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The present study investigated neuroendocrine and cardiovascular changes during experimentally-induced affective states in abstinent heroin-dependent subjects and healthy controls. The procedure for eliciting emotions in all subjects used pleasant and unpleasant stimuli that did not differ in subjective arousal properties. We investigated whether the valence of the stimuli differentially affected neuroendocrine responses by comparing neutral, pleasant and unpleasant pictures on heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP), methyl-OH-phenyl-glycol (MHPG), norepinephrine (NE), epinephrine (EPI), adrenocorticotrophic hormone (ACTH) and cortisol (CORT) plasma levels. Twelve abstinent heroin-dependent subjects, in comparison with 12 control subjects, were submitted to three experimental sessions, each on one of three experimental days a week apart, in counterbalanced order: day 1=unpleasant pictures, day 2=pleasant pictures, day 3=neutral pictures. In the rating of subjective arousal pleasant and unpleasant stimuli received the same high score in comparison with neutral stimuli; a different cardiovascular and neuroendocrine pattern was obtained in healthy subjects: unpleasant stimuli elicited increases in HR, SBP, MHPG, NE, ACTH, CORT, whereas neutral and pleasant stimuli did not induce any significant response in hormonal levels. In contrast, in heroin addicts, despite increased perceptions of unpleasantness, HR, SBP, MHPG and NE levels did not increase after disliked stimuli; these subjects also reported increased arousal during exposure to neutral stimuli. In comparison with controls, addicted individuals showed higher CORT and ACTH basal levels, and a consequent lack of response to unpleasant stimuli. The results indicate that neuroendocrine and cardiovascular systems respond selectively to affective, motivationally relevant stimuli, and that substance use disorders may be associated with dysregulation of emotion-processing mechanisms. [ABSTRACT FROM AUTHOR]

In this work, a convenient method for the therapeutic monitoring of seven common antipsychotic drugs in "dried plasma spot" samples has been developed. It is based on the liquid chromatography tandem mass spectrometry technique, operating in multiple reaction monitoring mode, and a straightforward procedure for the simultaneous extraction of all antipsychotics in a single step, with high extraction yield. The method was fully validated with proper accuracy, precision, selectivity and sensitivity, for all the drugs. Limits of quantification were 0.12, 1.09, 1.46, 1.47, 5.70, 1.32, 1.33 µg/L for haloperidol, aripiprazole, olanzapine, quetiapine, clozapine, risperidone, and paliperidone, respectively. Accuracy, intra- and interday precision values were <10% for all drugs at all concentration levels examined. The method was tested in the analysis of 30 plasma samples from real patients for each drug. The proposed analytical approach, by combining practical and logistical advantages of microsampling with liquid chromatography tandem mass spectrometry analytical performance, could offer an ideal strategy for accurate and timely therapeutic drug monitoring of antipsychotic drugs in most clinical settings, even in remote centers and/or in out-patient settings, bringing so many potential improvements in psychiatric patient care., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chinotto (Citrus×myrtifolia) is a uncommon fruit belonging to the Citrus genus, mainly cultivated in small areas of the Italian territory, where the main use concerns the eponymous drink, marketed with the name of "Chinotto". The lack of information about this fruit highlights the usefulness of nutraceutical compound characterization, as well as the need to identify genuineness markers in derived commercial products. An analytical strategy based on SPE-HPLC-F was developed to identify and quantify different bioactive compounds in Chinotto (Citrus×myrtifolia) fruits and commercial beverages. The method was fully validated and successfully applied to the analysis of nutraceutical compounds in Chinotto fruits of Italian origin and in some Chinotto-based beverages, granting reliable and consistent data. The obtained results provided preliminary key information about the bioactive profiling of Citrus×myrtifolia and proved the suitability of the selected compounds as authenticity markers of derived commercial soft drinks., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Skin adverse events associated with D-Penicillamine (DPA) are common and multi-faceted, although the presence of DPA or its metabolites has never been documented in the skin, because of inherent difficulties in determining its tissue levels. Thus, the association between DPA and DPA-related dermatoses has been only hypothesized on the basis of careful history, clinical observation and typical histopathological findings., Objective: To detect DPA in biopsy specimens in a unique case of 25-year-late-onset elastosis perforans serpiginosa and pseudo-pseudoxanthoma elasticum associated with a history of long-term high dose DPA, by applying a recently described analytical method to assess the presence of DPA in skin., Methods: We used a reliable analytical method based on high-performance liquid chromatography coupled with amperometric detection to look for the presence of DPA in skin biopsy specimens., Results: A chromatographic peak corresponding to DPA was evidenced in some affected skin samples collected from the patient., Conclusion: We documented the effective presence and the persistence after 25 years of DPA in the skin of a woman affected by elastotic cutaneous change due to a long-term therapy with DPA. This report provides further evidence of the relationship between DPA deposit in affected skin and clinical manifestation., (© 2014 European Academy of Dermatology and Venereology.)

A new microextraction by packed sorbent (MEPS) procedure coupled to a high-performance liquid chromatographic method has been developed for quantitation of catecholamines (i.e. norepinephrine, epinephrine and dopamine) in innovative biological samples, namely dried plasma and urine spots. Analyses were carried out on a C18 reversed-phase column using a mobile phase composed of 2.5% methanol and 97.5% aqueous citrate buffer, containing octanesulfonic acid. Coulometric detection was used, setting the first analytical cell at -0.350 V and the second analytical cell at +0.400 V. Dried matrices were purified by means of a fast and feasible MEPS procedure, optimized on C18 sorbent and requiring only a small amount of biological sample. The availability of miniaturized procedures allowed satisfying specific requirements that ought to be considered during pre-treatment intended for catecholamine analysis. The extraction yield values were always higher than 85% and sensitivity was good, with a limit of quantitation of 100 pg mL(-1) for all the analytes. Satisfactory results were also obtained in terms of linearity, precision and accuracy. The method was successfully applied to dried plasma and urine spots derived from two socially diversified groups, namely psychiatric patients and poly-drug abusers, in comparison to healthy volunteers., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Marijuana abuse is prominent among adolescents. Although Δ(9)-THC, one of its main components, has been demonstrated to modulate immunity in adults, little is known about its impact during adolescence on the immune system and the long-lasting effects in adulthood. We demonstrate that 10 days of Δ(9)-THC treatment induced a similar alteration of macrophage and splenocyte cytokines in adolescent and adult mice. Immediately at the end of chronic Δ(9)-THC, a decrease of proinflammatory cytokines IL- 1β and TNF-α and an increase of anti-inflammatory cytokine IL-10 production by macrophages were present as protein and mRNA in adolescent and adult mice. In splenocytes, Δ(9)-THC modulated Th1/Th2 cytokines skewing toward Th2: IFN-γ was reduced, and IL-4 and IL-10 increased. These effects were lost in adult animals, 47 days after the last administration. In contrast, in adult animals treated as adolescents, a perturbation of immune responses, although in an opposite direction, was present. In adults treated as adolescents, a proinflammatory macrophage phenotype was observed (IL-1β and TNF-α were elevated; IL-10 decreased), and the production of Th cytokines was blunted. IgM titers were also reduced. Corticosterone concentrations indicate a long-lasting dysregulation of HPA in adolescent mice. We measured blood concentrations of Δ(9)-THC and its metabolites, showing that Δ(9)-THC plasma levels in our mice are in the order of those achieved in human heavy smokers. Our data demonstrate that Δ(9)-THC in adolescent mice triggers immune dysfunctions that last long after the end of abuse, switching the murine immune system to proinflammatory status in adulthood., (© 2014 Society for Leukocyte Biology.)

A rapid and reliable analytical method has been developed to quantify the melatonergic antidepressant agomelatine in three matrices, and namely saliva, plasma and dried blood spots. The method is based on the use of liquid chromatography with fluorimetric detection exploiting the native fluorescence of agomelatine. For saliva and plasma samples an original microextraction by packed sorbent procedure was implemented obtaining satisfactory extraction yield of the analyte (always higher than 89%) and a good clean-up of the matrices. On the contrary, agomelatine was extracted from dried blood spots by suitable solvent microwave-assisted extraction and injected into chromatographic system. Satisfactory results in terms of sensitivity, linearity, precision, selectivity and accuracy were obtained. Thus, the developed method seems to be suitable for therapeutic drug monitoring of depressed patients under agomelatine therapy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: A novel analytical approach, based on dried blood spot (DBS) testing, has been developed, validated and applied for the first time to the analysis of ziprasidone (ZPR) for the therapeutic drug monitoring (TDM) of schizophrenic patients. DBS represent a more feasible but reliable matrix, alternative to blood and plasma., Methods: The assays were carried out using an HPLC method with native fluorescence. Blood drops were applied to DBS cards and dried by microwaves, an internal standard solution was added to the DBS and 5-mm punches were cut out for analysis. ZPR was extracted from DBS with methanol, giving good extraction yields, precision and selectivity results., Results: The method was applied with satisfactory results to DBS samples from psychiatric patients to determine ZPR levels for therapy optimization., Conclusion: This innovative methodology provides reliable and significant TDM information, with important advantages over classical blood sampling in terms of collection, storage and processing.

The aim of this paper was to investigate the subjective responses of abstinent heroin users to both neutral and negative stimuli and the related hypothalamus-pituitary-adrenal reactions to emotional experience in relationship to their perception of childhood adverse experiences. Thirty male abstinent heroin dependents were included in the study. Emotional responses and childhood neglect perception were measured utilizing the State-Trait Anxiety Inventory Y-1 and the Child Experience of Care and Abuse Questionnaire. Neutral and unpleasant pictures selected from the International Affective Picture System and the Self-Assessment Manikin procedure have been used to determine ratings of pleasure and arousal. These ratings were compared with normative values obtained from healthy volunteers used as control. Blood samples were collected before and after the experimental sessions to determine both adrenocorticotropic hormone and cortisol plasma levels. Basal anxiety scores, cortisol and adrenocorticotropic hormone levels were higher in abstinent heroin users than in controls. Tests showed that anxiety scores did not change in controls after the vision of neutral slides, whilst they did in abstinent heroin addicts, increasing significantly; and increased less significantly after the unpleasant task, in comparison to controls. Abstinent heroin users showed significantly higher levels of parent antipathy and childhood emotional neglect perception than controls for both the father and the mother. Plasma adrenocorticotropic hormone and cortisol levels did not significantly increase after unpleasant slide set viewing among addicted individuals, because of the significantly higher basal levels characterizing the addicted subjects in comparison with controls. Multiple regression correlation showed a significant relationship between childhood neglect perception, arousal reaction, impaired hypothalamus-pituitary-adrenal axis response and addiction severity. Early adverse experiences seem to affect the entire interaction between hyper-arousal, reduced hormonal response to stress and addiction severity. Our findings, although obtained in a small number of subjects, indicate a significant link between the perception of parental style/care/support during childhood and the ability to cope with stressful emotional stimuli in adulthood and addiction severity., (© 2013.)

An original high-performance liquid chromatographic method coupled to microextraction by packed sorbent (MEPS) was developed for the therapeutic drug monitoring (TDM) of psychiatric patients treated with the recent atypical antipsychotic ziprasidone. The chromatographic separation was achieved on a RP C18 column, using an isocratic mobile phase and setting the wavelength at 320nm. The analyte was extracted from human plasma by means of a fast and feasible innovative MEPS procedure, optimised on C2 sorbent and requiring only 100μL of biological sample. A second pre-treatment procedure, based on solid phase extraction (SPE), has been also developed for comparison. The availability of different pre-treatment procedures allows the choice of the one best suiting the specific clinical, economic and scientific needs. The extraction yield values were always higher than 90% and sensitivity was also good, with a limit of quantitation (LOQ) of 1ng/mL. The method was successfully applied to plasma samples from ten subjects undergoing therapy with ziprasidone, thus confirming its suitability for the TDM of psychiatric patients, in order to personalise their pharmacological treatments., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The development and validation of a bioanalytical assay for the simultaneous determination of cortisol, cortisone and corticosterone levels in several matrices, such as saliva, plasma, blood and urine samples have been described. The method is based on a rapid test which combines a microextraction by packed sorbent procedure and liquid chromatography-diode array technique. Chromatographic separation of the analytes (cortisol, cortisone and corticosterone) and the internal standard (methylprednisolone) was achieved in less than 10min on a reversed-phase pentafluorophenyl column using a mobile phase composed of phosphate buffer and acetonitrile. The assay was performed after an innovative microextraction procedure by means of C8 sorbent which guaranteed good clean-up of the matrices and satisfactory extraction yield of the analytes. Moreover, the method gave linear results over a range of 5-100ngmL(-1) and showed good selectivity and precision. This method was successfully applied for quantifying corticosteroids in specific matrices derived from some healthy volunteers in comparison to two socially diversified groups, namely former heroin addicts undergoing opioid replacement therapy and poly-drug abusers., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Social anxiety disorder (SAD) is an emerging, often invalidating, syndrome with deep personal, social and psychological implications. While multiple treatment strategies exist, presently none of them can be considered superior to all others., Areas Covered: The aim of this review is to provide the latest information on sertraline (SRT), one of the most important selective serotonin reuptake inhibitors (SSRIs) currently used for the pharmacological therapy of SAD. A literature search was carried out with the keywords 'sertraline', 'social anxiety', 'social phobia' and 'clinical trials'. In this process, particular attention is paid to the pharmacokinetic characteristics of the drug and its safety in clinical use., Expert Opinion: SRT is an effective drug in the treatment of SAD, especially when used in combination with some form of psychological support. While it does not seem to be significantly more effective than other SSRIs, SRT could offer some peculiar advantages: for example, it has a long half-life, allowing a single daily administration, and seems to be particularly indicated for the control of specific symptoms of SAD.

The amino acid content of fruit and fruit-derived foods is studied intensely because of the contribution to nutritional value, aroma, taste and health-promoting effects and their possible use as markers of origin and authenticity. In this review, based on 101 references, the most recent trends in the analysis of amino acids are presented: the most important techniques, the different sample treatment procedures (including derivatisation) and the most frequent applications are described and compared. Pertinent publications were retrieved from Scopus and Web of Knowledge database searches lastly performed in February 2012 with the keywords "amino acid", "analysis", "liquid chromatography", "gas chromatography", "electrophoresis", "fruit", and "vegetables"; the time limit was set from the year 2000 onwards. Although amino acids have been analysed in foods for decades, new technical possibilities and advancements have allowed ever-increasing accuracy and targeting of the methods in order to overcome the challenges posed by the complex plant matrices and their high intrinsic variability.

An advanced analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), has been developed for the identification and determination in hair of Δ(9)-tetrahydrocannabinol together with its major metabolite 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol. Since the latter is formed endogenously, it allows the assessment of chronic use excluding passive exposure to Cannabis. The sample pre-treatment procedure is based on a feasible incubative extraction followed by a liquid-liquid extraction step. Chromatographic separation was performed using a reversed-phase column and gradient elution with a formic acid/acetonitrile/water mobile phase. The limits of quantitation and of detection were 3pg/mg and 1pg/mg, respectively, for both analytes. The method was successfully applied to the analysis of hair samples from Cannabis abusers; the analyte concentrations found ranged from 55 to 100pg/mg for Δ(9)-tetrahydrocannabinol and from 5 to 10pg/mg for 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol. Accuracy studies also gave satisfactory results (recovery>87%), thus confirming the suitability of the assay for chronic consumption monitoring., (Copyright © 2012 Elsevier B.V. All rights reserved.)

An analytical strategy, based on the development of two HPLC methods with spectrophotometric (UV), spectrofluorometric (FL), and mass spectrometric (MS) detection, has been developed to investigate the presence of and to quantitate two important chemopreventive coumarins, auraptene and umbelliferone, in foodstuffs. The analytes were determined in fruits, and fruit parts, of plants belonging to the Citrus , Poncirus , and Fortunella genera, to test their nutraceutical potential. The method validation has been carried out according to international guidelines, with good results in terms of precision (RSD < 6.9%) and extraction yields (>91%). Application to the quantitative analysis of auraptene and umbelliferone in several kinds of citrus fruits was successful, providing reliable and consistent data. Exploiting three different kinds of detection, the analytical methodology proposed herein has been demonstrated to be sound but versatile, as well as reliable. Performances and results were compared and always found in good agreement among themselves. Thus, this approach is suitable for the identification and simultaneous quantitation of auraptene and umbelliferone in citrus fruits, with the aim of evaluating their nutraceutical potential.

D-penicillamine is a thiol drug mainly used for Wilson's disease, rheumatoid arthritis and cystinuria. Adverse effects during normal use of the drug are frequent and may include skin lesions. To evaluate its toxic effects in clinical cases an original method based on high performance liquid chromatography coupled to amperometric detection in a specific biological matrix such as skin has been developed. The chromatographic analysis of D-penicillamine was carried out on a C18 column using a mixture of acid phosphate buffer and methanol as the mobile phase. Satisfactory sensitivity was obtained by oxidizing the molecule at +0.95 V with respect to an Ag/AgCl reference electrode. A chemical reduction of D-penicillamine-protein disulphide bonds using dithioerythritol combined with microwaves was necessary for the determination of the total amount of D-penicillamine in skin specimens. A further solid-phase extraction procedure on C18 cartridges was implemented for the sample clean-up. The whole analytical procedure was validated: high extraction yield (>91.0%) and satisfactory precision (RSD<6.8%) values were obtained. It was successfully applied to skin samples from a patient who was previously under a long-term, high-dose treatment with the drug and presented serious D-penicillamine-related dermatoses. Thus, the method seems to be suitable for the analysis of D-penicillamine in skin tissues., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A sensitive and selective HPLC-MS/MS method has been developed for the first time for the analysis of Δ(9)-tetrahydrocannabinol (the most important active cannabinoid) and its hydroxylated and carboxylated metabolites in human Dried Blood Spots (DBSs). The simultaneous determination of Δ(9)-tetrahydrocannabinol and its two main metabolites allows assessing the time elapsed after the drug intake and distinguishing between acute or former consumption. This is an important information in specific contexts such as "on street" controls by police forces. DBSs have been chosen as the optimal biological matrix for this kind of testing, since they provide information on the actual state of intoxication, without storage and transportation problems usually associated with classical blood testing. The analysis is carried out on a C8 reversed phase column with a mobile phase composed of 0.1% formic acid in a water/methanol mixture and an electrospray ionisation (ESI) source, coupled to a triple quadrupole mass spectrometer. The method was validated according to international guidelines, with satisfactory results in terms of extraction yields, precision, stability and accuracy. Application to real DBS samples from Cannabis abusers gave reliable results, thus confirming the methodology suitability for roadside testing., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A novel test has been developed for the analysis of methadone in dried blood spot specimens from patients undergoing methadone maintenance treatment. An isocratic reversed-phase high-performance liquid chromatography method with coulometric detection has been optimized for the determination of methadone. The clean-up of dried blood spots was performed by means of an original microextraction by packed sorbent procedure after microwave-assisted extraction of the drug with a suitable solvent. Extraction yields were satisfactory, always being higher than 90.0 %. The calibration curve was linear over the 4-500 ng mL(-1) concentration range. The method had satisfactory sensitivity (limit of quantitation of 4 ng mL(-1)), precision (relative standard deviation less than 5.8 %), selectivity and accuracy (recovery greater than 87.0 %). It was successfully applied to dried blood spot samples collected from heroin-addicted patients undergoing methadone maintenance therapy at dosages between 40 and 240 mg day(-1). The statistical analysis (Bland-Altman plot) showed that the results were in good agreement with those found from the analysis of plasma samples obtained from the same patients. Thus, the method has proved to be suitable for the monitoring of methadone by means of dried blood spots.

The strong antioxidant activity of melatonin is well known and it is important to investigate its presence and levels in different foodstuffs, for the purpose of evaluating their nutraceutical properties. As a contribution towards this goal, an original analytical method has been developed for the simultaneous determination of melatonin and other indolic and phenolic antioxidants (including trans- and cis-resveratrol, ferulic acid, tryptophan, serotonin and 5-hydroxyindoleacetic acid) in grape-related foodstuffs and beverages: namely grape, grape juice, must, wine and grappa (Italian pomace brandy). These foodstuffs represent an important part of the diet, both traditionally and in recent times, especially in Mediterranean countries and could be (at least in part) responsible for the beneficial effects involved in the 'French paradox'. The analytical method is based on high-performance liquid chromatography coupled to fluorescence detection, exploiting the native fluorescence of the analytes. A C8 column was used as the stationary phase, while the mobile phase was composed of acidic phosphate buffer and acetonitrile; fluorescence intensity was monitored at λ=386nm while exciting at λ=298nm. The sample pretreatment was carried out by a fast and reliable microextraction by packed sorbent (MEPS) procedure. After validation, the method was applied to the analysis of melatonin and other antioxidants in food and beverages derived from grape, with very good results being obtained. Thus, this methodology may represent a promising tool for the evaluation of the antioxidant properties of nutraceuticals and functional foods., (© 2011 John Wiley & Sons A/S.)

A rapid, selective and sensitive bioanalytical method was developed and validated for cyclosporin A (CsA) in cat blood samples using dried blood spot (DBS) coupled with high pressure liquid chromatography hyphenated to positive electrospray tandem mass spectrometry (HPLC-ESI-MS/MS). CsA was quantified using a structural analog cyclosporin D (CsD) as internal standard in multiple reaction monitoring mode (MRM) using the transitions 1220→1203 for CsA and 1234→1217 for CsD. A 5-μL blood aliquot was spotted onto a DBS card, then after a drying step, blood spots were punched out from the cards and extracted with MeOH before injection into a LC-MS/MS system. The linear range of the method was 5-2000 ng/mL, with accuracy and precision within the FDA acceptance criteria (i.e., ±15% and ±20% for the lowest level). In the study presented herein a comparison was made between this new methodology, based on the use of DBS, and a previously developed solid phase extraction (SPE) procedure, applied to blood samples from a cat pharmacokinetic study. Good correlation (r(2)=0.97) was demonstrated between the data obtained with the two methods. The DBS methodology revealed to be cheaper, faster, less solvent-consuming and requiring less blood volume from animals than the previous SPE method. Thus, the proposed HPLC-ESI-MS/MS method, based on DBS, has demonstrated to be a suitable and advantageous approach for the analysis of CsA in cat blood., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aim of this paper is to investigate the psychobiological reactions to experimentally induced negative emotional states in active marijuana-dependent smokers and whether changes in emotional reactivity were reversed by prolonged abstinence. Twenty-eight patients were randomly included into group A (fourteen active marijuana-dependent smokers) or group B (fourteen abstinent marijuana-dependent subjects). Emotional response evaluation of group B subjects was assessed after 6 months of abstinence. Fourteen healthy volunteers, matched for age and sex, were used as controls. Psychometric and emotional response evaluations were performed by administering Symptoms Check List-90 and State-Trait Anxiety Inventory Y-1 (STAI). Neutral and unpleasant set of pictures selected from the international affective picture system and the Self-Assesment Manikin procedure (SAM) have been used to determine ratings of pleasure and arousal. Before and after the experimental session, blood samples were collected to determine ACTH and cortisol plasma levels. Active cannabis users displayed significantly higher levels of pleasantness SAM scores and lower levels of arousal SAM scores compared to abstinent cannabis users and controls in response to emotional task. In a close parallel with psychological data, hormonal findings indicate a persistent hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis in cannabis users, particularly among active marijuana smokers, and an impaired hormonal reaction to negative emotions, in comparison with healthy subjects. The capacity of the HPA axis to respond to stressful stimuli/negative emotions seems to be only partially recovered after 6 months of abstinence. Ours findings, although obtained in a small number of subjects, suggest an association between active cannabis use, subjective reduced sensitivity to negative emotions and threat and HPA axis dysfunction.

Membrane transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are efflux pumps that remove drugs from the brain back to the peripheral blood compartment, serving as a functional component of the blood-brain barrier (BBB). We report here that coadministration of the P-gp and BCRP inhibitor ketoconazole with risperidone may preferentially increase D2 receptor occupancy in the striatum compared to pituitary. Four male patients with schizophrenia or schizoaffective disorder who had received at least 4 prior injections of the long-acting risperidone at a stable dose of 25 to 50 mg participated in this positron emission tomography study. Multiple-dose ketoconazole coadministration reduced the P-gp activity as shown by fexofenadine oral challenge. Importantly, we found a strong statistical trend in this sample of 4 subjects who consistently showed a decrease in striatal fluorine 18 (F)-fallypride binding (an indication of increased D2 receptor occupancy) after ketoconazole coadministration (P = 0.057), whereas the pituitary (a region that lies outside the BBB) F-fallypride binding did not change (P = 0.99). These observations warrant further research with selective drug transporter inhibitors. We suggest that in neuroimaging studies, the pituitary drug occupancy can serve as a useful new "positive control" to evaluate whether drug occupancy is preferentially increased in brain regions that fall inside the BBB after cotreatment with P-gp and BCRP inhibitors. This is a noteworthy study design consideration regarding the future clinical testing of novel adjunct interventions aimed at modulating membrane transporter function at the BBB, with the goal of augmenting drug access into the brain compartment, particularly in treatment-resistant psychiatric illness.

New-generation antidepressants are a heterogeneous class of drugs used in the treatment of depression and related disorders. This review deals with the first new-generation antidepressant class to enter the pharmaceutical market, i.e., selective serotonin reuptake inhibitors (SSRIs), which are still the most prescribed and widely used ones. Their common characteristics are the comparable clinical efficacy, good tolerability and relative safety in comparison to "first generation antidepressants", i.e. classic tricyclic antidepressants and monoamine oxidase inhibitors. This class of drugs includes fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine and, since 2011, vilazodone. In this review, the main pharmacodynamic and pharmacokinetic properties of the six commercially available SSRIs are described, focusing on side and toxic effects, chemical-clinical correlations, interactions with other drugs, the role of therapeutic drug monitoring (TDM) and related bioanalytical methodologies.

A fast analytical method has been developed for the determination of nine amino acids, together with serotonin, in wine samples of different origin and vintage. The method is based on capillary electrophoresis coupled to laser-induced fluorescence detection. Separation was obtained by using a fused-silica capillary (75 μm id, 74.0 cm total length, 60.0 cm length to detector) and a background electrolyte composed of carbonate buffer (20 mM, pH 9.2), applying a 20 kV voltage. Direct hydrodynamic injection of wine samples was made after an original microwave-assisted derivatisation step with 5-(4,6-dichlorotriazinyl)aminofluorescein. Fluorescence was induced by an Ar-Ion laser, exciting at 488 nm. Good linearity (r(2) >0.9990) was obtained for all considered analytes and sensitivity was also good, with limits of detection in the 7-50 ng/mL range. The method was successfully applied for the analysis of commercial Italian wines and thus seems to be suitable for the determination of the relevant amino acids and serotonin, providing good results in terms of accuracy and precision, together with the advantage of a very fast, microwave-assisted derivatisation procedure. Future applications of the method are planned to check for wine adulterations and commercial frauds., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Amphetamines and methadone are synthetic chiral drugs with a high potential for abuse. As such, several analytical methods have been developed for their enantioseparation and analysis in biological tissues, and some of these are based on electrodriven techniques. In this review, the most important and recent of these latter methods are reviewed and their main advantages and disadvantages are discussed. Particular attention is paid to the suitability of each method for the application to the biological matrix of interest: while all methods have been successfully applied for one or more biological tissues, to reach this goal they must overcome the sensitivity problem that is common to almost all capillary electrophoretic techniques. Most methods use one or more cyclodextrin derivatives as the chiral selector, thus the separation mechanism is not particularly complicated or unusual., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The sublingual combination of buprenorphine and naloxone (Suboxone(®)) and Methadone Maintenance Therapy have been found effective in treating heroin addiction. A new analytical method suitable for the simultaneous determination of buprenorphine, norbuprenorphine, methadone and naloxone in human plasma by means of liquid chromatography with coulometric detection has been developed. The chromatographic separation was achieved with a phosphate buffer-acetonitrile mixture as the mobile phase on a cyano column. The monitoring cell of the coulometric detector was set at an oxidation potential of +0.600 V. A rapid clean-up procedure of the biological samples using a microextraction by packed sorbent technique has been implemented, employing a C8 sorbent inserted into a syringe needle. The extraction yield values were satisfactory for all analytes (>85%). The calibration curves were linear over a range of 0.25-20.0 ng mL(-1) for buprenorphine and norbuprenorphine, 3.0-1000.0 ng mL(-1) for methadone and 0.13-10.0 ng mL(-1) for naloxone. The sensitivity was also high with limits of detection of 0.08 ng mL(-1) for both buprenorphine and norbuprenorphine, 0.9 ng mL(-1) for methadone and 0.04 ng mL(-1) for naloxone. The intraday and interday precision data were always satisfactory. The method was successfully applied to plasma samples obtained from former heroin addicts treated with opioid replacement therapy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Epidemiological and clinical data show frequent associations between adverse childhood experiences (ACEs) and substance abuse susceptibility particularly in adolescents. A large body of evidences suggests that the possible dysregulation of neuroendocrine responses as well as neurotransmitters function induced by childhood traumatic experiences and emotional neglect could constitute one of the essential biological changes implementing substance abuse vulnerability. Moreover, genotype variables and its environment interactions have been associated with an increased risk for early onset substance abuse. In this paper we present several data that support the hypothesis of the involvement of hypothalamus-pituitary-adrenal (HPA) axis in mediating the combined effect of early adverse experiences and gene variants affecting neurotransmission. The presented data also confirm the relationship between basal plasma levels of cortisol and ACTH, on the one hand, and retrospective measures of neglect during childhood on the other hand: the higher the mother and father neglect (CECA-Q) scores are, the higher the plasma levels of the two HPA hormones are. Furthermore, such positive relationship has been proved to be particularly effective and important when associated with the "S" promoter polymorphism of the gene encoding the 5-HTT transporter, both in homozygote and heterozygote individuals., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents.

A novel analytical approach has been developed for the determination of clozapine and its metabolites in dried blood spots on filter paper, using a chromatographic method coupled with a microextraction by packed sorbent procedure. The analytes were separated on a RP-C18 column using a mobile phase composed of 20% methanol, 16% acetonitrile and 64% aqueous phosphate buffer. Coulometric detection was used, setting the guard cell at +0.050 V, the first analytical cell at -0.200 V and the second analytical cell at +0.500 V. Clozapine and its metabolites were extracted from dried blood spots with phosphate buffer and, then, a microextraction by packed sorbent procedure for the sample clean-up was implemented obtaining good extraction yields. The calibration curve was linear over the 2.5-1000 ng mL(-1) blood concentration ranges for all the analytes. The method validation gave satisfactory results in terms of sensitivity, precision, selectivity and accuracy. The analytical method was successfully applied to dried blood spots from several psychiatric patients for therapeutic drug monitoring purpose., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of the study was the development of analytical methods suitable for the quantification of L-dopa, carbidopa and entacapone in plasma of Parkinsonian patients treated with Stalevo(®). The metabolite 3-O-methyldopa was also determined to obtain some indications on the pharmacokinetics of L-dopa. For the simultaneous analysis of L-dopa, 3-O-methyldopa and carbidopa, a RP C18 column as the stationary phase and a mixture of methanol and a pH 2.88 phosphate buffer (8:92, v/v) as the mobile phase were used. A feasible plasma pre-treatment based on protein precipitation was implemented, obtaining extraction yield higher than 94% for all the analytes. For the analysis of entacapone a RP C8 column and a mixture of methanol, acetonitrile and a pH 1.90 phosphate buffer as the mobile phase (17.5:22.5:60, v/v/v) were used. A plasma pre-treatment procedure was developed, based on solid phase extraction of entacapone using Oasis HLB cartridges. Extraction yields were good, being always higher than 96%. Both methods, based on HPLC-ED (V=+0.8V), have been fully validated. Good linearity was obtained over the following concentration ranges: 100-4000 ng mL(-1) for L-dopa, 200-10,000 ng mL(-1) for 3-O-methyldopa, 25-4000 ng mL(-1) for carbidopa and 20-4000 ng mL(-1) for entacapone. Precision data were satisfactory, being R.S.D.% values lower than 5.64%; accuracy also resulted very good with recovery data higher than 90%. The proposed methods have been successfully applied to the analysis of patient plasma samples and seem to be suitable for therapeutic drug monitoring purposes., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Risperidone is currently one of the most frequently prescribed atypical antipsychotic drugs; its main active metabolite 9-hydroxyrisperidone contributes significantly to the therapeutic effects observed. An original analytical method is presented for the simultaneous analysis of risperidone and the metabolite in plasma, urine and saliva by high-performance liquid chromatography coupled to an original sample pre-treatment procedure based on micro-extraction by packed sorbent (MEPS). The assays were carried out using a C8 reversed-phase column and a mobile phase composed of 73% (v/v) acidic phosphate buffer (30 mM, pH 3.0) containing 0.23% triethylamine and 27% (v/v) acetonitrile. The UV detector was set at 238 nm and diphenhydramine was used as the internal standard. The sample pre-treatment by MEPS was carried out on a C8 sorbent. The extraction yields values were higher than 92% for risperidone and 90% for 9-hydroxyrisperidone, with RSD for precision always lower than 7.9% for both analytes. Limit of quantification values in the different matrices were 4 ng/mL or lower for risperidone and 6 ng/mL or lower for the metabolite. The method was successfully applied to plasma, urine and saliva samples from psychotic patients undergoing therapy with risperidone, with satisfactory accuracy results (recovery>89%) and no interference from other drugs. Thus, the method seems to be suitable for the therapeutic drug monitoring of schizophrenic patients using the three different biological matrices plasma, urine and saliva., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A rapid capillary zone electrophoresis method with indirect UV detection for the determination of topiramate in human plasma was developed and validated. The analyses were carried out with a background electrolyte composed of 10mM sulfamethoxazole as chromophore in phosphate buffer (25 mM, pH 12.0); gabapentin was selected as the internal standard. Application of a voltage of +15 kV led to an analysis time shorter than 5 min; indirect UV detection was operated at 256 nm. Isolation of topiramate from plasma was accomplished by a carefully implemented solid-phase extraction procedure on C18 cartridges. The method provided a linear response over the concentration range of 2-60 microg of topiramate per mL of plasma. The limit of detection (LOD) was 0.8 microg mL(-1) and the limit of quantitation (LOQ) was 2.0 microg mL(-1). Precision, expressed as relative standard deviation, was always lower than 7.3%, extraction yields were always greater than 92%. The results obtained analysing plasma samples from epileptic patients undergoing therapy with topiramate were satisfactory in terms of precision and selectivity., (Copyright 2010 Elsevier B.V. All rights reserved.)

An original HPLC method coupled to spectrofluorimetric detection is presented for the simultaneous analysis in dried blood spots (DBS) of cocaine and two important metabolites, namely benzoylecgonine (its main metabolite) and cocaethylene (the active metabolite formed in the presence of ethanol). The chromatographic analysis was carried out on a C8 column, using a mobile phase containing phosphate buffer (pH 3.0)-acetonitrile (85:15, v/v). Native analyte fluorescence was monitored at 315 nm while exciting at 230 nm. A fast and feasible sample pre-treatment was implemented by solvent extraction, obtaining good extraction yields (>91%) and satisfactory precision values (RSD<4.8%). The method was successfully applied to DBS samples collected from some cocaine users, both with and without concomitant ethanol intake. The results were in good agreement with those obtained from plasma samples subjected to an original solid-phase extraction procedure on C8 cartridges. The method has demonstrated to be suitable for the monitoring of cocaine/ethanol use by means of DBS or plasma testing. Assays are in progress to apply this method on the street, for the control of subjects suspected of driving under the influence of psychotropic substances., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A reliable chromatographic method for the determination of soy isoflavones (genistein, daidzein and glycitein) using a coulometric detection has been developed and applied to analyse plasma of postmenopausal women. The chromatographic separation was performed on a C18 reversed phase column with a mobile phase composed of acetonitrile-phosphate buffer mixture. Coulometric detection was carried out at +0.500 V. A careful and rapid solid phase extraction procedure on hydrophilic/lipophilic cartridges was chosen for plasma sample purification with and without hydrolysis obtaining good extraction yield values for all the analytes (>90.0%). The enzymatic hydrolysis step was necessary for the determination of the total amount of soy isoflavones. The limit of quantitation was 0.5 ng mL(-1) for genistein and 0.25 ng mL(-1) for daidzein and glycitein. The method was found to be precise and accurate. Thus, the proposed method is suitable for the analysis of soy isoflavones (free and total amounts) in plasma of postmenopausal women under treatment with the SoymenGN dietary supplement., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

An isocratic high-performance liquid-chromatographic method has been developed for the simultaneous determination of disulfiram and bupropion in human plasma samples. Analyses were carried out on a C(8) reversed-phase column using a mobile phase composed of 50% acetonitrile and 50% aqueous phosphate buffer, containing triethylamine. Diode-array detection was used, operating at a wavelength of 250 nm. For the clean-up of plasma samples, a solid phase extraction procedure, based on C(2) cartridges, was implemented. Extraction yields of the analytes were satisfactory, being always higher than 84%. The calibration curve was linear over the 5-500 ng mL(-1) plasma concentration range for both disulfiram and bupropion. The method showed a high sensitivity (limit of detection of 1.5 ng mL(-1)) and satisfactory precision, selectivity and accuracy. The application to human plasma samples obtained from some alcohol and nicotine abusers also gave good results.

A review with 132 references. Several kinds of anxiolytic and hypnotic drugs are currently available on the market. Although BZDs are surely the most frequently prescribed among them, several chemically unrelated compounds have been commercialised, which can provide similar or even higher efficacy and tolerability. These drugs can prove useful for patients who are non-responder or intolerant to benzodiazepine treatment, thus giving broader therapeutic options to the clinician. The most important studies on the metabolic characteristics of several non-benzodiazepine anxiolytics and hypnotics are reported and briefly discussed in this review; moreover, the analytical methods related to these studies are also described and commented upon and their characteristics are highlighted. Finally, an update is included on recent (2007-2010) metabolism and pharmacokinetic studies on benzodiazepines. A monograph is included for each of the following drugs: zolpidem, zaleplon, zopiclone, ramelteon, buspirone and tandospirone; updates are included for the following benzodiazepines: alprazolam, bromazepam, diazepam, flunitrazepam, lorazepam, midazolam, oxazepam and triazolam.

An original high-performance liquid chromatographic method with fluorescence detection is presented for the simultaneous determination of the three antiepileptic drugs gabapentin, vigabatrin and topiramate in human plasma. After pre-column derivatisation with dansyl chloride, the analytes were separated on a Hydro-RP column with a mobile phase composed of phosphate buffer (55%) and acetonitrile (45%) and detected at lambda(em)=500 nm, exciting at 300 nm. An original pre-treatment procedure on biological samples, based on solid-phase extraction with MCX cartridges for gabapentin and vigabatrin, and with Plexa cartridges for topiramate, gave high extraction yields (>91%), satisfactory precision (RSD<6.4%) and good selectivity. Linearity was found in the 0.2-50.0 microg mL(-1) range for gabapentin, in the 1.0-100.0 microg mL(-1) range for vigabatrin and in the 1.0-50.0 microg mL(-1) range for topiramate, with limits of detection (LODs) between 0.1 and 0.3 microg mL(-1). After validation, the method was successfully applied to some plasma samples from patients undergoing therapy with one or more of these drugs. Accuracy results were satisfactory (recovery >91%). Therefore, the method seems to be suitable for the therapeutic drug monitoring (TDM) of patients treated with gabapentin, vigabatrin and topiramate., (Copyright 2010 Elsevier B.V. All rights reserved.)

This article proposes a chromatographic method for the analysis of extracts of Aloe plants. The method was developed with a laboratory assembled nano-LC system coupled with a UV detector, followed by an IT-mass spectrometer. With a step gradient mode of ACN/H(2)O mixtures and employing a capillary column packed with C(18) (100 μm id), a complete separation of the following anthrones was achieved: aloin (in its two isomeric forms A and B), 5-hydroxyaloin and 7-hydroxyaloin (in its two isomeric forms A and B). The optimized nano-LC-MS method was validated for the quantification of aloin, the main component of Aloe with known pharmacological activities. RSD values obtained for retention time and peak areas were 1.3 and 12.1%, respectively. LOD and LOQ values of 0.4 and 1.5 μg/mL were obtained for each aloin isomer. The method was applied to the analysis of Aloe vera and A. ferox extracts in order to acquire a fingerprint, characteristic for each plant. Several phenolic compounds were detected by UV and identified by MS. A. vera and A. ferox showed different profiles and it was possible to discriminate them. Several commercial formulations, declared to contain Aloe extracts, were analyzed. Comparing their chromatograms with those obtained from A. vera and A. ferox, it was possible to recognize the Aloe species and to determine aloin.

A CE method has been developed for the simultaneous analysis of the adrenergic amines synephrine, octopamine and tyramine in Citrus aurantium (bitter orange) fruit extracts and in dietary supplements. The analytes were separated on a fused silica capillary (50 microm id, 40.0 cm effective length, 48.5 cm total length) using a BGE composed of phosphate buffer (pH 2.5, 50 mM) and applying a 30 kV potential. The samples were injected hydrodynamically at 50 mbar for 25 s. The use of photodiode array detection (lambda=195 nm) allowed the quantification of the analytes and the control of peak purity. The method has been fully validated, obtaining satisfactory values of precision and extraction yield. The analytes are extracted with water from the dried whole fruits or fruit parts (endocarp, mesocarp and exocarp) or from the commercial formulations and directly injected into the CE apparatus. The results obtained were satisfactory in terms of precision (RSD < 5.7%) and accuracy (recovery > 89%). Thus, the method has demonstrated to be suitable for the qualitative and quantitative determination of synephrine, octopamine and tyramine in C. aurantium extracts, for dietary supplement quality control and for food adulteration identification.

An isocratic high-performance liquid chromatographic method has been developed for the measurement of serotonin, 5-hydroxyindolacetic and homovanillic acids in dried blood spots and in platelet poor and rich plasma samples. Analyses were carried out on a C18 reversed-phase column using a mobile phase composed of 13% methanol and 87% aqueous citrate buffer, containing octanesulfonic and ethylendiaminotetracetic acids. Coulometric detection was used, setting the guard cell at +0.100 V, the first analytical cell at -0.200 V and the second analytical cell at +0.400 V. For the pre-treatment of biological samples a novel solid-phase extraction procedure, based on mixed-mode reversed-phase--strong anion exchange Oasis cartridges, was implemented. Extraction yields of the analytes from all these matrices were satisfactory, being always higher than 89.0%. The calibration curve was linear over the on-column concentration range of 0.1-22.5 ng mL(-1) for serotonin and 5-hydroxyindolacetic acid and of 0.25-22.5 ng mL(-1) for homovanillic acid. The sensitivity was good with a limit of detection of 0.05 ng mL(-1) for serotonin and 5-hydroxyindolacetic acid and 0.12 ng mL(-1) for homovanillic acid. Results were also satisfactory in terms of precision, selectivity and accuracy. The analytical method was successfully applied to human platelet poor and rich plasma samples and to dried blood spots from volunteers and psychiatric patients., (2010. Published by Elsevier B.V.)

A new analytical method, based on the use of liquid chromatography with coulometric detection, has been developed and applied to quantify risperidone and its main active metabolite 9-hydroxyrisperidone in human plasma and saliva. The analytes were separated on a reversed phase C18 column, using a mobile phase composed of acetonitrile (26%) and a pH 6.5 phosphate buffer (74%). Pipamperone was used as the internal standard. A high sensitivity coulometric detection analytical cell containing two flow-through working electrodes was used: electrode 1 was set at +0.500V and electrode 2 at +0.700V. The detector response was linear over a plasma and saliva concentration range of 0.5-50.0ngmL(-1) for risperidone and 0.5-100.0ngmL(-1) for 9-hydroxyrisperidone. The limit of quantitation and the limit of detection for risperidone and 9-hydroxyrisperidone were 0.5ngmL(-1) and 0.17ngmL(-1), respectively. A novel clean-up procedure of biological samples was developed using the microextraction by packed sorbent technique, which gave good extraction yield for both the analytes, with absolute recovery values higher than 90.1%. The intra-day and the inter-day precision results, expressed by relative standard deviation values, were lower than 5.8%. Accuracy and selectivity assays were also satisfactory. The validated method has been successfully applied to the analysis of risperidone and 9-hydroxyrisperidone in plasma and saliva of psychiatric patients undergoing therapy with risperidone.