Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations.

OBJECTIVE: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). METHODS: A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p < 0.001) with a mean reduction of 13.5% (95% confidence interval [CI] = 8.4-18.5) and at visit 9 (p < 0.001) with a mean reduction of 10.5% (95% CI = 5.2-15.8). INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. Ann Neurol 2017;81:837-848.

Quality of life and psychiatric co­morbidity in Indian migraine patients: a headache clinic sample.

BACKGROUND: There is a lack of data from India on the impact of migraine on health-related quality of life (HRQoL) and the extent of psychiatric co-morbidities in migraine. OBJECTIVE: The objectives of the study were to quantify the impairment in HRQoL in migraine patients compared to healthy controls, to compare the prevalence of clinically significant anxiety and depressive symptoms in these groups, and to identify patient and headache characteristics that may predict health-related quality of life. MATERIALS AND METHODS: We interviewed 71 consecutive newly diagnosed migraine patients seen in the headache clinic of a tertiary referral center between September and December 2008. Age- and sex-matched healthy subjects (n = 71) were used as controls. Short Form-36, Migraine Disability Assessment Score, and Hospital Anxiety and Depression Scale were administered. Predictors of HRQoL were identified using regression analysis. RESULTS: Migraineurs were significantly impaired in all subscales of the SF-36 compared to controls, with greatest impairments in role physical, general health, and role emotional subscales. Prevalence of clinically significant anxiety (48%) and depressive (41%) symptoms in patients was higher than in healthy controls. Female gender, headache-related disability, and severity of anxiety predicted worse Physical Component Summary scores, while severity of both anxiety and depressive symptoms predicted worse Mental Component Summary scores. CONCLUSION: HRQoL is significantly reduced in Indian migraine patients compared to healthy controls. Incidence of clinically significant anxiety and depressive symptoms is also much higher in these patients. These findings corroborate well with studies from other parts of the world and suggest that cultural differences do not significantly alter the subjective impact of migraine on quality of life.

Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: a phase I pilot study.

The mutated SOD1 protein appears to have a gene dose-dependent effect on the severity and progression of ALS. Lowering of SOD1 protein levels might reduce severity and progression of the disease. The antimalarial drug pyrimethamine (PYR) was identified to cause a dose-dependent reduction in SOD1 protein levels in human cells in vitro. To determine if there was a similar effect in humans, we performed a phase I pilot study in 16 ALS patients with SOD1 mutations, 18 weeks in duration. Blood samples were obtained during all visits. The actin normalized leukocyte SOD1 levels were analyzed using Western blot. SOD1 content in the cerebrospinal fluid (CSF) was determined by ELISA and the SOD1 enzymic activity by spectrophotometric analysis using KO2. Clinical assessment of disease severity was assessed using Appel ALS scale and ALSFRS-R. The leukocyte SOD1 levels showed a significant reduction (p > 0.0001) by the third study visit and this reduction was sustained throughout the remainder of the study. CSF also showed a decrease in SOD1 protein content and enzymic activity in the two patients so tested. Thus, PYR use may be associated with a reduction in SOD1 in ALS patients. The significance is uncertain and further detailed study is required.