Search

Introduction: Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. Primary tauopathies considered to be diseases correspond to a major class of frontotemporal lobar degeneration (FTLD) neuropathology (FTLD-Tau), including several forms of frontotemporal dementia (FTD) clinical syndromes. Little progress has been made in the past 20 years in developing effective disease-modifying drugs for primary tauopathies and available symptomatic treatments have limited efficacy. Areas covered: Potential disease-modifying drugs in clinical development to slow neuropathological progression of primary tauopathies. Expert opinion: Since the underlying pathology of primary tauopathies consists of abnormal tau protein aggregates, treatments are being developed to interfere with the aggregation process or to promote the clearance of this protein. Unfortunately, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. Further evidence will come from ongoing Phase I/II trials on novel drugs and immunotherapeutics with various targets–prevention of deposition or removal of tau aggregates, inhibition of tau phosphorylation/acetylation, modulation of O-GlcNAcylation, activation of autophagy or ubiquitin-proteasome system pathways, and rescue of selected tau loss of function or suppression of tau gene expression.

Introduction: Frontotemporal dementia (FTD) is a heterogeneous clinical entity that includes several disorders characterized by different cellular mechanisms. Distinctive clinical features in FTD include behavioral, affective, and cognitive symptoms. Unfortunately, little progress has been made over the past 20 years in terms of the development of effective disease-modifying drugs with the currently available symptomatic treatments having limited clinical utility. Areas covered: This article reviews the principal pharmacological intervention studies for FTD. These are predominantly randomized clinical trials and include symptomatic treatments and potential disease-modifying drugs. Expert opinion: There is insufficient evidence on effective treatments for FTD and studies with better methodological backgrounds are needed. Most studies reporting therapeutic benefits were conducted with selective serotonin reuptake inhibitors, while anti-dementia drugs have been ineffective in FTD. Since the underlying pathology of FTD mostly consists of abnormal tau protein or TDP-43 aggregates, treatments are being developed to interfere with their aggregation process or with the clearance of these proteins. Furthermore, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. The results from current ongoing Phase I/II trials will hopefully give light to future treatment options.

To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline bu

Rufloxacin is a new broad-spectrum fluoroquinolone antibacterial agent. The pharmacokinetics and safety of rufloxacin were evaluated after repeated oral administration to healthy volunteers. The drug was administered once a day for 6 consecutive days following two different dose schedules. The first group of 11 subjects was given a loading dose of 300 mg on the first day and 150 mg on the subsequent 5 days. The second group of 12 subjects was given a loading dose of 400 mg and 200 mg for 5 days. Serum levels and urine concentrations of rufloxacin were determined by microbiological assay. A simultaneous fit of all data points for each subject was done according to a one-compartment open model. The drug was rapidly absorbed (absorption half-life 17 +/- 6 min in the 300 + 150 mg and 11 +/- 5 min in the 400 + 200 mg dose regimen group) and reached maximal serum concentrations (2.77 +/- 0.24 and 3.62 +/- 0.35 micrograms/ml) 4.2 +/- 0.4 and 4.0 +/- 0.9 h after the first administration. Steady-state serum concentrations (3.19 +/- 0.31 and 4.06 +/- 0.33 micrograms/ml) were reached in 3.7 +/- 0.7 and 4.5 +/- 0.4 days. Elimination half-lives were 29.5 +/- 2.4 and 36.0 +/- 2.8 h. Apparent volumes of distribution were 111 +/- 8 and 136 +/- 16 liters and apparent plasma clearances were 46 +/- 5 and 44 +/- 4 ml/min. Renal clearances were 18 +/- 3 and 17 +/- 2 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Many agents have been reported to cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD) deficient subjects. We investigated whether cimetropium bromide, a new antispasmodic drug, can be safely given to these patients. In the first study, ten healthy volunteers were given 50 mg, p.o. 3 times per day, before meals for 1 week. Blood samples were drawn before and after treatment and stimulation of the hexose monophosphate shunt (HMS) was evaluated. No significant stimulation of HMS was observed. In a second study, 12 G6PD-deficient patients with spastic colon were given cimetropium bromide and placebo according to a double blind, cross-over design. None of the patients showed any significant abnormalities in any of the several hematologic parameters tested.