A New Paradigm Shift in Antidepressant Therapy: From Dual-action to Multitarget-directed Ligands.

Major Depressive Disorder is a chronic, recurring, and potentially fatal disease, affecting up to 20% of the global population. Since the monoamine hypothesis was proposed more than 60 years ago, only a few relevant advances have been made, with very little disease course changing from a pharmacological perspective. Moreover, since the negative efficacy of novel molecules is frequently reported in studies, many pharmaceutical companies have put new studies on hold. Fortunately, relevant clinical studies are currently being performed extensively, developing immense interest among universities, research centers, and other public and private institutions. Depression is no longer considered a simple disease but a multifactorial one. New research fields are emerging, occurring a paradigm shift, such as the multi-target approach beyond monoamines. In this review, we summarize antidepressant drug discovery aiming to shed some light on the current state-of-the-art clinical and preclinical advances to face this increasingly devastating disease.

From Hybrids to New Scaffolds: The Latest Medicinal Chemistry Goals in Multi-target Directed Ligands for Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder affecting cognition, behavior, and function, being one of the most common causes of mental deterioration in elderly people. Once thought as being just developed because of ß amyloid depositions or neurofibrillary Tau tangles, during the last decades, numerous AD-related targets have been established, the multifactorial nature of AD became evident. In this context, the one drug-one target paradigm has resulted in being inefficient in facing AD and other disorders with complex etiology, opening the field for the emergence of the multitarget approach. In this review, we highlight the recent advances within this area, emphasizing in hybridization tools of well-known chemical scaffolds endowed with pharmacological properties concerning AD, such as curcumin-, resveratrol-, chromone- and indole-. We focus mainly on well established and incipient AD therapeutic targets, AChE, BuChE, MAOs, ß-amyloid deposition, 5-HT4 and Serotonin transporter, with the aim to shed light about new insights in the AD multitarget therapy.

Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer's disease.

During the last decade, the one drug-one target strategy has resulted to be inefficient in facing diseases with complex ethiology like Alzheimer's disease and many others. In this context, the multitarget paradigm has emerged as a promising strategy. Based on this consideration, we aim to develop novel molecules as promiscuous ligands acting in two or more targets at the same time. For such purpose, a new series of indolylpropyl-piperazinyl oxoethyl-benzamido piperazines were synthesized and evaluated as multitarget-directed drugs for the serotonin transporter (SERT) and acetylcholinesterase (AChE). The ability to decrease ß-amyloid levels as well as cell toxicity of all compounds were also measured. In vitro results showed that at least four compounds displayed promising activity against SERT and AChE. Compounds 18 and 19 (IC50 = 3.4 and 3.6 µM respectively) exhibited AChE inhibition profile in the same order of magnitude as donepezil (DPZ, IC50 = 2.17 µM), also displaying nanomolar affinity in SERT. Moreover, compounds 17 and 24 displayed high SERT affinities (IC50 = 9.2 and 1.9 nM respectively) similar to the antidepressant citalopram, and significant micromolar AChE activity at the same time. All the bioactive compounds showed a low toxicity profile in the range of concentrations studied. Molecular docking allowed us to rationalize the binding mode of the synthesized compounds in both targets. In addition, we also show that compounds 11 and 25 exhibit significant ß-amyloid lowering activity in a cell-based assay, 11 (50% inhibition, 10 µM) and 25 (35% inhibition, 10 µM). These results suggest that indolylpropyl benzamidopiperazines based compounds constitute promising leads for a multitargeted approach for Alzheimer's disease.

Outbreak of hemodialysis vascular access site infections related to malfunctioning permanent tunneled catheters: making the case for active infection surveillance.

OBJECTIVE: To describe an outbreak of infections with permanent cuffed hemodialysis catheters recognized through ongoing surveillance and related to a specific malfunctioning permanent catheter. DESIGN: The outbreak was suspected from the results of prospective infection surveillance and confirmed by a retrospective cohort study using medical records for patients receiving dialysis between April 1, 1999, and March 31, 2000. SETTING: Integrated network of six outpatient hemodialysis facilities in southern Idaho and eastern Oregon. PATIENTS: Outpatients receiving long-term hemodialysis. RESULTS: During the 18 months prior to the outbreak, the overall infection rate was 4.1 infections per 1,000 dialysis sessions with a catheter rate of 8.9 per 1,000 dialysis sessions. During the 7 months of the outbreak, the overall rate increased to 5.8 per 1,000 dialysis sessions, whereas the catheter rate increased to 18.1 per 1,000 dialysis sessions. Reports of malfunctioning "Brand A" catheters prompted discontinuation of their placement. A manufacturer recall occurred in April 2000. During the 14 months after the outbreak, the overall infection rate decreased to 3.3 per 1,000 dialysis sessions and the catheter rate to 10.8 per 1,000 dialysis sessions. A 12-month retrospective cohort study recognized 96 patients with an identifiable catheter brand and 48 infections. Of these, 27 (56%) occurred in patients with Brand A catheters. The relative risk for infection when compared with other catheter brands was 1.96 (95% confidence interval, 1.32 to 2.92; P < .001). CONCLUSIONS: Ongoing infection surveillance in hemodialysis facilities can identify specific device-related outbreaks of infections and promote interventions to reduce infectious complications and promote patient safety. Surveillance for vascular access site infections is recommended as a routine activity in hemodialysis facilities.

Epidemiology of hemodialysis vascular access infections from longitudinal infection surveillance data: predicting the impact of NKF-DOQI clinical practice guidelines for vascular access.

National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Vascular Access Guidelines 29 (40% of prevalent patients should have a native fistula) and 30 (<10% use of catheters for chronic hemodialysis) are currently based on opinion, rather than published evidence. The impact of these guidelines on reducing vascular access infection rates is unknown and was tested using data from an outpatient prospective cohort analysis. Patients undergoing hemodialysis from January 1998 through December 2000 at six outpatient facilities in Idaho and Oregon were evaluated prospectively for vascular access infections. There were 111,383 dialysis sessions (DSs) with 471 infections identified (4.2 infections/1,000 DSs). The risk for infection relative to arteriovenous (AV) fistulae was highly dependent on type of access used: 2.2 (P = 0.002) for AV grafts, 13.6 (P < 0.0001) for tunneled catheters, and 32.6 (P < 0.0001) for temporary catheters. Based on incidence infection rates, the number of infections predicted to occur with implementation of guidelines 29 and 30 in this population was calculated, and the percentage of reduction in infection was determined. Following either guideline 29 or 30 alone would have predictably prevented 103 or 97 total infections (22% and 21% reduction) and 40 or 51 bloodstream infections (24% and 30% reduction), respectively. Following both guidelines simultaneously would have prevented 151 total infections (32% reduction) and 64 bloodstream infections (38% reduction). These epidemiological data firmly establish that a major risk for vascular access infections is the type of access used (temporary catheters > tunneled catheters > AV grafts > AV fistulae). Furthermore, they strongly support the role of these NKF-DOQI guidelines in preventing infectious complications attributed to vascular access.