St. John’s Wort: Safe and Effective?

Jerry Cott, PhD
Research Pharmacologist,
Scientific Advisor to the Health Professions,
College Park, MD.

St. John's Wort (Hypericum perforatum; SJW) is a common roadside plant that has gained much popularity in Europe and the United States as an alternative to synthetic antidepressants. The market for SJW in 1998 was $330 million in Europe and $210 million in the U.S. Hypericum appears to be an effective antidepressant with an excellent safety profile (with the interaction caveat discussed here). The NIH has just completed a multi-centre study comparing the efficacy of SJW to sertraline and placebo for treating patients with moderate to severe depression. This study was completed in December 2000, and results should be available in the summer of 2001.

Although SJW has been shown to inhibit monoamine oxidase (MAO) in vitro, this effect has not been demonstrated in vivo, nor have there been any reported cases of MAOI-associated hypertensive crises in humans using SJW.¹ Although SJW has been reported to inhibit uptake of serotonin, norepinephrine and dopamine in vitro,² the concentrations required to attain these effects are quite high and the chance of a patient attaining equivalent blood concentrations is low. In fact, a recent study suggests that the uptake inhibition is only an artifact of the assay since, in contrast to other inhibitors, it does not bind to the serotonin uptake site but does deplete storage vesicles in a similar fashion to reserpine.

From Clinical Trial to Clinical Practice: A Look at Statins

Cynthia Jackevicius, BScPhm, MSc
Practice Leader,
Pharmacy Department,
Associate, Women's Health Program,
University Health Network-Toronto General Hospital,
Assistant Professor,
University of Toronto, Toronto, ON.

Coronary heart disease (CHD) is a major economic burden on the health care system, with the total cost of the morbidity and mortality associated with cardiovascular disease in Canada estimated at $18.0 billion in 1994.¹ Effective prevention and treatment decrease morbidity and mortality associated with CHD. A controversial issue in recent years has been whether the reduction of cholesterol results in a decline in subsequent CHD events and mortality in patients older than 65 years of age.² Several observational studies have suggested that elevated cholesterol levels may not be a significant cardiovascular risk factor in older people. However, a recent study investigated this hypothesis and found that after adjustment for risk factors and indicators of frailty, such as low serum albumin, elevated total cholesterol levels do predict increased risk for death from CHD in older adults.³

Three recently published, landmark trials focusing on the benefits of statins in the prevention of secondary coronary events showed that statins improve patient outcomes with minimal adverse effects.

Amiodarone: The Pharmacological Management of Atrial Fibrillation

Rubina Sunderji, Pharm.D., FCSHP
Pharmacotherapeutic Specialist&emdash;Cardiology,
Pharmaceutical Sciences CSU,
Vancouver General Hospital,
Clinical Assistant Professor,
Faculty of Pharmaceutical Sciences,
University of British Columbia,
Vancouver, BC.

Kenneth Gin, MD, FRCPC
Director, Post Graduate Cardiology,
Training Program, and Clinical Assistant, Professor, Faculty of Medicine,
University of British Columbia,
Director, Coronary Care Unit, and Assistant, Director, Echocardiography Laboratory,
Vancouver General Hospital,
Vancouver, BC.

Amiodarone is a class III antiarrhythmic agent with a unique and complex pharmacological profile. The drug was originally used as an antianginal agent due to its potent coronary vasodilating activity.¹ It has subsequently been shown to be effective for both supraventricular and ventricular arrhythmias. The risk of inducing proarrhythmia is lower than with other antiarrhythmics and, unlike the class I antiarrhythmic agents, it has not been associated with increased mortality.² However, amiodarone can cause a variety of side effects and close monitoring of the patient is necessary.

Pharmacology
Amiodarone is a di-iodinated benzofuran compound containing 37.3% iodine by weight.

Vitamin E Loses its Status as a Cure-all

Thirty men and women received vitamin E supplements daily for 8 weeks, while others received placebo, in a study to determine the potential antioxidant effects of vitamin E. Previous studies have suggested that vitamin E supplementation may help protect against illnesses such as cancer and Alzheimer's disease, which are believed to result from accumulated free radical damage to tissues. Physicians measured the impact of vitamin E on three indices of lipid peroxidation, an indicator of oxidative stress in cells and tissues. These indices included urinary 4-hydroxynonenal (4-HNE), and two isoprostanes, iPF2-III and iPF2-VI, which were measured by gas chromatography and mass spectrometry. The study failed to find an impact of vitamin E on any of the three measurements.

Source

1. Meagher, E.A. et al. Journal of the American Medical Association. 2001;285:1178-1182.

Response to Therapy in Acute Myeloblastic Leukemia Dependent on Genetic Make-up of Leukemic Cells

M.D. Minden, M.D., Ph.D., FRCPC
Princess Margaret Hospital
University Health Network
Toronto, ON

Introduction
Leukemias are malignancies of the blood and bone marrow and are classified as either acute or chronic malignancies of the myeloid--red blood cell, granulocyte, platelet lineage--or lymphoid--T or B lymphocyte. In this article we will focus on acute myeloblastic leukemias (AML) and recent advances in their classification and therapy.

In the United States, approximately 10,100 cases of AML are diagnosed each year and the yearly mortality rate from this disease is approximately 6,900 individuals. The incidence of AML is low in children (<1/100,000) and increases with age, such that by the time a person reaches the age of 80 the incidence is approximately 15/100,000 (Figure 1).¹ Over 60% of patients are 55 years of age or older, making this a significant problem in the aging population.

AML develops as the result of genetic changes in hematopoietic stem cells of the bone marrow.² These changes block the ability of the cell to undergo normal differentiation resulting in a blast-like morphology. In some cases, the patient may have large numbers of circulating leukemic blast cells compromising blood flow to vital organs.

The Challenges of Prescribing Drug Therapy to Older People

Julie Dergal, MSc,
Baycrest Centre for Geriatric Care

Paula A. Rochon, MD, MPH, FRCPC
Baycrest Centre for Geriatric Care,
Assistant Professor of Medicine,
University of Toronto

Introduction
Older people often have multiple health conditions that require drug therapy. In Ontario in 1998, drug expenditure by people aged >65 years of age was estimated at 1.03 billion dollars, accounting for 74% of total drug costs to the Ontario Drug Benefit (ODB) Program. Prescribing drug therapy for older people presents a challenge to many physicians. Inappropriate prescribing such as the excessive and unnecessary use of drug therapy or the under prescribing of proven beneficial therapy, appears to be a common problem. Several factors place older people at risk for serious drug complications including advanced age, frailty, and increased drug use. Long-term care residents are a particularly vulnerable population, as they are primarily, older, frail women, who take an average of eight medications. Drug-related problems, including reaction to medication, are estimated to account for as many as 28% of hospital admissions.¹ With an increase in the aged population, and the associated increasing drug costs, it is imperative that older people receive optimal pharmacotherapy. Reducing drug related morbidity and mortality is, therefore, important both to improve the quality of life of older people, and to reduce health care costs.

Olanzapine Taken with Dinner Keeps Drowsiness at Bay

Richard W. Shulman, MDCM, FRCPC
Geriatric Psychiatrist, Trillium
Health Centre, Mississauga, Ontario
Member, Division of Geriatric Psychiatry,
University of Toronto, Toronto, Ontario

In elderly patients suffering from schizophrenia, psychosis due to Alzheimer's disease, or other illnesses, first line treatment with a second-generation (atypical) antipsychotic--as compared to a first generation (conventional) antipsychotic--should be considered standard therapy. The advantage of treatment with a second-generation antipsychotic is, at least in part, due to improved neurologic side effect profiles. The Canadian Clinical Practice Guidelines for the Treatment of Schizophrenia state that treatment with clozapine, olanzapine, quetiapine, and risperidone (at lower doses) markedly reduces acute extra-pyramidal side effects (EPSE).¹

Elderly patients treated with relatively low doses of first-generation antipsychotics have been shown to have a 29% cumulative annual incidence of tardive dyskinesia (TD). The incidence of TD in patients treated with atypical antipsychotics is likely to be lower given that EPSE has been found to be a risk factor for TD.²

Olanzapine (Zyprexa‚) is a second-generation antipsychotic that has shown promise as a safe and effective drug for the treatment of elderly patients suffering from either schizophrenia or psychosis secondary to dementia.

The Renoprotective Effects of Renin-Angiotensin Blockade

Chris Chan, MD, FRCPC
Fellow in Nephrology,
University of Toronto

Over the past two decades, the main strategies that have been used to protect patients against the loss of renal function include lowering their blood pressure and restricting the intake of dietary protein. The efficacy of the above treatments has been limited and a novel therapeutic target is required. In the past decade, landmark clinical trials with pharmaceutical agents that inhibit the renin-angiotensin system (RAS) have demonstrated a dramatic attenuation of the decline in renal function that is associated with diabetic and non-diabetic nephropathies. It is now recommended that inhibition of the RAS should be standard care for patients with proteinuric nephropathies.

Theoretical Basis of Renoprotective Benefits of RAS inhibition
Several authors have reviewed this topic in detail and interested readers should review the articles cited in the references.¹ The seminal studies were performed by Brenner et al. using the 5/6 nephrectomy animal model.^2,3 In these rats, extensive renal parenchyma is destroyed, which results in a compensatory increase in single nephron glomerular filtration rate and in the elevation of glomerular capillary hydraulic pressure. Pathologically, the rats developed focal glomerulosclerosis and proteinuria. This proteinuria was prevented, following treatment with enalapril.

What Have We Learned from the Hope Study

Introduction
The publication of the landmark Heart Outcomes Prevention Evaluation (HOPE) Study¹ in the New England Journal of Medicine in January 2000 was greeted by a great deal of excitement in the medical community. In essence, the trial confirmed beyond a doubt the cardiac and renal protective benefit of ACE inhibition and extended the patient base in whom ACE inhibition has been proven effective. Our understanding of the cardioprotective nature of ACE inhibitors has been built over the years by the various mega-studies that have been conducted, dating back to the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS),² published in 1987, which showed a 31% survival advantage for ACE inhibition in New York Heart Association (NYHA) class IV heart failure patients. Thirteen years and more than a dozen large trials later, the HOPE study has confirmed that patients need not be so sick--indeed, need only be considered at risk for cardiovascular events--for ACE inhibition to show similar benefits. Looking down the list, from CONSENSUS to HOPE and several landmark trials in between, one would be hard pressed to find a class of agents with a wealth of compelling evidence comparable to that accumulated for ACE inhibitors.

Main Results and Significance
The HOPE study investigators found that 17.