Use of Calcium Channel Blockers and Parkinson's Disease
Use of Calcium Channel Blockers and Parkinson's Disease
Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinson's disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinson's disease (1998–2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinson's disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinson's disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinson's disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinson's disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinson's disease, particularly in older patients, and with reduced mortality among patients with Parkinson's disease.
Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of the population over 60 years of age in industrialized countries. Degeneration and death of dopaminergic neurons leads to neurologic impairment, including tremor, rigidity, and bradykinesia. Patients also suffer from various nonmotor symptoms, and approximately 40% develop dementia. Current treatment strategies offer adequate symptom control in early stages of the disease but eventually fail or are associated with unacceptable side effects. Except for a recent study suggesting that the monoamine oxidase B inhibitor rasagiline may have disease-modifying effects, there are no drugs that prevent the disease or slow its progression.
The cellular pathogenesis of neurodegeneration in Parkinson's disease involves protein accumulation, mitochondrial dysfunction, oxidative and nitrative stress, neurotransmitter excitotoxicity, and inflammation. Several of these mechanisms involve calcium flux and overload and form the basis for why calcium regulation has been proposed to represent a possible therapeutic target. L-type calcium channels located on the plasma membrane of dopaminergic cells are responsible for the extra- to intracellular calcium flux that plays a part in generating autonomous pacemaking signals in substantia nigra neurons. These L-type channels may be inhibited by dihydropyridine calcium channel blockers (DiCCBs), drugs that are commonly used to treat hypertension. In animal models of Parkinson's disease, treatment with DiCCBs has been found to reduce toxin-induced loss of substantia nigra dopaminergic cells and to protect against toxin-induced motor deficits.
Epidemiologic data support a potential effect of DiCCBs in humans; 2 case-control studies found that use of DiCCBs was less likely to occur in patients with Parkinson's disease than in controls. Three smaller reports found no significant associations.
In a nationwide historical cohort study in Denmark, we investigated the association between DiCCB use and the risk of Parkinson's disease.
Abstract and Introduction
Abstract
Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinson's disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinson's disease (1998–2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinson's disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinson's disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinson's disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinson's disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinson's disease, particularly in older patients, and with reduced mortality among patients with Parkinson's disease.
Introduction
Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of the population over 60 years of age in industrialized countries. Degeneration and death of dopaminergic neurons leads to neurologic impairment, including tremor, rigidity, and bradykinesia. Patients also suffer from various nonmotor symptoms, and approximately 40% develop dementia. Current treatment strategies offer adequate symptom control in early stages of the disease but eventually fail or are associated with unacceptable side effects. Except for a recent study suggesting that the monoamine oxidase B inhibitor rasagiline may have disease-modifying effects, there are no drugs that prevent the disease or slow its progression.
The cellular pathogenesis of neurodegeneration in Parkinson's disease involves protein accumulation, mitochondrial dysfunction, oxidative and nitrative stress, neurotransmitter excitotoxicity, and inflammation. Several of these mechanisms involve calcium flux and overload and form the basis for why calcium regulation has been proposed to represent a possible therapeutic target. L-type calcium channels located on the plasma membrane of dopaminergic cells are responsible for the extra- to intracellular calcium flux that plays a part in generating autonomous pacemaking signals in substantia nigra neurons. These L-type channels may be inhibited by dihydropyridine calcium channel blockers (DiCCBs), drugs that are commonly used to treat hypertension. In animal models of Parkinson's disease, treatment with DiCCBs has been found to reduce toxin-induced loss of substantia nigra dopaminergic cells and to protect against toxin-induced motor deficits.
Epidemiologic data support a potential effect of DiCCBs in humans; 2 case-control studies found that use of DiCCBs was less likely to occur in patients with Parkinson's disease than in controls. Three smaller reports found no significant associations.
In a nationwide historical cohort study in Denmark, we investigated the association between DiCCB use and the risk of Parkinson's disease.
