Adjunctive therapy with pregabalin 150, 300, and 600 mg/d, given in twice-daily doses without titration, is significantly effective and well tolerated in the treatment of patients with partial seizures as demonstrated in patients with refractory partial seizures.

PGB, 150 mg/day and 600 mg/day, is highly effective and well-tolerated add-on therapy in patients with partial seizures.

Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice daily or three times daily schedule with similar efficacy and tolerability results.

Impaired mitochondrial function, oxidative stress and formation of excessive levels of reactive oxygen species play a key role in neurodegeneration in Parkinson's disease. Myeloperoxidase is a reactive oxygen generating enzyme and is expressed by microglia. The novel compound AZD3241 is a selective and irreversible inhibitor of myeloperoxidase. The hypothesized mechanism of action of AZD3241 involves reduction of oxidative stress leading to reduction of sustained neuroinflammation. The purpose of this phase 2a randomized placebo controlled multicentre positron emission tomography study was to examine the effect of 8 weeks treatment with AZD3241 on microglia in patients with Parkinson's disease. Parkinson patients received either AZD3241 600 mg orally twice a day or placebo (in 3:1 ratio) for 8 weeks. The binding of (11)C-PBR28 to the microglia marker 18 kDa translocator protein, was examined using positron emission tomography at baseline, 4 weeks and 8 weeks. The outcome measure was the total distribution volume, estimated with the invasive Logan graphical analysis. The primary statistical analysis examined changes in total distribution volume after treatment with AZD3241 compared to baseline. Assessments of safety and tolerability of AZD3241 included records of adverse events, vital signs, electrocardiogram, and laboratory tests. The patients had a mean age of 62 (standard deviation = 6) years; 21 were male, three female and mean Unified Parkinson's Disease Rating Scale III score (motor examination) ranged between 6 and 29. In the AD3241 treatment group (n = 18) the total distribution volume of (11)C-PBR28 binding to translocator protein was significantly reduced compared to baseline both at 4 and 8 weeks (P < 0.05). The distribution volume reduction across nigrostriatal regions at 8 weeks ranged from 13-16%, with an effect size equal to 0.5-0.6. There was no overall change in total distribution volume in the placebo group (n = 6). AZD3241 was safe and well tolerated. The reduction of (11)C-PBR28 binding to translocator protein in the brain of patients with Parkinson's disease after treatment with AZD3241 supports the hypothesis that inhibition of myeloperoxidase has an effect on microglia. The results of the present study provide support for proof of mechanism of AZD3241 and warrant extended studies on the efficacy of AZD3241 in neurodegenerative disorders.

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing.