Plasma dopamine concentrations following dopamine infusion to isoflurane-anesthetized New Zealand White rabbits.

OBJECTIVE: To determine the pharmacokinetics of dopamine following a short infusion in isoflurane-anesthetized rabbits. STUDY DESIGN: Prospective, descriptive pharmacokinetic study. ANIMALS: A group of six adult female New Zealand White rabbits weighing 4.4 ± 0.2 kg. METHODS: Rabbits were anesthetized with isoflurane in oxygen and maintained at 1.2 × minimum alveolar concentration of isoflurane (2.3% atmosphere). Dopamine (30 µg kg-1 minute-1) was infused for 10 minutes. Arterial blood was sampled prior, during and following the infusion at various intervals for 1 hour. RESULTS: A one-compartment model with baseline concentration best fitted the time-plasma dopamine concentration data. Estimated typical population value (interindividual variability) for volume of distribution and clearance were 10.3 (232%) L kg-1 and 9.9 (508%) L minute-1 kg-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: There was a large degree of interindividual variation in the disposition of dopamine. The large volume of distribution and high metabolic clearance rate reported for dopamine in this study likely explains the lack of clinical efficacy of dopamine in rabbits at doses up to 30 µg kg-1 minute-1.

Analysis of endogenous epinephrine and norepinephrine enantiomers in rat plasma and application to a stereoselective pharmacokinetics.

Epinephrine and norepinephrine are a class of chiral endogenous catecholamines, which are known as major neurotransmitters. This work described a new LC-MS/MS method coupled with pre-column derivatization, enabling the simultaneous enantiomeric separation of epinephrine and norepinephrine in rat plasma. After protein precipitation procedure, the samples were derivatized with (S)-N-(4-nitrophenoxycarbonyl) phenylalanine methoxyethyl ester, [(S)-NIFE]. The derivatives resolved with good baseline separation on an ACQUITY UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm) with mobile phase composed of methanol with 0.2% formic acid in water at a flow rate of 0.2 mL/min. Analysis was performed by multiple reaction monitoring in positive ionization mode. The linear ranges were 1.0-500 ng/mL for epinephrine enantiomers and 1.5-750 ng/mL for norepinephrine enantiomers. The lower limits of quantification for epinephrine and norepinephrine enantiomers were 1.0 and 1.5 ng/mL, respectively. The intra-day and inter-day precision were all less than 10.7% and accuracy ranged from 96.0 to 101.5%. Recoveries for all the analytes were more than 80.3%. The proposed method was successfully applied to simultaneously determine endogenous epinephrine and norepinephrine enantiomers in rat plasma. l-epinephrine and l-norepinephrine were sensitively and accurately quantified while both the d-enantiomers were not detected. Additionally, epinephrine enantiomers were analyzed for stereoselective pharmacokinetics in rats after intravenous administration of racemic epinephrine for the first time. The pharmacokinetic results indicated that the disposition of epinephrine enantiomers was stereoselective and chiral inversion did not occur in rats.

Pharmacokinetic effects of endotracheal, intraosseous, and intravenous epinephrine in a swine model of traumatic cardiac arrest.

INTRODUCTION: Limited prospective data exist regarding epinephrine's controversial role in managing traumatic cardiac arrest (TCA). This study compared the maximum concentration (Cmax), time to maximum concentration (Tmax), plasma concentration over time, return of spontaneous circulation (ROSC), time to ROSC, and odds of ROSC of epinephrine administered by the endotracheal (ETT), intraosseous (IO), and intravenous (IV) routes in a swine TCA model. METHODS: Forty-nine Yorkshire-cross swine were assigned to seven groups: ETT, tibial IO (TIO), sternal IO (SIO), humeral IO (HIO), IV, CPR with defibrillation (CPRD), and CPR only. Swine were exsanguinated 31% of their blood volume and cardiac arrest induced. Chest compressions began 2 min post-arrest. At 4 min post-arrest, 1 mg epinephrine was administered, and blood specimens collected over 4 min. Resuscitation continued until ROSC or 30 min elapsed. RESULTS: The Cmax of IV epinephrine was significantly higher than the TIO group (P = 0.049). No other differences in Cmax, Tmax, ROSC, and time to ROSC existed between the epinephrine groups (P > 0.05). Epinephrine levels were detectable in two of seven ETT swine. No significant difference in ROSC existed between the epinephrine groups and CPRD group (P > 0.05). Significant differences in ROSC existed between all groups and the CPR only group (P < 0.05). No significant differences in odds of ROSC were noted. CONCLUSIONS: The pharmacokinetics of IV, HIO, and SIO epinephrine were comparable. Endotracheal epinephrine absorption was highly variable and unreliable compared to IV and IO epinephrine. Epinephrine appeared to have a lesser role than volume replacement in resuscitating TCA.

Determination of d-amphetamine and diphenhydramine in beagle dog plasma by a 96-well formatted liquid-liquid extraction and capillary zone electrophoresis with field-amplified sample stacking.

This paper describes a method for quantification of d-amphetamine and diphenhydramine in beagle dog plasma by organic solvent field-amplified sample stacking (FASS)-capillary zone electrophoresis (CZE), using amlodipine as the internal standard. The separation was carried out at 25 °C in a 40.2 cm × 75 µm fused-silica capillary with an applied voltage of 20 kV using 25 mM phosphate-18.75 mM borate (pH 3.5). The detection wavelength was 200 nm. Clean-up and preconcentration of plasma biosamples were developed by 96-well formatted liquid- liquid extraction (LLE). In this study, the peak areas of d-amphetamine, diphenhydramine and amlodipine in the plasma sample increased by the factor of 48, 67 and 43 compared to the CZE without sample stacking. The method was suitably validated with respect to stability, specificity, linearity, lower limit of quantitation, accuracy, precision and extraction recovery. The calibration graph was linear from 2 to 500 ng/ml for d-amphetamine and 2-5000 ng/ml for diphenhydramine. All the validation data were within the required limits. Compared with the LC/MS/MS method that we previously established, there was no significant difference between the two methods in validation characteristics, except the LLOQs. The developed method was successfully applied to the evaluation of pharmacokinetic study of the Quick-Acting Anti-Motion Capsules (QAAMC) in beagle dogs.

Severe Sympathomimetic Toxidrome in a French Soldier: How Caffeine Overdose Can Lead to Severe Consequences.

We report the case of a French soldier, 29-yr-old, hospitalized in intensive care unit at Begin Military Hospital for the management of a sympathomimetic syndrome associated with severe metabolic disorders. Diagnosis of voluntary caffeine overdose was made. The evolution was favorable after metabolic disorders correction, without the need for dialysis. Caffeine is a molecule free of serious adverse effects when consumed at low doses. However, when consumed at high doses, it can become toxic and lead to death. Caffeine consumption has increased in recent years and especially in French Army. This toxicity remains unknown by a large part of population. We must be vigilant because this substance misuse can lead to serious consequences.

Clenbuterol Hydrochloride.

Clenbuterol (Broncodil and trade) is a direct-acting sympathomimetic agent with mainly beta-adrenergic activity and a selective action on ß2 receptors (a ß2 agonist). It has properties similar to those of salbutamol. It is used as a bronchodilator in the management of reversible airways obstruction, as in asthma and in certain patients with chronic obstructive pulmonary disease. The uses, applications, and the synthetic pathways of this drug are outlined. Physical characteristics including: ionization constant, solubility, X-ray powder diffraction pattern, thermal methods of analysis, UV spectrum, IR spectrum, mass spectrum are all produced. This profile also includes the monograph of British Pharmacopoeia, together with several reported analytical methods including spectrophotometric, electrochemical, chromatographic, immunochemical methods, and capillary electrophoretic methods. The stability, the pharmacokinetic behavior, and the pharmacology of the drug are also provided.

A Literature Review of the Pharmacokinetics and Pharmacodynamics of Dobutamine in Neonates.

Since its discovery in 1975 dobutamine has been used off-label for treating hemodynamic insufficiency in newborns and children. We present a structured literature review of pharmacokinetic and pharmacodynamic data for dobutamine in the pediatric population. Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria. Where possible, results for the pharmacodynamic and pharmacokinetic effect of dobutamine were reported as pooled data. Forty-six papers met the inclusion criteria. With regard to pharmacodynamic data a number of studies reported significant increases in a number of clinical parameters such as heart rate, blood pressure, cardiac output across a wide range of pediatric populations. With regard to pharmacokinetic data studies reported that the infusion rate was positively correlated to plasma dobutamine concentration. There was great variability with regard to dobutamine clearance between individuals and as to whether it followed first- or zero-order elimination kinetics. While the pharmacodynamic effects of dobutamine appear to reflect the pharmacological profile of the drug, the pharmacokinetic data are difficult to interpret due to inhomogeneity between study populations ages, comorbidities, dobutamine dosages and methodologies. High-quality prospective pharmacokinetic and pharmacodynamic data especially in newborns are urgently required prior to a large randomized study.

Pharmacokinetics of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler.

AIM: To compare salmeterol (SALM) and fluticasone propionate (FP) systemic exposure following inhaled salmeterol/fluticasone propionate combination (SFC) from a unit-dose capsule-based inhaler (Rotacaps(®)/Rotahaler(®)) and a multi-dose dry powder inhaler (Diskus(®)) in healthy volunteers. METHODS: An open-label, randomised, repeat-dose, cross-over, adaptive design study (n = 36 in each part) evaluated SFC 50/250 µg and SFC 50/100 µg in Rotacaps used with two types of Rotahaler inhalers (airflow resistance similar to (S) and lower than (L) Diskus) versus the Diskus. Primary endpoints were area under the concentration-time curve over the dosing interval [AUC0-τ] and maximum plasma concentration [Cmax]. RESULTS: SFC 50/250 µg Rotacaps/Rotahaler (S) showed 1.2-1.9-fold greater FP and SALM systemic exposure compared with Diskus. FP and SALM systemic exposure were comparable to DISKUS following SFC 50/250 µg Rotacaps/Rotahaler (L) (90% CI of ratio of Rotahaler to DISKUS within 0.8-1.25) for salmeterol (AUC0-τ and Cmax) and FP (AUC0-τ). Following SFC 50/100 µg Rotacaps/Rotahaler (L), FP and SALM systemic exposures were 1.2-1.4 fold higher in terms of FP (AUC0-τ and Cmax) and salmeterol (Cmax) compared with Diskus. SFC at both doses and via both inhalers was well tolerated. CONCLUSIONS: SFC 50/250 µg Rotacaps/Rotahaler (L) showed comparable systemic exposure to Diskus in terms of FP AUC and SALM AUC and Cmax. These results merit further progression of SFC 50/250 µg Rotacaps/Rotahaler (L) to phase 3 clinical evaluation in asthma and COPD patients. The lack of pharmacokinetic comparability between the inhalers for SFC 50/100 µg requires further evaluation.

Comparison of tibial intraosseous, sternal intraosseous, and intravenous routes of administration on pharmacokinetics of epinephrine during cardiac arrest: a pilot study.

The purpose of this study was to determine and compare the maximum concentration (C(max)) and time to maximum concentration (T(max)) of epinephrine administered via tibial intraosseous (IO), sternal IO, and intravenous (i.v.) routes in a porcine model of cardiac arrest during cardiopulmonary resuscitation. Five pigs each were randomly assigned to 3 groups: tibial IO, sternal IO, and i.v. Cardiac arrest was induced with i.v. potassium chloride. After 2 minutes, cardiopulmonary resuscitation was initiated. Epinephrine was administered to each animal, and serial blood samples were collected over the next 3 minutes. Enzyme-linked immunosorbent assay was used to determine the epinephrine concentration. Multivariate analysis of variance helped determine if there were statistically significant differences between groups. There were significant differences in Cmax between the sternal IO and i.v. (P = .009) and tibial IO and i.v. (P = .03) groups but no significant difference between tibial and sternal IO groups (P = .75). Significant differences existed in Tmax between the tibial IO and i.v. (P = .04) and between tibial IO and sternal IO (P = .02) groups but no difference between the sternal IO and i.v. groups (P = .56). Intravenous administration of 1 mg of epinephrine resulted in a serum concentration 5.87 and 2.86 times greater than for the tibial and sternal routes, respectively.

Reverse-phase liquid chromatography with electrospray ionization/mass spectrometry for the quantification of pseudoephedrine in human plasma and application to a bioequivalence study.

A sensitive and selective reverse-phase liquid chromatography electrospray ionization mass spectrometry (LC-ESI-MS) method was developed and validated to quantify pseudoephedrine (CAS 90-82-4) in human plasma. Phenacetin was used as the internal standard (I.S.). Sample preparation was performed with a deproteinization step using acetonitrile. Pseudoephedrine and I.S. were successfully separated using gradient elution with 0.5% trifluoroacetic acid (TFA) in water and 0.5% TFA in methanol at a flow-rate of 0.2 mL/min. Detection was performed on a single quadrupole mass spectrometer by a selected ion monitoring (SIM) mode via electrospray ionization (ESI) source. The ESI source was set at positive ionization mode. The ion signals of m/z 166.3 and 180.2 were measured for the protonated molecular ions of pseudoephedrine and I.S., respectively. The lower limit of quantification (LLOQ) of pseudoephedrine in human plasma was 10 ng/mL and good linearity was observed in the range of concentrations 10-500 ng/mL (R2 = 1). The intra-day accuracy of the drug containing plasma samples was more than 97.60% with a precision of 3.99-11.82%. The inter-day accuracy was 99.36% or more, with a precision of 7.65-18.42%. By using this analytical method, the bioequivalence study of the pseudoephedrine preparation was performed and evaluated by statistical analysis of the log transformed mean ratios of pharmacokinetic parameters. All the results fulfilled the standard criteria of bioequivalence, being within the 80-125% range which is required by the Korea FDA, US FDA, and EMEA to conclude bioequivalence. Consequently, the developed reverse-phase LC-ESI-MS method was successfully applied to bioequivalence studies of pseudoephedrine in healthy male volunteers.

The vascular effects of trace amines and amphetamines.

Trace amines, including tyramine, beta-phenylethylamine (beta-PEA), tryptamine and octopamine, are biologically active amines mostly based on phenylethylamine, occurring in the body in trace amounts. They are a diverse group of naturally occurring and synthetic amines, which are also found in the diet and in herbal plants, such as ephedrine and cathinone. They include amphetamine and its analogues, such as MDMA ('ecstasy'), and synthetic proprietary sympathomimetic agents such as phenylpropanolamine and pseudoephedrine. On the vascular system they cause vasoconstriction and a rise in blood pressure. This effect is the basis of their use as nasal decongestants. For over 50 years, they have been assumed to be indirectly acting sympathomimetic amines, their responses being due to the release of noradrenaline from sympathetic neurones. There are, however, results that suggest that this is not their only mechanism of action and that they may also exert direct vascular effects independent of a noradrenergic mechanism. Recently, a group of novel trace amine-associated receptors (TAARs) have been cloned and identified in the brain and peripheral tissues including blood vessels. Trace amines bind to these cloned receptors and it is suggested that their vasoconstrictor effects can in part be attributed to this mechanism. This review describes the cardiovascular pharmacology of this diverse group of amines, their structures and uses and their endogenous synthesis and metabolism. The review also considers their clinical relevance as constituents of the diet, as therapeutic agents (ritodrine, phenylpropanolamine, and pseudoephedrine) and as drugs of abuse (amphetamine, 'ecstasy') and their mechanisms of action.

Pharmacokinetic and pharmacodynamic effects of midodrine on blood pressure, the autonomic nervous system, and plasma natriuretic peptides: a prospective, randomized, single-blind, two-period, crossover, placebo-controlled study.

BACKGROUND: Midodrine is an alpha-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP). OBJECTIVE: The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers. METHODS: This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration. RESULTS: Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At Cmax, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL (P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm (P = 0.022). A significant correlation was found between DGM concentration and HR ( varphi -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed. CONCLUSION: This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.

Evaluation of the potential for pharmacodynamic and pharmacokinetic drug interactions between selegiline transdermal system and two sympathomimetic agents (pseudoephedrine and phenylpropanolamine) in healthy volunteers.

Selegiline transdermal system is a recently approved monoamine oxidase inhibitor antidepressant. Medications that inhibit monoamine oxidase type A can augment the pressor effects of sympathomimetic amines, increasing the potential for hypertensive crisis. This study examined the potential for drug-drug interactions during treatment with selegiline transdermal system and pseudoephedrine or phenylpropanolamine. Two studies were conducted with 25 healthy volunteers to assess changes in blood pressure and heart rate during administration of pseudoephedrine or phenylpropanolamine alone or together with selegiline transdermal system. No significant differences in mean maximum changes in vital signs occurred with pseudoephedrine. No significant differences were found in mean maximum changes in systolic heart rate with phenylpropanolamine; however, 4 of 12 subjects each experienced 1 isolated protocol-defined minimal pressor response without concurrent adverse effects (1 with phenylpropanolamine alone; 3 with phenylpropanolamine + selegiline transdermal system). Pharmacokinetic parameters obtained following selegiline transdermal system and pseudoephedrine or phenylpropanolamine were unremarkable. The results suggest that selegiline transdermal system 6 mg/24 h does not significantly alter the pharmacodynamics or pharmacokinetics of either pseudoephedrine or phenylpropanolamine when administered to healthy volunteers; however, it is prudent to avoid coadministration of selegiline transdermal system and sympathomimetics.

Norepinephrine induces endoplasmic reticulum stress and downregulation of norepinephrine transporter density in PC12 cells via oxidative stress.

Cardiac norepinephrine (NE) uptake is reduced in cardiomyopathy. This change is associated with a decrease of NE transporter (NET) receptor and can be reproduced in PC12 cells by extracellular NE. To study whether this effect of NE is mediated via impaired glycosylation and trafficking of NET in the endoplasmic reticulum (ER), we measured the distribution of glycosylated 80-kDa NET and unglycosylated 46-kDa NET in the membrane and cytosolic fractions of PC12 cells. We found that NE decreased glycosylated NET in both membrane and cytosolic fractions and increased cytosolic unglycosylated NET protein. Similar results were produced by tunicamycin and thapsigargin, two agents that induce ER stress by inhibiting N-glycosylation of membrane proteins and disrupting calcium homeostasis, respectively. Also, like the ER stressors, NE not only increased phosphorylation of both the alpha-subunit of eukaryotic initiation factor-2 and its upstream RNA-dependent protein kinase-like ER kinase over 12 h of treatment but also increased ER chaperone molecule glucose-regulated protein 78 and the nuclear transcription factor C/EBP homologous protein. Antioxidants superoxide dismutase and catalase prevented the downregulation of NET proteins and induction of ER stress signals produced by NE but not by tunicamycin or thapsigargin. The results indicate that the downregulation of membrane NET by NE is mediated by decreased N-glycosylation of NET proteins secondary to induction of ER stress pathways by NE-derived oxidative metabolites. Interventions involving the ER stress pathways may provide novel therapeutic strategies for the treatment of sympathetic dysfunction in heart failure.

Pharmacotherapy for excessive daytime sleepiness.

Excessive daytime sleepiness (EDS) has recognized detrimental consequences such as road traffic accidents, impaired psychological functioning and reduced work performance. EDS can result from multiple causes such as sleep deprivation, sleep fragmentation, neurological, psychiatric and circadian rhythm disorders. Treating the underlying cause of EDS remains the mainstay of therapy but in those who continue to be excessively sleepy, further treatment may be warranted. Traditionally, the amphetamine derivatives, methylphenidate and pemoline (collectively sympathomimetic) psychostimulants were the commonest form of therapy for EDS, particularly in conditions such as narcolepsy. More recently, the advent of modafinil has broadened the range of therapeutic options. Modafinil has a safer side-effect profile and as a result, interest in this drug for the management of EDS in other disorders, as well as narcolepsy, has increased considerably. There is a growing school of thought that modafinil may have a role to play in other indications such as obstructive sleep apnea/hypopnea syndrome already treated by nasal continuous positive airway pressure but persisting EDS, shift work sleep disorders, neurological causes of sleepiness, and healthy adults performing sustained operations, particularly those in the military. However, until adequately powered randomised-controlled trials confirm long-term efficacy and safety, the recommendation of wakefulness promoters in healthy adults cannot be justified.

Modelling the cardiovascular effects of ephedrine.

AIMS: Recent reports have called into question the safety of ephedra supplements especially with regards to their cardiovascular effects. The purpose of this analysis was to characterize, via pharmacokinetic/pharmacodynamic modelling, the cardiovascular effects of ephedrine, the main active ingredient of ephedra, in apparently healthy, overweight volunteers. METHODS: In a randomized, double-blind, crossover, placebo-controlled study, eight subjects received either placebo, 0.25, 0.5 or 1.0 mg kg(-1) ephedrine sulphate by mouth with a 7-day washout between treatments. Plasma ephedrine concentrations, heart rate and blood pressure were determined for 8 h postdose. RESULTS: The pharmacokinetics of ephedrine were best described by a one-compartment model with first-order absorption and elimination. The percentage change in heart rate was described by a linear model with a resulting slope of 0.14%.l microg(-1) (CV = 59%). The percentage change in systolic blood pressure demonstrated clockwise hysteresis, and a sigmoidal tolerance model was used to describe the data. The mean maximum predicted effect (Emax) was 53.7% (CV = 41%) with an EC50 of 107 microg.l(-1) (CV = 65%) and an inhibitory maximum (Imax) of 39.8% (CV = 60%). Tolerance developed with a mean half-life of 15 min (range 6-140 min). CONCLUSIONS: This is the first study to apply a comprehensive pharmacokinetic/pharmacodynamic model to the cardiovascular effects of orally administered ephedrine. Although systolic blood pressure increases quickly after administration, the increase is nearly abolished by compensatory mechanisms.

Compared with control subjects, the systemic sympathetic nervous system is activated in patients with mitral regurgitation.

BACKGROUND: Whether the systemic sympathetic nervous system is activated as a compensatory mechanism in response to mitral regurgitation (MR) in humans is unknown. We tested the hypotheses that the systemic sympathetic nervous system would be activated in patients with MR in comparison with control subjects and that this activation would occur early in the disease process as a compensatory mechanism for chronic left ventricular (LV) volume overload. METHODS: We studied 37 patients with MR who underwent right heart catheterization and biplane cineventriculography to obtain LV end-diastolic and end-systolic volumes, ejection fractions, and regurgitant volumes. In these 37 patients with MR and in 23 control subjects, an [(3)H]-norepinephrine ([(3)H]-NE) infusion and multiple arterial blood samples provided data for a 2-compartment modeling analysis to calculate extravascular NE release rates (NE(2)). RESULTS: The mean NE(2) (2.05 +/- 0.76 microg/min/m(2)) in the patients with MR was greater than that in the control subjects (1.48 +/- 0.75 microg/min/m(2), P =.007). Furthermore, the mean NE(2) values were also greater in the patients with MR who were in clinical class I (P =.05), with a pulmonary capillary wedge pressure <12 mm Hg (P =.05) or a LV ejection fraction >or=0.60 (P =.06) compared with the control subjects. The mean NE(2) values were increased further in patients with MR who had a LV ejection fraction <0.60 (P =.02). CONCLUSIONS: The systemic sympathetic nervous system is activated in patients with MR in comparison with control subjects, and this activation appears to occur early in the disease process as a compensatory mechanism for LV volume overload.

Tyramine pharmacokinetics and reduced bioavailability with food.

Tyramine challenge studies have demonstrated that it requires approximately twice the amount of tyramine administered with a meal compared to administration after a fast to elicit the same effect, suggesting a reduction in bioavailability of tyramine when administered with food. The pharmacokinetics of tyramine when administered in a fasted versus a fed state were studied. A single 200-mg dose of tyramine was administered orally to healthy subjects both after an overnight fast and during a meal. Systemic exposure to tyramine was reduced by 53% (p < 0.05), and the maximum concentration of tyramine was reduced by 72% (p < 0.05) when the dose was administered during a meal. Tyramine maximum serum concentration was observed between 20 minutes and 1 hour when the dose was administered after an overnight fast and appeared to be delayed and/or prolonged by administration during a meal. Tyramine oral clearance was 135 +/- 55.4 L/min, maximum observed serum concentration was 37.7 +/- 26.01 ng/mL, and tyramine elimination half-life was 0.533 (range: 0.330-0.668) hours after administration to fasted subjects. Tyramine bioavailability was significantly reduced when administered with a meal compared to after a fast. The results suggest that larger amounts of dietary tyramine will be required to induce a pressor response equivalent to that following encapsulated tyramine administered in the fasted state.

Interaction between FK 506 and isoproterenol in the modulation of glutamate release from cerebrocortical nerve terminals.

We have examined the interaction between FK 506 and isoproterenol in their modulation of glutamate release from cerebrocortical nerve terminals (synaptosomes). Application of FK 506, an inhibitor of protein phosphatase 2B (calcineurin), resulted in a concentration-dependent potentiation of 4AP-evoked glutamate release. The beta-adrenergic receptor agonist isoproterenol and the membrane-permeable activator of protein kinase A Sp-cAMP also caused a significant increase in evoked glutamate release, which was occluded by FK 506 pretreatment. By studying the voltage-dependent Ca2+ influx with fura-2, we show that, while FK 506 and isoproterenol alone produced a potentiation of the 4AP-evoked increase in intracellular Ca2+, the addition of FK 506 abolished the isoproterenol-mediated potentiation of Ca2+ influx. Based on these results, we suggest that the interaction between the two substances in their potentiating effect occurs, at least in part, at the level of the voltage-dependent Ca2+ entry that affects cell excitability and glutamate release.