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Background Midodrine was the first medication approved by the Food and Drug Administration (FDA) for the treatment of orthostatic hypotension. Pharmacologically, midodrine is a peripheral selective alpha-1-adrenergic agonist that can improve standing, sitting, and supine systolic blood pressure. Common side effects include bradycardia, supine hypertension, and paresthesia. A novel side effect of midodrine-induced nightmares has been reported in our patient. To our knowledge, this is the first reported case of midodrine-induced nightmares. Objective To investigate and report a clinically significant and unique drug adverse event of midodrine in the treatment of orthostatic hypotension. Case Presentation This report describes a case of persistent nightmares associated with midodrine use in an 83-year-old male who experienced frequent syncope episodes treated with midodrine for orthostatic hypotension (OH). After the initiation of midodrine, the patient complained of increased nightmares, which quickly led to his refusal of the medication, despite the initial improvements in his blood pressure. The timing of administration included an evening dose at 21:00. This novel adverse event of midodrine-induced nightmares will be highlighted and explored in this case report. Conclusion This case demonstrated a unique adverse event of nightmares caused by midodrine. It is hypothesized that autonomic dysfunction plays a role and further investigations should be conducted to confirm this theory. We hope that our case report highlights the importance of careful consideration when prescribing midodrine in older people with orthostatic hypotension.

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INTRODUCTION: Ocular allergies to brimonidine are frequent in patients treated for glaucoma. There is variability in reporting due to the lack of diagnostic criteria and the absence of cutaneous testing. Many false-negative patch tests (PT) have been described. Alternative methods, such as strip and scratch PT, have been used without a standardized method. OBJECTIVES: The primary objective is to identify the best method of cutaneous testing and brimonidine concentration for patch testing. The secondary objective is to identify clinical signs and symptoms suggestive of ocular allergy. PATIENTS AND METHODS: A retrospective review of patient files suspected of brimonidine ocular allergy was performed. Patch testing method, brimonidine concentration and clinical symptoms were reviewed. RESULTS: Of the 36 patients identified, half tested positive for brimonidine for at least one of the testing methods. The scratch PT demonstrated 17 positive reactions (94% detection rate). Three patients reacted with strip PT. No positive results were found with standard PT. The 5% brimonidine concentration demonstrated the highest sensitivity. The absence of eyelid pruritus was associated with negative testing. CONCLUSION: In the investigation of ocular allergy to brimonidine, scratch PT proved to be an essential tool. Brimonidine 5% pet. appeared as the most sensitive concentration for scratch PT.

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BACKGROUND: Intranasal sprays (INSs) are commonly used medications for the treatment of many rhinologic conditions. Despite their popularity, an analysis of a nationwide reporting database and comparison to the available literature has never been performed. METHODS: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was accessed to obtain adverse event (AE) records from 2014 to 2019 for varying INSs, including: 10 corticosteroids, 1 alpha adrenergic, and 3 antihistamines. The Proportional Reporting Ratios (PRR) and Reporting Odds Ratios (ROR) were calculated for dyspnea, anosmia, ageusia/dysgeusia, epistaxis, and headache. A PRR ≥ 2 or ROR ≥ 1 was considered significant. RESULTS: Corticosteroids had 98 864 total reported AEs to the database, followed by antihistamines (7011) and alpha adrenergics (2071). In total, dyspnea was reported 5843 times, followed by headache (4230), epistaxis (1205), ageusia/dysgeusia (920), and anosmia (312). Overall, PRR and ROR values for dyspnea ranged from 0.51 to 4.25 and 0.51 to 4.49; for dysgeusia/ageusia from 0.56 to 6.09 and 0.56 to 6.12; and for epistaxis from 1.03 to 27.24 and 1.03 to 30.76, respectively. All medications which listed anosmia within the top AEs had PRR and ROR values exceeding 2 and 1, respectively. The PRR for headache exceeded 2 for 1 medication and the ROR exceeded 1 in 7 medications. CONCLUSION: The AEs of dyspnea, anosmia, ageusia/dysgeusia, epistaxis, and headache are reported within the FAERS database for commonly prescribed INSs. When compared against the existing scientific literature, the clinical significance of this reporting tool from the FDA for these classes of medications remains unvalidated.

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Orbital complications after endoscopic sinus surgery are serious problems. Inadvertent contamination of the eye by pharmacological solution can lead to early postoperative anxiety to patients and high concern to surgeons. This is a rare case report of retrograde epinephrine flow through lacrimal duct in sinus surgery with learning tips during postoperative assessment for reassurance in temporary pharmacological effect rather than serious complication.

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Introduction: Though many unanswered questions about the pathophysiology of Tourette Syndrome remain, several pharmacotherapies for tics have been studied, with varying results in terms of efficacy and the strength of evidence.Areas covered: This literature review encompasses pharmacotherapies for tics. The pharmacotherapies discussed in this review include: alpha agonists, antipsychotics, topiramate, botulinum toxin, and dopamine depleters.Expert opinion: Once the presence of tics is confirmed and psychoeducation and support are provided to patients and caregivers, one must examine the degree of tic-related impairment and the presence of psychiatric comorbidities. These factors influence treatment decisions as the presence of comorbidity and related impairment may shift the treatment target. When selecting a medication for tics, the presence of ADHD (the most frequent comorbidity) strengthens the case for choosing an alpha agonist. The case for antipsychotic medications is strongest when tic-related impairment is severe and/or the tics are refractory to more conservative measures. All medications require drug safety monitoring procedures and reevaluation over time.

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Norepinephrine is secreted under conditions of stress in humans. The ability of bacteria to sense mammalian hormone may have a role in propagation of infection. The present study investigated the effect of norepinephrine on in vitro growth of uropathogenic E. coli (UPEC) and the effect of silodosin on norepinephrine-induced changes. The spot urine samples were collected from 56 individuals (14 diabetic patients with UTI, 14 diabetic without UTI, 14 non-diabetic UTI and 14 healthy volunteer controls) for the measurement of urinary norepinephrine concentrations. The concentration of norepinephrine, as found in urine of human subjects, was reproduced in artificial urine medium to study the growth of UPEC. The norepinephrine concentration showing maximum growth response was selected to study the effect of silodosin on the growth inhibition of UPEC. Result showed significantly elevated urinary norepinephrine in diabetic patients with and without UTI and also in nondiabetic UTI groups. The norepinephrine concentration equivalent to that in diabetic UTI patients enhanced the growth of UPEC. Furthermore, silodosin (0.32 µM) inhibited the growth of the UPEC.

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PURPOSE: To determine the relationship between the distribution of adrenergic receptors in the human eyelid and the eyelid elevation after topically instilling 0.5% apraclonidine in blepharoptosis patients. METHODS: A total of 26 blepharoptotic patients (30 eyelids) were included in the experimental study. Marginal reflex distance 1 was measured before and after topical instillation of 0.5% apraclonidine. Eyelids were divided into 2 groups according to the responses to topical 0.5% apraclonidine. Patients who positively responded to apraclonidine were classified as group A and those that negatively responded to it were classified as group B. Müller's muscle was obtained during the blepharoptotic surgery, followed by immunohistochemical staining and scoring. This study was approved by the Institutional Review Board of Kim's Eye Hospital and the study protocol adhered to the tenets of the Declaration of Helsinki. RESULTS: α-1D staining intensity was significantly higher in group A than in B (p < 0.001) and α-2C and ß-1 staining intensities were significantly higher in group B than in A (p < 0.001 and p < 0.05, respectively). The difference in ß-2 staining intensity between groups A and B was not statistically significant. CONCLUSIONS: α-1D adrenoceptor was predominant in patients showing a positive response to topical 0.5% apraclonidine. Because apraclonidine has an α-1 agonistic effect, α-1D adrenoceptor may contribute to apraclonidine's elevating effect in patients with blepharoptosis.

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BACKGROUND: The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may help prevent postoperative cardiac complications. OBJECTIVES: To determine the efficacy and safety of α-2 adrenergic agonists for reducing mortality and cardiac complications in adults undergoing cardiac surgery and non-cardiac surgery. SEARCH METHODS: We searched CENTRAL (2017, Issue 4), MEDLINE (1950 to April Week 4, 2017), Embase (1980 to May 2017), the Science Citation Index, clinical trial registries, and reference lists of included articles. SELECTION CRITERIA: We included randomized controlled trials that compared α-2 adrenergic agonists (i.e. clonidine, dexmedetomidine or mivazerol) against placebo or non-α-2 adrenergic agonists. Included trials had to evaluate the efficacy and safety of α-2 adrenergic agonists for preventing perioperative mortality or cardiac complications (or both), or measure one or more relevant outcomes (i.e. death, myocardial infarction, heart failure, acute stroke, supraventricular tachyarrhythmia and myocardial ischaemia). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality, extracted data and independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. We evaluated included studies using the Cochrane 'Risk of bias' tool, and the quality of the evidence underlying pooled treatment effects using GRADE methodology. Given the clinical heterogeneity between cardiac and non-cardiac surgery, we analysed these subgroups separately. We expressed treatment effects as pooled risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included 47 trials with 17,039 participants. Of these studies, 24 trials only included participants undergoing cardiac surgery, 23 only included participants undergoing non-cardiac surgery and eight only included participants undergoing vascular surgery. The α-2 adrenergic agonist studied was clonidine in 21 trials, dexmedetomidine in 24 trials and mivazerol in two trials.In non-cardiac surgery, there was high quality evidence that α-2 adrenergic agonists led to a similar risk of all-cause mortality compared with control groups (1.3% with α-2 adrenergic agonists versus 1.7% with control; RR 0.80, 95% CI 0.61 to 1.04; participants = 14,081; studies = 16). Additionally, the risk of cardiac mortality was similar between treatment groups (0.8% with α-2 adrenergic agonists versus 1.0% with control; RR 0.86, 95% CI 0.60 to 1.23; participants = 12,525; studies = 5, high quality evidence). The risk of myocardial infarction was probably similar between treatment groups (RR 0.94, 95% CI 0.69 to 1.27; participants = 13,907; studies = 12, moderate quality evidence). There was no associated effect on the risk of stroke (RR 0.93, 95% CI 0.55 to 1.56; participants = 11,542; studies = 7; high quality evidence). Conversely, α-2 adrenergic agonists probably increase the risks of clinically significant bradycardia (RR 1.59, 95% CI 1.18 to 2.13; participants = 14,035; studies = 16) and hypotension (RR 1.24, 95% CI 1.03 to 1.48; participants = 13,738; studies = 15), based on moderate quality evidence.There was insufficient evidence to determine the effect of α-2 adrenergic agonists on all-cause mortality in cardiac surgery (RR 0.52, 95% CI 0.26 to 1.04; participants = 1947; studies = 16) and myocardial infarction (RR 1.01, 95% CI 0.43 to 2.40; participants = 782; studies = 8), based on moderate quality evidence. There was one cardiac death in the clonidine arm of a study of 22 participants. Based on very limited data, α-2 adrenergic agonists may have reduced the risk of stroke (RR 0.37, 95% CI 0.15 to 0.93; participants = 1175; studies = 7; outcome events = 18; low quality evidence). Conversely, α-2 adrenergic agonists increased the risk of bradycardia from 6.4% to 12.0% (RR 1.88, 95% CI 1.35 to 2.62; participants = 1477; studies = 10; moderate quality evidence), but their effect on hypotension was uncertain (RR 1.19, 95% CI 0.87 to 1.64; participants = 1413; studies = 9; low quality evidence).These results were qualitatively unchanged in subgroup analyses and sensitivity analyses. AUTHORS' CONCLUSIONS: Our review concludes that prophylactic α-2 adrenergic agonists generally do not prevent perioperative death or major cardiac complications. For non-cardiac surgery, there is moderate-to-high quality evidence that these agents do not prevent death, myocardial infarction or stroke. Conversely, there is moderate quality evidence that these agents have important adverse effects, namely increased risks of hypotension and bradycardia. For cardiac surgery, there is moderate quality evidence that α-2 adrenergic agonists have no effect on the risk of mortality or myocardial infarction, and that they increase the risk of bradycardia. The quality of evidence was inadequate to draw conclusions regarding the effects of alpha-2 agonists on stroke or hypotension during cardiac surgery.

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BACKGROUND: Topical α-adrenergic agonist therapy has been developed to treat the persistent erythema of rosacea patients. Brimonidine and oxymetazoline are both topical α-adrenergic agonists. OBJECTIVES: The objective of this in vitro safety pharmacology study was to compare the potential safety profiles of brimonidine and oxymetazoline. METHODS: Brimonidine and oxymetazoline underwent pharmacological profiling with a standard panel of 151 assays, including α-adrenergic receptors and 5-hydroxytryptamine (5-HT) receptors. A valvular interstitial cell (VIC) proliferation assay was performed with oxymetazoline hydrochloride. RESULTS: Brimonidine was highly selective for the α2 adrenergic receptors, specifically α2A, whereas oxymetazoline was found to be much less selective and was highly active against a wide range of targets. Negligible activity was observed with brimonidine at the 5-HT2B receptor, whereas oxymetazoline had significant 5-HT2B receptor agonist activity and caused proliferation of mitral VICs in vitro. CONCLUSION: As the 5-HT2B receptor is potentially involved in drug-induced valvulopathy, the benefit/risk ratio should be carefully considered, especially in patients with cardiovascular disease or other comorbidities.

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An unmet need exists for a safe, tolerable, effective treatment for moderate to severe persistent facial erythema in patients with rosacea. This pivotal phase 3, multicenter, double-blind study evaluated the efficacy and safety of topical oxymetazoline in patients with facial erythema associated with moderate to severe rosacea. Patients were randomly assigned to treatment with oxymetazoline hydrochloride cream 1.0% or vehicle applied once daily for 29 days, and were followed for 28 days posttreatment. The primary efficacy outcome was having at least a 2-grade decrease from baseline on both the Clinician Erythema Assessment (CEA) and the Subject Self-Assessment for rosacea facial redness (SSA) scales (composite success) at 3, 6, 9, and 12 hours postdose on day 29. Safety assessments included treatment-emergent adverse events (TEAEs) and posttreatment worsening of erythema (composite CEA/SSA increase of 1-grade severity from baseline; rebound effect). A total of 440 patients (mean age, 49.5 years; 78.9% females) were randomized (oxymetazoline, n=222; vehicle, n=218); most had moderate erythema. On day 29, significantly greater proportions of oxymetazoline recipients achieved the primary efficacy outcome at each time point (P less than 0.02) and overall (P less than 0.001) compared with vehicle recipients. The incidence of discontinuation due to TEAEs was low in both groups (oxymetazoline group, 1.8%; vehicle group, 0.5%). The most common TEAEs reported during the entire study period were application-site dermatitis, application-site erythema, and headache in the oxymetazoline group (1.4% each), and headache (0.9%) in the vehicle group. Following cessation of treatment, low proportions of patients experienced rebound effect (oxymetazoline group, 2.2%; vehicle group, 1.1%). Oxymetazoline applied to the face once daily for 29 days was effective, safe, and well tolerated in patients with moderate to severe persistent facial erythema of rosacea.

J Drugs Dermatol. 2018;17(1):97-105.

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OBJECTIVE: To review and summarize topical oxymetazoline's pharmacology, pharmacokinetics, efficacy, safety, cost, and place in therapy for persistent redness associated with erythematotelangiectatic rosacea. DATA SOURCES: Literature searches of MEDLINE (1975 to September 2017), International Pharmaceutical Abstracts (1975 to September 2017), and Cochrane Database (publications through September 2017) using the terms rosacea, persistent redness, α -agonist, and oxymetazoline. STUDY SELECTION AND DATA EXTRACTION: Results were limited to studies of human subjects, English-language publications, and topical use of oxymetazoline. Relevant materials from government sources, industry, and reviews were also included. DATA SYNTHESIS: Data support the efficacy of oxymetazoline for persistent facial redness. Little study beyond clinical trials cited in the drug approval process has been conducted. Current data suggest that oxymetazoline is similar in safety and efficacy to brimonidine. Head-to-head comparisons of topical α-agonists for erythema caused by rosacea are needed. CONCLUSION: The topical α-agonist, oxymetazoline, is safe and effective for reducing persistent facial redness associated with erythematotelangiectatic subtype of rosacea. Health care practitioners selecting among treatments should consider not only the subtype of rosacea but also individual patient response, preference, and cost.

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Midodrine is an oral, peripherally acting alpha-adrenergic agonist. After gaining Food and Drug Administration (FDA) approval in 1996 for orthostatic hypotension, its use has evolved to target vasoplegic conditions such as intradialytic hypotension in the end-stage renal disease population, refractory ascites in cirrhotic patients to support diuresis, and in hepatorenal syndrome. Upon oral ingestion, the drug undergoes enzymatic hydrolysis to an active metabolite, desglymidodrine. Its use has been well tolerated at 2.5 mg, 5 mg, and 10 mg oral doses. The most frequently occurring side effects relate directly to its sympathomimetic profile and include piloerection, scalp pruritis, generalized paresthesias, and urinary retention. The vasoplegic profile of sepsis would be a potential target for midodrine therapy. While its use to mediate recovery from septic shock has been suggested, there is a paucity of clinical data supporting its use. Such therapy may be uniquely appropriate in septic patients who are not candidates for intensive care unit (ICU) level of care.

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INTRODUCTION: Rosacea is a chronic skin condition characterized by transient and persistent erythema of the central face. The symptom of persistent erythema can be particularly frustrating for both patients and physicians as it is difficult to treat. Areas covered: Current treatment options for the treatment of rosacea include metronidazole, azelaic acid, sodium sulfacetamide-sulfur, and brimonidine. Until recently, brimonidine gel was the only option approved specifically for the treatment of facial erythema. However, oxymetazoline hydrochloride 1% cream is a newly FDA approved topical medication for adult rosacea patients. A primarily alpha-1a agonist, oxymetazoline hydrochloride (HCl) is thought to diminish erythema through vasoconstriction. Our paper seeks to evaluate evidence for topical oxymetazoline HCl with respect to its efficacy and safety for its approved indication of treating the persistent erythema associated with rosacea. Expert commentary: While assessment of available clinical trial data indicates that the medication is as effective as other available treatment for controlling rosacea-associated erythema with minimal risk of adverse effects, studies of long-term duration and direct comparison will be necessary to establish its place in treatment guidelines and clinical practice. As further evidence becomes available, the real-world clinical potential of topical oxymetazoline cream will become clearer.

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The use of pseudoephedrine, an alpha agonist, for the treatment of retrograde ejaculation is well-known, however, there is no clear consensus from the literature regarding its efficacy and treatment protocol. We evaluated the efficacy of pseudoephedrine treatment in patients with retrograde ejaculation, utilizing a yet undescribed short-period treatment protocol. Twenty men were medically treated with pseudoephedrine for retrograde ejaculation between January 2010 and May 2016 (12 with complete retrograde ejaculation and 8 with partial retrograde ejaculation). All patients had a semen analysis and post-ejaculatory urinalysis before and after treatment. The treatment protocol consisted of 60 mg of pseudoephedrine every 6 h on the day before semen analysis and two more 60 mg doses on the day of the semen analysis. Diabetes was the most common etiology for complete retrograde ejaculation (60%), whereas an idiopathic cause was the most common etiology for partial retrograde ejaculation (82%). Of the 12 complete retrograde ejaculation patients treated with pseudoephedrine prior to semen analysis, 7 (58.3%) recovered spermatozoa in the antegrade ejaculate, with a mean total sperm count of 273.5 ± 172.5 million. Of the eight patients with partial retrograde ejaculation, five (62.5%) had a ≥50% increase in the antegrade total sperm count. In this group, the mean total sperm count increased from 26.9 ± 8.5 million before treatment to 84.2 ± 24.6 million after treatment, whereas the percentage of spermatozoa in the urine declined from 43.2 ± 9% to 17 ± 10%, respectively (both p < 0.05). Overall, in men with retrograde ejaculation treated with a pseudoephedrine regimen prior to ejaculation, some improvement in seminal parameters occurred in 14 (70%) patients, with 10 patients (38.5% of all patients) achieving antegrade total sperm counts over 39 million.

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BACKGROUND: Pituitary masses are common lesions accounting for about 15-20% of all brain tumours. Oozing blood is an annoyance in microscopic sublabial trans-sphenoidal approach for these masses. There have been many ways of reducing the ooze, having their own pros and cons. OBJECTIVE: To find out the efficacy and safety of clonidine in reducing blood loss in pituitary adenoma surgery through a randomized masked trial. METHODS: It was a prospective randomized controlled trial done. Total 50 patients of pituitary adenomas were randomized into two groups. Group A (25 patients) was given 200 µg clonidine orally, while Group B (25 patients) was given placebo. Surgeon, anaesthesiologist and patient were blinded for the trial. Sublabial trans-septal trans-sphenoidal approach to sella and excision of mass was performed in each patient. Patients were studied for pre-, intra- and post-operative blood pressure and heart rate, pre- and post-operative imaging findings, intra-operative blood loss, bleeding grading by surgeon, surgeon's satisfaction about condition of specific part and quality of surgical field, operative time and extent of resection. RESULTS: Blood loss during the surgery, operative time and bleeding grading by the surgeon were found significantly less in the clonidine group, while quality of surgical field, condition of the specific part and extent of resection were found significantly better in the clonidine group (p value <.05). There was no untoward adverse effect of the drug in the test group. CONCLUSION: Clonidine is a safe and effective drug to reduce bleeding in trans-sphenoidal microscopic pituitary adenoma surgeries.

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Cardiomyopathy and associated heart failure continues to be one of the most severe complications that threaten a large population. Curcumin, one of the three curcuminoids of the spice turmeric, is very well known for a multitude of health benefits and functions. Norepinephrine (NE), a catecholamine and also a stress hormone may cause the cardiomyocytes to develop increased sensitivity to death with its increasing concentrations. In this study, we investigated the cardioprotective effect of curcumin in NE-induced cardiac apoptosis using several fluorescent and nonfluorescent microscopic techniques like DAPI, PI, Giemsa, PicroSirius and TUNEL. The aim of the study was to assess the effect of curcumin in preventing the occurrence of features underlying apoptosis such as nuclear disruption, chromatin condensation, DNA fragmentation and alterations in mitochondrial membrane permeability. Our results show that curcumin protects the cardiomyocytes against apoptosis significantly and also helps them to revert to their normal physiological state. Hence, we propose that curcumin has the potential to act as a therapeutic agent for the attenuation of NE-induced cardiac cell death and modulation of apoptosis in H9c2 cardiomyocytes.

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Urinary incontinence is a common and debilitating problem, and post-prostatectomy incontinence (PPI) is becoming an increasing problem, with a higher risk among elderly men. Current treatment options for PPI include pelvic floor muscle exercises and surgery. Conservative treatment has disputable effects, and surgical treatment is expensive, is not always effective, and may have complications. This article describes the prevalence and causes of PPI and the current treatment methods. We conducted a search of the PUBMED database and reviewed the current literature on novel medical treatments of PPI, with special focus on the aging man. Antimuscarinic drugs, phosphodiesterase inhibitors, duloxetine, and α-adrenergic drugs have been proposed as medical treatments for PPI. Most studies were small and used different criteria for quantifying incontinence and assessing treatment results. Thus, there is not enough evidence to recommend the use of these medications as standard treatment of PPI. To determine whether medical therapy is a viable option in the treatment of PPI, randomized, placebo-controlled studies are needed that also assess side effects in the elderly population.

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