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Nature Reviews. Neurology Apr 2019Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable... (Review)
Review
Parkinson disease (PD) treatment options have conventionally focused on dopamine replacement and provision of symptomatic relief. Current treatments cause undesirable adverse effects, and a large unmet clinical need remains for treatments that offer disease modification and that address symptoms resistant to levodopa. Advances in high-throughput drug screening methods for small molecules, developments in disease modelling and improvements in analytical technologies have collectively contributed to the emergence of novel compounds, repurposed drugs and new technologies. In this Review, we focus on disease-modifying and symptomatic therapies under development for PD. We review cellular therapies and repurposed drugs, such as nilotinib, inosine, isradipine, iron chelators and anti-inflammatories, and discuss how their success in preclinical models has paved the way for clinical trials. We provide an update on immunotherapies and vaccines. In addition, we review non-pharmacological interventions targeting motor symptoms, including gene therapy, adaptive deep brain stimulation (DBS) and optogenetically inspired DBS. Given the many clinical phenotypes of PD, individualization of therapy and precision of treatment are likely to become important in the future.
Topics: Antiparkinson Agents; Deep Brain Stimulation; Genetic Therapy; Humans; Parkinson Disease
PubMed: 30867588
DOI: 10.1038/s41582-019-0155-7 -
Clinical Toxicology (Philadelphia, Pa.) Nov 2014Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. (Review)
Review
CONTEXT
Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion.
OBJECTIVE
To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations.
METHODS
Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types.
RESULTS
The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue.
CONCLUSIONS
The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.
Topics: Animals; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Overdose; Guidelines as Topic; Hospitalization; Humans; Insulin; Length of Stay; Observational Studies as Topic; Treatment Outcome; Vasoconstrictor Agents
PubMed: 25283255
DOI: 10.3109/15563650.2014.965827 -
Journal of Clinical Hypertension... Apr 2006Most antihypertensive drugs have known side effects that are elicited by the careful clinician taking care of hypertensive patients. However, many antihypertensive...
Most antihypertensive drugs have known side effects that are elicited by the careful clinician taking care of hypertensive patients. However, many antihypertensive medications utilize drug delivery systems that prolong the duration of blood pressure reduction. The gastrointestinal therapeutic system that is used with nifedipine, isradipine, and verapamil has a unique side effect. Obstruction may occur at the site of a previous surgical repair (pyloric stenosis or gastroplasty) or stenosis of the esophagus, small intestine, or colon. The same delivery system is used with methylphenidate, oxybutynin, glipizide, and doxazosin. Although this complication is rare, physicians who prescribe and care for hypertensive patients should recognize this potential problem.
Topics: Antihypertensive Agents; Bezoars; Calcium Channel Blockers; Drug Delivery Systems; Gastrointestinal Diseases; Humans; Isradipine; Nifedipine; Postoperative Complications; Tablets; Verapamil
PubMed: 16596036
DOI: 10.1111/j.1524-6175.2006.05179.x -
Annals of Clinical and Translational... Mar 2021Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
Isradipine is a dihydropyridine calcium channel inhibitor that has demonstrated concentration-dependent neuroprotective effects in animal models of Parkinson's disease (PD) but failed to show efficacy in a phase 3 clinical trial. The objectives of this study were to model the plasma pharmacokinetics of isradipine in study participants from the phase 3 trial; and, to investigate associations between drug exposure and longitudinal clinical outcome measures of PD progression.
METHODS
Plasma samples from nearly all study participants randomized to immediate-release isradipine 5-mg twice daily (166 of 170) were collected for population pharmacokinetic modeling. Estimates of isradipine exposure included apparent oral clearance and area under the concentration-time curve. Isradipine exposure parameters were tested for correlations with 36-month changes in disease severity clinical assessment scores, and time-to-event analyses for initiation of antiparkinson therapy.
RESULTS
Isradipine exposures did not correlate with the primary clinical outcome, changes in the antiparkinson therapy-adjusted Unified Parkinson's Disease Rating Scale parts I-III score over 36 months (Spearman rank correlation coefficient, r : 0.09, P = 0.23). Cumulative levodopa equivalent dose at month 36 was weakly correlated with isradipine plasma clearance (r : 0.18, P = 0.035). This correlation was sex dependent and significant in males, but not females. Those with higher isradipine exposure had decreased risk of needing antiparkinson treatment over 36 months compared with placebo (hazard ratio: 0.87, 95% CI: 0.78-0.98, P = 0.02).
INTERPRETATION
In this clinical trial, higher isradipine plasma exposure did not affect clinical assessment measures of PD severity but modestly decreased cumulative levodopa equivalent dose and the time needed for antiparkinson treatment initiation.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02168842.
Topics: Aged; Calcium Channel Blockers; Disease Progression; Double-Blind Method; Female; Humans; Isradipine; Male; Middle Aged; Outcome Assessment, Health Care; Parkinson Disease; Severity of Illness Index
PubMed: 33460320
DOI: 10.1002/acn3.51300 -
Biochemical and Biophysical Research... Feb 2017Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Its causes are poorly understood and there is no proven therapeutic strategy... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world. Its causes are poorly understood and there is no proven therapeutic strategy for slowing disease progression. The core motor symptoms of PD are caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNc). In these neurons, Caentry through plasma membrane Cav1 channels drives a sustained feed-forward stimulation of mitochondrial oxidative phosphorylation. Although this design helps prevent bioenergetic failure when activity needs to be sustained, it leads to basal mitochondrial oxidant stress. Over decades, this basal oxidant stress could compromise mitochondrial function and increase mitophagy, resulting in increased vulnerability to other proteostatic stressors, like elevated alpha synuclein expression. Because this feedforward mechanism is no longer demanded by our lifestyle, it could be dispensed with. Indeed, use of dihydropyridines - negative allosteric modulators of Cav1 Ca channels - comes with little or no effect on brain function but is associated with decreased risk and progression of PD. An ongoing, NIH sponsored, Phase 3 clinical trial in North America is testing the ability of one member of the dihydropyridine class (isradipine) to slow PD progression in early stage patients. The review summarizes the rationale for the trial and outlines some unanswered questions.
Topics: Animals; Calcium; Calcium Channels, L-Type; Cytosol; Humans; Ion Transport; Neurons; Parkinson Disease
PubMed: 27590583
DOI: 10.1016/j.bbrc.2016.08.168 -
JCI Insight Oct 2023Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline...
Somatic gain-of-function mutations in the L-type calcium channel CaV1.3 (CACNA1D gene) cause adrenal aldosterone-producing adenomas and micronodules. De novo germline mutations are found in a syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA) as well as in autism spectrum disorder. Using CRISPR/Cas9, we here generated mice with a Cacna1d gain-of-function mutation found in both adenomas and PASNA syndrome (Cacna1dIle772Met/+). These mice show reduced body weight and increased mortality from weaning to approximately 100 days of age. Male mice do not breed, likely due to neuromotor impairment, and the offspring of female mice die perinatally, likely due to lack of maternal care. Mice generated by in vitro fertilization showed elevated intracellular calcium in the aldosterone-producing zona glomerulosa, an elevated aldosterone/renin ratio, and persistently elevated serum aldosterone on a high-salt diet as signs of primary aldosteronism. Anesthesia with ketamine and xylazine induced tonic-clonic seizures. Neurologic abnormalities included hyperlocomotion, impaired performance in the rotarod test, impaired nest building, and slight changes in social behavior. Intracellular calcium in the zona glomerulosa, aldosterone levels, and rotarod performance responded to treatment with the calcium channel blocker isradipine, with implications for the therapy of patients with aldosterone-producing lesions and with PASNA syndrome.
Topics: Humans; Male; Female; Mice; Animals; Aldosterone; Hyperaldosteronism; Isradipine; Calcium; Autism Spectrum Disorder; Mutation; Adenoma; Seizures
PubMed: 37698934
DOI: 10.1172/jci.insight.162468 -
Experimental and Clinical... Apr 2023Given the personal and public health burden of addictive disorders, innovative approaches to treatment are sorely needed. This systematic review examined the use of the...
Given the personal and public health burden of addictive disorders, innovative approaches to treatment are sorely needed. This systematic review examined the use of the pharmacological agent isradipine in the context of potential applications for addiction treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided a comprehensive search of PubMed, Cochrane Library, and PsycINFO between the years 1985 to July 2022. Studies were included if isradipine was administered to adults with a current diagnosis of a substance use disorder and/or to healthy volunteers alone and in conjunction with a substance (i.e, cocaine, methamphetamine, alcohol). A total of 16 studies with 252 participants were included in this review. Substantial variability was identified with study designs, isradipine dosages/dosing, and addictive substance of interest. Outcomes clustered in four categories: (a) cerebral blood flow (CBF), (b) hemodynamic effects, (c) subjective effects, and (d) cognitive effects. Isradipine was found to improve CBF in individuals with cocaine-induced hypoperfusion and in several studies was found to reduce parameters of blood pressure elevation after stimulant use. There were no significant findings on isradipine's effect on subjective reporting (i.e., craving, mood, drug affect) or cognition/attention. Given the limited number of studies identified in this review, there is insufficient data to draw clear conclusions. The direct effects of isradipine as a pharmacologic agent for addictive disorder treatment appear minimal, however, future work may benefit from examining the impact of isradipine as an augmentative agent within existing cue exposure paradigms for preventing cue-induced drug relapse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Topics: Adult; Humans; Isradipine; Calcium Channel Blockers; Cocaine; Methamphetamine; Substance-Related Disorders
PubMed: 36595455
DOI: 10.1037/pha0000633