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.

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.

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.

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 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.

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.

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.

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.

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.

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.

Ischemic-like condition releases norepinephrine and purines from different sources in superfused rat spleen strips.

Transmitters and cotransmitters of the sympathetic nervous system are involved in the regulation of a variety of immune cell functions. However, it is not entirely clear what stimuli lead to the release of these molecules in immune organs. In this study, we investigated whether local ischemia can cause the parallel release of norepinephrine and its cotransmitter, ATP, in the spleen. Ischemic-like conditions, simulated by transient (15 min) O(2) and glucose deprivation, elicited a reversible increase in the release of both norepinephrine and purines from superfused spleen strips preloaded with [3H]norepinephrine or [3H]adenosine. HPLC analysis of the released tritium label revealed a net increase in the amount of ATP, ADP, AMP, adenosine, inosine, hypoxanthine and xanthine in response to ischemic-like condition. Selective O(2) or glucose deprivation, and Ca(2+)-free conditions differentially affected the outflow of [3H]norepinephrine and [3H]purines, indicating that they derived from different sources. The ABC transporter inhibitors glibenclamide (100 microM) and verapamil (100 microM) as well as low-temperature inhibited [3H]purine release evoked by ischemic-like conditions. Surgical denervation of the spleen reduced endogenous catecholamine content and [3H]norepinephrine uptake of the spleen, but not that of [3H]adenosine. In summary, these results demonstrate the release of norepinephrine and purines in response to an ischemic-like condition in an immune organ. Although both could provide an important source of extracellular catecholamines and purines involved at various levels of immunomodulation, the source and mechanism of norepinephrine and purine efflux seem different.

Relation of systemic sympathetic nervous system activation to echocardiographic left ventricular size and performance and its implications in patients with mitral regurgitation.

We have previously demonstrated that the systemic sympathetic nervous system (SNS) is activated in proportion to an increase in cineventriculographic left ventricular (LV) end-systolic volume and decrease in ejection fraction (EF) in patients with chronic mitral regurgitation (MR). However, the relation between noninvasive echocardiographic measures of LV size and performance and systemic SNS activation and their clinical implications in patients with MR is not known. We studied 17 MR patients with echocardiography, arterial norepinephrine (NE) sampling, and [3H]-NE infusions and arterial blood sampling to determine NE kinetic parameters using a 2-compartment analysis, including extravascular NE release rates (NE2, index of SNS activity) and the metabolic clearance rate from the vascular compartment. The arterial NE values correlated with LV end-systolic dimensions (r = 0.50, p = 0.04), but not with LV end-diastolic dimensions, and EF or fractional shortening measures. The NE2 values correlated with LV end-systolic dimensions (r = 0.53, p = 0.03) and inversely with LVEF (r = -0.45, p = 0.07) and fractional shortening (r = 0.43, p = 0.08) measures, but not with LV end-diastolic dimensions. The metabolic clearance rate values showed an inverse correlation with LV end-diastolic (r = -0.52, p = 0.03) and end-systolic (r = -0.49, p = 0.04) dimensions, but not with LV performance measures. The increase in NE2 values was progressive as the LV endsystolic dimensions increased and more marked at LV end-systolic dimensions > or = 40 mm. Thus, activation of the SNS is related to an increase in echocardiographic LV end-systolic dimensions and a decrease in LV performance measures in chronic MR. Medica, Inc.

Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin.

As expected on the basis of published research in both humans and animals, treatment with phentermine/fenfluramine lowers plasma 5-hydroxytryptamine [corrected], whereas treatment with phentermine had no significant effect. In light of these findings, future research should focus on mechanisms other than increased plasma 5-hydroxytryptamine [corrected] to explain how fenfluramine increases the risk of primary pulmonary hypertension and valvular heart disease.

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.

Nerve growth factor down-regulates the expression of norepinephrine transporter in rat pheochromocytoma (PC12) cells.

Functional expression of norepinephrine transporter (NET) and its regulation were examined in rat pheochromocytoma cell line, PC12. Nerve growth factor (NGF) decreased [3H]-norepinephrine (NE) uptake in association with a decrease in NET mRNA levels. On the other hand, levels of tyrosine hydroxylase mRNA increased in PC12 cells treated with NGF for 4-24 h, while Oct-2 mRNA levels decreased at 4 h with NGF then recovered for 8-24 h in the presence of NGF. Both bFGF and EGF reduced [3H]NE uptake, although they failed to affect NET mRNA levels. To examine the NET transcriptional regulation, we identified the 5'-noncoding region of rat NET mRNA by the rapid amplification of cDNA end (RACE) method and cloned the 5'-flanking region of NET gene. The newly identified exon encodes the untranslated region of rat NET mRNA upstream of the known 5'-region including ATG start codon. Constructs having green fluorescent protein (GFP) as reporter were made with the cloned NET gene, and promoter activity was examined in CHO and SK-N-SH cells transiently transfected and in PC12 cells stably transfected with NET-GFP constructs. The results indicate that the 2.1 kb NET flanking region displays promoter activity and is responsible for the NGF-induced down-regulation of NET expression.

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.

Cisapride. Drug interactions of clinical significance.

Cisapride is a prokinetic agent which restores motility of the gastrointestinal tract in conditions of decreased bowel transit. It may also alter the absorption of coadministered drugs. The absorption of morphine, diazepam, cyclosporin, alcohol (ethanol) and levodopa are increased. Initial absorption of cimetidine and raniditine is also increased, but overall absorption is lower due to increased bowel transit. The absorption of digoxin, propranolol and the anticoagulants warfarin and phenprocoumon appears unaffected by cisapride, although increase thrombotest values were seen with acenocoumarol (nicoumalone). Drug interactions leading to increased plasma concentrations of cisapride may produce an increase in adverse effects. The most important of these is QT interval prolongation and ventricular arrhythmias. Phenytoin does not appear to affect protein binding of cisapride. Cisapride metabolism is inhibited by the antifungals ketoconazole, fluconazole, itraconazole and miconazole, and by the antibacterials erythromycin, troleandomycin and clarithromycin. Cisapride should not be coadministered with these drugs. Cimetidine produces a small increase in cisapride plasma concentrations, which may be due to inhibition of metabolism. Cisapride absorption is unaffected by other antacids. Atropine may reverse the cisapride-induced increase in peristalsis. Prescribers should remain vigilant to the presence of these and other, as yet unreported, reactions.

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.