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Objective: To determine the pharmacokinetic and pharmacodynamic properties of once-daily versus twice-daily doses of Adderall., Method: Following a 1-week wash-out, 12 subjects with attention-deficit/hyperactivity disorder (ADHD) entered a double-blind crossover study comparing two conditions: QD (10 mg of Adderall at 7:30 a.m. and placebo at noon) or BID (10 mg of Adderall at 7:30 a.m. and at noon). At two sites, cohorts of six subjects each were assessed on two different days by a 12-hour laboratory school protocol. Plasma concentrations of d- and l-amphetamine, vital signs, teacher ratings of classroom behavior on the SKAMP, and 10-minute Math Test performance were measured repeatedly over 12 hours. An analysis of variance used center, subject-within-center, condition, and time-after-second-dose as independent variables., Results: The pharmacokinetic profiles revealed similar morning concentrations of d- and l-amphetamine. However, concentrations were twice as high in the afternoon for BID as QD. The two conditions showed similar pharmacodynamic profiles in the morning, although improvement in math performance and behavior was maintained into the afternoon only in the BID condition (p <.05)., Conclusions: This study suggests that twice-daily dosing of Adderall may be an effective strategy for afternoon control of attention and deportment for children with ADHD.

Rationale: Exposure to chronic stress can affect the serotoninergic (5-HT) system and behavioral measures associated with 5-HT. Repeated stress increases 5-HT receptor subtype 2 (5-HT2) mediated behaviors in rodents, such as wet dog shakes and head twitch., Objectives: The current study investigated whether exposure to chronic unpredictable stress would augment 5-HT(2A/C) receptor-mediated hyperthermia. Furthermore, the persistence of these hyperthermic effects was investigated by testing rats up to 60 days after the stress procedure terminated., Methods: For 2 or 10 days, rats were either not stressed (controls) or exposed to chronic unpredictable stress, i.e. two stressors per day of the following: cage rotation, cold exposure, swim, restraint, light cycle manipulations, single housing, and food and water deprivation. After the termination of stress (day 3 or 11), the 5-HT(2A/C) receptor agonist DOI (1.5 mg/kg) or saline, was injected and the rectal temperature of the rats was monitored. In a separate experiment, the 5-HT2 receptor antagonist, LY-53,587, was injected 30 min prior to the injection of DOI or saline. Finally, DOI was injected into rats 8, 30 or 60 days after the 10-day stress procedure ended., Results: Rats exposed to 10 days, but not 2 days, of unpredictable stress exhibited higher rectal temperatures following DOI than non-stressed rats. The DOI-induced hyperthermia was attenuated by LY-53,587. The augmentation of DOI-induced hyperthermia in stressed rats persisted when examined 8, 30 and 60 days following the stress procedure., Conclusions: The enhancement of 5-HT receptor function by chronic stress persists even after the environmental stressor is removed. This lasting increase in 5-HT receptor function may have implications for clinical disorders associated with stress, such as depression or post-traumatic stress disorder.

Objective: To assess the pharmacokinetic (PK) properties of a single daily dose of Adderall (mixed amphetamine salts) and the extended-release formulation, SLI381 (ADDERALL XR), in pediatric attention-deficit/hyperactivity disorder (ADHD)., Method: Fifty-one children (aged 6-12 years) with ADHD participated in a 6-week, seven-visit, PK and pharmacodynamic study. PK sampling occurred during visit 1 and again at visit 7. At visit 1, subjects received an initial oral dose of SLI381, 20 mg. At visit 7 subjects completed 1 week of medication treatment following random assignment to once-daily orally dosed SLI381 10 mg, 20 mg, or 30 mg; Adderall 10 mg; or placebo., Results: PK parameters evidenced substantial intersubject variability (coefficients of variation = 28-56%). Time to maximum concentration (Tmax) for SLI381 versus Adderall showed average increases of 3.0 hours for dextroamphetamine (t = -2.35, p = .04, df = 8.6) and 3.2 hours for levoamphetamine (t = -2.39, p = .04, df = 9.2). The d- and l-isomer concentrations were highly correlated and approximated a 3:1 ratio., Conclusions: SLI381 showed extended Tmax values compared with Adderall and appears suitable for once-daily dosing. Intersubject variability underscores the need for individual dose titration.

Injection of 3,4-methylenedioxyamphetamine (MDA) or 3,4-methylenedioxymethylamphetamine (MDMA or ecstasy) directly into the brain fails to reproduce the long-term effects observed after peripheral administration, implying an essential role for systemic metabolites in the development of toxicity. However, the precise identity of the metabolites participating in MDA and MDMA-mediated serotonergic neurotoxicity remains unclear: neither 3,4-alpha-methyldopamine, nor N-methyl-alpha-methyldopamine, major metabolites, produce neurotoxicity following peripheral administration. In vivo, these metabolites are oxidized to the corresponding orthoquinones, that readily react with protein and nonprotein sulphydryls including glutathione (GSH). The resulting quinol-thioether conjugates exhibit a variety of toxicological activities, which can be regulated by intramolecular cyclisation reactions that occur subsequent to oxidation. The ability of quinol-thioether conjugates to redox cycle and produce reactive oxygen species provides a rationale for the potential role of these metabolites in MDA and MDMA neurotoxicity. A biomimetic one-pot synthesis of 5-(GSH-S-yl)-N-Me-alpha-Me-DA involving addition of GSH to the electrogenerated orthoquinone species, is reported to evaluate its in vivo potential neurotoxicity.

Using extracellular ex vivo recording we studied changes in the reactivity of rat frontal cortical neurons to the 5-HT(1A), 5-HT(2) and 5-HT(4) receptor agonists (+/-)-2-dipropyloamino-8-hydroxy-1,2,3,4-tetrahydronaphtalene hydrobromide (8-OH-DPAT), (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) and zacopride, respectively, induced by a repeated treatment with imipramine or citalopram. Rats were treated with imipramine or citalopram for 14 days (10 mg/kg p.o.) twice daily. Frontal cortical slices were prepared 2 days after the last drug administration. Spontaneous epileptiform discharges were induced in slices by perfusion with a medium devoid of Mg(2+) ions and with added picrotoxin (30 microM). While the application of 2 microM 8-OH-DPAT resulted in a reversible decrease of the discharge frequency, in the presence of DOI (1 microM) or zacopride (5 microM), the discharge frequency was increased. Both repeated imipramine and citalopram enhanced the effect of the activation of 5-HT(1A) receptor and attenuated the effect related to 5-HT(2) receptor activation, while the effect of the activation of 5-HT(4) receptor remained unchanged. Moreover, imipramine, but not citalopram, induced a reduction of epileptiform discharge frequency and an increase of the time of occurrence of epileptiform activity. These data indicate that antidepressants enhance the 5-HT-mediated inhibition in neuronal circuitry of the frontal cortex.

Cerebral venous hypertension (VH) is a pathological condition associated with arteriovenous malformation, and is an important determinant factor for clinical symptom and outcome. Using a rat whole brain VH model created by a carotid-jugular fistula and contralateral jugular vein ligation we measured superior sagittal sinus pressure (SSSP) and cerebral blood flow (CBF) by the 14C-iodoamphetamine (IMP) indicator fractionation technique under isoflurane anesthesia with controlled ventilation. SSSP was significantly elevated in the fistula group (15 +/- 1 mmHg) (mean +/- SEM) compared to the vessel occlusion (5 +/- 1) and sham operated groups (5 +/- 1) (P < 0.05). Mean absolute CBF in the fistula (103 +/- 3 ml/ min/100 g) and vessel occlusion (90 +/- 4) groups were elevated compared to the sham group (77 +/- 3) (P < 0.05). Physiological parameters (mean blood pressure, heart rate, and blood gas analysis) before measurement were not different. In this VH model we found increases in SSSP and IMP uptake in the brain. We assume the mechanism of IMP uptake increase in VH animal may be slow circulation with a possible change of first pass extraction of IMP.

Study Objectives: To assess the bioavailability of three test formulations of a single dose of extended-release Adderall 20-mg capsules compared with two doses of immediate-release Adderall 10-mg tablets, and to assess the bioequivalence of a single 30-mg dose of the chosen extended-release Adderall formulation (designated as SLI381) administered in applesauce (sprinkled) and the same dose administered as an intact capsule with or without food., Design: Randomized, open-label, crossover study., Setting: Clinical research unit., Patients: Forty-one healthy adults., Interventions: Study A had four treatment sequences: three test formulations (A, B, and C) of a single dose of extended-release Adderall 20 mg, and two 10-mg doses of Adderall given 4 hours apart. Study B had three treatment sequences: a single dose of SLI381 30 mg as an intact capsule after overnight fast, an intact capsule after a high-fat breakfast, and the contents of a capsule sprinkled in 1 tablespoon of applesauce., Measurements and Main Results: The 20-mg test formulation A had comparable pharmacokinetic profiles and bioequivalence in rate and extent of drug absorption to Adderall 10 mg twice/day for both d- and l-amphetamine. Formulations B and C had statistically significant differences from the reference drug in some pharmacokinetic parameters. A 30-mg dose of SLI381 showed no significant differences in rate and extent of absorption of d- and l-amphetamine for fasted or sprinkled conditions compared with the high-fat meal condition., Conclusion: SLI381 20 mg/day is bioequivalent to Adderall 10 mg twice/day. SLI381 30 mg administered in applesauce is bioequivalent in terms of both rate and extent of absorption to the same dose administered as an intact capsule in both fasted and fed states.

Because methylphenidate is currently the most widely prescribed medication for attention-deficit/ hyperactivity disorder, several studies have used it as the active comparator medication for evaluating the efficacy of a newer stimulant, Adderall. These prior studies show Adderall to be superior to placebo and suggest it is at least as effective as the standard-release form of methylphenidate and has a longer duration of action. Although these initial studies provide useful information for clinicians treating children with attention-deficit/hyperactivity disorder, they are difficult to interpret because findings vary among studies and among the different types of measures used within each study. To provide a clearer picture of what conclusions can be drawn from these studies, we performed a meta-analysis. Data from the four available studies suggest that Adderall has a small but statistically significant advantage over the standard-release form of methylphenidate. This advantage was observed for both symptom measures and global ratings but was strongest for global ratings. The effect of Adderall was significant for clinician and parent ratings but not for teacher ratings and was significant for both fixed-dose and best-dose designs.

Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[123I]iodophenyl)-2-aminopropane [R(-)[123I]DOI], an in vitro potent and selective 5-HT(2A/2C) serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT(2) receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [123I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[123I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f(1)), was 31 +/- 0.9% (n = 3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[123I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin displacement suggest high nonspecific uptake, therefore non potentially useful as brain imaging radiotracer for visualization of the agonist high-affinity state of 5-HT(2A) receptors and for visualizing 5-HT(2C) receptors by SPECT.

To establish an in vitro model of drug incorporation into hair and to elucidate the potential roles of hair cell selectivity and hair color in the incorporation of certain drugs into hair, the basic drug amphetamine and its nonbasic analog N-acetylamphetamine (N-AcAp) were analyzed for influx and efflux into and out of keratinocytes, pigmented melanocytes (PM), and nonpigmented melanocytes (NPM) as a model for incorporation and efflux of these drugs from hair cells. NPM were of the same melan-a cell line as PM, but cultured in the presence of the tyrosinase inhibitor phenylthiocarbamide. Results show that PM take up large amounts of the basic drug amphetamine (levels of uptake dependent on melanin content), whereas keratinocytes and NPM take up only small amounts of amphetamine. None of the cells take up N-AcAp above background levels. Interestingly, whereas keratinocytes and NPM quickly efflux most of the influxed drug, PM are slow to efflux and only efflux approximately 65% of influxed drug, if efflux media is not refreshed. (If efflux media is periodically refreshed, PM will eventually redistribute essentially all influxed drug back into the media.) These results demonstrate that pigmented cells take up greater amounts of the basic drug amphetamine, and efflux it more slowly than nonpigmented cells. Also, these results are consistent with previous data for in vivo incorporation of amphetamine in animal hair. In combination with previous data, an overall comparison of the amphetamine and N-AcAp incorporation data support a non-diffusion mediated model for drug incorporation into hair cells., (Copyright 2002 Wiley-Liss, Inc.)

This paper reviews the toxicokinetics of amphetamines. The designer drugs MDA (methylenedioxy-amphetamine, R,S-1-(3;,4;-methylenedioxyphenyl)2-propanamine), MDMA (R,S-methylenedioxymethamphetamine), and MDE (R,S-methylenedioxyethylamphetamine), as well as BDB (benzodioxolylbutanamine; R,S-1-(1;,3;-benzodioxol-5;-yl)-2-butanamine or R,S-1-(3;,4;-methylenedioxyphenyl)-2-butanamine) and MBDB (R,S-N-methyl-benzodioxolylbutanamine), were taken into consideration, as were the following N-alkylated amphetamine derivatives: amphetaminil, benzphetamine, clobenzorex, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, fenethylline, fenproporex, furfenorex, mefenorex, mesocarb, methamphetamine, prenylamine, and selegiline. English-language publications from 1995 to 2000 were reviewed. Papers describing identification of metabolites or cytochrome P450 isoenzyme-dependent metabolism and papers containing pharmacokinetic/toxicokinetic data were considered and summarized. The implications of toxicokinetics for toxicologic assessment or for interpretation in forensic cases are discussed.

Stimulant therapy is the mainstay of treatment for children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). Once-daily, extended-release oral formulations offer long acting control of symptoms by modifying drug delivery and absorption. In particular, consistency in early drug exposure is important for symptom control during school or work hours. Because these once-daily formulations are usually taken in the morning, the timing of the doses with breakfast is important. This study compared the effect of a high-fat breakfast on early drug exposure from a morning dose of two extended-release stimulant formulations: the osmotic-controlled OROS tablet of methylphenidate HCI (CONCERTA) and the capsule containing extended-release beads of mixed amphetamine salts (ADDERALL XR). The study had a single-dose, open-label, randomised, four-treatment, crossover design in which healthy subjects received either 36 mg CONCERTA or 20 mg ADDERALL XR in the morning after an overnight fast or a high-fat breakfast. Serial blood samples were collected over 28h to determine plasma concentrations of methylphenidate and amphetamine. The food effect on early drug exposure and the pharmacokinetic profiles up to 8 h after dosing of the two extended-release stimulants were directly compared using partial area (AUC(p4h), AUC(p6h) and AUC(p8h)) fed/fasted ratios. Amphetamine concentrations were markedly lower when the subjects had eaten breakfast, resulting in lower early drug exposures (p < 0.0001). By contrast, methylphenidate concentrations over the same 8 h were unaffected by breakfast, providing consistent levels of early drug exposure. Therefore, as a child's or adult's eating pattern varies, methylphenidate exposure over the first 8 h would be expected to have less day-to-day variation compared with amphetamine exposure. The osmotic-controlled OROS tablet provides a reliable and consistent delivery of methylphenidate HCI, independent of food, for patients with ADHD.

The dopamine transporter (DAT) is a transmembrane spanning protein that catalyzes the transport of dopamine across the neuronal membrane to concentrate the neurotransmitter inside the cell. Although the uptake of dopamine has been studied since the 1960s, more recent advances in knowledge of the protein itself and in making kinetically resolved measurements of its action have led to more insights into its mechanism and pharmacology. The literature of the kinetics of transporters and kinetic measurements of DAT activity is reviewed to provide an overview of the multisubstrate mechanism of DAT activity, its pharmacology with regard to amphetamine, cocaine and methylphenidate, and correlations of DAT activity with some behavioral outputs.

SLI381 (Adderall-XR) is a longer-acting form of Adderall, a compound of mixed amphetamine salts that is now the most frequently prescribed brand of psychostimulant medication for attention-deficit hyperactivity disorder (ADHD) in the US. It has been demonstrated to be a safe and effective treatment for ADHD in school-age children. To date, the efficacy of SLI381 has been evaluated in controlled studies of over 500 patients. The therapeutic effects of SLI381 on the core symptoms of ADHD, as well as the duration of action of the formulation, have been demonstrated to persist for 12 h, with both greater efficacy and duration of effects seen at higher doses. Both behavioural and cognitive performance measures are improved throughout the school day and into post-school activities. The incidence of common stimulant-emergent side effects with SLI381 was no different than that seen with the existing Adderall preparation. Additionally, the frequency with which most stimulant-related side effects were experienced did not demonstrate a consistent dose-related incidence, with the exception of anorexia. SLI381 received a letter of approvability in August 2001 and will probably be approved in the immediate future by the US FDA. This formulation represents a valuable addition to the available pharmacotherapeutic options for ADHD by providing an amphetamine-based stimulant offering the advantages of once-daily dosing accompanied by the clinical benefits of ADHD symptom control associated with the now widely used Adderall preparation.

The case history and toxicological findings of an overdose fatality involving 4-methylthioamphetamine (4-MTA) and 3,4-methylenedioxymethamphetamine (MDMA) are reported along with a description of the analytical method. Detection and quantitation of 4-MTA and MDMA were performed by liquid chromatography-tandem mass spectrometry using phentermine as internal standard. Application of this technique to a variety of matrices allowed an insight in the distribution of 4-MTA. Several blood samples including femoral vein blood (5.23 mg/L), urine (95.5 mg/L), vitreous humor (1.31 mg/L), bile (36.4 mg/L), and numerous tissue samples such as liver (30.8 mg/kg), spleen (4.10 mg/kg), and frontal lobe (31.7 mg/kg) were assayed. These values indicated that 4-MTA could be identified as the cause of this fatality, whereas the concentrations of MDMA, also described, are less important because the concentrations found are lower. This case reports, for the first time, an extensive toxicological analysis of 4-MTA, by which the data presented may shed some light on the distribution of 4-MTA.

Fenproporex is a sympathomimetic agent with a pharmacological profile similar to that of amphetamine. It is available in many countries throughout the world, but it is currently not available in the United States. Because of its stimulant effects, it has a great potential for abuse. To the best of our knowledge, there have been no literature reports of blood or serum concentrations found in therapeutic, toxic, or fatal cases. We report a case where fenproporex was a finding in the death of a young adult. Blood, urine, and gastric contents were analyzed. The following drug concentrations were found: 0.90 mg/L (inferior vena cava blood), 1.2 mg/L (urine), and 120 mg total (gastric) for fenproporex and 0.084 mg/L (inferior vena cava blood), 0.94 mg/L (urine), and 0.14 mg total (gastric) for amphetamine. In addition to the fenproporex, other medications detected and their blood concentrations found in this case were H diazepam (0.54 mg/L), nordiazepam (0.46 mg/L), diphenhydramine (0.12 mg/L), and gamma hydroxybutyric acid (GHB) (1100 mg/L).

Objectives: To address the relevance of cytochrome P-450 (CYP) 2C19 polymorphism for the pharmacokinetics and dynamics of selegiline and its two known primary metabolites, desmethylselegiline and l-methamphetamine., Methods: Six extensive (mephenytoin S/R ratio < 0.3; EM) and six poor (mephenytoin S/R ratio > 0.8; PM) hydroxylators of S-mephenytoin ingested a single 10-mg oral dose of selegiline hydrochloride. Serum concentrations of selegiline, desmethylselegiline and l-methamphetamine were measured by gas chromatography--mass spectrometry for up to 48 h. In addition, the platelet monoamine oxidase type B (MAO-B) activity was measured for 14 days to describe possible differences in the pharmacodynamics of selegiline and its metabolites between EM and PM., Results: The CYP2C19 phenotype had no significant effects on the pharmacokinetic variables of selegiline. PM of S-mephenytoin had 68% higher mean AUC of desmethylselegiline (P = 0.0017) than EM, but no significant differences were observed in other pharmacokinetic parameters of desmethylselegiline. Contrary to desmethylselegiline, the serum l-methamphetamine concentrations were slightly lower in PM, but no statistically significant differences were observed in l-methamphetamine pharmacokinetics between the two CYP2C19 phenotypes. Accordingly, the magnitude of MAO-B inhibition showed no significant differences between the study groups., Conclusions: CYP2C19 polymorphism does not seem to be crucial for the metabolism or clinical effects of selegiline.

Objective: To characterise the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of selegiline in healthy volunteers., Methods: In this randomised, placebo-controlled crossover study with two phases, 12 healthy volunteers took either 200 mg itraconazole or matched placebo once daily for 4 days. On day 4, a single 10-mg oral dose of selegiline hydrochloride was administered. Serum concentrations of selegiline and its primary metabolites desmethylselegiline and l-methamphetamine were determined up to 32 h. A caffeine test was performed on day 3 of both phases, by measuring the plasma paraxanthine/caffeine concentration ratio 6 h after caffeine intake, to examine the role of CYP1A2 in selegiline pharmacokinetics. In addition, the effects of itraconazole on the metabolism of selegiline in vitro were characterised by using human liver microsomes., Results: Itraconazole had no significant effects on the pharmacokinetic variables of selegiline, desmethylselegiline or l-methamphetamine, with the exception that the AUC of desmethylselegiline was increased by about 10% (P < 0.05). There was a significant correlation between the AUC(desmethylselegiline)/AUC(selegiline) ratio and the paraxanthine/caffeine ratio (r = 0.41; P < 0.05), suggesting involvement of CYP1A2 in the formation of desmethylselegiline. In experiments with human liver microsomes, itraconazole had no inhibitory effect on the formation of either desmethylselegiline or l-methamphetamine from selegiline., Conclusions: The pharmacokinetics of selegiline in healthy volunteers were unaffected by the potent CYP3A4 inhibitor itraconazole. In addition, itraconazole showed no inhibitory effect on the biotransformation of selegiline to desmethylselegiline and l-methamphetamine by human liver microsomes. These findings suggest that selegiline is not susceptible to interaction with CYP3A4 inhibitors.

Clobenzorex (Asenlix) is an anorectic drug used as part of a weight-management program. The drug is metabolized by the body to amphetamine, which is then excreted in the urine, thus causing difficulty in interpretation of amphetamine-positive drug tests. Previous studies have shown that the parent drug and several metabolites are excreted in urine. Clobenzorex itself has been detected for as long as 29 h following administration of a single dose. However, the parent drug was not always detected in samples that contained amphetamine at > or =500 ng/mL, the administrative cutoff for a positive result. Consequently, the parent compound clobenzorex is not ideal for ascertaining whether the drug was the origin of the amphetamine. Several metabolites of clobenzorex have been shown to be detected for a longer period of time than the parent. One of these, a hydroxy metabolite, was shown to be detected for an extended period of time. In a study of urine samples provided following administration of a single 30-mg dose of this drug, 4-hydroxyclobenzorex could be detected for up to 91.5 h. More significantly, that study showed all samples that were positive for amphetamine also contained detectable amounts of 4-hydroxyclobenzorex. This metabolite proved to be easily detected and was typically found at higher levels than amphetamine in urine samples positive for amphetamine long after clobenzorex itself could no longer be detected. The present study analyzed samples from a controlled multidose administration (30 mg of clobenzorex daily for seven days) for the presence of 4-hydroxyclobenzorex. The analytical procedure used acid hydrolysis followed by liquid-liquid extraction and gas chromatographic-mass spectrometric analysis with monitoring of ions at m/z 125, 330, and 364 for 4-hydroxyclobenzorex and its 3-Cl regioisomer, which was used as an internal standard. Peak concentrations of 4-hydroxyclobenzorex ranged from 17,786 to 99,044 ng/mL. Most importantly, this study also found that all samples that contained amphetamine at > or =500 ng/mL also contained detectable amounts of this hydroxy metabolite (LOD 10 ng/mL), making it a valuable tool in differentiating use of clobenzorex from illicit amphetamine use.

Background: Interictal brain single photon emission computed tomography (SPECT) is useful for the detection of seizure focus. Recent reports indicate a hypoperfusion in the ipsilateral thalamus as a seizure focus on interictal SPECT in temporal lobe epilepsy. In frontal lobe epilepsy (FLE), however, the alteration of perfusion in the thalamus has not been well documented. This study aimed to assess whether perfusion analysis on the thalamus may add useful information for the detection of epileptic foci in patients with FLE., Methods: Interictal brain SPECT was performed in 11 patients with FLE. The asymmetry index for the thalamus and frontal area in the SPECT image was calculated in order to compare the laterality of the seizure foci., Results: Thalamic asymmetry was seen in seven patients (64%), while cortial asymmetry was seen in six patients (55%). The concordance with the lateralization of the seizure foci was 6/7 (86%) in the thalamus, and 4/6 (67%) in the frontal area. Four patients showed only thalamic asymmetry. Concordance with the lateralization of the seizure focus was found in all of them., Conclusion: These preliminary results suggest that hypoperfusion in the thalamus may have a complementary role to lateralize the epileptic foci in patients with FLE.

This article outlines the main pharmacokinetic and toxicokinetic parameters of selected addicting compounds often being abused. Described parameters affect the way the compounds behave in the body. The article shows the usual dosage and "therapeutic", toxic and fatal concentrations. Knowledge of described parameters is important in the process of detoxication in patients poisoned with this group of psychoactive compounds.

Clobenzorex (Asenlix) is an anorectic drug metabolized by the body to amphetamine, thus causing difficulty in the interpretation of amphetamine-positive drug tests. Previous studies have shown the parent drug and several metabolites are excreted in urine. Clobenzorex itself has been detected for as long as 29 h postdose using a detection limit of 1 ng/mL. Despite this fact, several amphetamine-positive samples (> or = 500 ng/mL) contained no detectable clobenzorex. Thus, the absence of clobenzorex in the urine does not exclude the possibility of its use. To more definitively assess the possibility of clobenzorex use, evaluation of another metabolite was considered. One study reported the presence of unidentified hydroxy metabolites of clobenzorex for as long as amphetamine was detected in some subjects. To assess the viability of using a hydroxy metabolite to confirm the use of clobenzorex in samples containing amphetamine, 4-hydroxyclobenzorex was synthesized for this study. This metabolite proved to be easily detected and was typically found at levels higher than amphetamine in amphetamine-positive urines, long after clobenzorex itself was no longer detected. Samples obtained from a controlled single-dose study involving the administration of clobenzorex (30 mg) were analyzed for the presence of the 4-hydroxy metabolite. The analytical procedure used acid hydrolysis followed by liquid-liquid extraction and analysis with gas chromatography-mass spectrometry by monitoring ions at m/z 125, 330, and 364. 4-Hydroxyclobenzorex and its 3-Cl regioisomer were used in the identification and quantitation of the metabolite. Peak concentrations of 4-hydroxyclobenzorex were found at approximately 1:30-5:00 h postdose and ranged from approximately 5705 to 88,410 ng/mL. Most importantly, however, all samples that contained amphetamine at > or = 500 ng/mL also contained detectable amounts of this hydroxy metabolite (LOD 10 ng/mL), making it a valuable tool in differentiating use of clobenzorex from illicit amphetamine use.

Tc-99m DTPA galactosyl human serum albumin (Tc-99m GSA) hepatic scintigraphy was performed in two patients with patent ductus venosus before and after operation. To evaluate the portosystemic shunt flow, per-rectal portal scintigraphy with I-123 N-isopropyl-p-iodoamphetamine (IMP) was undergone in the same period. The portosystemic shunt indices (PSS index) were decreased from 67.9% to 7.3% in the patient 1, and from 77.3% to 22.7% in the patient 2, respectively. Quantitative indices of Tc-99m GSA hepatic scintigraphy improved dramatically in both patients. Under microscopic examination, nearly all the hepatic cells showed signs of severe fatty degeneration. After the operation, the severe fatty degeneration was alleviated and all the hepatic cells appeared normal. I-123 IMP per-rectal portal scintigraphy and Tc-99m GSA hepatic scintigraphy were useful in evaluating the quantitative shunt flow of the persistent ductus venosus and its hepatic functional reserve.

The phase I and II metabolites of the designer drugs methylenedioxyamphetamine (MDA), R,S-methylenedioxymethamphetamine (MDMA), R,S-methylenedioxyethylamphetamine (MDE), R, S-benzodioxazolylbutanamine (BDB) and R, S-N-methyl-benzodioxazolylbutanamine (MBDB) were identified by gas chromatography-mass spectrometry (GC-MS) or liquid chromotography-mass spectrometry (LC-MS) in urine and liver microsomes of humans and rats. Two overlapping pathways could be postulated: (1) demethylenation followed by catechol-O-methyl-transferase (COMT) catalyzed methylation and/or glucuronidation/sulfatation; (2) N-dealkylation, deamination and only for MDA, MDMA, MDE oxidation to the corresponding benzoic acid derivatives conjugated with glycine. Demethylenation was mainly catalyzed by CYP2D1/6 or CYP3A2/4, but also by CYP independent mechanisms. In humans, MDMA and MBDB could also be demethylenated by CYP1A2. N-demethylation was mainly catalyzed by CYP1A2, N-deethylation by CYP3A2/4. Based on these studies, GC-MS procedures were developed for the toxicological analysis in urine and plasma. Finally, toxicokinetic parameters are reviewed.

We describe gas chromatography-mass spectrometry studies of the metabolism of the antispasmodic drug mebeverine [Duspatal, (MB)]. MB is the veratric acid (VA) ester of 4-¿ethyl-[2-(4-methoxyphenyl)-1-methylethyl]amino¿butan-1-ol (MB-OH), which is an N-substituted ethylamphetamine derivative. The metabolites were first identified in rat liver microsome incubates and then detected in urine samples of volunteers through the use of electron impact and positive chemical ionization gas chromatography-mass spectrometry. Urinary conjugates were enzymatically cleaved before analysis. The following phase I metabolites of MB could be identified: VA, O-demethyl VA (vanillic and/or isovanillic acid), O-bisdemethyl VA (protocatechuic acid), MB-OH, hydroxy MB-OH, O-demethyl MB-OH, O-demethyl-hydroxy MB-OH, N-desethyl MB-OH, N-desethyl-O-demethyl MB-OH, N-de(hydroxybutyl) MB-OH (methoxy-ethylamphetamine), N-de(hydroxybutyl)-O-demethyl MB-OH (hydroxy-ethylamphetamine), and N-bisdealkyl MB-OH (p-methoxy-amphetamine, known as the designer drug PMA). The following, partly overlapping metabolic pathways of MB could be postulated: ester hydrolysis, O-demethylation, ring hydroxylation, N-deethylation, and N-de(hydroxybutylation). The latter pathway led to ethylamphetamine derivatives and bisdealkylation led to PMA, which are substances of forensic interest. The metabolites containing alcoholic or phenolic hydroxy groups were partly excreted into urine as conjugates.

The goal of this study was to examine the multiple-dose pharmacokinetics of selegiline and its metabolites desmethylselegiline, 1-methamphetamine, and 1-amphetamine after oral administration of selegiline HCl. Twelve healthy volunteers received 10 mg of selegiline HCl once daily for 8 days. The pharmacokinetic profiles of selegiline and the metabolites were examined from serum samples for 24 hours (i.e., the dosing interval, tau) on days 1, 4, and 8. The results indicated significant apparent accumulation of selegiline and desmethylselegiline during the 8-day period of selegiline administration. The AUC tau S of selegiline and desmethylselegiline were increased 2.7 fold (p < 0.001) and 1.5 fold (p < 0.001), respectively, from day 1 to day 8. However, the half-lives of selegiline (range, 1.5-3.5 h) and desmethylselegiline (range, 3.4-5.3 h) were found to be relatively short. Accordingly, the short half-lives of these compounds failed to predict the apparent accumulation. With both of the 1-amphetamine metabolites of selegiline, steady state was reached by day 4. We suggest that the most likely explanation for the apparent accumulation of selegiline and desmethylselegiline was the saturation of the MAO-B binding sites in tissues, although decreased first-pass metabolism of selegiline cannot be ruled out. The observed increase in selegiline and desmethylselegiline concentrations on multiple dosing is not likely to significantly increase the pharmacodynamic effect or adverse effects of selegiline compared with what has been found after a single 10-mg dose.

Monitoring of amphetamines and designer drugs in human urine is a timely topic in clinical toxicology, surveillance of drug substitution, forensic science, drug testing at the workplace, and doping control. Confirmation testing of urinary amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) and 3,4-methylenedioxyamphetamine (MDA) by capillary electrophoresis (CE) combined with atmospheric pressure electrospray ionization and ion trap mass spectrometry (MS) is described. Using an aqueous pH 4.6 buffer composed of ammonium acetate/acetic acid, CE-MS and CE-MS2 provided data that permitted the unambiguous confirmation of these drugs in external quality control urines. Furthermore, other drugs of abuse present in alkaline urinary extracts, including methadone and morphine, could also be monitored. The data presented illustrate that the sensitivity achieved with the benchtop MS is comparable to that observed by CE with UV absorption detection. CE-MS2 is further shown to be capable of identifying comigrating compounds, including the comigration of amphetamine with nicotine.

Background: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified., Methods: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question., Results: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase., Conclusions: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.

1. Amphetamine (AM) and five amphetamine derivatives, N-ethylamphetamine (NEA), N-butylamphetamine (NBA), 4-methoxyamphetamine (M-AM), 4-methoxy-N-ethylamphetamine (M-NEA) and 4-methoxy-N-butylamphetamine (M-NBA) were incubated with microsomal preparations from cells expressing human CYP2D6 to determine whether the enzyme was capable of catalyzing the direct ring oxidation of all substrates; the N-dealkylation of NEA, NBA, M-NEA and M-NBA; and the O-demethylation of M-AM, M-NEA and M-NBA. 2. None of the six compounds examined was N-dealkylated to any extent. 3. The only metabolites produced from AM, NEA and NBA were the corresponding ring 4-hydroxylated compounds, and the rates of formation were low. 4. All ring 4-methoxylated substrates were efficiently O-demethylated by CYP2D6 to their corresponding phenols. The size of the N-alkyl group influenced the rates of formation of these phenolamines. In contrast to reported findings with 2- and 3-methoxyamphetamines, none of the 4-methoxyamphetamines was ring-oxidized in the CYP2D6 enzyme system to 2- or 3-hydroxy-4-methoxyamphetamines or to dihydroxyamphetamines.

Objective: To determine the possible impact of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of selegiline., Methods: Five poor metabolizers and 8 extensive metabolizers of debrisoquin (INN, debrisoquine) were given 10 mg selegiline hydrochloride. The concentrations of selegiline and its main metabolites in serum were determined for 4 days. The pharmacodynamics were quantitated by measuring platelet monoamine oxidase type B activity for 3 weeks. In addition, the effect of selegiline and its main metabolites on the CYP2D6-catalyzed dextromethorphan O-demethylase activity and the effect of quinidine on the metabolism of selegiline were studied in human liver microsomes., Results: Peak serum concentrations of selegiline were reached rapidly and ranged from 1 to 32 nmol/L. The metabolite concentrations were considerably higher and remained so for a longer period. There were no significant differences in the pharmacokinetic parameters of selegiline, desmethylselegiline, and l-amphetamine between poor metabolizers and extensive metabolizers. However, the area under the serum concentration-time curve (AUC) values of l-methamphetamine were, on average, 46% higher (P = .01) in poor metabolizers than in extensive metabolizers. No significant correlations were found between debrisoquin metabolic ratio and AUC values of selegiline or its metabolites, except for l-methamphetamine (rs = 0.90; P < .001). The maximum monoamine oxidase type B inhibition was 97% in both groups. The inhibitory potency of selegiline, desmethylselegiline, and l-methamphetamine toward dextromethorphan O-demethylase was very low (50% inhibitory concentration values from 160 to 580 mumol/L). Quinidine (< or = 100 mumol/L) did not inhibit the formation of desmethylselegiline or l-methamphetamine from selegiline., Conclusions: CYP2D6 is not important in the primary elimination of selegiline, and the biological effect of selegiline seems to be similar in poor metabolizers and extensive metabolizers of debrisoquin. The inhibitory effect of selegiline and its main metabolites on CYP2D6 activity seems to be negligible.

A sensitive enzyme-linked immunosorbent assay (ELISA) for TA-2005-glucuronide, a main metabolite of new adrenergic beta-receptor agonist TA-2005, has been investigated without prior deconjugation. Coupling of the hapten with bovine serum albumin (BSA) or beta-D-galactosidase was carried out by the N-hydroxysuccinimide ester method. An anti-TA-2005-glucuronide antiserum was obtained from guinea pig immunized with the hapten-BSA conjugate. The ELISA was based upon a competitive assay in which the separation of bound from free fraction was performed by the double antibody technique using rabbit anti guinea pig immunoglobulin antibody adsorbed to microtiter plates. A satisfactory standard curve for the ELISA of TA-2005-glucuronide was observed in the range of 30 pg-3 ng ml-1 using 25 microliters of human plasma. Inter-day and intra-assay variations were 7.0-17.5% and 1.0-11.7% respectively. The recoveries of TA-2005-glucuronide spiked to plasma samples were 95.5-120% (inter-assay) and 96.0-123.3% (intra-assay). The cross-reactivities of the prepared antiserum with the related compound of TA-2005-glucuronide were quite low though there was a considerable cross-reaction with TA-2005. However, TA-2005-glucuronide could be easily separated from TA-2005 by a simple pretreatment of the plasma sample with a C18 cartridge column. This method was applied to the determination of TA-2005-glucuronide in human plasma samples for the evaluation of the pharmacokinetics of TA-2005. From the results, it was demonstrated that the ELISA developed was useful for the determination of TA-2005-glucuronide in human plasma and that the method was applicable to pharmacokinetic studies in humans.

This study was performed to evaluate the usefulness of spectral analysis (SA) applied to dynamic single photon emission computed tomography studies with N-isopropyl-p-(123I)iodoamphetamine (IMP). The unidirectional clearance of IMP from the blood to the brain tissue (K1) obtained by SA (y (ml/g/min)) agreed well with that obtained from a two-compartment model using the nonlinear least-squares (NLSQ) method (x (ml/g/min)) (y = 0.994x + 0.003, r = 0.999, standard error of the estimate (SEE) = 0.005 ml/g/min). The rate constant for back diffusion of IMP from the brain tissue to the blood (k2) obtained by SA (y (min(-1))) also agreed well with that obtained by the NLSQ method (x (min(-1))) (y = 0.985x + 0.000, r = 0.948, SEE = 0.001 min(-1)). The brain vascular volume (V0) obtained by SA (y (ml/g)) correlated well with that obtained by the NLSQ method (x (ml/g)) (y = 1.138x + 0.000, r = 0.867, SEE = 0.012 ml/g). These results indicate that SA is applicable and useful for quantification of the kinetic parameters of IMP in the human brain, and can be an alternative approach to compartment analysis.

Radiotracers called chemical microsphere are widely accepted as brain perfusion agents. Following the intravenous administration, these drugs are transported via the artery to the brain, cross the intact blood-brain barrier, and enter the brain tissue. Once the tracer flows into the brain, the efflux of the tracer is prevented by some trapping mechanism, resulting in prolonged retention. Because the distribution of the accumulated tracer remains approximately consistent with regional cerebral blood flow for a relatively long period, high-quality SPECT images reflecting the distribution pattern of cerebral blood flow can be acquired. However, unlike true microsphere, cerebral kinetics of the brain perfusion agents is complicated, and various causes may produce discrepancy between the distributions of the tracer and blood flow. In this review, cerebral kinetics of the brain perfusion agents used commonly is discussed. The knowledge of the mechanism of brain accumulation appears to be essential to appropriately determine the tracer of choice and interpret the obtained images.

Drugs and endogenous compounds circulating in the blood are partially incorporated into the growing hair and are retained there for a long time. Therefore, hair analysis has been used as a useful method for detecting and monitoring drugs from days to years after ingestion. Although numerous drugs and metabolites have been detected in hair, many factors are still not cleared on the mechanisms responsible for the incorporation and retention of drugs in hair. In this study, the incorporation mechanisms of drugs from blood into hair were investigated with respect to the contributions of the physicochemical properties of the drugs. The following conclusions were drawn from the results. 1. Drug concentrations in hair were compared to their pharmacokinetic parameters using an animal model, and it was shown that the incorporation of drugs from plasma into hair distinctly depended upon the physicochemical properties of each drug. 2. As an index of facility of incorporation of a drug into hair, Incorporation Rate (ICR) was defined as the ratio of drug concentration in hair to the area under the concentration versus time curve (AUC) in plasma. The effects of structural factors on ICRs were determined using amphetamine analogs, and it was shown that the basicity and lipophilicity affected the drug incorporation into hair. 3. In in vitro experiments, ICRs positively correlated with melanin affinity and lipophilicity. In particular, melanin affinity principally controls the incorporation of basic drugs into hair. 4. In distinguishing legitimate amphetamine--like OTC drug use from illegal amphetamine/methamphetamine use, hair samples were more useful than urine samples due to the easier long term detection of parent drugs or specific metabolites in hair.

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO-B. This study investigated the inhibitory potential of MAO-B and the pharmacokinetics of desmethylselegiline in humans. A double-blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO-B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO-B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO-B by both compounds. Desmethylselegiline caused a 63.7 +/- 12.7% inhibition of platelet MAO-B compared with 96.4 +/- 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 +/- 20 hours) than after selegiline administration (tmax, 1.4 +/- 1.4 hours). The platelet MAO-B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48-hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO-B and could possibly be used to treat Parkinson's disease in the same way as selegiline.

The stimulant effects of N-cyanomethylmethamphetamine (CMMA), a product derived from smoking methamphetamine (MA) mixed in tobacco, were studied by observing stereotyped behavior and measuring spontaneous motor activity in mice and rats over 180 min CMMA. 1.3 and 10 mg/kg IP, elicited strong stimulant-like effects which were almost equivalent to those produced by MA. Drug monitoring for 180 min in mouse and rat plasma revealed that the principal substances responsible for the stimulant effect of CMMA were MA and amphetamine (AP) which were metabolized from CMMA by the animal. There was a species difference in metabolism of CMMA between mice and rats. The major metabolites were MA and AP in mouse plasma, followed by N-formylmethamphetamine (FMA), whereas the major metabolite was FMA in rat plasma, followed by MA and AP. The differences in the stimulant effects of CMMA between mice and rats were discussed in relation to its metabolic fate in mice and rats.

In order to clarify the mechanism of drug incorporation into hair, disposition of 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), 3-methoxy-4,5-methylenedioxyamphetamine (MMDA) and metabolites of MDMA, 4-hydroxy-3-methoxyamphetamine (HMAP) and 4-hydroxy-3-methoxymethamphetamine (HMMA), into hair was investigated with an animal model. After the intraperitoneal administration of those six drugs to pigmented hairy rats (5 mg/kg/day, 10 days, n = 3), the parent compounds and their metabolites in the rat plasma (5, 15, 30, 60, 120, 360 min after administration) and in the newly grown rat hair for 4 weeks were determined by GC/MS-SIM. When the ratio of hair concentration to area under the concentration versus time curves (AUCs) in plasma was represented as an index of incorporation rate (ICR) of drugs into hair, the order of ICRs was HMAP < MDA < HMMA < MDMA < MDEA < MMDA. In the comparison between MDA, MDMA and MDEA, their ICRs increased according to the length of carbon branches from proton to ethyl at the N position. From the point of view that the ICRs of MMDA was 2.3 times as much as that of MDA, the methoxy group on the benzene ring seemed to serve as a positive factor for the ICR. However, the ICRs of 4-hydroxy-3-methoxy compounds, HMAP and HMMA, were lower in comparison with those of MDA and MDMA, respectively. On the other hand, the ICRs of MDA, MDMA and MDEA were 5.5-6.1 times larger than those of amphetamine, methamphetamine and ethylamphetamine, suggesting that the methylenedioxy group on the benzene ring raises their ICRs very positively. Moreover, in order to apply the results from the animal experiments to human cases, the scalp hair samples of seven MDMA abusers were analyzed. MDMA and its metabolites, MDA; were simultaneously detected in all the samples by GC/MS. In the two samples, MDEA was found in addition to MDMA and MDA. It was shown that a hair sample is a good specimen for the confirmation of retrospective use of methylenedioxyamphetamines.

A bioavailability study of 2 different selegiline preparations were conducted in 20 healthy volunteers to test the bioequivalence. Almost no bioavailability study of selegiline has been published. As plasma levels of selegiline are very low and the elimination half-life is very short being about 9 minutes, therefore, a very sensitive and selective method for determining the 3 main metabolites desmethylselegiline (DMS), methamphetamine (MA) and amphetamine (A) was developed. After application of a single oral dose of 5 mg selegiline the Cmax values of DMS reached 5-6 ng/ml, of MA 6-7 ng/ml and of A about 2 ng/ml. The AUC infinity values were with DMS about 11 ng/ml x h +/- 4.5, with MA about 130 g/ml x h +/- 50 and with A about 50 ng/ml x h +/- 15. The 90% confidence interval was with logarithmic transformed AUC infinity values 92-107% with DMS, 89-107% with MA, and 84-104% with A. The logarithmic transformed Cmax values showed a 90% confidence interval of 92-127% with DMS, 91-101% with MA, and 90-103% with A. All relevant pharmacokinetic parameters showed bioequivalence with all 3 metabolites (DMS, MA, and A).

Serotonin (5-hydroxytryptamine, 5-HT)-releasing drugs are important experimental tools to examine the role of serotonergic nerve terminals in the secretion of hormones. The drugs 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butane (MBDB), 5-methoxy-6-methyl-2-aminoindan (MMAI) and p-methylthioamphetamine (MTA) have been suggested to be 5-HT releasers. The present study characterized MBDB, MMAI and MTA by using their effects on the secretion of the hormones adrenal corticotrophin (ACTH), corticosterone, prolactin, oxytocin and renin. The time course of the effect of MBDB, MMAI and MTA (5 mg/kg, i.p.) showed that the peak effect on plasma ACTH occurred 10 min after the injection, whereas the prolactin response did not reach a maximum until 30 min after injection. MBDB increased plasma renin concentration within 10 min, whereas the effect of MTA was significant only at 30 min after injection. All three 5-HT releasers decreased HR (within 5 min) and blood pressure (at 15 min after injection). MBDB, MMAI and MTA increased plasma ACTH, corticosterone, prolactin and renin levels in a dose-dependent manner, whereas no changes were observed in plasma vasopressin concentrations. MTA and MMAI, but not MBDB, significantly increased plasma oxytocin concentrations in a dose-dependent manner. Pretreatment of rats with fluoxetine blocked the ACTH response to MBDB and MMAI, but not to MTA. The prolactin response to all three 5-HT releasers was blocked by fluoxetine. The oxytocin response to MTA and MMAI was inhibited by fluoxetine. The renin responses to all three 5-HT releasers were not significantly inhibited by fluoxetine. The results suggest that MBDB, MMAI and MTA can increase the secretion of several hormones, at least in part, through stimulation of serotonergic neurotransmission. However, these three 5-HT releasers seem to have effects on other (and as yet uncharacterized) mechanisms that can stimulate the secretion of some hormones.

Purpose: The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability., Methods: An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS., Results: Selegiline exposure was greatest following administration to the stomach (approximately 150% > duodenum or jejunum) and least in the terminal ileum (approximately 33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (approximately 18%) at the terminal ileum., Conclusions: The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.

Selective high uptake of N-isopropyl-p-[123I]-iodoamphetamine (123I-IMP) in the brain tumors is not common, the mechanism of uptake in the brain tumor is not yet clearly understood. Among 26 cases of gliomas investigated by dynamic SPECT, 4 cases including 2 cases of anaplastic astrocytoma and 2 cases of oligodendroglioma, showed high uptake of 123I-IMP. New three detector type camera which enables us to investigate rapid successive scanning, was used in our study. In dynamic SPECT, 15 successive scans of 2 minutes interval were made for 30 minutes after administration of 123I-IMP. In addition, quick dynamic SPECT was tried in 2 cases, in which 10 quick successive scans of 24 seconds interval were investigated for initial 4 minutes immediately after administration of 123I-IMP. Radioactivity in the region of interest inside the tumor (T) and radioactivity of the corresponding site in the contralateral hemisphere (C) was measured respectively, and T/C ratio was calculated. Time course change of radioactivity (time activity curve: TAC) was analyzed in all cases. Radioactivity was always higher in the tumor and the average T/C ratio was 1.40. TAC showed rapid increase of 123I-IMP in the tumor during initial 2 minutes after administration and keeping its high plateau level for 30 minutes. Angiography in these cases revealed a remarkable tumor stain. On the other hand, these gliomas showed no or slight enhancement effect in CT or MRI. These findings are interpretable as that early high uptake of 123I-IMP in some gliomas is attributable to an increased vascular bed and blood flow with no or minimal derangement of blood brain barrier in these tumors.

To measure distribution volume of 123I-IMP with one-point sampling of arterial blood and 2 times SPECT scans using the Magic square method (Rate constant square method), we introduced a program on a SPECT computer system. In this program four functional images; distribution volume, CBF (K1), k2 and delayed/early ratio, and absolute values with S.D. are obtained on the computer. We have been using the program on daily SPECT studies. In this study we discussed the usefulness of the method. Redistribution phenomenon of 123I-IMP, which is not exactly enough investigated, can be transformed into a functional parameter, distribution volume. Since distribution volume represents an extent of retention of 123I-IMP in brain tissue, it can play an important role to evaluate functional activity in the brain and to diagnose cerebral diseases.

SPECT and associated imaging procedures were used in beagle dogs to (1) evaluate the uptake, distribution, and clearance properties of i.v.-injected 123I IMP (IMP) and 99mTc HMPAO (HMPAO) in the brain, lungs, liver, and kidneys; (2) quantify the acute effects (after 15 sec) of very low doses (0.5 or 1.0 mg/kg) cocaine on the kinetics and localization properties of IMP and HMPAO; and (3) evaluate comparative imaging properties of IMP and HMPAO for measuring regional cerebral blood flow (rCBF). Regional and global uptake and localization of IMP or HMPAO were evaluated in control studies using dynamic planar (0-30 min) and SPECT imaging (at 35 min). The regional distribution properties of IMP and HMPAO in the brain were estimated from regions of interest (ROIs) drawn around anatomic structures on MR slices and manually registered with corresponding SPECT slices. Cocaine significantly reduced the 30-min IMP uptake in the brain and lungs by approximately 15%, but only slightly changed HMPAO uptake in the brain and other organs. In the control studies, the respective uptakes of IMP in the brain and lungs were 9 and 39% greater (p < 0.01) than those of HMPAO. In control SPECT studies, the highest uptake of IMP was observed in the thalamus and progressively less activity was observed in the parietal lobe, frontal lobe, cerebellum, occipital lobe, and entire brain; activity in the olfactory bulb was lower than in all other regions. Cocaine reduced IMP uptake in the cerebellum (p < 0.01), occipital lobe (p < 0.01), and entire brain (p < 0.05). IMP uptake (cpm/pixel-mCi) in the different brain regions was 1.3 to 2.1 times greater than that of HMPAO (p < 0.001). HMPAO uptake was more homogeneous throughout the gray matter of the brain; no significant uptake differences were observed among flagged regions. Results indicate that single, acute doses of cocaine, 0.5 and 1.0 mg/kg, significantly altered the uptake and localization properties of IMP in the dog's brain, lungs, liver, and kidneys. Variations in regional uptake of IMP in the parietal, frontal, and occipital lobes, cerebellum, and thalamus were greater than with HMPAO.

Radial columns in the cerebral cortex, sometimes seen in autoradiographic methods for measuring cerebral blood flow, were studied. Radioactively labeled tracers were injected into the internal carotid artery in pentobarbital sodium-anesthetized rats. The cortical patterns of tracer uptake were determined using autoradiography. When tracers for measuring cerebral blood flow were administered, cortical columns were apparent in the autoradiograph. The darker columns (higher tracer concentration) in the image aligned with penetrating arterioles, suggesting that the tracer was being removed from the penetrating arterioles. In another experiment, [14C]glucose was used as a qualitative blood flow tracer. Modeling of glucose uptake predicts that 26-29% more glucose should be extracted in the dark columns than the light columns if the columns represent capillary blood flow. [14C]glucose did not produce the cortical columns consistent with the model prediction. We conclude that capillary blood flow in the cortex is not organized in radial columns of higher and lower flow. The results support the idea that the flow tracers are removed from blood primarily in the penetrating arterioles.

The analysis of time-lapse changes of d- and l-enantiomers after administration of racemic dl-ethylamphetamine (EAMP) to rats was performed by a high-performance liquid chromatograph equipped with a chiral activity column. After oral administration of dl-EAMP to five rats (dose, 15 mg/kg), the rat urine specimens were collected at four time intervals, 0-4, 4-12, 12-20, and 20-24 h. The two enantiomers of nonmetabolized EAMP and the two enantiomers of metabolized amphetamine (AMP) in urine were simultaneously detected within 20 min. The rate of urinary excretion during 24 h was 3.67% for d-EAMP, 1.03% for l-EAMP, 2.14% for d-AMP, and 1.92% for l-AMP. The total percent of the excreted doses of EAMP and AMP was approximately 8.8% of the administered dosage of dl-EAMP (5.81% for the d-enantiomers and 2.95% for the l-enantiomers). The l/d ratio was 0.51, which was significantly smaller than that (1.01) of the original dl-EAMP powder used (p < .01). The percentages of the doses of l-EAMP in each collection time were significantly less than those of d-EAMP (p < .01), and the l/d ratios of nonmetabolized EAMP decreased to 0.17 within 24 h. For the AMP metabolites, there was a somewhat greater percentage of l-AMP in urine collected up to 4 h than d-AMP (p < .05). Thereafter, it decreased more slowly than d-AMP with time. The l/d ratios of AMP changed from 1.57 to 0.76 within 24 h. The greater decrease of l-EAMP as compared with d-EAMP suggested the stereoselective metabolism of dl-EAMP in rats.

Single-photon emission computed tomography (SPECT) imaging with n-isopropyliodoamphetamine (IMP) was performed on 11 patients with bipolar mania, 21 acute schizophrenics, and 15 healthy control subjects. Subjects were evaluated with neuropsychological tests and psychiatric rating scales. SPECT brain studies were blindly evaluated to assess the degree of radiopharmaceutical uptake in three neuroanatomical regions of interest in each hemisphere. All the control subjects, 1 manic patient, and 1 schizophrenic patient had normal brain SPECT uptake patterns. The scans of all others were read as abnormal. Hypofrontality was noted in some schizophrenics and maniacs. A significant increase in tracer uptake in temporal lobes was observed in both patient groups, more prominently in the manic patients. Increased and decreased basal ganglia uptake was also observed in patients. Both manic and schizophrenic patients showed cortical tracer heterogeneity of varying degree. The patterns of cerebral SPECT uptake seen in these acute psychoses were not specific for a diagnosis, but may be associated with dimensions of psychopathology. Because the patterns are different from those seen in cerebrovascular disease and the dementias, they may prove to be helpful in differential diagnosis.

Pharmacological interactions are important when nuclear medical procedures are applied to patients under drug therapy, or drug provocation. This study compares in baboon models (regional) cerebral blood flow [(r)CBF] results from 99mTc-HMPAO and 123I-iodoamphetamine [123I(IMP)] each with and without acetazolamide, the latter a suggested drug for testing cerebrovascular reserve. Expected differences in cerebral uptake were observed between the two radio-tracers without acetazolamide. The increase in tracer uptake resulting from acetazolamide is significantly enhanced for 123I(IMP), which could have diagnostic implications.