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Physiological Interaction (physiological + interaction)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Migraine Headache Recurrence: Relationship to Clinical, Pharmacological, and Pharmacokinetic Properties of Triptans

HEADACHE, Issue 4 2003
Gilles Géraud MD
Background and Objectives.,Triptan use is associated with headache recurrence, and this has been cited as an important reason for patient dissatisfaction with the treatment. The mechanism by which recurrence occurs is not clear, and the incidence of recurrence varies with the triptan used. In order to explore the pharmacological and physiological interaction of triptans and migraine headache recurrence further, some specific clinical, pharmacological, and pharmacokinetic factors that might influence migraine recurrence were evaluated in a review of the major efficacy data for the drugs in the triptan class. These factors were 5-HT1B and 5-HT1D receptor activities, the pharmacokinetic elimination half-life of each triptan, and the clinical efficacy of each compound, determined by the proportion of patients with headache relief and the therapeutic gain over placebo. Methods.,Clinical data were derived from 31 triptan, placebo-controlled, major efficacy studies used in a previous meta-analysis. The mean recurrence rate, mean headache response, and therapeutic gain were calculated using the results from the individual clinical studies. Mean headache response and therapeutic gain were calculated at the time point used to define recurrence in each study. Data for binding affinity and potency were taken from a direct-comparison in vitro pharmacology study, and the elimination half-life quoted in the data sheet for each triptan was used. Rank correlation with recurrence rate was performed for each of the test parameters. Results.,Mean headache recurrence rates ranged from 17% for frovatriptan 2.5 mg to 40% for rizatriptan. Elimination half-life and recurrence were inversely correlated (r = ,1.0, P = .0016). There was also a significant inverse correlation between 5-HT1B receptor potency and recurrence (r = ,0.68, P = .034), but 5-HT1D receptor potency was not correlated with recurrence (r = ,0.20, P = .54). In addition, the binding affinities for the 5-HT1B and 5-HT1D receptors were not correlated to headache recurrence. Importantly, it also was demonstrated that initial clinical efficacy was not correlated to headache recurrence. The correlation coefficient for headache response was 0.18 (P = .53) and for therapeutic gain, ,0.11 (P = .71). Conclusion.,The incidence of migraine headache recurrence varies between drugs in the triptan class. Migraine recurrence does not appear to be related to initial clinical efficacy, but is influenced by the pharmacological and pharmacokinetic properties of the individual triptans. The triptans with longer half-lives and greater 5-HT1B receptor potency had the lowest rates of headache recurrence. [source]

Voltage-Gated Sodium Channels: Therapeutic Targets for Pain

PAIN MEDICINE, Issue 7 2009
Sulayman D. Dib-Hajj PhD
ABSTRACT Objective., To provide an overview of the role of voltage-gated sodium channels in pathophysiology of acquired and inherited pain states, and of recent developments that validate these channels as therapeutic targets for treating chronic pain. Background., Neuropathic and inflammatory pain conditions are major medical needs worldwide with only partial or low efficacy treatment options currently available. An important role of voltage-gated sodium channels in many different pain states has been established in animal models and, empirically, in humans, where sodium channel blockers partially ameliorate pain. Animal studies have causally linked changes in sodium channel expression and modulation that alter channel gating properties or current density in nociceptor neurons to different pain states. Biophysical and pharmacological studies have identified the sodium channel isoforms Nav1.3, Nav1.7, Nav1.8, and Nav1.9 as particularly important in the pathophysiology of different pain syndromes. Recently, gain-of-function mutations in SCN9A, the gene which encodes Nav1.7, have been linked to two human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain. Studies on firing properties of sensory neurons of dorsal root ganglia demonstrate that the effects of gain-of-function mutations in Nav1.7 on the excitability of these neurons depend on the presence of Nav1.8, which suggests a similar physiological interaction of these two channels in humans carrying the Nav1.7 pain mutation. Conclusions., These studies suggest that isoform-specific blockers of these channels or targeting of their modulators may provide novel approaches to treatment of pain. [source]

Optimizing the Response From a Passively Controlled Biventricular Assist Device

ARTIFICIAL ORGANS, Issue 5 2010
Nicholas Richard Gaddum
Abstract Recent studies into rotary biventricular support have indicated that inadequate left/right flow balancing may lead to vascular congestion and/or ventricular suckdown. The implementation of a passive controller that automatically adjusts left/right flow during total and partial cardiac support would improve physiological interaction. This has encouraged the development of a biventricular assist device (BiVAD) prototype that achieves passive control of the two rotary pumps' hydraulic output by way of a nonrotating double pressure plate configuration, the hub, suspended between the ventricular assist device (VAD) impellers. Fluctuations in either the VAD's inlet or outlet pressure will cause the hub to translate, and in doing so, affect each pump's hydraulic outputs. In order to achieve partial support, the floating assembly needed to respond to pathologic blood pressure signals while being insensitive to residual ventricular function. An incorporated mechanical spring,mass,damper assembly affects the passive response to optimize the dynamic interaction between the prototype and the supported cardiovascular system. It was found that increasing the damping from a medium to a high level was effective in filtering out the higher frequency ventricular pressure signals, reducing a modified amplitude ratio by up to 72%. A spring response was also identified as being inherent in the passive response and was characterized as being highly nonlinear at the extremes of the floating assembly's translation range. The results from this study introduce a new means of BiVAD control as well as the characterization of a fully passive mechanical physiological controller. [source]

So how do you know you have a macromolecular complex?

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 1 2007
Timothy R. Dafforn
Protein in crystal form is at an extremely high concentration and yet retains the complex secondary structure that defines an active protein. The protein crystal itself is made up of a repeating lattice of protein,protein and protein,solvent interactions. The problem that confronts any crystallographer is to identify those interactions that represent physiological interactions and those that do not. This review explores the tools that are available to provide such information using the original crystal liquor as a sample. The review is aimed at postgraduate and postdoctoral researchers who may well be coming up against this problem for the first time. Techniques are discussed that will provide information on the stoichiometry of complexes as well as low-resolution information on complex structure. Together, these data will help to identify the physiological complex. [source]