Targeting Impaired Antimicrobial Immunity in the Brain for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia and aging is the most common risk factor for developing the disease. The etiology of AD is not known but AD may be considered as a clinical syndrome with multiple causal pathways contributing to it. The amyloid cascade hypothesis, claiming that excess production or reduced clearance of amyloid-beta (Aß) and its aggregation into amyloid plaques, was accepted for a long time as the main cause of AD. However, many studies showed that Aß is a frequent consequence of many challenges/pathologic processes occurring in the brain for decades. A key factor, sustained by experimental data, is that low-grade infection leading to production and deposition of Aß, which has antimicrobial activity, precedes the development of clinically apparent AD. This infection is chronic, low grade, largely clinically silent for decades because of a nearly efficient antimicrobial immune response in the brain. A chronic inflammatory state is induced that results in neurodegeneration. Interventions that appear to prevent, retard or mitigate the development of AD also appear to modify the disease. In this review, we conceptualize further that the changes in the brain antimicrobial immune response during aging and especially in AD sufferers serve as a foundation that could lead to improved treatment strategies for preventing or decreasing the progression of AD in a disease-modifying treatment.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

Expression and Cellular Distribution of P-Glycoprotein and Breast Cancer Resistance Protein in Amyotrophic Lateral Sclerosis Patients.

For amyotrophic lateral sclerosis (ALS), achieving and maintaining effective drug levels in the brain is challenging due to the activity of ATP-binding cassette (ABC) transporters which efflux drugs that affect drug exposure and response in the brain. We investigated the expression and cellular distribution of the ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) using immunohistochemistry in spinal cord (SC), motor cortex, and cerebellum from a large cohort of genetically well characterized ALS patients (n = 25) and controls (n = 14). The ALS group included 17 sporadic (sALS) and 8 familial (fALS) patients. Strong P-gp expression was observed in endothelial cells in both control and ALS specimens. Immunohistochemical analysis showed higher P-gp expression in reactive astroglial cells in both gray (ventral horn) and white matter of the SC, as well as in the motor cortex of all ALS patients, as compared with controls. BCRP expression was higher in glia in the SC and in blood vessels and glia in the motor cortex of ALS patients, as compared with controls. P-gp and BCRP immunoreactivity did not differ between sALS and fALS cases. The upregulation of both ABC transporters in the brain may explain multidrug resistance in ALS patients and has implications for the use of both approved and experimental therapeutics.

Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial.

AIM: Although primary angioplasty is effective despite additional transportation delay, improved patency before PCI might be obtained by starting pharmacological pre-treatment before transportation. METHODS AND RESULTS: From June 2001 to November 2002, 507 patients with acute myocardial infarction, who were transferred to a PCI centre, were randomised to early, pre-hospital initiation of Tirofiban (Early) or to initiation in the catheterisation laboratory (Late). The primary end-point was TIMI flow grade 3 of the infarct-related vessel (IRV) at initial angiography, as assessed by an independent core-lab. The effect of Tirofiban on each TIMI flow component, the presence of thrombus at initial angiography and pre-PCI myocardial blush grade were secondary end-points. A large proportion of patients (41%) was diagnosed and randomised in the ambulance, without intervention of a physician. In the Early group, Tirofiban was administered a median of 59 min (range 11-178 min) earlier than in the Late group. At initial angiography, TIMI 3 flow was present in 19% the Early group and in 15% in the Late group (P = 0.22). The combined incidence of TIMI 2 or 3 flow was present in 43% in the Early group and in 34% in the Late group, respectively (P = 0.04). Thrombus or a fresh occlusion was present in 60% and 73% in the Early and Late group, respectively (P = 0.002). A pre-PCI myocardial blush grades 2 or 3 was more often present in the Early group (30% vs. 22%, P = 0.04). However, no difference in TIMI 3 flow or myocardial blush grade was found between the groups, post-PCI. At one-year follow-up, the combined incidence of death or recurrent MI was not different between the groups (7.0% vs. 7.0%, P = 0.99). CONCLUSION: Early initiation of Tirofiban did not improve initial TIMI 3 flow of the IRV significantly. Despite a better patency (TIMI 2 or 3 flow), a lower prevalence of thrombus or fresh occlusion and a better myocardial perfusion in the infarct-related region pre-PCI, no beneficial effect on post-PCI angiographic or clinical outcome was found, as compared to initiation of Tirofiban in the catheterisation laboratory.

A multicenter study of the tolerability of tirofiban versus placebo in patients undergoing planned intracoronary stent placement.

BACKGROUND: The use of intravenous glycoprotein IIb/IIIa-receptor antagonists has been shown to improve outcomes in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Tirofiban has shown benefit in a wide range of patients presenting with acute coronary syndromes. Although this agent has been used in patients undergoing percutaneous coronary intervention, a literature search identified no prospective data comparing tirofiban with placebo in patients undergoing planned intracoronary stent placement. OBJECTIVE: This study examined the tolerability of tirofiban in patients undergoing percutaneous intervention with planned intracoronary stent placement. METHODS: This was a multinational, multicenter, prospective, randomized, double-blind, placebo-controlled trial in patients scheduled to undergo PTCA with planned intracoronary stent placement. Patients were randomized in a 3:2 ratio to receive tirofiban as an intravenous bolus (10 microg/kg over 3 minutes) and maintenance infusion (0.10 microg/kg per minute for 36 hours) or a bolus and infusion of placebo. All patients received periprocedural aspirin and heparin and an optional postprocedural thienopyridine (ticlopidine or clopidogrel). Laboratory and safety monitoring were performed throughout the 36 hours after the procedure and at hour 40 or hospital discharge. The primary end point was the proportion of patients with bleeding, defined according to Thrombolysis in Myocardial Infarction (TIMI) trial criteria. The number of patients with cardiac events (death, myo- cardial infarction, urgent revascularization) during the first 30 days after stent placement was also assessed. RESULTS: Eight hundred ninety-four patients (536 tirofiban, 358 placebo) were enrolled, all of whom received aspirin and heparin periprocedurally and optional ticlopidine or clopidogrel after the procedure. No significant between-group differences were observed in the incidence of TIMI major bleeding (0.2% tirofiban, 0.6% placebo) or any TIMI bleeding (3.2% and 1.7%, respectively). The incidence of TIMI minor bleeding was higher with tirofiban than with placebo (2.8% vs 0.6%). The 30-day incidence of the composite end point of any cardiac event was 3.9% in both groups. CONCLUSIONS: On a background of concomitant aspirin, heparin, and a thienopyridine, tirofiban was generally well tolerated in patients undergoing PTCA with planned intracoronary stent placement. Further investigation is needed to ascertain the optimal dosing of tirofiban and heparin to achieve reductions in ischemic complications of intracoronary stenting with an acceptable incidence of bleeding complications.