Stephen M. Setter

Phosphodiesterase 5 Inhibitors for Erectile Dysfunction

OBJECTIVE To review the pharmacologic and clinical trial data of the Food and Drug Administration–approved phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction (ED). DATA SOURCES Primary research and review articles were identified through a search of ScienceDirect, PubMed/MEDLINE, and International Pharmaceutical Abstracts (1990–August 2004). The following search terms were used in the Medicine Dentistry and Pharmacology, Toxicology, and Pharmaceutical Sciences subcategories: phosphodiesterase 5 inhibitor, PDE5 inhibitor, erectile dysfunction, sildenafil, vardenafil, tadalafil, prostatectomy, and diabetes. Web of Science (1990–August 2004) was used to search for additional abstracts using the same search terms as above. The package inserts for sildenafil, vardenafil, and tadalafil were also consulted. STUDY SELECTION AND DATA EXTRACTION All identified research, review articles, and abstracts were assessed for relevance, and all relevant information was included. Priority was given to the primary medical literature and clinical trial reports. DATA SYNTHESIS ED is a common disorder in males with increased prevalence associated with age and presence of cardiovascular disease, prostatectomy, or diabetes mellitus. Sildenafil, vardenafil, and tadalafil are selective PDE5 inhibitors currently available for treatment of ED. Their pharmacology and pharmacokinetics vary slightly, but with potentially important clinical differences in duration of activity; all have similar clinical efficacy and adverse effect profiles in patients with ED of various causes. CONCLUSIONS Sildenafil, vardenafil, and tadalafil are safe and effective PDE5 inhibitors for the treatment of ED.

Pharmacologic management of the older patient with type 2 diabetes mellitus

BACKGROUND Pharmacologic options for the treatment of elderly patients with type 2 diabetes mellitus (T2DM) are the same as in younger adults; however, treatment considerations differ in the elderly due to changes in renal and hepatic function, life expectancy, and various other clinical and practical considerations. OBJECTIVE This article discusses geriatric considerations in the pharmacologic management of T2DM and reviews the potential clinical advantages and disadvantages of pharmacologic agents currently available for the treatment of T2DM, including oral and injectable medications. METHODS A search of MEDLINE was conducted for articles published in English between January 1966 and September 2009 using the terms type 2 diabetes mellitus, elderly, geriatric, treatment, insulin, metformin, sulfonylurea, thiazolidinedione, alpha-glucosidase inhibitor, meglitinide, DPP-4 inhibitor, colesevelam, exenatide, and pramlintide. Meta-analyses, randomized controlled trials of pharmacologic treatment, and evidence-based reviews and/or expert opinions regarding the treatment of T2DM in the elderly were selected for review. RESULTS In overweight patients, metformin has been associated with reductions in risk for all-cause mortality and stroke compared with insulin and sulfonylureas. Older patients who are frail, anorexic, or underweight and those with congestive heart failure (CHF), renal or hepatic insufficiency, or dehydration may not be appropriate candidates for metformin therapy. The substantial risk of hypoglycemia with insulin secretagogues is increased by 36% in the elderly compared with younger adults; however, this risk is counterbalanced by the extensive clinical experience with these agents in the geriatric population. Thiazolidinediones should generally be avoided in patients with CHF and are absolutely contraindicated in patients with class II-IV heart failure. They have been associated with peripheral edema, as well as with decreases in bone mineral density in women. There is limited information on the use of dipeptidyl peptidase-4 inhibitors in the elderly, although dose adjustment is required in patients with renal compromise. In practice, substantial gastrointestinal adverse effects limit the use of alpha-glucosidase inhibitors in older patients. Colesevelam is associated with numerous drug interactions and can cause new or worsening constipation. There are limited data on the use of exenatide in the elderly. It may be beneficial in older patients with limited mobility who could benefit from weight loss, whereas it may not be a good option for frail, underweight adults. Use of exenatide is not recommended in patients with a creatinine clearance <30 mL/min. Given the increased monitoring required to avoid hypoglycemic events with pramlintide, this agent should be used with caution in older adults, particularly the frail elderly. Most patients with T2DM eventually require insulin; however, due to the risk of hypoglycemia and related morbidity, careful use of insulin is warranted in the geriatric population. CONCLUSIONS Overall, there is a scarcity of data regarding the use of pharmacologic agents in older adults with T2DM, and clinical guidance is largely based on data obtained from younger populations. The selection of appropriate drug regimens for these patients remains challenging.

Biochemical Pathways for Microvascular Complications of Diabetes Mellitus

OBJECTIVE: To review the current biochemical theories on how diabetes contributes to microvascular disease. DATA SOURCES: MEDLINE search (1980–June 2003) and bibliographies of articles obtained on this topic. STUDY SELECTION AND DATA EXTRACTION: Articles identified from the data sources were evaluated and those deemed relevant to this review were incorporated. DATA SYNTHESIS: The prevailing biochemical theories on how diabetes leads to microvascular disease include increased polyol (sorbitol/aldose reductase) pathway flux, production of advanced glycation end-products, generation of reactive oxygen species, and activation of diacylglycerol and protein kinase C isoforms. These pathways contribute to endothelial damage and dysfunction and may alter gene functioning. CONCLUSIONS: Each pathway, via varied and often overlapping mechanisms, contributes to altered microvascular function that leads to the development of retinopathy, neuropathy, and nephropathy, the major microvascular complications associated with diabetes.

Clinical review of treatment options for select nonmotor symptoms of Parkinson's disease

BACKGROUND Parkinsons disease (PD) is associated with a host of nonmotor symptoms, including psychosis, cognitive impairment, depression, sleep disturbance, swallowing disorders, gastrointestinal symptoms, and autonomic dysfunction. The nonmotor symptoms of PD have the potential to be more debilitating than the motor features of the disorder. OBJECTIVE The aim of this article was to review treatment options for the nonmotor manifestations of PD, including pharmacologic and nonpharmacologic interventions. METHODS The PubMed and MEDLINE databases were searched for articles published in English between January 1966 and April 2010, using the terms Parkinsons disease, nonmotor, psychosis, hallucination, antipsychotic, cognitive impairment, dementia, depression, sleep disturbance, sleepiness, REM (rapid eye movement) sleep behavior disorder, dysphagia, swallowing disorder, sialorrhea, gastrointestinal, constipation, autonomic dysfunction, orthostatic hypotension, gastroparesis, erectile dysfunction, sexual dysfunction, and urinary dysfunction. Articles were selected for review if they were randomized controlled trials (RCTs), meta-analyses, or evidence-based reviews of treatment of patients with PD, and/or expert opinion regarding the treatment of nonmotor symptoms of PD. RESULTS A total of 148 articles, including RCTs, meta-analyses, and evidence-based reviews, were included in this review. The treatment of hallucinations or psychosis in PD should include a stepwise reduction in medications for motor symptoms, followed by the use of quetiapine or clozapine. Dementia may be treated with acetylcholinesterase inhibitors. Evidence is lacking concerning the optimal pharmacologic treatment for depression in PD, with expert opinions indicating selective serotonin reuptake inhibitors as the antidepressants of choice. However, the largest study to date found nortriptyline therapy to be efficacious compared with placebo, whereas paroxetine controlled release was not. A variety of sleep disturbances may plague a person with PD, and treatment must be individualized to the patients specific sleep disturbance pattern and contributing factors. Swallowing disorders may lead to aspiration and pneumonia, and patients with dysphagia should be referred to a speech therapist for further evaluation and treatment. Orthostasis may be treated with nonpharmacologic interventions as well as pharmacologic treatments (eg, fludrocortisone, midodrine, indomethacin). Other autonomic symptoms are managed in a manner similar to that in patients without PD, although careful attention must be aimed at avoiding dopamine-blocking therapies in the treatment of gastrointestinal dysfunction and gastroparesis. CONCLUSIONS Various pharmacologic and nonpharmacologic strategies are available for the management of the nonmotor symptoms of PD. The challenges associated with nonmotor symptoms must not be forgotten in light of the motor symptoms of PD, and treatment of nonmotor symptoms should be encouraged.

Meloxicam: a reappraisal of pharmacokinetics, efficacy and safety

The discovery of two distinct isoenzymes of COX has led to the development and clinical introduction of COX-2 inhibitors with increased selectivity onto the market. Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) of the oxicam class, and is a preferential inhibitor of COX-2, demonstrating effectiveness with anti-inflammatory, analgesic and antipyretic activity. Meloxicam is therapeutically utilised in the management of osteoarthritis and rheumatoid arthritis. Trials have examined the risk of gastrointestinal ulceration of meloxicam when compared with traditional non-specific COX-inhibiting NSAIDs with mixed results; meloxicam seems to have a greater gastrointestinal risk than the highly specific COX-2 NSAIDs. Meloxicam has a plasma half-life of ∼ 20 h and is convenient for once daily administration. Neither moderate renal nor hepatic insufficiency significantly alters the pharmacokinetics of meloxicam in short-term studies. Furthermore, dose adjustment is not required in the elderly. Recent drug–drug interaction studies have demonstrated that meloxicam interacts with some medications, including cholestyramine, lithium and some inhibitors of cytochrome P450 -2C9 and -3A4. Consequently, increased clinical vigilance should be maintained when coprescribing some medications with meloxicam. Concentration-dependent therapeutic and toxicological effects have yet to be extensively elucidated for meloxicam. Long-term safety in various organ systems, especially in the heart and vascular system and with concomitant drug administration, remains to be proven. The pharmacokinetics of meloxicam enables once daily application, which increases compliance compared with some shorter acting NSAIDs; however, long-term clinical data clearly demonstrating safety and efficacy advantages are lacking.

Pregabalin for the treatment of painful neuropathy

Pregabalin is an α2-δ ligand that binds to and modulates voltage-gated calcium channels, exerting its intended effect to reduce neuropathic pain. Pregabalin is the second of only two medications that are US FDA approved for the treatment of neuropathic pain associated with diabetic peripheral neuropathy; it is also the third medication for the treatment of postherpetic neuralgia. Currently, there are three pivotal clinical studies documenting the efficacy and safety of pregabalin for the treatment of painful diabetic neuropathy, and three clinical studies regarding the use of pregabalin for pain associated with postherpetic neuralgia. This article will review each of these studies, as well as provide a clinical review for the use of pregabalin in the treatment of neuropathic pain.

Colesevelam Hydrochloride for the Treatment of Type 2 Diabetes Mellitus

BACKGROUND Colesevelam hydrochloride is a bile acid sequestrant approved in January 2008 by the US Food and Drug Administration (FDA) for the treatment of adult patients with type 2 diabetes mellitus (DM) in combination with a sulfonylurea, metformin, and/or insulin therapy. OBJECTIVE The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, adverse effects and tolerability, drug-drug interactions, contraindications/precautions, dosage and administration, pharmacoeconomics, and the overall role of colesevelam in the management of adult patients with type 2 DM. METHODS A literature search using MEDLINE (1966-October 27, 2008), PubMed (1950-October 27, 2008), Science Direct (1994-October 27, 2008), Web of Science (1980-October 27, 2008), American Diabetes Association Scientific Abstracts (2004-2008), and International Pharmaceutical Abstracts (1970-October 27, 2008) was performed using the term colesevelam. English-language, original research and review articles were examined, and citations from these articles were assessed. Manufacturer prescribing information and the FDA review of the new drug application for colesevelam were also examined. RESULTS Colesevelam is a hydrophilic, water-insoluble polymer, with negligible absorption and systemic distribution, that is excreted primarily in the feces. Through a mechanism still under investigation, colesevelam effectively lowers glycosylated hemoglobin (HbA(1c)) when used in combination with a sulfonylurea, metformin, and/or insulin therapy. Three completed, published Phase III clinical trials investigating colesevelam for the treatment of type 2 DM were evaluated for information, data, and conclusions. At dosing of 1.875 g BID or 3.75 g once daily in combination with one of the aforementioned agents versus placebo, reductions in HbA(1c) in all 3 Phase III clinical trials of colesevelam ranged from 0.5% to 0.7% (P < 0.02). In clinical trials, colesevelam was well tolerated, with hypoglycemia occurring in approximately 3% of studied patients. CONCLUSIONS When used in combination with a sulfonylurea, metformin, and/or insulin therapy, colesevelam has been reported to significantly reduce HbA(1c) in adult patients with type 2 DM. Colesevelams role in the management of type 2 DM remains undefined, however; further investigation into its mechanism of action and long-term efficacy and safety should be performed.

Update in the Pharmacologic Treatment of Diabetes Mellitus Focus on Pramlintide and Exenatide

There are now more than 20 million people in America with diabetes mellitus (DM), and the prevalence of this illness continues to increase especially in those with type 2 DM. Over the past decade, research in the area of DM treatment has focused on pharmacologic approaches to modifying glucose metabolism as well as on lifestyle interventions to prevent and manage DM. Pharmacologic research has been guided by an improved understanding of the human physiology of glucose metabolism, allowing for development of new hormonal drug therapies and improved insulin formulations. As a result, there are several new pharmacologic treatments now available or on the horizon for DM. In this article, the authors review the first of the new hormonal therapies for DM, with a focus on information that will be useful for diabetes educators including the medication actions, side effects, patient counseling points, monitoring, and place in therapy in comparison to existing DM treatments. This series on new therapies has been divided into 3 parts, with this first part devoted to an update on the new incretin mimetic and amylin analog agents recently approved for use in DM. Subsequent parts in this series will focus on the new insulin products and oral therapies available or soon to be available. Cases will be used to assist with understanding the type of patient who will benefit from each of these new therapies.

Assessing the Impact of Ease of Administration and Tolerability on Treatment Choices in Parkinson's Disease

Historically Parkinsons disease (PD) has been treated primarily with oral agents, with patients learning quickly that their clinical response is tied closely to their level of medication compliance. Studies, however, have found that compliance is less than ideal, and erratic medication consumption is commonplace. When prescribing antiparkinsonian therapies, the clinician should consider ease of administration, tolerability, and efficacy, along with other factors that are likely to contribute to optimal compliance by the patient.

A Comparison of Educational Methods to Improve NSAID Knowledge and Use of a Medication List in an Elderly Population

The objective of this study is to compare the effectiveness of pharmacist-provided individualized education with standardized video education for(a) improving patient understanding of gastropathy caused by nonsteroidal anti-inflammatory drugs (NSAIDs) and (b) stimulating the use of a medication list. Home care patients were assessed and then randomized to receive either video education or a tailored intervention from a home care pharmacist. Patients in the tailored group were more likely to keep an updated list (p = .033) and utilize it before purchasing over-the-counter medications (p = .043). Tailored education may be more effective than standardized video education for changing behaviors related to NSAID-induced gastropathy.