Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p

Molecular evolution of herpesviruses: genomic and protein sequence comparisons.

Phylogenetic reconstruction of herpesvirus evolution is generally founded on amino acid sequence comparisons of specific proteins. These are relevant to the evolution of the specific gene (or set of genes), but the resulting phylogeny may vary depending on the particular sequence chosen for analysis (or comparison). In the first part of this report, we compare 13 herpesvirus genomes by using a new multidimensional methodology based on distance measures and partial orderings of dinucleotide relative abundances. The sequences were analyzed with respect to (i) genomic compositional extremes; (ii) total distances within and between genomes; (iii) partial orderings among genomes relative to a set of sequence standards; (iv) concordance correlations of genome distances; and (v) consistency with the alpha-, beta-, gammaherpesvirus classification. Distance assessments within individual herpesvirus genomes show each to be quite homogeneous relative to the comparisons between genomes. The gammaherpesviruses, Epstein-Barr virus (EBV), herpesvirus saimiri, and bovine herpesvirus 4 are both diverse and separate from other herpesvirus classes, whereas alpha- and betaherpesviruses overlap. The analysis revealed that the most central genome (closest to a consensus herpesvirus genome and most individual herpesvirus sequences of different classes) is that of human herpesvirus 6, suggesting that this genome is closest to a progenitor herpesvirus. The shorter DNA distances among alphaherpesviruses supports the hypothesis that the alpha class is of relatively recent ancestry. In our collection, equine herpesvirus 1 (EHV1) stands out as the most central alphaherpesvirus, suggesting it may approximate an ancestral alphaherpesvirus. Among all herpesviruses, the EBV genome is closest to human sequences. In the DNA partial orderings, the chicken sequence collection is invariably as close as or closer to all herpesvirus sequences than the human sequence collection is, which may imply that the chicken (or other avian species) is a more natural or more ancient host of herpesviruses. In the second part of this report, evolutionary relationships among the 13 herpesvirus genomes are evaluated on the basis of recent methods of amino acid alignment applied to four essential protein sequences. In this analysis, the alignment of the two betaherpesviruses (human cytomegalovirus versus human herpesvirus 6) showed lower scores compared with alignments within alphaherpesviruses (i.e., among EHV1, herpes simplex virus type 1, varicella-zoster virus, pseudorabies virus type 1 and Marek's disease virus) and within gammaherpesviruses (EBV versus herpesvirus saimiri).(ABSTRACT TRUNCATED AT 400 WORDS

Evidence for selective evolution in codon usage in conserved amino acid segments of human alphaherpesvirus proteins

The genomes of human viruses herpes simplex 1 (HSV1) and varicella zoster (VZV), although similar in biology, largely concordant in gene order, and identical in many amino acid segments, differ widely in their genomic G + C (abbreviated S) content, which is high in HSV1 (68%) and low in VZV (46%). This paper analyzes several striking codon usage contrasts. The S difference in coding regions is dramatically large in codon site 3, S3, about 42%. The large difference in S3 is maintained at the same level in a subset of closely similar genes and even in corresponding identical amino acid blocks. A similar difference in S levels in silent site 1 (S1) is found in leucine and arginine. The difference in S3 levels occurs in every gene and in every multicodon amino acid form. The S difference also exists in amino acid usage, with HSV1 using significantly more codon types SSN, while VZV uses more codon types WWN (where W stands for A or T). The nonoverlapping and narrow histograms of S3 gene frequencies in both viruses suggest that the difference has arisen and been maintained by a process of selective rather than nonselective effects. This is in sharp contrast to the relatively large variance seen for highly similar genes in the human versus yeast analysis. Interpretations and hypotheses to explain the HSV1 vs VZV codon usage disparity relate to virus-host interactions, to the role of viral genes in DNA metabolism, to availability of molecular resources (molecular Gause exclusion principle), and to differences in genomic structure