Treatment of spinal anaesthesia-induced hypotension with cafedrine/theodrenaline versus ephedrine during caesarean section: Results from HYPOTENS, a national, multicentre, prospective, noninterventional study.

BACKGROUND: In Germany, hypotension induced by spinal anaesthesia is commonly treated with a combination of cafedrine hydrochloride (C, 200 mg) and theodrenaline hydrochloride (T, 10 mg) in 2 ml. We compared the effectiveness of C/T with ephedrine. OBJECTIVES: The primary objectives were to assess the speed of onset and the ability to restore blood pressure without an increase in heart rate. Secondary objectives were to evaluate maternal/foetal outcomes and the number of required additional boluses or other additional measures. DESIGN: HYPOTENS was a national, multicentre, prospective, open-label, two-armed, noninterventional study comparing C/T with ephedrine in two prospectively defined cohorts. This study relates to the cohort of patients receiving spinal anaesthesia for caesarean section. SETTING: German hospitals using either C/T or ephedrine in their routine clinical practice. PATIENTS: Women aged at least 18 years receiving spinal anaesthesia for caesarean section. INTERVENTIONS: Bolus administration of C/T or ephedrine at the discretion of the attending anaesthesiologist. MAIN OUTCOME MEASURES: Endpoints within 15 min after initial administration of C/T or ephedrine were area under the curve between the observed SBP and the minimum target SBP; and incidence of newly occurring heart rate of at least 100 beats min-1. RESULTS: Although effective blood pressure stabilisation was achieved with both treatments, this effect was faster and more pronounced with C/T (P < 0.0001). The incidence of tachycardia and changes in heart rate were higher with ephedrine (P < 0.01). Fewer additional boluses (P < 0.01) were required with C/T. Although favourable neonatal outcomes were reported in both groups, base deficit and lactate values were greater with ephedrine (P < 0.01). Physician satisfaction was higher with C/T. CONCLUSIONS: After C/T, tachycardia was not a problem, providing an advantage over ephedrine. Fewer additional boluses were required with C/T, suggesting greater effectiveness. An increased base deficit with ephedrine suggests reduced oxygen supply or increased demands in foetal circulation. TRIALS REGISTRATION: Clinicaltrials.gov: NCT02893241, German Clinical Trials Register: DRKS00010740.

Treatment of intraoperative hypotension with cafedrine/theodrenaline versus ephedrine : A prospective, national, multicenter, non-interventional study-the HYPOTENS trial.

BACKGROUND: Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally. METHODS: HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures. RESULTS: A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E. CONCLUSION: Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.

The Methylene Alkoxy Carbamate Self-Immolative Unit: Utilization for the Targeted Delivery of Alcohol-Containing Payloads with Antibody-Drug Conjugates.

A strategy for the conjugation of alcohol-containing payloads to antibodies has been developed and involves the methylene alkoxy carbamate (MAC) self-immolative unit. A series of MAC ß-glucuronide model constructs were prepared to evaluate stability and enzymatic release, and the results demonstrated high stability at physiological pH in a substitution-dependent manner. All the MAC model compounds efficiently released alcohol drug surrogates under the action of ß-glucuronidase. To assess the MAC technology for ADCs, the potent microtubule-disrupting agent auristatin E (AE) was incorporated through the norephedrine alcohol. Conjugation of the MAC ß-glucuronide AE drug linker to the anti-CD30 antibody cAC10, and an IgG control antibody, gave potent and immunologically specific activities in vitro and in vivo. These studies validate the MAC self-immolative unit for alcohol-containing payloads within ADCs, a class that has not been widely exploited.

The efficacy of the appetite suppressant, diethylpropion, is dependent on both when it is given (day vs. night) and under conditions of high fat dietary restriction.

Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets.

ESIPT inspired dual fluorescent probe (Z)-3-((4-(4-aminobenzyl) phenyl) amino)-1,3-diphenylprop-2-en-1-one: experimental and DFT based approach to photophysical properties.

A fluorescent probe (Z)-3-((4-(4-aminobenzyl) phenyl) amino)-1,3-diphenylprop-2-en-1-one (L) was synthesized and characterized by IR, (1)H NMR, ESI mass, UV-visible and fluorescence spectroscopy and by single crystal X-ray diffraction. The molecule has a stable helical structure due to intermolecular CH π interaction. The thermal stability of L was studied by TG analysis. The electronic structure calculations of L have been carried out using DFT at B3LYP/6-31G (d,p) level. The vibrational frequencies and (1)H NMR spectra were computed at this level and compared with experimental values. Major orbital contributions for the electronic transitions were assigned with the help of time-dependent density functional theory (TD-DFT). The observed electronic absorption spectra of L in different solvents coincide with the computed spectra in keto form. The dual emission and high Stokes shift values support the excited state intramolecular proton transfer (ESIPT) process. The molecular docking has been employed to get information about the interaction of L with DNA [6BNA].

Antibacterial activities of 4-substituted-2-[(E)-{(1S,2R)/(1R,2S)-1-hydroxy-1-phenylpropan-2-ylimino}methyl]phenol.

A series of norephedrine-based Schiff bases (1a-6a and 1b-6b) were synthesized by reacting substituted salicylaldehydes with d-norephedrine or l-norephedrine. The structure of these compounds was confirmed by elemental analyses and spectroscopic techniques. The molecular structures of 5a and 6a have been determined by X-ray crystallography, which revealed that the compounds are in the oxoamino form, with bent intramolecular N-H···O (N···O ≈ 2.58 Å) hydrogen bonds and that they are associated in dimers bridged by linear intermolecular O-H···O (O···O ≈ 2.69 Å) hydrogen bonds. The density functional theory calculations on 5a confirmed that the oxoamino form is more stable than the phenolimino form by 12.2 kcal/mol. All the compounds were evaluated for their antibacterial activity using resazurin dye as indicator by twofold dilution method against four bacteria namely, Bacillus subtilis (NCIM2718), Staphylococcus aureus (NCIM5021), Escherichia coli (NCIM2931), and Proteus vulgaris (NCIM2813).

Akrinor-induced relaxation of pig coronary artery in vitro is transformed into alpha1-adrenoreceptor-mediated contraction by pretreatment with propranolol.

Akrinor (AKR), a mixture of theodrenaline (TDR) and cafedrine (CDR), is a sympathomimetic agent used to counter transitory hypotension. Although some cases of vascular complications associated with AKR have been reported there are no experimental data about its direct effects on coronary arteries. The effects of AKR, TDR, CDR, and ephedrine (EDR) were studied on the isometric contraction of the ring preparations of pig coronary arteries precontracted with KCl. The influence of endothelium removal and preincubation with nonselective beta-adrenoreceptor antagonist propranolol (PROP), alpha(1)-adrenoreceptor antagonist prazosin, dopamine receptor antagonist SCH 23390, and adenosine receptor antagonist CGS 15943 were also tested. AKR, TDR, and CDR produced relaxation of the preparations. Preparations without endothelium were more sensitive to AKR relaxing effects. EDR produced an increase of vascular ring tonus. AKR, TDR, and EDR produced contraction in preparations pretreated with PROP. Higher concentrations of AKR relaxed PROP-pretreated preparations. AKR-induced contraction could be prevented by pretreatment with prazosin. Dopamine and adenosine receptor antagonists did not influence relaxing effects of AKR. In conclusion, AKR and its constituents induce the relaxation of pig coronary artery preparations precontracted with KCl. The observed contraction in the preparations pretreated with PROP was probably due to stimulation of unmasked alpha(1)-adrenoreceptors.

Effects of cafedrine/theodrenaline, etilefrine and ephedrine on uterine blood flow during epidural-induced hypotension in pregnant sheep.

INTRODUCTION: Maternal hypotension is a major concern in obstetric anesthesia, and concerns have been raised about standard vasopressor therapy with ephedrine. Therefore, we evaluated the maternal and fetal hemodynamic effects of two potential alternatives to ephedrine. METHODS: Hypotension was induced by epidural administration of lidocaine in 6 chronically instrumented pregnant ewes (at 118-122 days of gestation, term 145 days). Three treatments were studied: 25 mg ephedrine, 5 mg etilefrine and 100 mg cafedrine/5 mg theodrenaline (C/T) intravenously. Mean fetal and maternal blood pressure and heart rate, uterine blood flow, as well as fetal and maternal arterial blood gases were recorded for 60 min. RESULTS: All three vasopressors increased maternal blood pressure, accompanied by a significant increase in uterine blood flow. C/T caused marked maternal tachycardia, whereas ephedrine decreased maternal heart rate. Maternal and fetal blood gases did not change during any of the three treatment regimens. CONCLUSION: All three vasopressors restored maternal blood pressure and uterine blood flow after epidurally induced maternal hypotension. However, restoration of uterine perfusion was delayed and less pronounced with C/T.

Efficient synthesis of B-alkylated oxazaborolidines derived from ephedrine and norephedrine.

[reaction: see text] Representative B-butyl- and B-methyl-1,3,2-oxazaborolidines derived from ephedrine and norephedrine were prepared in good yield and excellent purity by one-pot treatment of B-H oxazaborolidines with the corresponding organolithium reagent and subsequent hydrolysis of the cyclic borohydride intermediate with anhydrous ammonium chloride.

A novel mixed dimer of a norephedrine-derived chiral lithium amide and 2-lithium-1-methylimidazole, and catalytic enantioselective deprotonation of cyclohexene oxide.

Improved stereoselectivity has been obtained by using 2-lithium-1-methylimidazole, 2, as a replacement for lithium diisopropylamide (LDA) as a bulk base in catalytic deprotonations. The chiral lithium amide 6 of (1R,2S)-N-methyl-1-phenyl-2-pyrrolidinylpropanamine, 5, has been found to deprotonate cyclohexene oxide 3 in the presence of compound 2 to yield (S)-cyclohex-2-en-1-ol, 4, in 96% ee. Compound 2 is a carbenoid species conveniently generated from nBuLi and 1-methylimidazole, 1. The base 2 has also been found to play a more intimate role in the deprotonation. Investigations by 1H, 6Li and 13C NMR of the 6Li/15N isotopologue 8 of 6 have shown that 6 is homodimeric in THF and that, in the presence of 2, it forms a novel heterodimer 10. This heterodimer is found to be the dominant reagent in the initial state, rather than the homodimer of 6. Computational investigations with PM3 and B3LYP/6-311 + G(d,p) have shown possible structures of the heterodimers, as well as the role of THF and I in the solvation of the dimers. The results are in line with the NMR results. Favoured complexes in the equilibria between homo- and heterocomplexes are also reported.

[Clinical tolerance of a new antidepressant -- milnacipran]. / Tolérance clinique d'un nouvel antidépresseur, le milnacipran.

Milnacipran is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake with a good safety and tolerability profile. The efficacy and tolerance profile of this antidepressant have been compared with those of tricyclic and selective serotonin reuptake inhibitor antidepressants (SSRIs) in open-label and placebo-controlled trials. But no data in clinical practice are available. The authors studied the tolerability of milnacipran (100 to 200 mg/d) in 28 depressed inpatients receiving usual comedications during a mean period of 33 days (3 to 107 days). The incidence of adverse events was determined with the help of the Pharmacovigilance Center of the Centre Hospitalo-Universitaire (Besançon, France). Among the 28 patients, milnacipran was well tolerated by 18 of them. Side-effects were noted in 10 patients, but they led to withdrawal of the antidepressant in only 2 cases, where dyspnea, palpitations, pollakiuria in a case and headache, nausea, dysuria in the other case occurred. The most frequent adverse event observed was hypotension (n = 6), but in each case it occurred just after the addition of sedative phenothiazines (n = 5) or of a comedication with phenothiazines and valpromide (n = 1). So this side-effect could not be attributed to milnacipran alone. Treatments with heptaminol or theodrenaline and cafedrine were useful. An increase of the cardiac frequency seemed to occur with milnacipran (p < 0.06). It was observed in the 5 inpatients for whom this cardiovascular parameter was recorded before and during the milnacipran treatment. In 5 other patients, the cardiac frequency seemed to decrease when milnacipran was stopped for lack of good efficacy or adverse events. Gastrointestinal disturbances were scarce isolated (nausea n = 1), but necessitated a treatment with metopimazine. The milnacipran prescription (100 mg/d) after an other antidepressant treatment had been done without a withdrawal period and without problem, even when the previous antidepressant was a SSRIs with a long half-life and CYP450 inhibitory properties. The authors concluded to the good tolerability of milnacipran in usual clinical practice.

Design of scytalone dehydratase inhibitors as rice blast fungicides: derivatives of norephedrine.

Five X-ray crystal structures of scytalone dehydratase complexed with different inhibitors have delineated conformationally flexible regions of the binding pocket. This information was used for the design and synthesis of a norephedrine-derived cyanoacetamide class of inhibitors leading to potent fungicides.

[Cerebral infarction in an adolescent girl following an overdose of paroxetine and caffedrine combined with theodrenaline]. / Infarto cerebral en una adolescente tras una autointoxicación con paroxetina y una asociación de cafedrina y teodrenalina.

Selective serotonin reuptake inhibitors (SSRI) have demonstrated to be effective, well tolerated and relatively safe drugs in cases of overdosage. However, and related to the potentiation of the serotonergic transmission elicited by them, these drugs have been associated by some authors with the possibility of causing vascular complications. Serotonin is a vasoactive substance with complex actions on vessel wall as a result of its interaction with specific receptors existing at this level. We present the case of an adolescent girl who suffered a cerebral infarction after consuming a toxic dose of paroxetine and two other products, one of them containing caffedrine and theodrenaline, and the other one a phlebotonic agent. In connection with the possible pathophysiological mecanism the implied products as well as the serotonergic vascular receptors are briefly reviewed. Finally, a reference is made to Calls syndrome as a possible entity related to the unfortunate event suffered by the patient. As a conclusion risks of the combined pharmacotherapy, especially in cases of overdosage and in child and adolescent populations, are underlined.

In vitro evaluation of N-(fluoro)isopropyl norephedrine as potential cardiac imaging agents for PET.

N-Isopropylnorephedrine (INE) and N-fluoroisopropylnorephedrine (FINE) were found to have a poor affinity for either beta-adrenoceptors and the norepinephrine carrier protein. The low affinity of both compounds for Uptake-1 is probably due to the introduction of a bulky substituent on the nitrogen atom. It is concluded that INE and FINE cannot be used for cardiac imaging with PET.

Comparison between phenylpropanolamine and structurally related compounds on gastric transit in the rat.

Our laboratory previously reported several pharmacological differences between phenylpropanolamine [PPA; (+/-)-norephedrine] and its structurally related compounds in regard to their activity on cardiovascular and appetite-suppressant parameters. The present study investigates the pharmacological differences between PPA, [1R,2R]-(-)-norephedrine [(-)-NOR], [1S,2S]-(+)-norephedrine [(+)-NOR], [1R,2S]-(-)-ephedrine [(-)-EPH], [1S,2R]-(+)-ephedrine [(+)-EPH], [1R,2S]-(-)-norpseudoephedrine [(-)-NORP], [1S,2R]-(+)-norpseudoephedrine [(+)-NORP], [1R,2R]-(-)-pseudoephedrine [(-)-PSE], and [1S,2S]-(+)-pseudoephedrine [(+)-PSE], as determined by their ability to inhibit gastric transit in the rat. (-)-Norephedrine was approximately three times more potent in inhibiting gastric transit than (+)-NOR (p < 0.01). As anticipated, the racemic mixture, PPA, demonstrated an ED50 (25.1 mg/kg) of approximately the mean of the ED50s from the component enantiomers (14.7 and 47.0 mg/kg, respectively). Similarly, administration of 20 mg/kg of either (-)-EPH, (+)-EPH, (-)-PSE, or (+)-PSE significantly decreased gastric transit by 26% (p < 0.001), 12% (p < 0.01), 10% (p < 0.01), and 11% (p < 0.01), respectively. Administration of (-)-NORP and (+)-NORP were without effect. These data confirm and extend previous findings demonstrating pharmacological differences between PPA and its structurally related compounds.

A controlled trial of acute and long-term medical therapy in tilt-induced neurally mediated syncope.

To study the efficacy of medical treatment for preventing syncopal recurrences in patients affected by tilt-induced neurally mediated syncope, a randomized placebo-treatment prospective study was performed in 30 patients (10 men and 20 women, mean age 42 +/- 21 years) who had syncope reproduced in 2 consecutive head-up tilt-table tests without pharmacologic intervention (n = 20) or during isoproterenol infusion (n = 10). Patients were randomly assigned to 2 groups: 15 to placebo, and 15 to drug therapy (determined on the basis of serial pharmacologic tilting tests). Therapy was either atenolol (n = 7), dihydroergotamine (n = 2), domperidone (n = 2), cafedrine (n = 1), or elastic compression stockings, alone or in association with drugs (n = 3). During a mean of 10 +/- 7 months of follow-up, syncope recurred in 3 patients (20%) in the treatment group and in 4 (27%) in the placebo group; actuarial rates of absence of syncopal recurrences after 20 months were 70 and 67%, respectively. Thus, the outcome of either treated or untreated patients was favorable (with a low recurrence rate of syncope), and the usefulness of tilting-guided medical therapy remains uncertain.

Inhibition of brain type A monoamine oxidase and 5-hydroxytryptamine uptake by two amphetamine metabolites, p-hydroxyamphetamine and p-hydroxynorephedrine.

Two amphetamine metabolites, p-hydroxyamphetamine (p-OHA) and p-hydroxynorephedrine (p-OHN), selectively inhibited the A form of monoamine oxidase (MAO) in rat and mouse forebrain homogenates. Of these two metabolites, p-OHA inhibited MAO-A more strongly than p-OHN. This MAO-A-selective inhibition by p-OHA or p-OHN was found to be competitive with respect to deamination of its substrate, 5-hydroxytryptamine (5-HT). The degree of MAO-A inhibition was not changed by 90 min of preincubation of the enzyme preparations with either metabolite, and the activity inhibited by p-OHA after the preincubation recovered completely to the control level after repeated washing. Uptake of 5-HT or dopamine into mouse forebrain synaptosomes was highly reduced by both p-OHA and p-OHN. Both metabolites were more potent in reducing dopamine uptake than in reducing 5-HT uptake. In reduction of 5-HT and of dopamine uptake, p-OHA was more potent than p-OHN. These results indicate that p-OHA is a more selective inhibitor of brain MAO-A activity and 5-HT uptake than its subsequent metabolite, p-OHN. These two actions of p-OHA might, together with possible 5-HT efflux into the synaptic cleft, greatly contribute to head twitch, a brain 5-HT-mediated animal behavior induced by p-OHA.

Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems.

Intrastriatal administration of the hydroxylated metabolites of amphetamine, p-hydroxyamphetamine (p-OHA) or p-hydroxy-norephedrine (p-OHNor), decreased local concentrations of dopamine and serotonin in a dose-dependent manner. Although both compounds reduced concentrations of the metabolites of dopamine, 5-hydroxyindoleacetic acid concentrations were elevated. After systemic treatment with p-OHA, striatal dopamine was also reduced. In contrast, only hypothalamic and hippocampal serotonin stores were altered significantly in rats treated with p-OHA systemically. Neither compound decreased the activities of tryptophan hydroxylase or tyrosine hydroxylase. Because p-OHA is metabolized to p-OHNor via dopamine beta-hydroxylase present in noradrenergic neurons, the direct effects of these compounds on dopaminergic and serotonergic variables can be observed in rats which receive intrastriatal drug treatment. p-OHA and p-OHNor were equally potent in decreasing dopamine concentrations. However, p-OHNor was more potent than p-OHA in decreasing serotonin concentrations. Both compounds more readily depleted dopamine compared to serotonin stores. Complete recovery of p-OHA-induced decreases in striatal dopamine occurred within 48 hr of intrastriatal administration and concurrent treatment with the dopamine uptake blocker, amfonelic acid, significantly attenuated the p-OHA-induced effects on dopamine.

Modification of behavioral responses to methamphetamine evoked by the stimulant's metabolite p-hydroxynorephedrine in rats.

The central effect of p-hydroxynorephedrine (OH-NE), one of the p-hydroxylated metabolites of methamphetamine (MAP) and amphetamine (AMP), was investigated in rats. Locomotion and stereotypy were examined after SC injections of 0.5-5 mg/kg of MAP or 0.02-0.5 mg/kg of apomorphine (APO) in animals treated with either saline or 5-50 mg/kg of OH-NE IP 20 hr before behavioral assessment. The locomotor stimulating effect of both 0.5-2 mg/kg of MAP and 0.2 mg/kg of APO was enhanced by 5 mg/kg of OH-NE. On the other hand, 30 mg/kg of OH-NE severely suppressed the stimulating effect of MAP but had no influence on that induced by 0.2 mg/kg of APO. The stereotypy induced by 5 mg/kg of MAP or 0.5 mg/kg of APO was enhanced and prolonged in the OH-NE-treated rats. Subsequently, examinations were performed to determine whether OH-NE had any effect on the dopaminergic mechanism. Hypomotility induced by 0.02 mg/kg of APO was alleviated by 5 mg/kg of OH-NE, but was aggravated by 30 mg/kg. These results suggest that OH-NE administered prior to SC injections of MAP or APO influences their behavioral effects via the dopaminergic mechanism. The possibility that other neural mechanisms may be involved in this OH-NE-induced behavioral modification is also discussed.

P-hydroxy-norephedrine as a possible mediator causing the reduction of oral intake of D-amphetamine in rats.

In rats D-amphetamine is predominantly metabolized by hydroxylation to p-hydroxy-norephedrine (p-HNE); in guinea pigs, however, by deamination to benzoic acid. After 2-3 days on dosages of 1 mg/kg per day and more rats begin to reduce their oral intake of the stimulant whereas guinea pigs do not. In the present study we examined the hypothesis that the formation of p-HNE in the CNS is partially responsible for this aversion. To determine the elimination of D-amphetamine and the increase in p-HNE, groups of male Wistar rats were given various doses (0.5-5 mg/kg per day) of D-amphetamine in their drinking water intragastrically and intravenously. D-Amphetamine in the brain was determined by radioimmunoassay, p-HNE by high performance liquid chromatography followed by electrochemical detection. In contrast to the concentration of D-amphetamine, the p-HNE-content is independent of the route of administration; after oral treatment it showed a linear increase. The results reveal that p-HNE induces the aversion to the stimulant and that the ratio of D-amphetamine to its metabolite determines the onset of this aversion. No p-HNE was found in the brain of guinea pigs. Guinea pigs do not show any aversion to drinking D-amphetamine solutions, even in high dosages.