot be excluded. That said, most authorities now attribute a causal role to the relationship: moderate alcohol consumption reduces the risk of CHD, and current research centers on the mechanistic underpinnings and whether patterns of drinking are important. Here, I review the association between alcohol use and CHD risk, explore putative mechanisms, and make recommendations.

Severe Neurologic Toxicity Induced by Cyclosporine A in Three Renal Transplant Patients

Cyclosporine A (CyA) is a potent immunosuppressive agent that is used in organ transplantation and in a variety of immunological diseases. It has a variety of adverse side effects, some of which can be serious and even life-threatening. CyA-associated neurotoxicity is generally mild, consisting of fine tremor. However, more complex neurologic abnormalities, including motor spinal cord and cerebellar syndromes, have rarely been described in bone marrow and liver transplant patients. Renal transplant patients have been spared from such CyA-induced toxicity. In this report, three renal transplant patients are described who developed complex and severe neurologic toxicity in the setting of therapeutic blood levels of CyA, which was completely reversible on discontinuation of the drug. No patient had a prior history of neurological or psychiatric dysfunction and there was no evidence of known psychoactive substance abuse. The toxicity was manifested as flaccid hemiparesis in one and dementia in a second patient. The third patient developed a previously unreported Guillain-Barré-like syndrome consisting of an ascending motor neuropathy. One patient developed reversible lesions involving the cerebral white matter. Whereas similar complex neurologic syndromes have been confined to patients who are intensely immunosuppressed, often debilitated, and have toxic levels of the drug, these three patients serve to emphasize that complex neurotoxicity can occur in stable patients who have therapeutic levels of CyA. Given the use of CyA in an ever-expanding list of disease processes, an appreciation of these potential neurologic syndromes is of paramount importance. At present, CyA-induced neurologic disease remains a diagnosis of exclusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Etiology and Management of Delirium

Delirium has been recognized for the last 3 millennia and is the most common complication found in hospitalized patients aged 65 and older in the United States. However, critical basic science and clinical research did not progress until the DSM III criteria clearly defined delirium 20 years ago. The term delirium then replaced many nonspecific entities, such as acute confusion state, acute brain syndrome, metabolic encephalopathy, and toxic psychosis. This review discusses the epidemiology, risk factors, interventions, causes, management, and outcomes of delirium. The pathophysiology of delirium has the potential to radically alter our management of delirium and is a controversial area of research.

Metabolic Syndrome and Its Association With Colorectal Cancer: A Review

Currently, significant amount of epidemiologic evidence is present to suggest that metabolic syndrome increases the risk of developing colorectal cancer. This evidence is based on studies of the evaluate determinants of the metabolic syndrome (obesity), clinical consequences of metabolic syndrome (type 2 diabetes and hypertension) and serum component of metabolic syndrome (hypertriglyceridemia, hyperglycemia and low high-density lipoprotein cholesterol), as well as markers of hyperinsulinemia. Although the exact pathogenesis of this relationship is unknown, it seems that hyperinsulinemia may play a pivotal role in increasing CRC risk.

Vasopressin Receptor Antagonists

Arginine vasopressin (AVP) is the principal hormone involved in regulating the tonicity of body fluids. Less appreciated is the role that AVP plays in a variety of other physiologic functions including glucose metabolism, cardiovascular homeostasis, bone metabolism, and cognitive behavior. AVP receptor antagonists are now available and currently approved to treat hyponatremia. There is a great deal of interest in exploring the potential benefits that these drugs may play in blocking AVP-mediated effects in other organ systems. The purpose of this report is to provide an update on the expanding role of AVP receptor antagonists and what disease states these drugs may eventually be used for.

Electrolyte and Acid–Base Disturbances in Patients with Diabetes Mellitus

Electrolyte disturbances are common in patients with diabetes mellitus. This review highlights the ways in which specific electrolytes may be influenced by the dysregulation of glucose homeostasis.

Safety and Tolerability of the Direct Renin Inhibitor Aliskiren: A Pooled Analysis of Clinical Experience in More Than 12,000 Patients With Hypertension

J Clin Hypertens (Greenwich). 2010;12:765‐775.

Post-transplantation diabetes mellitus.

Post-transplantation diabetes mellitus (PTDM) is defined as sustained hyperglycemia developing in any patient without history of diabetes before transplantation, that meets the current diagnostic criteria by the American Diabetes Association or the World Health Organization. Several risk factors have been identified: age, nonwhite ethnicity, and glucocorticoid therapy for rejection and chronic immunosuppression with cyclosporine and especially tacrolimus. The pathophysiology of this condition resembles that of type 2 diabetes mellitus: pretransplantation end-stage liver/renal and heart disease are insulin-resistant states, and after transplantation, glucocorticoids induce further peripheral insulin insensitivity. The “second hit” appears to be an acquired (yet reversible) insulin secretion defect resulting from the calcineurin inhibitors cyclosporine and tacrolimus. An international panel of experts has recently published the proceeding of a Consensus Conference proposing strategies for the screening, prevention and management of PTDM. Future directions include pre- and post-transplantation glucose load testing for high-risk individuals and pharmacological agents to decrease insulin resistance and to preserve &bgr;-cell function