Drug Interaction in Psycho-Oncology: Antidepressants and Antineoplastics

Background and Objectives: Although there is a growing impact of psychiatric and depressive disorders in cancer patients, literature on the idiosyncrasies of antidepressants (ADs) used in those conditions and their interactions with antineoplastic agents (ANs) is scarce. Sharing the same biotransformation pathways enhances the risk of drug interaction between ADs and ANs, specifically when compounds are inducers, inhibitors or substrates of cytochrome P450 (CYP 450). In cancer patients, such drug interactions may result in less efficacy of the drug and/or increase of their side effects. Therefore, the choice of AD should be cautious (safe and effective) and well supported. The main purpose of this review was to analyze the individual pharmacokinetic properties of the most used ADs and ANs in order to summarize the risk of possible drug interactions between them, anticipating the consequences of their coadministration. Methods: The authors reviewed books and PubMed online articles published in the last 6 years. Results: Most of the ANs are subject to transformation by CYP 450 3A4 and their coadministration with ADs, that have inhibitory properties of this CYP isoform, such as fluoxetine, sertraline, paroxetine and fluvoxamine, may result in the loss of the AN's efficacy or higher toxicity. Conclusion: Among the ADs, escitalopram, citalopram, venlafaxine, mirtazapine and milnacipran stand out for their weak CYP 450 inhibitory potential and their safety profile in those patients

Failure of the work-Hamiltonian connection for free energy calculations

Extensions of statistical mechanics are routinely being used to infer free energies from the work performed over single-molecule nonequilibrium trajectories. A key element of this approach is the ubiquitous expression dW/dt=\partial H(x,t)/ \partial t which connects the microscopic work W performed by a time-dependent force on the coordinate x with the corresponding Hamiltonian H(x,t) at time t. Here we show that this connection, as pivotal as it is, cannot be used to estimate free energy changes. We discuss the implications of this result for single-molecule experiments and atomistic molecular simulations and point out possible avenues to overcome these limitations

Poly(amido amine)s as Gene Delivery Vectors: Effects of Quaternary Nicotinamide Moieties in the Side Chains

To evaluate the effect of quaternary nicotinamide pendant groups on gene delivery properties, a series of poly(amido amine) (co)polymers were synthesized by Michael addition polymerization of N, N-cystaminebisacrylamide with variable ratios of 1-(4-aminobutyl)-3-carbamoylpyridinium (Nic-BuNH2), and tert-butyl-4-aminobutyl carbamate (BocNH-BuNH2), yielding poly(amido amine)s (NicX-NHBoc) with X=0, 10, 30, and 50 % of quaternary nicotinamide groups in the polymer side chains. Deprotection of the pendant Boc-NH groups afforded an analogous series of polymers (NicX-NH2) with higher charge density (due to the presence of protonated primary amino groups in the side chains) and subsequent acetylation yielded a series of polymers (NicX-NHAc) of lower hydrophobicity than the Boc-protected polymers. The polymers with the Boc-protected or the acetylated amino groups showed high buffer capacity in the range pH 5.1-7.4, which is a property that can contribute to endosomal escape of polyplexes. The presence of quaternary nicotinamide groups has distinct beneficial effects on the gene vector properties of these polymers. The polymers containing 30 % of quaternary nicotinamide groups in their side chains condense DNA into small, nanosized particles (200 nm) with positive surface charge (+15 mV). Fluorescence experiments using ethidium bromide as a competitor showed that the quaternary nicotinamide groups intercalate with DNA, contributing to a more intimate polymer-DNA binding and shielding. Polyplexes of nicotinamide-functionalized poly(amido amine)s NicX-NHBoc and NicX-NHAc, formed at 12/1 polymerDNA mass ratio, efficiently transfect COS-7 cells with efficacies up to four times higher than that of PEI (Exgen 500), and with essentially absence of cytotoxicity. NicX-NH2 polymers, possessing protonated primary amino groups in their side chains, have a higher cytotoxicity profile under these conditions, but at lower 3/1 polymer-DNA mass ratio also these polymers are capable of efficient transfection, while retaining full cell viability

Exact f(R)f(R)-cosmological model coming from the request of the existence of a Noether symmetry

We present an $f(R)$-cosmological model with an exact analytic solution, coming from the request of the existence of a Noether symmetry, which is able to describe a dust-dominated decelerated phase before the current accelerated phase of the universe.Comment: 4 pages, 2 figures, Contribution to the proceedings of Spanish Relativity Meeting 2008, Salamanca, Sapin, 15-19 September 200

A new representation in evolutionary algorithms for the optimization of bioprocesses

Evolutionary Algorithms (EAs) have been used to achieve optimal feedforward control in a number of fed-batch fermentation processes. Typically, the optimization purpose is to set the optimal feeding trajectory, being the feeding profile over time given by a piecewise linear function, in order to reduce the number of parameters to the optimization algorithm. In this work, a novel representation scheme for the encoding of the feeding trajectory over time is proposed. Each gene in the variable sized chromosome has two components: a time label and the real value of the variable. The new approach is compared with a traditional real-valued EA, with chromosomes of constant size and fixed discretization steps. Three distinct case studies are presented, taken from previous work from the authors and literature, all considering the optimization of fed-batch fermentation processes. The experimental results show that the proposed approach is capable of results better or at the same level of quality of the best traditional EAs and is able to automatically evolve the best discretization steps for each case, thus simplifying the EA's setup.Fundação para a Ciência e Tecnologia (FCT) - 59899/EIA/POSC/2004

Triggering rogue waves in opposing currents

We show that rogue waves can be triggered naturally when a stable wave train enters a region of an opposing current flow. We demonstrate that the maximum amplitude of the rogue wave depends on the ratio between the current velocity, $U_0$, and the wave group velocity, $c_g$. We also reveal that an opposing current can force the development of rogue waves in random wave fields, resulting in a substantial change of the statistical properties of the surface elevation. The present results can be directly adopted in any field of physics in which the focusing Nonlinear Schrodinger equation with non constant coefficient is applicable. In particular, nonlinear optics laboratory experiments are natural candidates for verifying experimentally our results.Comment: 5 pages, 5 figure

Elucidation of molecular kinetic schemes from macroscopic traces using system identification

Overall cellular responses to biologically-relevant stimuli are mediated by networks of simpler lower-level processes. Although information about some of these processes can now be obtained by visualizing and recording events at the molecular level, this is still possible only in especially favorable cases. Therefore the development of methods to extract the dynamics and relationships between the different lower-level (microscopic) processes from the overall (macroscopic) response remains a crucial challenge in the understanding of many aspects of physiology. Here we have devised a hybrid computational-analytical method to accomplish this task, the SYStems-based MOLecular kinetic scheme Extractor (SYSMOLE). SYSMOLE utilizes system-identification input-output analysis to obtain a transfer function between the stimulus and the overall cellular response in the Laplace-transformed domain. It then derives a Markov-chain state molecular kinetic scheme uniquely associated with the transfer function by means of a classification procedure and an analytical step that imposes general biological constraints. We first tested SYSMOLE with synthetic data and evaluated its performance in terms of its rate of convergence to the correct molecular kinetic scheme and its robustness to noise. We then examined its performance on real experimental traces by analyzing macroscopic calcium-current traces elicited by membrane depolarization. SYSMOLE derived the correct, previously known molecular kinetic scheme describing the activation and inactivation of the underlying calcium channels and correctly identified the accepted mechanism of action of nifedipine, a calcium-channel blocker clinically used in patients with cardiovascular disease. Finally, we applied SYSMOLE to study the pharmacology of a new class of glutamate antipsychotic drugs and their crosstalk mechanism through a heteromeric complex of G protein-coupled receptors. Our results indicate that our methodology can be successfully applied to accurately derive molecular kinetic schemes from experimental macroscopic traces, and we anticipate that it may be useful in the study of a wide variety of biological systems