The impact of alpha-1-adrenergic receptor antagonists on the progression of Parkinson disease.

BACKGROUND: Alpha-1-adrenergic receptor antagonists (AARAs) are used in the treatment of benign prostatic hypertrophy. Some AARAs, such as terazosin, stimulate glycolysis and increase cellular adenosine triphosphate levels through activation of phosphoglycerate kinase 1 (PGK1), which has been suggested to be of therapeutic benefit in patients with Parkinson disease (PD). OBJECTIVE: This study aimed to determine whether exposure to PGK1-activating AARAs was associated with slower PD progression. METHODS: National Veterans Affairs administrative data were used to identify patients who initiated PD-related pharmacotherapy during 2000 to 2019 and were concurrently prescribed an AARA. Using a retrospective cohort design, the count of incident PD-related outcome events within 1 year of follow-up was contrasted between patients prescribed a PGK1-activating AARA versus tamsulosin (an AARA without PKG1 stimulation), using multivariable negative binomial regression. PD-related outcome events were identified using ICD codes indicating motor symptoms, nonmotor symptoms, and other potential complications as clinical markers for the progression of PD. RESULTS: A total of 127,142 patients initiated drug therapy for PD during the observation period, of whom 24,539 concurrently received an AARA. Incident PD-related events were observed significantly less often in patients receiving a PGK1 AARA (n = 14,571) than tamsulosin (n = 9968) (incidence rate ratio [IRR] 0.80 [95% CI 0.77-0.83]). These results remained significant after adjustment for confounding factors (IRR 0.85 [95% CI 0.81-0.88]) and in sensitivity analyses. CONCLUSION: Patients prescribed a PGK1-activating AARA experienced fewer PD-related outcome events than patients prescribed tamsulosin. These results may indicate a role for terazosin and other PGK1 activators in slowing disease progression of PD; however, randomized controlled trials are needed.

Reprint of: The impact of alpha-1-adrenergic receptor antagonists on the progression of Parkinson disease.

BACKGROUND: Alpha-1-adrenergic receptor antagonists (AARAs) are used in the treatment of benign prostatic hypertrophy. Some AARAs, such as terazosin, stimulate glycolysis and increase cellular adenosine triphosphate levels through activation of phosphoglycerate kinase 1 (PGK1), which has been suggested to be of therapeutic benefit in patients with Parkinson disease (PD). OBJECTIVE: This study aimed to determine whether exposure to PGK1-activating AARAs was associated with slower PD progression. METHODS: National Veterans Affairs administrative data were used to identify patients who initiated PD-related pharmacotherapy during 2000 to 2019 and were concurrently prescribed an AARA. Using a retrospective cohort design, the count of incident PD-related outcome events within 1 year of follow-up was contrasted between patients prescribed a PGK1-activating AARA versus tamsulosin (an AARA without PKG1 stimulation), using multivariable negative binomial regression. PD-related outcome events were identified using ICD codes indicating motor symptoms, nonmotor symptoms, and other potential complications as clinical markers for the progression of PD. RESULTS: A total of 127,142 patients initiated drug therapy for PD during the observation period, of whom 24,539 concurrently received an AARA. Incident PD-related events were observed significantly less often in patients receiving a PGK1 AARA (n = 14,571) than tamsulosin (n = 9968) (incidence rate ratio [IRR] 0.80 [95% CI 0.77-0.83]). These results remained significant after adjustment for confounding factors (IRR 0.85 [95% CI 0.81-0.88]) and in sensitivity analyses. CONCLUSION: Patients prescribed a PGK1-activating AARA experienced fewer PD-related outcome events than patients prescribed tamsulosin. These results may indicate a role for terazosin and other PGK1 activators in slowing disease progression of PD; however, randomized controlled trials are needed.

Lack of Association between 5α-Reductase Inhibitors and Depression.

PURPOSE: Depressed mood and suicidality reported with 5α-reductase inhibitors (finasteride and dutasteride) during post-marketing surveillance resulted in the addition of depression risk to finasteride labeling. As peer reviewed studies are limited and have reported mixed findings, we further evaluated 5α-reductase inhibitor exposure and depression risk using sequence symmetry analysis. MATERIALS AND METHODS: National Veterans Health Administration administrative data were used to identify 53,848 male patients initiating 5α-reductase inhibitor therapy during fiscal year 2014. Incident depression events were assessed separately using the 2 measures of antidepressant prescription and depression diagnosis. Symmetry ratios were calculated as the ratio of patients with an incident depression event in the year following 5α-reductase inhibitor initiation to the year preceding initiation. An identical exposure counterfactual analysis was conducted among veterans initiating α1-adrenergic receptor antagonists. RESULTS: Incident antidepressant prescribing was observed in 2,563 patients following 5α-reductase inhibitor initiation and 3,051 patients preceding 5α-reductase inhibitor initiation (SR 0.84, 95% CI 0.80-0.89). Similar findings were observed for incident depression diagnosis (SR 0.83, 95% CI 0.79-0.86). Stratification by age group, 5α-reductase inhibitor agent, antidepressant class, prior α1-adrenergic receptor antagonist exposure and depression diagnosis type failed to demonstrate any positive association between 5α-reductase inhibitor and depression. Nearly identical results were observed in the α1-adrenergic receptor antagonist analysis (SR 0.87, 95% CI 0.84-0.90). CONCLUSIONS: Initiation of a 5α-reductase inhibitor was not associated with increased risk of depression. Our findings support the hypothesis that depression is more likely attributable to underlying benign prostatic hyperplasia and associated lower urinary tract symptoms than 5α-reductase inhibitor exposure.

Glucagon-like peptide receptor agonists and risk for depression.

AIMS: Package labeling for weight loss formulations of semaglutide and liraglutide include a warning for suicidal thoughts and behaviors. The objective was to examine the association between glucagon-like peptide-1 receptor agonists (GLP-1RA) and incident depression. METHODS: This retrospective cohort study compared Veterans Health Administration patients initiated on a GLP-1RA versus a dipeptidyl peptidase-4 inhibitor (DPP-4i) between June 1, 2013 and June 30, 2020. The primary outcome was incident depression, defined as a new diagnosis of depression or new antidepressant prescription, within 1 year following drug initiation. Multivariable log-binomial regression was used to estimate relative risk, adjusted for confounding factors including patient demographics, comorbid conditions, and prior medication. RESULTS: Of 34,130 patients initiated on a GLP-1RA and 105,478 initiated on a DPP-4i, incident depression occurred in 7.7 % (n= 2263) and 6.3 % (n= 6602), respectively. After adjustment, the relative risk was 1.02 (95 % CI: 0.97 - 1.07), thus failing to demonstrate a significant increase in risk for incident depression following initiation of a GLP-1RA compared to DPP-4i. Relative risk estimates in all sensitivity analyses were also non-significant. CONCLUSIONS: This study did not demonstrate a significant increase in risk for incident depression following GLP-1RA initiation.

Silodosin for benign prostatic hyperplasia.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, and safety of silodosin, a recently approved alpha(1A)-adrenergic receptor (AR) antagonist for benign prostatic hyperplasia (BPH). DATA SOURCES: English-only articles obtained from MEDLINE (1966-October 2009) using the search terms silodosin and KMD-3213 were reviewed. In addition, a search of International Pharmaceutical Abstracts (1970-October 2009) was conducted. STUDY SELECTION AND DATA EXTRACTION: Available English-language articles were reviewed, as well as abstracts from available non-English articles. DATA SYNTHESIS: Silodosin reduces urinary symptoms associated with BPH in as little as 1 day after initiation. The largest clinical trial conducted to date demonstrated a decrease in International Prostate Symptom Score of -6.4 +/- 6.63 points compared to -3.5 +/- 5.84 in patients receiving placebo (p < 0.0001). Silodosin also improved urinary flow rates by approximately 2.8 +/- 3.44 mL/sec, which is comparable to other alpha(1)-AR antagonists. The usual dose of silodosin is 8 mg once daily and should be reduced to 4 mg for patients with moderate renal dysfunction. Use is contraindicated in patients with severe renal and hepatic impairment or taking strong CYP3A4 inhibitors. In clinical trials, the most prevalent adverse effects were ejaculatory disturbances, occurring in approximately 28% of patients, although only 2.8% of patients discontinued treatment due to this adverse effect. Preliminary data suggest that, similar to other third-generation alpha(1A)-AR antagonists, silodosin has little potential to cause significant cardiovascular adverse effects such as orthostatic hypotension or syncope. To confirm these findings, long-term studies are still needed, especially in patients taking antihypertensive agents and in those with a history of intolerance to other alpha(1)-AR antagonists. CONCLUSIONS: Silodosin was approved by the Food and Drug Administration in 2008. Long-term studies demonstrating improvement in clinically important outcomes of BPH have yet to be published. In addition, pharmacoeconomic analyses would assist in defining its current place in therapy. Until this information is available, silodosin may be best reserved as an alternative to other second- and third-generation alpha(1)-AR antagonists.

Preemptive dose reduction of warfarin in patients initiating metronidazole.

BACKGROUND: The goal of this study was to determine if preemptive dose reduction (PDR) of warfarin is effective in maintaining therapeutic anticoagulation in patients initiating metronidazole. METHODS: This is a retrospective, single-center, cohort study in a pharmacist-managed anticoagulation clinic of a university affiliated Veteran's Affairs (VA) Medical Center. Subjects were anticoagulation patients initiating metronidazole between 1 January 2002 and 30 March 2009. At the time of metronidazole initiation, patients were managed with PDR of warfarin or no dose reduction. The primary outcome was the average change in International Normalized Ratio (INR) between patients that received PDR vs. those that did not. RESULTS: In total, 20 patients met inclusion criteria with seven patients receiving PDR at the time of initiation of metronidazole, whereas 13 did not. Patients managed with PDR and those that were not were similar in age (mean±SD 69.4±12.9 years vs. 72.1±9.9 years, p=0.61), mean baseline INR before metronidazole (2.58±0.49 vs. 2.57±0.66, p=0.98), and mean time to follow-up after initiation of metronidazole (5.6±2.9 days vs. 7.0±3.7 days, p=0.40), respectively. The primary outcome was statistically significant with a mean difference in INR of 1.28 (p=0.01) between patients manag-ed with PDR vs. those that were not. The mean preemptive warfarin dose reduction was 34.6%±13.4% which resulted in no significant increase in INR (p=0.61). Secondary outcomes including INR values >4.0 (0% vs. 46%, p=0.05), the average number of warfarin doses omitted (0.43±0.79 vs. 1.15±1.27, p=0.17), use of phytonadione or fresh frozen plasma, and rates of bleeding events were not significantly different be-tween groups. No thromboembolic events occurred during the 30 days following metronidazole therapy. CONCLUSIONS: In patients determined to be appropriate candidates for PDR, a 30%-35% reduction in mean daily warfarin dose was effective in maintaining therapeutic anticoagulation in patients started on concomitant metronidazole.

Intraoperative floppy iris syndrome associated with alpha1-adrenergic receptor antagonists.

OBJECTIVE: To describe intraoperative floppy iris syndrome (IFIS) in association with alpha(1)-adrenergic receptor (alpha(1)AR) antagonists by conducting a thorough literature review. DATA SOURCES: Literature retrieval was accomplished by searching MEDLINE (2000-December 2007) using the terms intraoperative floppy iris syndrome (IFIS), adrenergic alpha-antagonist(s), tamsulosin, doxazosin, terazosin, and/or alfuzosin. In addition, reference lists from identified publications were reviewed to identify additional reports and studies of interest. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from data sources were reviewed for relevance and uniqueness prior to inclusion. DATA SYNTHESIS: IFIS was first described in 2005 as a clinical triad observed during cataract surgery that includes fluttering and billowing of the iris stroma, propensity for iris prolapse, and constriction of the pupil. IFIS increases the risk of complications during cataract surgery. Numerous reports have linked IFIS to use of alpha(1)AR antagonists, most notably tamsulosin, which is prescribed for benign prostatic hyperplasia. Tamsulosin blocks prostatic alpha(1A)ARs but may also selectively block alpha(1A)ARs in the iris dilator muscle, preventing mydriasis during cataract surgery. Other alpha(1)AR antagonists, including terazosin, doxazosin, and alfuzosin, have also been linked to IFIS; however, their relationship to the syndrome is not as definitive. When ophthalmologists are aware of a patient's previous alpha(1)AR antagonist exposure, specific steps can be taken to reduce the risk of surgical complications. Corrective measures used during surgery have included iris expansion hooks, intracameral phenylephrine, and preoperative atropine. CONCLUSIONS: IFIS is a clinical syndrome observed during cataract surgery reported in patients taking systemic alpha(1)AR antagonists. It has been most strongly linked to use of tamsulosin. Medication washout periods of up to 2 weeks and specific surgical procedures have been attempted to reduce risk of complications from alpha(1)AR antagonists in the setting of cataract surgery. Patients should be educated regarding potential risks of this drug class so that they can discuss them with their healthcare providers, specifically ophthalmologists, prior to cataract surgery.

Promoting health communication between the community-dwelling well-elderly and pharmacists: the Ask Me 3 program.

OBJECTIVE: To describe readiness to use clear health communication principles with a pharmacist before and after participating in the Ask Me 3 (What is my main problem?, What do I need to do?, Why is it important for me to do this?) program. DESIGN: Modified, separate-sample, pretest-posttest study. SETTING: Senior centers in Polk County, IA, between March 2006 and February 2007. PARTICIPANTS: 106 community-dwelling well-elderly. INTERVENTION: Information on demographic characteristics, regularity of health care and medication use, health literacy level, and a measurement of multidimensional health locus of control were collected from participants, who were then were randomly allocated to one of three assessment subgroups: (1) pretest-posttest, (2) pretest only, and (3) posttest only during each of 12 Ask Me 3 program educational sessions. MAIN OUTCOME MEASURE: Readiness to use the seven principles of clear health communication described in the Ask Me 3 program. RESULTS: Participants were predominantly women and white, had a high school education or higher, had a yearly income of $25,000 or less, and had a mean age of 75.1 years. A majority reported good to excellent health status and visited their physician two or more times per year. All took medications regularly for a medical problem. A minority had inadequate to marginal health literacy. Before the Ask Me 3 program, a majority reported planning to or actively asking their pharmacist (1) for help with questions about their medications (88.2%), (2) to explain how to take their medication (82.6%), (3) to describe the main problem for which their medication is being prescribed (78.6%), and (4) to describe what can happen if they don't take their medication (74.3%). Approximately one-half of participants (55.2%) made a list of health or medication concerns to tell their pharmacist. A minority brought a list of current medications (47.8%) or brought a friend or family member to help when visiting their pharmacist (27.9%). A significantly higher proportion of participants reported planning to or actively bringing a list of current medications when visiting the pharmacist (P < or = 0.025) after participating in the Ask Me 3 program. Increases were not statistically significant for the remaining principles. CONCLUSION: The Ask Me 3 program is a practical tool that creates awareness and reinforces principles of clear health communication. The Ask Me 3 program should be evaluated in diverse pharmacy and health care settings with patients at high risk for poor health communication.

Comparative Effectiveness of Anticholinergic Agents for Lower Urinary Tract Symptoms.

BACKGROUND: Limited data from short-term clinical trials suggest efficacy advantages of solifenacin and fesoterodine over other anticholinergic agents in the treatment of lower urinary tract symptoms. OBJECTIVES: To (a) determine the real-world comparative effectiveness of newer anticholinergic agents for lower urinary tract symptoms, as assessed by 1-year persistence, and (b) identify patient factors independently associated with persistence. METHODS: We conducted a retrospective cohort study of U.S. veterans initiating newer anticholinergic therapy between October 2007 and August 2015. Multiple log-binomial regression was used to contrast 1-year persistence rates across anticholinergic agents while adjusting for measured confounders. Persistence was selected as a measure of effectiveness because nonpersistence is a common pathway encompassing inefficacy and intolerability, particularly in symptom-driven conditions. RESULTS: A total of 26,775 patients were included, of which 10,386 (38.8%) persisted with anticholinergic therapy at 1 year. Using long-acting tolterodine as the reference agent, superior persistence rates were observed for solifenacin (RR = 1.08, 95% CI = 1.03-1.13) and fesoterodine (RR = 1.25, 95% CI = 1.09-1.43), and a lower rate for short-acting tolterodine (RR = 0.90, 95% CI = 0.85-0.94). Patient factors associated with higher persistence rates included older age, male sex, and comorbidities such as multiple sclerosis, Parkinson's disease, and diabetes. CONCLUSIONS: Consistent with clinical trial reports, we found evidence for superior effectiveness of solifenacin and fesoterodine relative to other anti-cholinergics and for long-acting formulations over short-acting formulations. DISCLOSURES: This work was supported by the Iowa City VA Health Care System and by the Department of Veterans Affairs, Office of Research and Development, Health Services Research and Development Service (CDA 10-017). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. The authors have no conflicts of interest. Study concept and design were contributed by all the authors. Shaw took the lead in data collection, along with Lund, and data interpretation was performed by Lund, Goodson, and Cantrell. The manuscript was written by Goodson, Cantrell, Lund, and Shaw and revised by Lund, Goodson, Cantrell, and Shaw.

Effect of selected clinical trial publication on adjunctive nonstatin medication prescribing in the Veterans Health Administration system.

PURPOSE: The question of whether publication of selected clinical trials is temporally followed by changes in prescribing of adjunctive lipid-lowering medications was evaluated. METHODS: In this retrospective preanalysis and postanalysis, Veterans Health Administration (VHA) patients 18 years or older who received a new or renewed order for any lipid-lowering medication between April 2, 2004, and September 2, 2014, were included. This period was chosen based on the publication dates of three trials investigating the efficacy of nonstatin medications: Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia (ENHANCE, April 3, 2008), Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus (ACCORD Lipid, March 14, 2010), and Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy (AIM-HIGH, December 15, 2011). Annual prescribing rates for ezetimibe, fibrates, and niacin were analyzed for 4 years before and after the ENHANCE, ACCORD, and AIM-HIGH trial publication dates, respectively (3 years for niacin in AIM-HIGH) and reported as percent of patients in the cohort. RESULTS: Among patients receiving lipid-lowering medications, relatively low overall prescribing rates were observed for all three target medications. Prescribing rates for each medication decreased after its respective trial publication, with ezetimibe having the greatest change. CONCLUSION: Prescribing of fibrates, niacin, and ezetimibe in the VHA system decreased after the publication of landmark trials assessing their addition to a statin, consistent with the recommendations in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline, which did not encourage routine use of adjunctive therapies to lower the risk of cardiovascular disease.

Tadalafil: a phosphodiesterase-5 inhibitor for benign prostatic hyperplasia.

Tadalafil is a phosphodiesterase (PDE)-5 inhibitor recently approved by the United States Food and Drug Administration for lower urinary tracts symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). The mechanism for improved LUTS is thought to be related to three principal theories: alterations in nitric oxide levels, Rho-associated protein kinase deactivation, and reductions in pelvic atherosclerosis. The efficacy of PDE-5 inhibitors for the treatment of LUTS associated with BPH has been demonstrated in several randomized placebo-controlled trials. Tadalafil is thought to be superior based on an extended half-life; however, other PDE-5 inhibitors have positive results in BPH and have not been proved to be inferior to tadalafil. Before administration, concomitant use of medications such as nonselective α-adrenergic antagonists, nitrates, and cytochrome P450 inhibitors should be assessed for possible drug interactions. Potential adverse drug events seen in Food and Drug Administration-approved tadalafil include back pain, dyspepsia, headache, and dizziness. Given the efficacy and safety data currently available, the PDE-5 inhibitor tadalafil represents a reasonable alternative for selected male patients with LUTS associated with BPH, especially with concomitant erectile dysfunction.

Alvimopan for postoperative ileus.

PURPOSE: The efficacy, safety, pharmacology, pharmacokinetics, drug-drug interactions, and administration of alvimopan for postoperative ileus are reviewed. SUMMARY: Alvimopan is a selective mu-opioid receptor antagonist with no central nervous system activity. When orally administered after partial small- or large-bowel resection in patients with primary anastomosis, alvimopan shortened the return of bowel function and time to discharge by approximately one day without compromising analgesia. Alvimopan was not shown to be beneficial on these same outcomes after hysterectomy and has not been studied in other surgical populations. Alvimopan is generally well tolerated, with the frequency of adverse events being similar to placebo when used postoperatively for one week or less. Long-term studies of alvimopan in opioid-induced bowel dysfunction have shown an association with adverse cardiovascular outcomes, neoplasms, and fractures. Because of these concerns, the Entereg Access Support and Education program was developed. The recommended dosage of alvimopan is 12 mg administered with a sip of water 30 minutes to five hours before surgery, followed by 12 mg twice daily beginning the day after surgery for a maximum of seven days, 15 total doses, or until discharge. There is a limited amount of pharmacoeconomic analysis concerning alvimopan. CONCLUSION: Alvimopan, a peripherally acting mu-opioid receptor antagonist, is a novel agent for the treatment of postoperative ileus. It appears to decrease the duration of postoperative ileus and hospitalization by approximately one day, theoretically offsetting its acquisition costs. Unresolved long-term safety issues, a limited indication, and its restricted-access program are likely to hinder its widespread use in the surgical population.