Martin M. Zdanowicz

Therapeutic potential of n-3 polyunsaturated fatty acids in disease

PURPOSE The potential therapeutic benefits of supplementation with n-3 polyunsaturated fatty acids (PUFAs) in various diseases are reviewed, and the antiinflammatory actions, activity, and potential drug interactions and adverse effects of n-3 PUFAs are discussed. SUMMARY Fish oils are an excellent source of long-chain n-3 PUFAs, such as eicosapentaenoic acid and docosahexaenoic acid. After consumption, n-3 PUFAs can be incorporated into cell membranes and reduce the amount of arachidonic acid available for the synthesis of proinflammatory eicosanoids (e.g., prostaglandins, leukotrienes). Likewise, n-3 PUFAs can also reduce the production of inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1, and interleukin-6. Considerable research has been conducted to evaluate the potential therapeutic effects of fish oils in numerous conditions, including arthritis, coronary artery disease, inflammatory bowel disease, asthma, and sepsis, all of which have inflammation as a key component of their pathology. Additional investigations into the use of supplementation with fish oils in patients with neural injury, cancer, ocular diseases, and critical illness have recently been conducted. The most commonly reported adverse effects of fish oil supplements are a fishy aftertaste and gastrointestinal upset. When recommending an n-3 PUFA, clinicians should be aware of any possible adverse effect or drug interaction that, although not necessarily clinically significant, may occur, especially for patients who may be susceptible to increased bleeding (e.g., patients taking warfarin). CONCLUSION The n-3 PUFAs have been shown to be efficacious in treating and preventing various diseases. The wide variation in dosages and formulations used in studies makes it difficult to recommend dosages for specific treatment goals.

Insulin-Like Growth Factor-I and High Protein Diet Decrease Calpain-Mediated Proteolysis in Murine Muscular Dystrophy

Abstract In muscular dystrophy (MD) the imbalance between muscle protein synthesis and degradation may be an important factor leading to muscle wasting. The three major pathways of muscle proteolysis identified in skeletal muscle are: the lysosomal cathepsin pathway, the calcium-dependent calpain pathway, and the ATP-dependent ubiquitin pathway. Insulin-like growth factor I (IGF-I) and a high-protein diet (HPD) have been shown to reduce proteolysis in skeletal muscle. We examined the effect of 6 weeks of recombinant human IGF-I (rhIGF-l) alone or in combination with HPD treatment on the proteolytic pathways in skeletal muscle of 129 ReJ dystrophic (dy) mice. (A group of normal (Norm) nondystrophic (129 J) mice were included as controls). Untreated dy mice exhibited increased net proteolysis (P < 0.05), elevated net calpain activity (P < 0.01), and increased ubiquitin levels when compared to control mice (P < 0.05). Our evidence suggests that HPD and rhIGF-l decrease proteolysis in the 129 ReJ dy mouse. This effect appears attributable, at least in part, to reduced calpain-mediated myofibrillar breakdown (P < 0.05) due to decreased calpain autolysis or increased calpastatin levels. In contrast to calpain, cathepsin B activity was increased in HPD and rhIGF-l + HPD-treated dy muscle (P < 0.05) and unaltered in the rhIGF-l treated animals. Levels of free and protein-conjugated ubiquitin were also increased in rhIGF-l, and rhIGF-l + HPD treated dy animals (P < 0.05). The amelioration of muscle wasting in the 129 ReJ dy model by HPD and/or rhIGF-l may have potential implications in the treatment of human MD.

Effects of Insulin-Like Growth Factor-1/Binding Protein-3 Complex on Muscle Atrophy in Rats

Muscle atrophy and wasting is a serious problem that occurs in patients with prolonged debilitating illness, burn injury, spinal injury, as well as with space flight. Current treatment for such atrophy, which often relies on nutritional supplementation and physical therapy, is of limited value in preventing the muscle wasting that occurs. Considerable recent attention has focused on the use of anabolic growth factors such as insulin-like growth factor (IGF-1) in preventing muscle atrophy during limb disuse or with various catabolic conditions. However, potential side effects such as hypoglycemia appear to be limiting factors in the usefulness of IGF-1 for clinical treatment of muscle wasting conditions. The formulation of IGF-1 used in this study (IGF-1/BP3) is already bound to its endogenous-binding protein (BP3) and, as a result, has a greater specificity of action and significantly less hypoglycemic effect. Using a rat model of hind limb suspension (HLS) for 10 days, we induced marked muscle atrophy that was accompanied by enhanced muscle proteolysis and reduced muscle protein content. When HLS rats were treated with IGF-1/BP3 (50 mg/kg, b.i.d.), they retained greater body and muscle mass. Muscle protein degradation was significantly reduced and muscle protein content was preserved. The rate of protein synthesis, although somewhat reduced in HLS muscle, was not significantly elevated by IGF-1/BP3 treatment. Volume density of HLS-treated muscles were increased compared to untreated HLS rats and the actual number of fibers per area of muscle was likewise increased. The results of the current study suggest that IGF-1/BP3 might be useful for inhibiting muscle proteolysis in catabolic conditions and thus preserving muscle protein content and mass.

Systemic corticosteroids in the treatment of acute exacerbations of chronic obstructive pulmonary disease

PURPOSE The literature was reviewed to determine whether data support current treatment guideline recommendations regarding the use of systemic corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD) exacerbations. SUMMARY Exacerbations of COPD are common and can be detrimental to both patient health and health care costs. Corticosteroids are recommended by consensus guidelines for patients during exacerbations of COPD. Although guidelines make very specific recommendations, clinical data are conflicting and inconsistent. A search of the English-language medical literature was performed, and all randomized, double-blind, placebo-controlled trials or meta-analyses that examined the use of systemic corticosteroids in COPD exacerbations were included. Trials that included nebulized corticosteroids were also included as long as they were compared to a systemic corticosteroid and a placebo. Recommendations regarding the use of systemic corticosteroids are not optimal or completely supported. Data support recommendations if patients are treated on an outpatient basis. However, hospitalized patients might also benefit from higher doses of systemic steroids initially, followed by an oral taper dose. CONCLUSION In the treatment of COPD exacerbations, systemic corticosteroids improve airflow limitations, decrease treatment failure rates, decrease the risk of relapse, and may improve symptoms and decrease the length of hospital stay. Because of the risks of adverse effects, the lowest dose and shortest duration of corticosteroid therapy that will provide therapeutic benefit should be chosen. The literature suggests that hospitalized patients should benefit from a higher initial dosage of systemic corticosteroids than the 30-40 mg of i.v. or oral prednisolone for 7-10 days recommended in current guidelines.

The Pharmacogenetics of Nicotine Dependence and Smoking Cessation Therapies

Tobacco-related diseases place a tremendous burden on health-care systems world-wide. Overall mortality for smokers is nearly three-fold higher than for similar non-smokers. This increased mortality results from higher rates of cancers, vascular disease or respiratory disease. Great strides have been made in recent years with regards to understanding the neurophysiologic pathways of nicotine addiction. While a number of pharmacologic interventions have been developed to aid patients in smoking cessation, overall success rates for long-term smoking abstinence remain disappointingly low. A growing body of evidence suggests that a number of genetic factors might influence both the severity of an individual’s nicotine addiction as well as the potential efficacy of various treatment modalities they might employ. The neurophysiology of nicotine addiction will be discussed along with genetic variants that can impact both nicotine pharmacodynamics and pharmacokinetics. The role that genetic variation plays in altering the efficacy of various smoking-cessation therapies will also be reviewed along with the potential therapeutic and economic benefits of utilizing genetic testing to optimize such drug therapies.

Teaching the pharmacology of antiarrhythmic drugs.

Objective. To provide doctor of pharmacy (PharmD) students with highly integrated, comprehensive and up-to-date instruction related to the pharmacology of antiarrhythmic drugs. Design. Students were taught the medicinal chemistry, pharmacology, and therapeutics of antiarrhythmic agents in the cardiology module presented in quarter 7 of the PharmD curriculum. Important foundational information for this topic was presented to students in prerequisite physiology courses and pathophysiology courses offered earlier in the curriculum. Emphasis was placed on student critical thinking and active involvement. Weekly recitation sessions afforded students the opportunity to apply the information they learned regarding arrhythmia pharmacotherapy to comprehensive patient cases. Assessment. Student comprehension was measured using class exercises, short quizzes, case write-ups, comprehensive examinations, group exercises, and classroom discussion. Students were afforded the opportunity to evaluate the course, and the instructors as well as rate the degree to which the course achieved its educational outcomes. Conclusion. Students learned about cardiac arrhythmias through a high-quality, interdisciplinary series of classes presented by faculty members with extensive experience related to the pharmacology and pharmacotherapy of cardiac arrhythmias.

Expectations of students enrolled in doctor of pharmacy, master's physician assistant, and anesthesia assistant programs

Purpose: To qualify educational perceptions and instructional expectations for students and faculty in three health professions training programs: master’s in physician assistant (PA), master’s in anesthesia assistant (AA), and doctor of pharmacy (PharmD). Methods: This study surveyed preclinical students enrolled in PA, AA, and PharmD programs, as well as faculty involved in their didactic instruction. A 30‐question survey sought data on study and reading habits, preferred lecture style, career goals, and previous undergraduate educational experiences. Results: Baseline demographic data were stratified and survey results were compared within as well as across the target study population. PA students routinely purchased texts and read systematically, while AA and PharmD students often relied on faculty PowerPoint slides. Conclusion: Despite numerous baseline similarities, there were strikingly different educational expectations among students in the three programs as well as significant disparities between students and faculty with regards to course design, study habits, and expectations.

Use of growth hormone and insulin-like growth factor 1 for treatment of tissue wasting in catabolic conditions

Trauma, surgery, burn injury, sepsis, prolonged bed rest, cancer, and AIDS are examples of catabolic states that can lead to a significant loss of lean body tissues and skeletal muscle. The physiologic stresses associated with these catabolic conditions can impair immune function, alter drug response, and delay the recovery process. Although enhanced nutritional supplementation is a mainstay for treating tissue wasting in these conditions, it is of limited effectiveness in reversing skeletal muscle protein loss or enhancing anabolism in lean body tissues. The use of anabolic hormones such as Growth Hormone (GH) or Insulin-Like Growth Factor 1 (IGF-1) to limit lean body wasting and preserve muscle mass in these conditions has been widely investigated. This article was designed to give pharmacists and patient care professionals an overview of recent literature involving anabolic hormone treatment of tissue wasting. The use of these agents in the clinical setting may undergo significant expansion in the near future.