Lithium Therapy in Old Age: Recommendations from a Delphi Survey.

INTRODUCTION: While lithium (Li) has been well established for the treatment of bipolar disorder, geriatric patients require special attention when it comes to issues of drug safety. Declining renal function, amongst other medical conditions, and polypharmacy may pose increased risks. Only a few previous studies have addressed the management of Li in geriatric patients. METHODS: Twenty-four German medical experts on geriatric medicine and Li treatment participated in a Delphi survey, consisting of two rounds of questionnaires and a final formulation of treatment recommendations. Three major issues of Li therapy were outlined: initiation of treatment, monitoring of ongoing therapy, and withdrawal due to medical reasons. Final recommendations were consented to at a threshold of at least 80% expert agreement. RESULTS: Final consensus was achieved on 21 clinical recommendations. The approved recommendations covered aspects of necessary laboratory checks, concomitant medication, and target Li serum concentration in geriatric patients. Concerning the termination of Li therapy, an agreement was reached on the appropriate time span for tapering and on potential alternatives to Li. No consensus was achieved on whether concomitant dementia or frailty should be considered contraindications for Li treatment and the appropriate threshold of the estimated glomerular function rate for withdrawing Li. CONCLUSION: According to the view of German experts, Li may be used in geriatric patients, but it should be monitored carefully. However, the lack of consent in several specific treatment situations underlines the need for research on specific issues of Li therapy.

MD simulation of protein-ligand interaction: formation and dissociation of an insulin-phenol complex.

Complexes of proteins with small ligands are of utmost importance in biochemistry, and therefore equilibria, formation, and decay have been investigated extensively by means of biochemical and biophysical methods. Theoretical studies of the molecular dynamics of such systems in solution are restricted to 10 ns, i.e., to fast processes. Only recently new theoretical methods have been developed not to observe the process in real time, but to explore its pathway(s) through the energy landscape. From the profiles of free energy, equilibrium and kinetic quantities can be determined using transition-state theory. This study is dedicated to the pharmacologically relevant insulin-phenol complex. The distance of the center of mass chosen as a reaction coordinate allows a reasonable description over most of the pathway. The analysis is facilitated by analytical expressions we recently derived for distance-type reaction coordinates. Only the sudden onset of rotations at the very release of the ligand cannot be parameterized by a distance. They obviously require a particular treatment. Like a preliminary study on a peptide, the present case emphasizes the contribution of internal friction inside a protein, which can be computed from simulation data. The calculated equilibrium constant and the friction-corrected rates agree well with experimental data.

Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease.

To characterize antibodies produced in humans in response to Abeta42 vaccination, we carried out immunohistochemical examinations of the brains of both transgenic mice and human patients with beta-amyloid pathology. We collected sera from patients with Alzheimer disease who received a primary injection of pre-aggregated Abeta42 followed by one booster injection in a placebo-controlled study. Antibodies in immune sera recognized beta-amyloid plaques, diffuse Abeta deposits and vascular beta-amyloid in brain blood vessels. The antibodies did not cross-react with native full-length beta-amyloid precursor protein or its physiological derivatives, including soluble Abeta42. These findings indicate that vaccination of AD patients with Abeta42 induces antibodies that have a high degree of selectivity for the pathogenic target structures. Whether vaccination to produce antibodies against beta-amyloid will halt the cognitive decline in AD will depend upon clinical assessments over time.