Current anaesthesia and critical care最新文献

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. To date, glutamate modulator riluzole is the only drug that has proved effective against disease progression. Based on this evidence, it has been proposed that glutamate excitotoxicity contributes to the neurodegeneration observed in ALS, with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) emerging as a likely candidate for glutamate receptor-mediated excitotoxicity. The calcium (Ca²⁺) conductance of AMPARs is determined by the presence of the edited GluR2 subunit, which renders the AMPAR Ca²⁺ impermeable. Of particular significance, reduced GluR2 editing at the Q/R site of AMPARs has been reported in spinal motor neurons of sporadic ALS patients. This review will examine the role of AMPAR-mediated excitotoxicity as a plausible mechanism to explain in part the selective motor neuron death observed in the pathogenesis of sporadic ALS.

Sepsis continues to be a major unresolved medical challenge of the present. Despite earlier diagnosis and treatment initiation, source control, improvements in the standard of care and attempts at standardization of treatment and resuscitation protocols intensive care unit mortality rates for severe sepsis is 32.2% and 54.1% for septic shock. Further reduction in mortality may be achievable through knowledge and use of the expanding field of adjunctive therapy: a supplement to optimal, supportive, intensive therapy and antibiotic treatment.

Numerous and unsuccessful trials targeted at inhibiting various essential inflammatory mediators and receptors involved in the sepsis syndrome have failed to show a reduction in mortality, raising the question whether mortality in sepsis actually derives from an uncontrolled pro-inflammatory response. Thus, more broad based attempts at modulating the inflammatory response to infection like corticosteroids and drotrecogin alfa (activated) are to date the only drugs to have demonstrated mortality benefits in large randomized controlled trials. Advances in understanding the pathophysiology of sepsis as a heterogeneous, dynamic syndrome caused by imbalances in the inflammatory network have provided newer hemofiltration techniques with a strong treatment rationale. Furthermore, endotoxin adsorption, if effective, has the potential to prevent further progression of the biological cascade of gram-negative sepsis.

Schizophrenia is a psychiatric disorder involving the impairment of normal thinking, emotion, and everyday behaviours. Characteristics of schizophrenia can be divided into positive, negative and cognitive symptoms. Contributory factors of the disorder include genetics, early environmental factors and neuropsychological factors. Many years of research has investigated the dopamine hypothesis and glutamate hypothesis of schizophrenia, but more recently the field is scrutinizing the combined interactions of the glutamatergic and dopaminergic systems.

The indications for sodium bicarbonate administration have more or less remained unchanged for years although enthusiasm for its use has waxed and waned. This article explores the combination of a bicarbonate challenge test with defined endpoints of haemodynamic resuscitation as a semi-quantitative method for differentiating between simultaneous reasons for severe metabolic acidosis.

The prevalence of neuropathic pain is rising, and is expected to further increase in aging populations. However, drug treatment for neuropathic pain remains inadequate, with the best available treatments having limited efficacy and dose-limiting side effects. Cannabinoids have been shown in clinical trials to be moderately effective at reducing neuropathic pain, but doses of cannabinoids currently in use are severely curtailed by psychoactive side effects through actions on the cannabinoid CB1 receptor. A relatively new class of drugs, selective cannabinoid CB2 receptor agonists, have shown considerable efficacy in a variety of animal models of neuropathic pain. Importantly, these drugs lack the psychoactivity of non-selective cannabinoid receptor agonists. The mechanisms by which CB2 receptor agonists reduce neuropathic pain are under intense investigation, and there are a number of plausible mechanisms by which CB2 agonists have antinociceptive effects. In this article, we review the preclinical evidence for the efficacy of CB2 agonists in the treatment of neuropathic pain. We also review the state of clinical development and trial of CB2 agonists, and argue that the need to test CB2 agonists for neuropathic pain in humans is urgent.

Voltage-gated sodium channels are important in the pathophysiology of chronic neuropathic pain and as targets for analgesic drugs. This review will cover the molecular structure and signalling roles for this ion channel super-family with a focus on the channels thought to be involved in nociception. We highlight the mode of action of current analgesic drugs and the difficulty of treating chronic inflammatory or neuropathic pain states. The discovery of key channel classes, or familial mutations, associated with chronic pain syndromes has resulted in intensive drug discovery programmes. The quest for selective drugs or toxins which safely and effectively block diseased channels without interfering with normal conduction in the central or peripheral nervous system has been frustratingly difficult. Nevertheless new small molecule drugs or channel selective toxins are in the development pipeline. It remains to be seen whether these will represent a significant development in the safe and effective treatment of chronic pain states.

AMPA receptors are one of the major excitatory receptors within the CNS with many of their functional effects being mediated by alterations in their trafficking to the cell surface and targeting into the synapse. Integral to these functions, and consequently, AMPA receptor activity is a class of proteins termed transmembrane AMPA receptor regulatory proteins (TARPs) which also possess diverse effects on AMPA receptor pharmacology. Incredibly, despite the evident importance of TARPs in AMPA receptor function, very few studies even allude to the potential significance of their potential role within the glutamatergic pathology of neurological disorder. This review brushes upon the importance of these proteins as potential targets for therapeutic agents in several psychological disorders where an increasingly significant glutamatergic component is being recognised with a rapidly expanding range of AMPA receptor modulatory compounds – AMPAkines – potentially offering new pharmacological intervention for disorders originally treated by targeting other neurotransmitter systems.