Oral Pharmacologic Therapy Research Articles

A proof‐of‐concept study: Mirabegron, a new therapy for overactive bladder

To evaluate the potential of mirabegron, a selective β3-adrenoceptor agonist, for treatment of overactive bladder (OAB) symptoms. A multicenter, randomized, double-blind, double-dummy, parallel group, placebo and active-controlled, Phase 2, proof-of-concept study was conducted. Eligible patients (n = 314) were enrolled into a single-blind, 2-week placebo run-in period followed by a randomized, double-blind, placebo-controlled treatment period. Patients received mirabegron 100 or 150 mg twice-daily (BID), placebo or tolterodine 4 mg extended release (ER) once-daily for 4 weeks. Primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes per 24 hr. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes per 24 hr; severity of urgency; nocturia, and quality of life measures. Safety parameters included adverse events, laboratory tests, electrocardiogram parameters and post-void residual volume. Mirabegron 100 and 150 mg BID resulted in a statistically significant improvement versus placebo in mean change from baseline to end-of-treatment in the primary endpoint of micturition frequency (2.2 micturitions/24 hr vs. 1.2 micturitions/24 hr for both doses, adjusted P ≤ 0.01 for both comparisons). Mirabegron had a statistically significant effect versus placebo for most secondary endpoints, including quality of life variables. Despite a small increase in pulse rate, mirabegron demonstrated good safety and tolerability. Mirabegron was efficacious and well tolerated in patients with OAB symptoms and heralds the first of a new class of oral pharmacological therapy for OAB for more than 30 years.

Oral Pharmacologic Treatment of Type 2 Diabetes Mellitus: A Clinical Practice Guideline From the American College of Physicians

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the comparative effectiveness and safety of type 2 diabetes medications. This guideline is based on a systematic evidence review evaluating literature published on this topic from 1966 through April 2010 that was identified by using MEDLINE (updated through December 2010), EMBASE, and the Cochrane Central Register of Controlled Trials. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular morbidity and mortality, cerebrovascular morbidity, neuropathy, nephropathy, and retinopathy. This guideline grades the evidence and recommendations by using the American College of Physicians clinical practice guidelines grading system. RECOMMENDATION 1: ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with type 2 diabetes when lifestyle modifications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence). RECOMMENDATION 2: ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence). RECOMMENDATION 3: ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; high-quality evidence).

A Novel Drug Delivery System of Oral Curcumin Markedly Improves Efficacy of Treatment for Heart Failure after Myocardial Infarction in Rats

Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with the deterioration of heart failure. We reported that native curcumin, at a dosage of 50 mg/kg, prevented deterioration of the systolic function in rat models of heart failure. To achieve more efficient oral pharmacological therapy against heart failure by curcumin, we have developed a novel drug delivery system (DDS) which markedly increases plasma curcumin levels. At the dosage of 0.5 mg/kg, DDS curcumin but not native curcumin restored left ventricular fractional shortening in post-myocardial infarction rats. Thus, our DDS strategy will be applicable to the clinical setting in humans.

Implementing and managing intrathecal pumps

The use of intrathecal therapy is associated with increase quality of analgesia and a decrease in side effects in patients who have not tolerated oral pharmacological therapy AND have had a successful epidural trial. Steps to achieve a high degree of success are delineated in this article, including ideal catheter tip position, indication and use of medications for the infusion, rate of infusion, etc. Moreover, recommendations to follow before and after a myelogram through the pump are given.

Diagnostic Tests for Male Erectile Dysfunction Revisited: Committee Consensus Report of the International Consultation in Sexual Medicine

The Committee on "Clinical Evaluation and Scales in Sexual Medicine" of the third International Consultation in Sexual Medicine reviewed current practice and new developments in the field of physiological testing in male erectile dysfunction (ED). To provide an overview of current practice and new developments in the field of diagnostic testing in male ED. The Pubmed literature was reviewed. Since the 1980s of the last century, a broad array of specialized physiological tests has been used for assessing ED. The notion that ED often is an (early) symptom of generalized cardiovascular disease and the introduction of oral pharmacological therapies that are effective irrespective of etiology has reduced the application of the "classical" tests to a minimum and has shifted the scope toward tests with demonstrated reliability in cardiovascular medicine. (i) The clinical utility of specialized tests in the evaluation of male ED is limited to a small minority of men; (ii) the scope of physiological testing has shifted toward tests with demonstrated reliability in cardiovascular medicine.

Multimodal therapy for painful bladder syndrome / interstitial cystitis: pilot study combining behavioral, pharmacologic, and endoscopic therapies

We evaluated the effectiveness of combining behavioral therapy, pharmacologic therapy and endoscopic hydrodistension for treating painful bladder syndrome / interstitial cystitis (PBS/IC). Twenty-five patients with PBS/IC were prospectively enrolled in a pilot multimodal behavioral, pharmacologic and endoscopic treatment protocol. Behavioral modification included diet recommendations, fluid restriction to 64 oz. /day, progressive timed voiding and Kegel exercises. Oral pharmacologic therapy consisted of daily doses of macrodantin 100 mg, hydroxyzine 10-20 mg and urised 4 tablets. Patients underwent endoscopic bladder hydrodistention under anesthesia at least 2 weeks after protocol enrollment. Behavioral and pharmacological treatments were continued after the hydrodistention. O'Leary-Sant questionnaire scores were recorded before starting the protocol, after pharmacologic/behavioral therapy, 2 months post-hydrodistension, and at scheduled follow-up. Eighteen patients (72%) completed the pilot multimodal treatment protocol and were followed for a mean of 10.2 months. All patients were female with a median age of 36.3 years and had mean bladder capacity under anesthesia of 836 milliliters. Mean O'Leary-Sant symptom index scores for baseline symptoms, after behavioral/pharmacologic treatment, post-hydrodistension and during follow up were 12.5, 8.6, 7.0, and 6.7 (p < 0.05). Mean O'Leary-Sant problem index scores for baseline, after behavioral/pharmacologic treatment, post-hydrodistention and during follow up were 12.7, 8.9, 6.7, and 7.7 (p < 0.05). Our pilot multimodal protocol of behavioral modification, pharmacologic therapy and endoscopic hydrodistention demonstrated a significant progressive improvement in PBS/IC quality of life scores, compared to a pre-treatment baseline. These results should be validated in a larger, placebo controlled trial.

Pharmacological management of sleep apnoea

Obstructive sleep apnoea poses a significant health hazard that is associated with leading causes of mortality and morbidity. Nasal continuous positive airway pressure is the primary treatment modality, with surgical treatments as alternatives. Oral appliances and pharmacological therapy remain adjunctive modalities. Non-specific treatments include weight loss, postural therapy and behavioural measures. Pharmacotherapy goals include the reduction of risk factors for sleep apnoea; correction of underlying predisposing metabolic diseases, such as hypothyroidism or acromegaly; treatment of associated symptoms, including excessive daytime sleepiness; and prevention of apnoeas/hypopnoeas. This paper reviews data supporting the treatment of sleep apnoea with various pharmacological agents, including intranasal corticosteroids, decongestant sprays, nicotine therapy, opiate antagonists, methylxanthine derivatives, oestrogen and progesterone, testosterone, thyroid hormone, growth hormone therapy for acromegaly, β-blockers, α-adrenergic agonists, angiotensin-converting enzyme inhibitors, glutamate antagonists, acetazolamide, selective serotonin re-uptake inhibitors, tricyclic antidepressants, physostigmine, modafinil and TNF-α antagonists, in addition to supplemental oxygen, and carbon dioxide inhalation. Some of these drugs have received very little testing and are the subject of few research articles.

Oral Agents for Type 2 Diabetes: An Update

IN BRIEFThe paradigms for oral pharmacological therapy in type 2 diabetes are shifting as we attain new insights into the optimal metabolic control in our patients. Each drug category has unique advantages and disadvantages, and their proper use necessitates a full understanding of their mechanisms of action, glycemic and nonglycemic effects, and prescribing indications. This article reviews published clinical trial data and places them into the context of contemporary, rational therapeutic strategies for this increasingly common condition.

Update on oral treatments for male erectile dysfunction.

Impairment of erectile function compromises quality of life in millions of men and their partners, many of whom prefer to suffer in silence. It is important to maintain an elevated index of clinical suspicion in patients with erectile dysfunction (ED) risk factors (e.g. hypertension, diabetes, coronary heart disease). There remains a high rate of voluntary discontinuation of therapy associated with most treatment modalities. Since the introduction of sildenafil, a greater awareness and openness regarding the epidemiology and treatment of male erectile dysfunction has emerged. The development of newer and potentially more efficacious phosphodiesterase type 5 (PDE5) inhibitors will serve to treat an even greater number of patients, allowing once daily and more convenient dosing. An increased understanding of the physiological principles of penile erection has allowed the development of novel oral pharmacological therapies. The new agents offer a potential benefit in a broader range of patients and clinical situations. They may provide a more acceptable alternative than other more invasive options (intracavernosal/urethral injection, implant surgery). The dopamine agonist apomorphine acts on the central control of penile erection to allow a sublingual preparation to produce a prompt response. It is not contraindicated in patients on nitrate medication for coronary artery disease, or in patients with depression or on antidepressants. As with any other treatment, the clinician's responsibility in the care of ED patients does not end with the writing of a prescription. Adequate education and follow-up are needed to optimize the efficacy and safety of oral ED therapy. Furthermore, patients and their partners need to be advised that the agents are not effective in the absence of sexual stimulation. Communicating with both the patient and his partner in a discreet, non-judgmental manner that fosters the physician-patient alliance can facilitate the recognition and treatment of ED.

Cancer patients: special considerations

Despite advances in understanding the pathophysiology of pain associated with cancer and the implementation of aggressive therapies with oral/transdermal medications, many patients do not achieve adequate analgesia. Intraspinal drug-delivery techniques have been successful in providing adequate pain control for these patients. However, there are several caveats in attaining this goal. The site of the tip of the catheter is of paramount importance. It must be placed close to the spinal segment corresponding to the site of nociception. Moreover, the use of bupivacaine and/or clonidine will not only enhance the quality of analgesia but will also decrease the incidence of opiate-induced side effects. Implementing protocols for the management of these patients with intraspinal techniques will not only yield better analgesia in patients unresponsive to oral pharmacologic therapy, but may also be associated with improved survival. This study examines the implementation of intraspinal therapy in patients with oncologic pain unresponsive to oral pharmacologic therapy.

Investigations in erectile dysfunction.

This is an update of recent developments in the investigation of erectile dysfunction in the period since March 2002. Three developments in the field of medical sexology redirected the approach towards the investigation of erectile dysfunction. First, the emergence of oral pharmacological therapy; second, the notion that sexual relationship issues have an important impact on the successful outcome of pharmacological therapy; and finally, the concept that erectile dysfunction is often a sequel or even a sentinel of cardiovascular disease. Consequently, the current evaluation of men with erectile dysfunction may be divided into two steps: a basic diagnostic evaluation for the majority of men, and specific diagnostic procedures for a small minority. The basic evaluation is aimed at the identification of the underlying pathological condition and erectile dysfunction-associated risk factors. Such screening may diagnose reversible causes of erectile dysfunction and also unmask medical and psychological conditions that manifest with erectile dysfunction. The basic evaluation consists of a comprehensive medical, sexual and psychosocial history and a physical examination. Patients who have failed first-line treatment or complicated cases qualify for specific diagnostic procedures, traditionally performed by urologists. Current research into the investigation of erectile dysfunction emphasizes the notion that erectile dysfunction is often a result of an interplay between medical and psychosexual conditions. Recognition of the underlying conditions and an estimation of their relative contribution to the patient's and his partner's sexual problem are key issues in the current evaluation of the man with erectile dysfunction.

Drug therapy of diabetes in the elderly

The prevalence of type 2 diabetes mellitus is increasing in the elderly. Although type 1 diabetic patients are living longer, over 95% of elderly people affected with diabetes have type 2 diabetes. This segment of the population, comprising men and women older than 65 years of age, is more likely to develop coexisting illnesses predisposing to the development of diabetes and complicating its management. In addition to changes in lifestyle, inherent age-related changes in carbohydrate metabolism contribute to the development of type 2 diabetes in old age. The long-term outcome of tight blood sugar control in the elderly is not known. Nevertheless the principles of management of type 2 diabetes in the elderly are essentially the same as in young- or middle-aged diabetic patients. Lifestyle modifications remain the cornerstone of medical therapy. When diet and exercise fail to achieve proper glycemic control, oral pharmacologic therapy and/or insulin therapy is indicated. The recently available oral glucose lowering agents in the market along with the newer types of insulin can be used in elderly diabetic patients. The effect of aging on metabolism and drug elimination kinetics must, however, be taken into consideration. In particular, it should be borne in mind that the risk of hypoglycemia is more deleterious in the elderly and should be avoided. In this review, the various pharmacologic agents available for the management of diabetes will be reviewed and some pertinent clinical guidelines will be suggested.

Use of finasteride in the treatment of men with androgenetic alopecia (male pattern hair loss).

Finasteride, a type 2-selective 5alpha-reductase inhibitor, was approved in 1997 as the first oral pharmacologic therapy for the treatment of men with androgenetic alopecia (AGA; male pattern hair loss). Originally developed for the treatment of men with benign prostatic hyperplasia (BPH) at a dose of 5 mg/day, finasteride has a well-established, excellent safety profile. Subsequent studies demonstrated that finasteride was an effective treatment for men with AGA at an optimal dose of 1 mg/day. This report summarizes the published peer-reviewed literature on the use of finasteride in the treatment of men with AGA, including the data on long-term (5 years) use of finasteride in a placebo-controlled clinical trial environment.

Advanced strategies for cancer pain management with intraspinal therapy

The treatment of pain associated with cancer that does not respond to oral pharmacological therapy has been greatly facilitated by the implementation of intraspinal techniques. The use of intrathecal catheters and programmable pumps provide an excellent alternative for these patients who are expected to survive for more than three months. However, it is recognized that neuropathic pain is the most frequent cause of failure when aggressive pharmacological therapy is implemented and as a result of it, the use of adjuvants such as bupivacaine and clonidine is necessary. This article deals with the steps to be implemented to guarantee a high degree of success when using this approach.

Intravesical Resiniferatoxin For Refractory Detrusor Hyperreflexia: A Multicenter, Blinded, Randomized, Placebo-Controlled Trial

Objective: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH).Methods: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 ml of placebo (n = 8 patients) or 0.005, 0.025, 0.05 , 0.10 , 0.2, 0.5, or 1.0 fLM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 1 2 posttreatment.Results: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-j-μM and 1.0-j-μM RTX treatment groups, respectively. Patients in the 0.5-j-μM and 1.0-j-μM groups with MCC < 300 ml at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. There were no long-term complications.Conclusion: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.

Critical evaluation of chemical neurolysis of the sympathetic axis for cancer pain.

Patients with pain caused by cancer frequently experience visceral pain. In addition to oral pharmacologic therapy to manage pain, neurolytic blocks of the sympathetic axis are also effective in controlling visceral cancer pain. Four types of neurolytic blocks (interpleural phenol, celiac plexus, superior hypogastric plexus, and ganglion impar) used in the treatment of visceral cancer pain are reviewed. Several studies have documented the efficacy of neurolytic blocks in reducing pain intensity and opioid consumption. However, the narrow risk-benefit ratio associated with neurolysis techniques requires knowledge of the implications associated with the different neurolytic blocks to minimize undesirable effects. Neurolysis of the sympathetic axis has been shown to be an effective and safe approach to treat visceral pain in cancer patients and should be incorporated in the armamentarium of the pain specialist as a useful adjunct to oral pharmacologic therapy.

Prognostic indices in heart transplant candidates after the first hospitalization triggered by the need for intravenous pharmacologic circulatory support

Background: Patients with heart failure refractory to optimal oral pharmacologic therapy have a dismal short term prognosis. Heart transplantation is the only therapy shown to improve survival in these patients. Unfortunately, due to the critical shortage of donor organs, approximately 30% of listed patients with end-stage heart failure die before a suitable donor heart becomes available. The principal aim of this study was to determine whether intravenous pharmacologic circulatory support favorably influences the clinical course of heart transplant candidates or whether mechanical circulatory support should be instituted in this high risk patient population. Methods Data from 154 consecutive hospitalizations in 125 patients 49 ± 12 years were retrospectively reviewed. The product limit method was used to estimate survival. Multiple logistic regression analysis was used to identify the clinical and hemodynamic variables that independently predict outcome after each admission in which heart transplantation did not occur. Results One year survival for the study population was 65%. This survival is significantly lower than the 91% 1 year survival in similarly ill patients undergoing heart transplantation. The Cox proportional hazard method identified serum bilirubin, blood urea nitrogen (BUN), serum sodium levels and right atrial pressure as independent prognostic indices. Serum bilirubin, BUN levels and duration of intravenous pharmacologic circulatory support were associated with a poor outcome. A composite index including serum bilirubin and BUN levels predicted outcome with a sensitivity and specificity of 79% and 77%, respectively. The addition of pharmacologic support duration increased the model’s sensitivity to 95%, but did not significantly alter specificity that was 74%. Of the 125 patients hospitalized due to the need to initiate intravenous pharmacologic support for the first time (index hospitalization), 69 (55%) were discharged after optimization of medical therapy. Of 21 patients who did not undergo transplantation during the follow-up period, 18 (86%) died within 2 years of the index hospitalization. The duration of intravenous pharmacologic support beyond which prognosis dramatically worsens without heart transplantation is 21 days. Conclusion Heart transplant candidates who require intravenous pharmacologic circulatory support for more than 21 days and do not receive a suitable donor heart within this period of time have a high mortality. Alternative therapies, such as implantation of a mechanical circulatory assist device should be considered in this high risk population.

Neurolytic Blocks of the Sympathetic Axis for the Treatment of Visceral Pain in Cancer.

Pain due to cancer is frequently visceral, and neurolysis of the sympathetic axis has been shown to be an effective and safe method for treating this visceral pain. Several studies have documented the efficacy of neurolytic blocks both by a reduction in the intensity of pain and by a decrease in opioid consumption. Neurolysis of the sympathetic axis should be incorporated into the pain specialist's arsenal as an adjuvant to oral pharmacologic therapy.

Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor.

Increased vascular permeability and excessive neovascularization are the hallmarks of endothelial dysfunction, which can lead to diabetic macular edema and proliferative diabetic retinopathy in the eye. Vascular endothelial growth factor (VEGF) is an important mediator of ocular neovascularization and a known vasopermeability factor in nonocular tissues. In these studies, we demonstrate that intravitreal injection of VEGF rapidly activates protein kinase C (PKC) in the retina at concentrations observed clinically, inducing membrane translocation of PKC isoforms alpha, betaII, and delta and >threefold increases in retinal vasopermeability in vivo. The effect of VEGF on retinal vascular permeability appears to be mediated predominantly by the beta-isoform of PKC with >95% inhibition of VEGF-induced permeability by intravitreal or oral administration of a PKC beta-isoform-selective inhibitor that did not inhibit histamine-mediated effects. These studies represent the first direct demonstration that VEGF can increase intraocular vascular permeability through activation of PKC in vivo and suggest that oral pharmacological therapies involving PKC beta-isoform-selective inhibitors may prove efficacious for the treatment of VEGF-associated ocular disorders such as diabetic retinopathy.