Metabolic effects of vasoactive agents.

After adequate volume resuscitation, the mainstay of therapy in critically ill patients with shock is treatment with vasoactive substances to restore haemodynamics or to improve regional perfusion. These agents include adrenoceptor agonists with inotropic combined with either vasoconstricting or vasodilating effects, and predominantly vasodilating drugs such as prostacyclin and related compounds. However, vasoactive agents not only affect the cardiovascular system, but also have profound metabolic effects.

The broad-spectrum cation channel blocker pinokalant (LOE 908 MS) reduces brain infarct volume in rats: a temperature-controlled histological study.

Activation of cation channels conducting Ca2+, Na+ and K+ is involved in the pathogenesis of infarction in experimental focal cerebral ischaemia. Pinokalant (LOE 908 MS) is a novel broad-spectrum inhibitor of several subtypes of such channels and has previously been shown to improve the metabolic and electrophysiologic status of the ischemic penumbra and to reduce lesion size on magnetic resonance images in the acute phase following middle cerebral artery occlusion in rats. The purpose of the present study was to investigate whether these beneficial effects of pinokalant are translated into permanent neuroprotection in terms of a reduction in infarct size one week after middle cerebral artery occlusion in rats.

Effects of dopexamine in comparison with fenoterol on carbohydrate, fat and protein metabolism in healthy volunteers.

Objective: In critically ill patients adrenergic agonists are used to treat haemodynamic disorders. Their metabolic actions should be considered in controlling metabolic homeostasis. Dopexamine has assumed effects on carbohydrate, fat and protein metabolism.

Metabolic effects of norepinephrine and dobutamine in healthy volunteers.

The objective of the present study was to evaluate the effects of norepinephrine (n = 9) and dobutamine (n = 7) on carbohydrate and protein metabolism in healthy volunteers in comparison with a control group (n = 9). Norepinephrine (0.1 microg/kg min), dobutamine (5 microg/kg min), or placebo was infused for 240 min.

Pharmacokinetics of pinokalant, a new nonselective cation channel blocker in the rat.

The pharmacokinetics of 1-isoquinolineacetamide, 3,4-dihydro-6,7-dimethoxy-alpha-phenyl-N,N-bis [2-(2,3,4-trimethoxyphenyl)ethyl]-, monomethanesulfonate (pinokalant, salt form of the active entity LOE 908 BS, CAS 143482-63-7), a nonselective cation channel blocker, was studied in rats. Drug plasma levels declined rapidly in a polyphasic manner after intravenous bolus administration of 8.8 mg/kg LOE 908 BS.

Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man.

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting.

Metabolic changes after cardiac surgery.

The metabolic changes that occur after cardiac surgery result from a complex interaction between the effects of surgery and extracorporeal circulation per se, the inflammatory response to surgical trauma and extracorporeal circulation, perioperative use of hypothermia, the cardiovascular and neuroendocrine responses characteristic to cardiac surgery, and the drugs and blood products used to support circulation during and after operation. These changes include among others increased oxygen consumption and energy expenditure and increased secretion of insulin, growth hormone, adrenocorticotrophic hormone, cortisol, epinephrine and norepinephrine. Other changes include decreased total-Trijodthyronine levels, hyperglycemia, hyperlactatemia, increased glutamate, aspartate and free fatty acid concentrations, hypokalemia, an increased production of inflammatory cytokines and increased consumption of complement and adhesion molecules.

The novel compound LOE 908 attenuates acute neuromotor dysfunction but not cognitive impairment or cortical tissue loss following traumatic brain injury in rats.

Experimental traumatic brain injury (TBI) initiates massive disturbances in Ca2+ concentrations in the brain that may contribute to neuronal damage. Intracellular Ca2+ may be elevated via influx through voltage-operated cation channels, ligand-gated ionotropic channels, and store-operated cation channels (SOCs). In the present study, we evaluated the neurobehavioral and histological effects of acute posttraumatic administration of (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di[2-(2 ,3,4-trimethoxyphenyl)ethyl]-acetamide (LOE 908), a broad spectrum inhibitor of voltage-operated cation channels and SOCs.

Effect of dobutamine on splanchnic carbohydrate metabolism and amino acid balance after cardiac surgery.

Background: As a predominant beta-adrenergic agonist, dobutamine may modify blood flow distribution and increase metabolic demands. The authors investigated the effect of a dobutamine-induced increase in cardiac output on splanchnic and femoral blood flow and metabolism in patients after cardiac surgery.

Methods: Seventeen stable patients were randomized to receive dobutamine or placebo (n = 8 per group, one dropout).

BIIR 561 CL: a novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties.

Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium channels, exhibit anticonvulsive and neuroprotective properties in vivo. One can postulate that a compound that combines both principles might be useful for the treatment of disorders of the central nervous system, like focal or global ischemia. Here, we present data on the effects of dimethyl-(2-[2-(3-phenyl-[1,2, 4]oxadiazol-5-yl)-phenoxy]ethyl)-amine hydrochloride (BIIR 561 CL) on neuronal AMPA receptors and voltage-dependent sodium channels.

Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex.

We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects.

Metabolic and calorigenic effects of dopexamine in healthy volunteers.

Objective: To evaluate metabolic and calorigenic effects of dopexamine in healthy volunteers.

Design: Prospective, randomized trial.

Setting: Laboratory of the University Department of Anesthesiology.

[Liver urea and glucose production in patients with alcohol-induced cirrhosis].

Objective: To use stable isotopes for the analysis of hepatic metabolic pathways (urea synthesis, glucose production), comparing them in alcoholic and normal liver, in order to obtain specific and quantitative information on metabolic functions of the liver.

Patients And Methods: Urea and glucose production as well as alanine metabolism in the liver were studied by means of stable isotopes in 7 males with alcoholic liver cirrhosis (mean age 46 +/- 4 years; height 173 +/- 5 cm; weight 73 +/- 3 kg) and 7 healthy male volunteers as controls (age 26 +/- 3 years; height 180 +/- 5 cm; weight 75 +/- 6 kg). The plasma concentrations of adrenaline, noradrenaline, insulin, glucagon and amino-acids were also measured.

[The effect of anesthetic method on enflurane air pollution in non-air conditioned operating rooms].

Unlabelled: Pollution of work areas by volatile anaesthetics and nitrous oxide occurs during general anaesthesia. Short anaesthesia procedures are often carried out in operating theatres that are not equipped with air-conditioning systems. Methods of lowering exposure during short procedures, where mask anaesthesia is the usual procedure, are double masks and the laryngeal mask.

In vivo role of the adenosine A3 receptor: N6-2-(4-aminophenyl)ethyladenosine induces bronchospasm in BDE rats by a neurally mediated mechanism involving cells resembling mast cells.

Activation of the adenosine A3 receptor subtype by the agonist N6-2-(4-aminophenyl)ethyladenosine is shown here to induce bronchospasm (increased pulmonary resistance and decreased pulmonary compliance) in BDE strain rats. The effect is substantially reduced by pretreating the rats with compound 48/80, disodium cromoglycate (30 micrograms/kg) or epinastine (10 micrograms/kg), which is compatible with involvement of mast cells. It is also substantially reduced by combined vagotomy and atropinization or by pretreatment with the NK2 receptor antagonist L-659,877, suggesting involvement of neuropeptide-mediated neural pathways.

Effects of epinephrine on glucose metabolism in patients with alcoholic cirrhosis.

The cirrhotic liver has been shown to be resistant to the actions of various glucoregulatory hormones. The objective of this study was to investigate the effects of epinephrine on hepatic glucose metabolism in cirrhotic patients. Thirteen cirrhotic and eight healthy subjects were studied.

[Is infection and septic shock caused by a global oxygen deficiency? An overview in 2 parts. 1: Infection and correlation between DO2 and VO2].

A global hypoxia resulting in an oxygen debt is assumed to be present in patients who suffer from the different stages and degrees of sepsis including septic shock and ARDS. As a consequence, the therapeutic concept of optimal values for cardiac output and oxygen delivery for these patients was proposed. This article reviews the literature with the objective of determining whether investigations dealing with oxygen delivery and consumption and with the plasma lactate concentration support the idea of the global hypoxia in septic patients.

Glycerol metabolism in patients with alcohol-induced liver cirrhosis.

The clearance rate of glycerol has been found to be impaired in alcoholic liver disease. However it remains unclear, if this can be ascribed to a defect of hepatic gluconeogenesis. Thus, the purpose of this work was to investigate glycerol clearance and hepatic glucose production in patients with liver cirrhosis.

Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors.

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzthiazole-dihydrochlor ide) is a potent dopamine autoreceptor agonist. We have carried out an analysis of the binding affinities of dopamine D2L, D2S, D3, and D4 receptors for pramipexole using both [3H]pramipexole and [3H]spiperone as radioligands at cloned and heterologously expressed receptors. Studies were carried out using rat and human D2L, D2S and D3 receptors with equivalent results.

Are the effects of noradrenaline, adrenaline and dopamine infusions on VO2 and metabolism transient?

Objective: To determine whether noradrenaline, adrenaline and dopamine have persistent actions on VO2 and metabolism.

Design: Descriptive laboratory investigation.

Setting: Laboratory of the Department of Anaesthesiology at a University Hospital.

Glucose and urea production and leucine, ketoisocaproate and alanine fluxes at supraphysiological plasma adrenaline concentrations in volunteers.

Objective: To determine the magnitude and time course of adrenergic effects on metabolism in volunteers and possible implications for the use of sympathomimetics in the critically ill.

Design: Descriptive laboratory investigation.

Subjects: 7 volunteers.

Effects of norepinephrine, epinephrine, and dopamine infusions on oxygen consumption in volunteers.

Objective: To determine the relationships between plasma concentrations of norepinephrine, epinephrine, and dopamine and oxygen consumption (VO2) during infusion of these catecholamines.

Design: Prospective, randomized variable dose, pharmacologic study in which a noncumulative infusion-rate design was used.

Setting: Laboratory of the Department of Anesthesiology at a University Hospital.

Therapeutic potential of CNS-active M2 antagonists: novel structures and pharmacology.

Clinical trials with muscarinic agonists or acetylcholine esterase inhibitors for the treatment of Alzheimer's dementia have shown disappointing or equivocal results. An alternative treatment of this disease is the development of drugs which enhance the release of acetylcholine. It is believed, that of the five muscarinic receptor subtypes so far identified in the brain, M2 receptors are located presynaptically in the cortex and hippocampus and upon stimulation inhibit the release of acetylcholine.