Terazosin Therapy for Parkinson's Disease
Recruiting in Palo Alto (17 mi)
Overseen byMichele Tagliati, MD, FAAN
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Cedars-Sinai Medical Center
Must not be taking: Beta-blockers, Phosphodiesterase inhibitors
Disqualifiers: Dementia, Severe depression, Hypertension, Diabetes, others
No Placebo Group
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial is testing terazosin, a medication that helps relax muscles and improve blood flow, on people with early signs of Parkinson's disease risks. The goal is to see if it can slow down or prevent the progression of the disease. Terazosin and similar drugs were recently found to enhance energy production and reduce Parkinson's disease progression in animal studies and human data.
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications, such as beta-adrenergic antagonists and phosphodiesterase type 5 inhibitors like Viagra, Cialis, or Levitra. If you are using any investigational drugs, you must stop them at least 30 days before screening.
What data supports the effectiveness of the drug Terazosin for Parkinson's disease?
Research suggests that Terazosin, a drug that enhances energy production in cells, may slow the progression of motor symptoms and protect against cognitive decline in Parkinson's disease patients. Studies in animals and humans indicate that it could be neuroprotective, potentially reducing the risk of developing Parkinson's disease.
12345Is Terazosin safe for humans?
Terazosin, also known as Hytrin, is generally considered safe for human use as it has been used for treating conditions like high blood pressure and benign prostatic hyperplasia (enlarged prostate) for many years. While specific safety data for Parkinson's disease is limited, its long history of use in other conditions suggests a well-established safety profile.
678910How does the drug Terazosin differ from other treatments for Parkinson's disease?
Terazosin is unique because it is primarily used to treat high blood pressure and benign prostatic hyperplasia (enlarged prostate), but it is being explored for Parkinson's disease due to its potential effects on cellular energy production, which may help protect nerve cells.
1112131415Eligibility Criteria
This trial is for people who were part of a previous Parkinson's study, can consent, and don't have conditions like secondary Parkinsonism, dementia, severe depression, recent heart issues or certain other health problems. It's not for those with low blood pressure, untreated sleep apnea, heart failure or kidney issues.Inclusion Criteria
I understand the details of the clinical trial and can consent to participate.
Enrolled in the study 'The Effect of alpha1- adrenergic receptor antagonist Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease' (STUDY #000540)
Exclusion Criteria
I have no health issues that prevent me from taking terazosin.
Use of investigational drugs within 30 days before screening
I have had a severe heart condition causing very low blood pressure.
+22 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive terazosin therapy and undergo MIBG scan, DAT scan, and NM-MRI. Subjects return for research visits and imaging every six months.
3 years
Every 6 months
Follow-up
Participants are monitored for safety and effectiveness after treatment, with assessments of motor and non-motor symptoms.
6 months
Open-label extension (optional)
Participants may opt into continuation of treatment long-term to further assess the effects of terazosin.
Long-term
Participant Groups
The study tests the long-term effects of Terazosin on people at risk for pre-motor Parkinson's disease. Researchers will look at brain imaging changes and compare them to motor and non-motor symptoms as well as cardiac function over time.
1Treatment groups
Experimental Treatment
Group I: terazosin therapy extensionExperimental Treatment1 Intervention
Primary procedures in this study are MIBG scan, DAT scan, NM-MRI, and terazosin medication. Subjects will return for research visits and imaging every six months for three years. The investigators hypothesize that the rate of decline in DAT scan123I-Ioflupane uptake will be slower in subjects who have received the alpha1- adrenergic receptor antagonist terazosin, resulting in a decreased clinical conversion rate to parkinsonism.
Terazosin is already approved in United States, United States for the following indications:
🇺🇸 Approved in United States as Hytrin for:
- Benign prostatic hyperplasia (enlarged prostate)
- Hypertension (high blood pressure)
🇺🇸 Approved in United States as Tezruly for:
- Benign prostatic hyperplasia (enlarged prostate)
- Hypertension (high blood pressure)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Cedars Sinai Medical CenterLos Angeles, CA
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Who Is Running the Clinical Trial?
Cedars-Sinai Medical CenterLead Sponsor
References
Glycolysis-enhancing α1-adrenergic antagonists modify cognitive symptoms related to Parkinson's disease. [2023]Terazosin is an α1-adrenergic receptor antagonist that enhances glycolysis and increases cellular ATP by binding to the enzyme phosphoglycerate kinase 1 (PGK1). Recent work has shown that terazosin is protective against motor dysfunction in rodent models of Parkinson's disease (PD) and is associated with slowed motor symptom progression in PD patients. However, PD is also characterized by profound cognitive symptoms. We tested the hypothesis that terazosin protects against cognitive symptoms associated with PD. We report two main results. First, in rodents with ventral tegmental area (VTA) dopamine depletion modeling aspects of PD-related cognitive dysfunction, we found that terazosin preserved cognitive function. Second, we found that after matching for demographics, comorbidities, and disease duration, PD patients newly started on terazosin, alfuzosin, or doxazosin had a lower hazard of being diagnosed with dementia compared to tamsulosin, an α1-adrenergic receptor antagonist that does not enhance glycolysis. Together, these findings suggest that in addition to slowing motor symptom progression, glycolysis-enhancing drugs protect against cognitive symptoms of PD.
A pilot to assess target engagement of terazosin in Parkinson's disease. [2023]Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD.
Association of Glycolysis-Enhancing α-1 Blockers With Risk of Developing Parkinson Disease. [2023]Parkinson disease (PD) is a common neurodegenerative disease. A treatment that prevents or delays development of PD is a critical unmet need. Terazosin and closely related drugs were recently discovered to enhance glycolysis and reduce PD progression in animal models and human clinical databases.
Therapeutic efficacy of a partial dopamine agonist in drug-free parkinsonian patients. [2019]Terguride, a mixed agonist-antagonist of central dopamine receptors, was administered to eight patients with Parkinson's Disease. The clinical symptomatology of all patients improved significantly. The maximum neurological effect of terguride was noted at the highest daily dose (1.2 mg) after 21 days of treatment in all subjects, with a statistically significant average of 50.6% neurological improvement on the Webster scale in respect to admission. All single scores of the Webster scale decreased significantly: swing of the arms, facial expression, bradikinesia, rigidity and gait, particularly. No significant adverse reactions were observed during treatment. Our study in drug-free parkinsonian patients demonstrated that terguride is able to improve the neurological symptoms similar to DA agonists, but without their typical side effects.
[Tandospirone citrate, a selective 5-HT1A agonist, alleviates L-DOPA-induced dyskinesia in patients with Parkinson's disease]. [2013]A rapid and excessive increase in extracellular dopamine(DA) after L-DOPA administration is considered one of the major causes for L-DOPA-induced peak-dose dyskinesia. Therefore, inhibition of excessive rise in L-DOPA-derived DA is likely to be an ideal treatment for L-DOPA-induced dyskinesia. Based on our previous experimental studies that 8-OH-DPAT, a potent 5-HT1A agonist, attenuates an increase in L-DOPA-induced extracellular DA in the striatum of the rat model of Parkinson's disease, we hypothesized that L-DOPA-induced dyskinesia in patients with Parkinson's disease is alleviated by a 5-HT1A agonist. In the present study, we administered tandospirone citrate, a selective 5-HT1A agonist, to patients with Parkinson's disease suffering from L-DOPA-induced dyskinesia. Tandospirone(15-60 mg/day) was administered to 10 patients with L-DOPA-induced peak-dose dyskinesia. Twelve weeks after tandospirone treatment, duration of dyskinesia, subjective and objective severity of dyskinesia, and parkinsonian features were evaluated. Severity of dyskinesia was decreased in 5 patients; among these, 3 patients experienced slight worsening of parkinsonian features. Four patients showed no change in dyskinesia; among these, 2 patients showed worsening of parkinsonian features. One patient had slight worsening of dyskinesia without any change in parkinsonian features. The present study demonstrated that tandospirone is effective in alleviating L-DOPA-induced dyskinesia in 50% of the patients. However, at the same time 50% patients showed slight worsening of parkinsonian features. Both the anti-dyskinetic effect and the worsening of parkinsonian features are thought to be induced by tandospirone's potent 5-HT1A agonistic activity. Diverse effect of tandospirone may be caused by its partial agonist activity on 5-HT1A receptors, or may indicate that other causes for the expression of dyskinesia exist apart from excessive rise in brain DA levels. Administration of a 5-HT1A agonist is a choice for patients with dyskinesia if the care is taken so as not to induce worsening of parkinsonian features. Further studies such as double-blind trials are needed to confirm the usefulness of a 5-HT1A agonist for L-DOPA-induced dyskinesia.
Tolerability profile of aripiprazole in patients with Tourette syndrome. [2015]Over the last few years, aripiprazole has been proposed as a potentially useful medication for tics in patients with Tourette syndrome (TS). Aripiprazole has been associated with fewer adverse effects compared with other atypicals; however, little is known about its tolerability profile in the TS population. This study assessed the prevalence and characteristics of adverse effects resulting from the use of aripiprazole in a retrospective chart review of 29 patients with TS. Six patients (20.7%) discontinued aripiprazole because of the severity of specific adverse effects. The most commonly reported adverse effects were sedation (n = 9, 30%) and sleep problems (n = 5, 17%). In the majority of cases, adverse effects were not severe. There were no differences in demographic or clinical variables between the patients who did or did not experience adverse effects. The discontinuation rate of 20.7% suggests that aripiprazole is safe and reasonably well tolerated for use in TS. The prevalence of adverse effects appears to increase with treatment duration.
A pilot study on the motor effects of rimantadine in Parkinson's disease. [2019]The purpose of this pilot study was to determine whether rimantadine, the alpha-methyl derivative of amantadine, might have any antiparkinsonian properties. In an open-label trial, 14 patients (12 de novo and 2 on levodopa treatment) with Hoehn and Yahr stage 2 to 3 Parkinson's disease were placed on rimantadine at doses of 100 to 300 mg/d. No patients had dyskinesias or motor fluctuations. Ten of 14 (71%) reported a mean subjective response of 33% (range 10%-60%) to rimantadine. After treatment, there was a 13% improvement in Hoehn and Yahr staging (p = .01) and a 20% improvement in mean motor Unified Parkinsons Disease Rating Scale scores (p = .02). Rigidity was the most consistently improved feature among the responders. Mean effective dose was 256 mg/d (range 200-300 mg/d). Side effects were mild and transient, with nausea being most common (4/14). We conclude that rimantadine has some motor benefits in Parkinson's disease. A double-blind placebo-controlled study is warranted to validate our findings.
Acute dystonia with low-dosage aripiprazole in Tourette's disorder. [2015]To report a case of an acute dystonic episode in a patient with Tourette's disorder (TD) treated with the partial dopamine agonist aripiprazole.
Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia. [2022]Preclinical and clinical studies suggest amantadine immediate-release (IR) may reduce dyskinesia in Parkinson's disease (PD), although higher doses are associated with increased CNS adverse events (AEs). ADS-5102 is an extended release amantadine capsule formulation, designed for once-daily dosing at bedtime (qhs) to provide high concentrations upon waking and throughout the day, with lower concentrations in the evening. The pharmacokinetics (PK) of ADS-5102 were assessed in two phase I studies in healthy subjects, and a blinded, randomized phase II/III dose-finding study in PD patients.
A proof-of-concept, randomized, placebo-controlled, multiple cross-overs (n-of-1) study of naftazone in Parkinson's disease. [2022]To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson's disease (PD). Proof-of-concept, randomized, double-blind, placebo-controlled, multiple-cross-over n-of-1 study in patients with PD with wearing-off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single-blind dose-finding phase. Seven patients entered the placebo-controlled phase (four consecutive 28-day cross-overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48-h ON-OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven-point Likert scale to assess "patients' discomfort caused by dyskinesias" (Q1) and 'disability during OFF-periods' (Q2). A 'responder' analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross-over periods) was used. Treatment effects were derived from mixed-effects anova. On diaries, 5/7 patients responded to naftazone for 'ON-time with troublesome dyskinesia' (reduced time, treatment effect: -49 [95% CI: -93/-4] min, P = 0.03), 6/7 regarding 'ON-time without troublesome dyskinesia' (increased time, treatment effect: 35 [-19/88], P = 0.2). No trend was observed for 'OFF' time. There were 7/7 'responders' regarding UPDRSIII (reduced score, treatment effect: -2.1[-4.5/0.2], P = 0.08). The 7-point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.
Terguride in the treatment of Parkinson disease: preliminary experience. [2019]Terguride, a partial DA-agonist with both dopaminergic and antidopaminergic properties, was tested in 11 PD patients in the "decompensated" phase of the disease, characterized by the presence of dyskinesias and motor fluctuations. Combined treatment of these patients with 1 mg/day of terguride and stabilized doses of levodopa reduced the severity and frequency of dyskinesias and motor fluctuations along with a slight but significant improvement of parkinsonian clinical picture. The "modulatory" effect of terguride on DA receptors, in this experimental conditions, is discussed.
Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. [2019]We studied trihexyphenidyl in the treatment of torsion dystonia in a prospective, double-blind crossover protocol. Thirty-one patients completed the protocol. Twenty-two (71%) had a clinically significant response. After a mean follow-up of 2.4 years, 68% of patients continued to take trihexyphenidyl, and 42% continued to show a considerable or dramatic benefit. The 30-mg dose used was generally well tolerated. High-dosage trihexyphenidyl therapy is effective in the management of torsion dystonia.
The effect of chronic administration of sarizotan, 5-HT1A agonist/D3/D4 ligand, on haloperidol-induced repetitive jaw movements in rat model of tardive dyskinesia. [2013]Dyskinesia is the most troublesome side effect in long-term treatment of both Parkinson's disease (PD) and schizophrenia. The 5-HT1A agonist and D3/D4 ligand sarizotan [Bartoszyk, G.D., van Amsterdam, C., Greiner, H.E., Rautenberg, W., Russ, H., Seyfried, C.A., 2004. Sarizotan, a serotonin 5-HT1A receptor agonist and dopamine receptor ligand. 1. Neurochemical profile. J. Neural Transm. 111, 113-126.] is in clinical development for the treatment of PD-associated dyskinesia. Because 5-HT1A agonists are known to counteract antipsychotic-induced motor side effects, sarizotan was investigated for its effects in two rat models of tardive dyskinesia (TD). The acute administration of sarizotan (0.17-13.5 mg/kg i.p.) reduced episodes of SKF 38393-induced repetitive jaw movements (RJM) in rats with a maximal effect at 1.5 mg/kg. In a chronic study, sarizotan (0.04-9 mg/kg/day), administered in the drinking water for 7 weeks during withdrawal from chronic haloperidol treatment (1.5 mg/kg/day), dose-dependently reversed haloperidol-induced RJM, significant at the doses of 1.5 and 9 mg/kg. Agonism at 5-HT1A receptors may be mediating the inhibitory effect of sarizotan on RJM in rat models of tardive dyskinesia.
Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson's disease. [2017]The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior.
Activity of serotonin 5-HT(1A) receptor 'biased agonists' in rat models of Parkinson's disease and L-DOPA-induced dyskinesia. [2015]Serotonin 5-HT1A receptor agonists reduce L-DOPA-induced dyskinesia (LID) in animal models of Parkinson's disease (PD). Here, we compared the effects of novel 5-HT1A receptor 'biased agonists' on LID in hemiparkinsonian rats. F13714 preferentially activates pre-synaptic 5-HT1A autoreceptors. F15599 preferentially activates cortical postsynaptic 5-HT1A heteroreceptors. The partial agonist, tandospirone, does not differentiate these receptor subpopulations. The drugs were also tested on rotational behavior, rotarod and cylinder test for evaluation of locomotor activity, motor coordination and forelimb akinesia. Finally, the effects of F13714 and F15599 on 5-HT, DA, glutamate, and GABA release were investigated by microdialysis. F13714 abolished L-DOPA-induced AIMs even at very low doses (0.02-0.04 mg/kg). This effect was reversed by the selective 5-HT1A receptor antagonist, WAY100635. F13714 also elicited ipsilateral rotations (which were blocked by WAY100635) and potentiated the rotational activity of a sub-threshold dose of L-DOPA (2 mg/kg). F13714 profoundly inhibited striatal 5-HT release on both sides of the brain, and slightly increased DA release on the intact side. F15599 inhibited the L-DOPA-induced AIMs only at a dose (0.16 mg/kg) that reduced 5-HT release. Tandospirone produced a modest attenuation of peak AIMs severity and did not elicit rotations. F13714, F15599 and tandospirone did not modify the action of L-DOPA in the cylinder test but impaired rotarod performance at the highest doses tested. Targeting 5-HT1A receptors with selective biased agonists exerts distinct effects in the rat model of PD and LID. Preferential activation of 5-HT1A autoreceptors could potentially translate to superior antidyskinetic and L-DOPA dose-sparing effects in PD patients.