Estimating the In Vivo Function of CYP2D6 Alleles through Population Pharmacokinetic Modeling of Brexpiprazole.

Accurate prediction of CYP2D6 phenotype from genotype information is important to support safe and efficacious pharmacotherapy with CYP2D6 substrates. To facilitate accurate CYP2D6 genotype-phenotype translation, there remains a need to investigate the enzyme activity associated with individual CYP2D6 alleles using large clinical data sets. This study aimed to quantify and compare the in vivo function of different CYP2D6 alleles through population pharmacokinetic (PopPK) modeling of brexpiprazole using data from 13 clinical studies. A PopPK model of brexpiprazole and its two metabolites, DM-3411 and DM-3412, was developed based on plasma concentration samples from 826 individuals. As the minor metabolite, DM-3412, is formed via CYP2D6, the metabolic ratio of DM-3412:brexpiprazole calculated from the PopPK parameter estimates was used as a surrogate measure of CYP2D6 activity. A CYP2D6 genotype-phenotype analysis based on 496 subjects showed that the CYP2D6*2 allele (n = 183) was associated with only 10% enzyme activity relative to the wild-type allele (CYP2D6*1) and a low enzyme activity was consistently observed across genotypes containing CYP2D6*2. Among the decreased function alleles, the following enzyme activities relative to CYP2D6*1 were estimated: 23% for CYP2D6*9 (n = 20), 32% for CYP2D6*10 (n = 62), 64% for CYP2D6*14 (n = 1), 4% for CYP2D6*17 (n = 37), 4% for CYP2D6*29 (n = 13), and 9% for CYP2D6*41 (n = 64). These findings imply that a lower functional value would more accurately reflect the in vivo function of many reduced function CYP2D6 alleles in the metabolism of brexpiprazole. The low enzyme activity observed for CYP2D6*2, which has also been reported by others, suggests that the allele exhibits substrate-specific enzyme activity.

Pitfalls and challenges associated with phenoconversion in forensic toxcicology.

PURPOSE: In recent years, several publications have demonstrated the interest and the usefulness of pharmacogenetics in forensic toxicology. However, this approach remains namely focused on DNA-based phenotype, which may potentially lead to misinterpretation. Other determinants such as co-medication or physiological parameters may also impact the phenotype. This article aims to highlight the importance of considering such determinants in forensic toxicology, through the original case of a heroin-related fatality. METHOD: Ethanol concentration determination and toxicological screening were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection and gas chromatography with mass spectrometry detection. CYP2C19 and CYP2D6 genotypes were determined by Taqman® real-time PCR analyses. RESULTS: Femoral blood analyses revealed the presence of ethanol, morphine, codeine, venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV), paroxetine, and risperidone. 6-acetylmorphine was also identified in urine. VEN, paroxetine and risperidone were quantified at supra-therapeutic or toxic blood concentrations. NDV was not quantified. The metabolic ratio of VEN (ODV to VEN) was exceptionally low (about 0.7). Pharmacogenetics testing showed that the patient was heterozygous for the CYP2C19*2 loss-of-function allele, which predict an intermediate metabolism for CYP2C19. None of the deficient CYP2D6 alleles investigated were identified. Those results suggest an extensive CYP2D6-metabolism phenotype. CONCLUSION: A discrepancy was seen between the results of the genomic evaluation and the observed metabolic ratio of VEN. This tends to exclude a genetic origin and lead us to formulate other hypotheses, such as phenoconversion that may have been induced by drug interaction involving patients' regular medications. Phenoconversion is as a complex phenomenon that leads to genotype-phenotype mismatch without any genetic abnormality particularly described for cytochromes P450 2D6 and 2C19. Although transient, phenoconversion can have a significant impact on the analysis and interpretation of genotype-focused clinical outcomes correlation and in forensic toxicology conclusions.

CYP2D6 function moderates the pharmacokinetics and pharmacodynamics of 3,4-methylene-dioxymethamphetamine in a controlled study in healthy individuals.

The role of genetic polymorphisms in cytochrome (CYP) 2D6 involved in the metabolism of 3,4-methylene-dioxymethamphetamine (MDMA, ecstasy) is unclear. Effects of genetic variants in CYP2D6 on the pharmacokinetics and pharmacodynamic effects of MDMA were characterized in 139 healthy individuals (70 men, 69 women) in a pooled analysis of eight double-blind, placebo-controlled crossover studies. In CYP2D6 poor metabolizers, the maximum concentrations (Cmax) of MDMA and its active metabolite 3,4-methylene-dioxyamphetamine were +15 and +50% higher, respectively, compared with extensive metabolizers and the Cmax of the inactive metabolite 4-hydroxy-3-methoxymethamphetamine was 50-70% lower. Blood pressure and subjective drug effects increased more rapidly after MDMA administration in poor metabolizers than in extensive metabolizers. In conclusion, the disposition of MDMA and its effects in humans are altered by polymorphic CYP2D6 activity, but the effects are small because of the autoinhibition of CYP2D6.

Serotonin pathway polymorphisms and the treatment of major depressive disorder and anxiety disorders.

While antidepressants are widely used to treat major depressive disorder and anxiety disorders, only half of the patients will respond to antidepressant treatment and only a third of patients will experience a remission of symptoms. Identification of genetic biomarkers that predict antidepressant treatment response could thus greatly improve current clinical practice by providing guidance on which drug to use for which patient. Most antidepressant drugs for the treatment of depression and anxiety disorders have effects on the serotonergic neurotransmitter system; thus, genetic polymorphisms in the genes involved in this pathway represent logical candidates for investigation. This article reviews recent findings on the pharmacogenetics of antidepressant drugs with a focus on serotonergic pathway polymorphisms and discusses future clinical applications.

Chronic betahistine co-treatment reverses olanzapine's effects on dopamine D2 but not 5-HT2A/2C bindings in rat brains.

Olanzapine is widely prescribed for treating schizophrenia and other mental disorders, although it leads to severe body weight gain/obesity. Chronic co-treatment with betahistine has been found to significantly decrease olanzapine-induced weight gain; however, it is not clear whether this co-treatment affects the therapeutic effects of olanzapine. This study investigated the effects of chronic treatment of olanzapine and/or betahistine on the binding density of the serotonergic 5-HT2A (5-HT2AR) and 5-HT2C (5-HT2CR) receptors, 5-HT transporter (5-HTT), and dopaminergic D2 receptors (D2R) in the brain regions involved in antipsychotic efficacy, including the prefrontal cortex (PFC), cingulate cortex (Cg), nucleus accumbens (NAc), and caudate putamen (CPu). Rats were treated with olanzapine (1 mg/kg, t.i.d.) or vehicle for 3.5 weeks, and then olanzapine treatment was withdrawn for 19 days. From week 6, the two groups were divided into 4 groups (n=6) for 5 weeks' treatment: (1) olanzapine-only (1 mg/kg, t.i.d.), (2) betahistine-only (9.6 mg/kg, t.i.d.), (3) olanzapine and betahistine co-treatment (O+B), and (4) vehicle. Compared to the control, the olanzapine-only treatment significantly decreased the bindings of 5-HT2AR, 5-HT2CR, and 5-HTT in the PFC, Cg, and NAc. Similar changes were observed in the rats receiving the O+B co-treatment. The olanzapine-only treatment significantly increased the D2R binding in the Cg, NAc, and CPu, while the betahistine-only treatment reduced D2R binding. The co-treatment of betahistine reversed the D2R bindings in the NAc and CPu that were increased by olanzapine. Therefore, chronic O+B co-treatment has similar effects on serotonin transmission as the olanzapine-only treatment, but reverses the D2R that is up-regulated by chronic olanzapine treatment. The co-treatment maintains the therapeutic effects of olanzapine but decreases/prevents the excess weight gain.

Characterizing new fluorescent tools for studying 5-HT3 receptor pharmacology.

The pharmacological characterization of ligands depends upon the ability to accurately measure their binding properties. Fluorescence provides an alternative to more traditional approaches such as radioligand binding. Here we describe the binding and spectroscopic properties of eight fluorescent 5-HT3 receptor ligands. These were tested on purified receptors, expressed receptors on live cells, or in vivo. All compounds had nanomolar affinities with fluorescent properties extending from blue to near infra-red emission. A fluorescein-derivative had the highest affinity as measured by fluorescence polarization (FP; 1.14 nM), flow cytometry (FC; 3.23 nM) and radioligand binding (RB; 1.90 nM). Competition binding with unlabeled 5-HT3 receptor agonists (5-HT, mCPBG, quipazine) and antagonists (granisetron, palonosetron, tropisetron) yielded similar affinities in all three assays. When cysteine substitutions were introduced into the 5-HT3 receptor binding site the same changes in binding affinity were seen for both granisetron and the fluorescein-derivative, suggesting that they both adopt orientations that are consistent with co-crystal structures of granisetron with a homologous protein (5HTBP). As expected, in vivo live imaging in anaesthetized mice revealed staining in the abdominal cavity in intestines, but also in salivary glands. The unexpected presence of 5-HT3 receptors in mouse salivary glands was confirmed by Western blots. Overall, these results demonstrate the wide utility of our new high-affinity fluorescently-labeled 5-HT3 receptor probes, ranging from in vitro receptor pharmacology, including FC and FP ligand competition, to live imaging of 5-HT3 expressing tissues.

An altered spinal serotonergic system contributes to increased thermal nociception in an animal model of depression.

The olfactory bulbectomized (OB) rat, an animal model of chronic depression with comorbid anxiety, exhibits a profound dysregulation of the brain serotonergic signalling, a neurotransmission system involved in pain transmission and modulation. We here report an increased nociceptive response of OB rats in the tail flick test which is reverted after chronic, but not acute, administration of fluoxetine. Autoradiographic studies demonstrated down-regulation of 5-HT transporters ([(3)H]citalopram binding) and decreased functionality of 5-HT1A receptors (8-OH-DPAT-stimulated [(35)S]GTPγS binding) in the dorsal horn of the lumbar spinal cord in OB rats. Acute administration of fluoxetine (5-40 mg/kg i.p.) did not modify tail flick latencies in OB rats. However, chronic fluoxetine (10 mg/kg/day s.c., 14 days; osmotic minipumps) progressively attenuated OB-associated thermal hyperalgesia, and a total normalization of the nociceptive response was achieved at the end of the treatment with the antidepressant. In these animals, autoradiographic studies revealed further down-regulation of 5-HT transporters and normalization in the functionality of 5-HT1A receptors on the spinal cord. On the other hand, acute morphine (0.5-10 mg/kg s.c.) produced a similar analgesic effect in OB and sham and OB rats, and no changes were detected in the density ([(3)H]DAMGO binding) and functionality (DAMGO-stimulated [(35)S]GTPγS binding) of spinal µ-opioid receptors in OB rats before and after chronic fluoxetine. Our findings demonstrate the participation of the spinal serotonergic system in the increased thermal nociception exhibited by the OB rat and the antinociceptive effect of chronic fluoxetine in this animal model of depression.

How MDMA's pharmacology and pharmacokinetics drive desired effects and harms.

3,4-Methylenedioxymethamphetamine (MDMA) is an agent of abuse that has been used by over 16 million Americans. Increased energy, elevated mood, bonding with others, and psychedelic effects are desired effects while liver damage, extended depressed mood, sexual assault, rhabdomyolysis, serotonin syndrome, multiorgan failure, cardiovascular events, arrhythmias, and death are possible adverse effects. These desirable and adverse effects of MDMA are extensions of its fascinating pharmacologic and pharmacokinetic profile. In addition to methamphatemine like effects, MDMA also has mescaline like effects and increases the release of cortisol, oxytocin, and antidiuretic hormone. The desirable effects of MDMA are accentuated by the rave or electronic dance music scene where warm temperatures, vigorous dancing, loud music, and light shows accentuate some of the responses. However, the same environment increases the risk of certain harms. Knowledge of the constellation of these factors is needed for education, prevention of harm, and treatment.

The effects of benzofury (5-APB) on the dopamine transporter and 5-HT2-dependent vasoconstriction in the rat.

5-APB, commonly marketed as 'benzofury' is a new psychoactive substance and erstwhile 'legal high' which has been implicated in 10 recent drug-related deaths in the UK. This drug was available on the internet and in 'head shops' and was one of the most commonly sold legal highs up until its recent UK temporary ban (UK Home Office). Despite its prominence, very little is known about its pharmacology. This study was undertaken to examine the pharmacology of 5-APB in vitro. We hypothesised that 5-APB would activate the dopamine and 5-HT systems which may underlie its putative stimulant and hallucinogenic effects. Autoradiographic studies showed that 5-APB displaced both [(125)I] RTI-121 and [(3)H] ketanserin from rat brain tissue suggesting affinity at the dopamine transporter and 5-HT2 receptor sites respectively. Voltammetric studies in rat accumbens brain slices revealed that 5-APB slowed dopamine reuptake, and at high concentrations caused reverse transport of dopamine. 5-APB also caused vasoconstriction of rat aorta, an effect antagonised by the 5-HT2A receptor antagonist ketanserin, and caused contraction of rat stomach fundus, which was reversed by the 5-HT2B receptor antagonist RS-127445. These data show that 5-APB interacts with the dopamine transporter and is an agonist at the 5-HT2A and 5-HT2B receptors in the rat. Thus 5-APB's pharmacology is consistent with it having both stimulant and hallucinogenic properties. In addition, 5-APB's activity at the 5-HT2B receptor may cause cardiotoxicity.

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

BACKGROUND: At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. OBJECTIVE: The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. DATA SOURCES: An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. RESULTS: MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. CONCLUSION: The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity.

N,N-dimethyltryptamine (DMT) is classified as a naturally occurring serotonergic hallucinogen of plant origin. It has also been found in animal tissues and regarded as an endogenous trace amine transmitter. The vast majority of research on DMT has targeted its psychotropic/psychedelic properties with less focus on its effects beyond the nervous system. The recent discovery that DMT is an endogenous ligand of the sigma-1 receptor may shed light on yet undiscovered physiological mechanisms of DMT activity and reveal some of its putative biological functions. A three-step active uptake process of DMT from peripheral sources to neurons underscores a presumed physiological significance of this endogenous hallucinogen. In this paper, we overview the literature on the effects of sigma-1 receptor ligands on cellular bioenergetics, the role of serotonin, and serotoninergic analogues in immunoregulation and the data regarding gene expression of the DMT synthesizing enzyme indolethylamine-N-methyltransferase in carcinogenesis. We conclude that the function of DMT may extend central nervous activity and involve a more universal role in cellular protective mechanisms. Suggestions are offered for future directions of indole alkaloid research in the general medical field. We provide converging evidence that while DMT is a substance which produces powerful psychedelic experiences, it is better understood not as a hallucinogenic drug of abuse, but rather an agent of significant adaptive mechanisms that can also serve as a promising tool in the development of future medical therapies.

Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.

Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects. Due to the urgent need for highly potent and selective anti-obesity agents, the serotonin receptors (5-HTR) have been the focus of much interest as a novel therapeutic target. In this report, we have developed pyrimidoazepine analogs targeting the 5-HT2A and 5-HT2C receptors and evaluated their biological activity in vitro and in vivo as novel anti-obesity agents. We were able to identify 6p as the most potent 5-HT2A and 5-HT2C ligand in vitro (IC50 = 3 nM and 2.3 nM, respectively), and this compound also demonstrated the greatest potency in vivo. In an acute obesity model, mice treated with 6p showed significant decrease in body weight gain and food intake over approximately 77-94% compared to a control group. In a chronic obesity model, mice treated with 6p also showed a marked decrease in food intake and body weight gain.

Drug interactions with triptans : which are clinically significant?

The triptans are a group of compounds with high efficacy for the acute treatment of migraine and cluster headache. They have a relatively wide therapeutic index, and although a number of minor pharmacokinetic interactions have been observed, few are likely to be clinically significant. Given the differences in principal elimination pathways, potentially interacting drugs on a pharmacokinetic basis are not common across all compounds. Of more concern than pharmacokinetic interactions are pharmacodynamic interactions. Of most concern, additive vasoconstrictor effects are likely to occur with other vasoconstrictors, especially the ergots used for migraine. Serotonin syndrome has been observed due to coadministration of triptans with selective serotonin reuptake inhibitors (SSRIs), but the absolute rate of such a clinical response to coadministration is probably low. Most patients can take triptans with other medications without dose alteration, although vigilance is required for pharmacodynamic interactions.

Neuron density and serotonin receptor binding in prefrontal cortex in suicide.

Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and serotonin transporter (SERT), 5-HT1A and 5-HT2A binding in matched suicides and controls. Suicides and normal controls (n=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal [Brodmann area (BA) 9] and ventral (BA 47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density. Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for SERT in BA 47 but not in BA9; the 5-HT1A binding index was higher in BA 9 but not in BA 47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA 47 but not BA 9, while 5-HT1A binding was higher in BA 9 but not BA 47. SERT binding negatively correlated with 5-HT1A binding in BA 47 in suicides. Neuron density decreased with age. The 5-HT1A binding index was higher in females than males. We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor up-regulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies will need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.

Effects of repeated 3,4-methylenedioxymethamphetamine administration on neurotransmitter efflux and sensory-evoked discharge in the ventral posterior medial thalamus.

3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may "distort," rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.

Safety of rasagiline for the treatment of Parkinson's disease.

INTRODUCTION: Levodopa remains the gold standard treatment for Parkinson's disease (PD), but chronic treatment induces motor fluctuations and dyskinesias. Other dopaminergic agents, such as dopamine agonists, catechol-O-methyl transferase inhibitors and monoamine oxidase B enzyme inhibitors (MAO-B I) have also been developed to treat patients with PD. Rasagiline is a second generation MAO-B I inducing moderate symptomatic and possibly disease-modifying benefits with apparently good tolerability and safety profile in PD patients. AREAS COVERED: The safety of rasagiline in early or advanced PD is discussed. Details about clinical trial data, post hoc analysis in the elderly or regarding cognitive or behavioral effects, food-drug interactions and effects on levodopa-induced dyskinesias are given. EXPERT OPINION: Rasagiline is effective and well tolerated in PD as monotherapy or in combination with levodopa. There was no evidence of a difference in tolerability between younger or older PD patients included in published trials. Food interactions studies with tyramine did not provide evidence of clinical concerns. Drug interaction should be monitored. The risk of serotonin toxicity with serotoninergic antidepressants remains insufficiently characterized, while current available data in small groups of subjects suggest a low risk.

Review: Pharmacogenetic aspects of the effect of cytochrome P450 polymorphisms on serotonergic drug metabolism, response, interactions, and adverse effects.

The field of pharmacogenetics contains a wealth of potential for the enhancement of clinical practice by providing a more effective match between patient and drug, consequently reducing the probability of an adverse drug reaction. Although a relatively novel concept in the forensic context, pharmacogenetics has the capability to assist in the interpretation of drug related deaths, particularly in unintentional drug poisonings where the cause of death remains unclear. However, the complex pharmacology of the drugs when subjected to genetic variations in metabolism makes interpretation of the expected response and adverse events difficult. Many possess multiple metabolic pathways, narrow therapeutic indices and active metabolites or enantiomers which may be eliminated via different pathways to the parent drug. A number of these drugs, which are metabolised primarily by the CYP450 system, are also associated with serotonin syndrome, or serotonin toxicity, especially when used concomitantly with other serotonin active drugs which rely on the same metabolic pathways for drug elimination. A comprehensive understanding of polymorphic drug metabolism and its expected outcomes is therefore essential when interpreting the involvement of drugs in adverse reactions. This review examines the genetically variable CYP450-mediated metabolism of a number of serotonin-active drugs that are often implicated in cases of serotonin toxicity, to assess the impact of pharmacogenetics on drug metabolism, response, interactions and adverse effects.

Increased effects of 3,4-methylenedioxymethamphetamine (ecstasy) in a rat model of depression.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is associated with increases in core body temperature (T(C)) and depressive mood states in users. Flinders Sensitive Line (FSL) rats represent a rat model of depression originally bred from Sprague-Dawley (SD) rats. They are more sensitive to both muscarinic and serotonergic agonists and have altered thermoregulatory responses to various drugs. To examine the link between MDMA and depression, eight FSL and eight SD rats were administered saline and 5 and 7.5 mg/kg MDMA. Immediately following administration, rats were confined to an area with an ambient temperature (T(A)) of 30 ± 1°C for 30 minutes before being allowed access to a thermal gradient for four hours. The brains were removed one week after final dose of MDMA and concentrations of serotonin and dopamine were measured. Treatment with MDMA at both doses led to a higher T(C) in the FSL rats than the SD rats at high T(A) (P < 0.01). Fatalities due to hyperthermia occurred in the FSL rats after both doses, whereas all but one of the SD rats recovered well. Heart rate was also much higher after MDMA in the FSL rats throughout the experiments. The FSL rats showed significant decreases in all transmitters measured (P < 0.05). These differences between strains were not accounted for by altered blood or brain concentrations of MDMA. The results indicate that the FSL rats may be more susceptible to developing MDMA-induced hyperthermia and possible damage to the brain. These findings may be of importance to human users of MDMA who also have depression.

Psychotropic drugs and renal failure: translating the evidence for clinical practice.

INTRODUCTION: The kidney is a primary route of drug elimination; abnormal kidney function is predicted to alter the pharmacokinetics of agents metabolized and/or excreted predominantly through this route. The high prevalence of mental disorders associated with psychotropic drug use in individuals with deteriorating renal function suggests there is a need to investigate the effects of renal failure on psychotropic pharmacokinetics. The aim of this review is to provide a clinically accessible overview of the effect of chronic renal failure on the pharmacokinetics for each of the major classes of prescribed psychotropic agents. METHODS: All English language articles published between 1977 and 2008 were searched through PubMed, using the following keywords: "renal," "kidney," "pharmacokinetics," "renal impairment," "renal insufficiency," and "renal failure." Each of these search words was cross-referenced with the non-proprietary name of each psychotropic agent. The manufacturer's product insert was also reviewed for some agents for updated dosing. Owing to the lack of adequately powered studies, an inclusive manner was used. RESULTS: Chronic renal failure variably affects the pharmacokinetic parameters of psychotropic drugs. A review of each psychotropic drug is provided, with an emphasis on the individual pharmacokinetic parameters and recommended dosing. CONCLUSIONS: The adjudication of safe and effective doses for any psychotropic agent needs to be individualized. Tactics including dosage adjustment, slow titration, and careful monitoring for serious adverse events should be incorporated into practice.

Método de cromatografía líquida de alto rendimiento para la cuantificación de duloxetina en plasma de ratas / High-performance liquid chromatography method for the quantifi cation of duloxetine in rat plasma

Se desarrolló un método HPLC selectivo y sensible para la cuantificación de duloxetina en plasma de ratas. Se utilizó trifluoperacina como estándar interno (IS). El presente método utilizó la precipitación de proteínas para la extracción del fármaco del plasma de las ratas. La separación y cuantificación se realizaron en modo isocrático utilizando como fase móvil tampón fosfato de 25 mM (pH 3,0)/acetonitrilo (60:40, % v/v) y en fase reversa una columna fenil C18 (250 mm x 4,6 mm, 5µ). El efluente de la columna se monitorizó con un detector UV a 217 nm. Este método fue lineal en el intervalo 44 – 2816,00 ng/ml con un coeficiente de regresión superior a 0,99. La recuperación media de duloxetina e IS fue 82,33 ± 2,10 y 75,37 ± 1,07, respectivamente y el método fue exacto, preciso y específi co durante el estudio. Este método validado es sensible y reproducible y puede utilizarse para estudios farmacocinéticos (AU)

A sensitive and selective HPLC method was developed for quantification of duloxetine, in rat plasma. Trifluoperazine was used as an internal standard (IS). The present method used protein precipitation for extraction of the drug from rat plasma. Separation and quantification was carried using in isocratic mode using 25 mM phosphate buffer (pH 3.0)/acetonitrile (60:40, % v/v) as mobile phase and on reverse-phase C18 phenyl column (250 mm x 4.6 mm, 5µ) and the column effluent was monitored by UV detector at 217 nm. This method was linear over the range of 44 - 2816.00 ng/ml with regression coefficient greater than 0.99. The mean recovery of duloxetine and IS were 82.33 ± 2.10 and 75.37 ± 1.07, respectively and the method was found to be precise, accurate and specific during the study. This validated method is sensitive and reproducible and it can be used for pharmacokinetic studies (AU)