Attenuation of the effects of <Emphasis Type="Italic">d</Emphasis>-amphetamine on interval timing behavior by central 5-hydroxytryptamine depletion

Rationale  Interval timing in the free-operant psychophysical procedure is sensitive to the monoamine-releasing agent d-amphetamine, the D₂-like dopamine receptor agonist quinpirole, and the D₁-like agonist 6-chloro-2,3,4,5-tetrahydro-1-phenyl-1H-3-benzepine (SKF-81297). The effect of d-amphetamine can be antagonized by selective D₁-like and 5-HT_2A receptor antagonists. It is not known whether d-amphetamine’s effect requires an intact 5-hydroxytryptamine (5-HT) pathway. Objective  The objective of this study was to examine the effects of d-amphetamine, quinpirole, and SKF-81297 on timing in intact rats and rats whose 5-hydroxytryptaminergic (5-HTergic) pathways had been ablated. Materials and methods  Rats were trained under the free-operant psychophysical procedure to press levers A and B in 50-s trials in which reinforcement was provided intermittently for responding on A in the first half, and B in the second half of the trial. Percent responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic functions were fitted to the data for derivation of timing indices (T ₅₀, time corresponding to %B = 50%; Weber fraction). The effects of d-amphetamine (0.4 mg kg⁻¹ i.p.), quinpirole (0.08 mg kg⁻¹ i.p.), and SKF-81297 (0.4 mg kg⁻¹ s.c.) were compared between intact rats and rats whose 5-HTergic pathways had been destroyed by intra-raphe injection of 5,7-dihydroxytryptamine. Results  Quinpirole and SKF-81297 reduced T ₅₀ in both groups; d-amphetamine reduced T ₅₀ only in the sham-lesioned group. The lesion reduced 5-HT levels by 80%; catecholamine levels were not affected. Conclusions   d-Amphetamine’s effect on performance in the free-operant psychophysical procedure requires an intact 5-HTergic system. 5-HT, possibly acting at 5-HT_2A receptors, may play a ‘permissive’ role in dopamine release.

Effects of MDMA on sociability and neural response to social threat and social reward

Rationale  There has been controversy over the abuse potential of methylphenidate (MPH) in the context of treatment for attention deficit hyperactivity disorder (ADHD). Objective  The objective of this study was to compare the reinforcing and subjective effects of oral MPH in adults with and without ADHD. Materials and methods  Following screening, 33 adults (n = 16 with ADHD; n = 17 free from psychiatric diagnoses) completed four pairs of experimental sessions, each of which included a sampling session and a self-administration session. During sampling sessions, subjects received in randomized order 0 (placebo), 20, 40, and 60 mg MPH. During self-administration sessions, subjects completed a progressive ratio (PR) task to earn portions of the dose received on the corresponding sampling session. Subjective effects were recorded throughout all sessions. The main outcome measure for the study was the number of ratios completed on the PR task. Secondary measures included peak subjective effects and area-under-the-curve values for subjective effects. Results  Compared to the control group, the ADHD group completed more ratios on the PR task. Both groups showed robust effects of methylphenidate on subjective endpoints. Main effects of group were noted on subjective effects involving concentration and arousal. Conclusions  Compared to placebo, MPH produced reinforcing effects only for the ADHD group and not for the control group. Increases in stimulant-related subjective effects in non-ADHD subjects were not associated with drug reinforcement.

Acute tryptophan depletion and self-injurious behavior in aggressive patients and healthy volunteers

Rationale  An association between serotonin (5-HT) activity and self-injurious (i.e., self-aggressive) behavior across the spectrum of lethality (from self-mutilation through completed suicide) is a well-replicated finding. Studies to date, however, have relied on nonexperimental designs to examine this relationship, limiting the causal inferences that can be drawn about the role of 5-HT in self-aggressive behavior. Objective  Examine the effect of experimentally altered 5-HT activity (via dietary tryptophan depletion) on self-aggressive behavior among adults with and without intermittent explosive disorder (IED). Individuals with a marked history of aggression, such as those with IED, are characterized by compromised 5-HT and heightened risk for self-aggression, making this a population of interest for examining the proposed relations. Materials and methods  IED patients (n = 16) and healthy controls (n = 16) received a tryptophan depletion and a placebo drink on separate days at least 1 week apart. Self-aggressive behavior was assessed on both study days using a well-validated laboratory-based behavioral assessment with self-aggression defined as the intensity of shock self-administered. Results  Tryptophan depletion facilitated selection of more intense shocks, on average, in both groups. Patients with IED were also more self-aggressive overall than healthy volunteers. No IED by drink condition interactions were found. Conclusion  Experimentally lowered 5-HT bioavailability enhances overall self-injurious behavior irrespective of aggression history.

Facilitators for practice change in Spanish community pharmacy

Objective To identify and prioritise facilitators for practice change in Spanish community pharmacy. Setting Spanish community pharmacies. Method Qualitative study. Thirty-three semi-structured interviews were conducted with community pharmacists (n = 15) and pharmacy strategists (n = 18), and the results were examined using the content analysis method. In addition, two nominal groups (seven community pharmacists and seven strategists) were formed to identify and prioritise facilitators. Results of both techniques were then triangulated. Main outcome measures Facilitators for practice change. Results Twelve facilitators were identified and grouped into four domains (D1: Pharmacist; D2: Pharmacy as an organisation; D3: Pharmaceutical profession; D4: Miscellaneous). Facilitators identified in D1 include: the need for more clinical education at both pre- and post-graduate levels; the need for clearer and unequivocal messages from professional leaders about the future of the professional practice; and the need for a change in pharmacists’ attitudes. Facilitators in D2 are: the need to change the reimbursement system to accommodate cognitive service delivery as well as dispensing; and the need to change the front office of pharmacies. Facilitators identified in D3 are: the need for the Spanish National Professional Association to take a leadership role in the implementation of cognitive services; the need to reduce administrative workload; and the need for universities to reduce the gap between education and research. Other facilitators identified in this study include: the need to increase patients’ demand for cognitive services at pharmacies; the need to improve pharmacist-physician relationships; the need for support from health care authorities; and the need for improved marketing of cognitive services and their benefits to society, including physicians and health care authorities. Conclusion Twelve facilitators were identified. Strategists considered clinical education and pharmacists’ attitude as the most important, and remuneration of little importance. Community pharmacists, in contrast, considered remuneration as the most important facilitator for practice change.

Identification of Novel Specific and General Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp,BCRP and MRP2 Among Registered Drugs

Purpose  To study the inhibition patterns of the three major human ABC transporters P-gp (ABCB1), BCRP (ABCG2) and MRP2 (ABCC2), using a dataset of 122 structurally diverse drugs. Methods  Inhibition was investigated in cellular and vesicular systems over-expressing single transporters. Computational models discriminating either single or general inhibitors from non-inhibitors were developed using multivariate statistics. Results  Specific (n = 23) and overlapping (n = 19) inhibitors of the three ABC transporters were identified. GF120918 and Ko143 were verified to specifically inhibit P-gp/BCRP and BCRP in defined concentration intervals, whereas the MRP inhibitor MK571 was revealed to inhibit all three transporters within one log unit of concentration. Virtual docking experiments showed that MK571 binds to the ATP catalytic site, which could contribute to its multi-specific inhibition profile. A computational model predicting general ABC inhibition correctly classified 80% of both ABC transporter inhibitors and non-inhibitors in an external test set. Conclusions  The inhibitor specificities of P-gp, BCRP and MRP2 were shown to be highly overlapping. General ABC inhibitors were more lipophilic and aromatic than specific inhibitors and non-inhibitors. The identified specific inhibitors can be used to delineate transport processes in complex experimental systems, whereas the multi-specific inhibitors are useful in primary ABC transporter screening in drug discovery settings. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response

Purpose  The success of nucleic acid therapies depends upon delivery vehicle’s ability to selectively and efficiently deliver therapeutic nucleic acids to target organ with minimal toxicity. The cationic polymer polyethylenimine (PEI) has been widely used for nucleic acid delivery due to its versatility and efficiency. In particular, the last generation of linear PEI (L-PEI) is being more efficient in vivo than the first generation of branched PEI. This led to several clinical trials including phase II bladder cancer therapy and human immunodeficiency virus immunotherapy. When moving towards to the clinic, it is crucial to identify potential side-effects induced by the delivery vehicle. Materials and Methods  For this purpose we have analyzed the production of pro-inflammatory cytokines [tumor necrosis factor-α, interferon (IFN)-γ, interleukin (IL)-6, IL-12/IL-23, IFN-β and IL-1β] and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase) in the blood serum of mice after systemic injection of DNA or siRNAs delivered with L-PEI. Results  Our data show no major production of pro-inflammatory cytokines or hepatic enzymes after injection of DNA or oligonucleotides active for RNA interference (siRNAs or sticky siRNAs) complexed with L-PEI. Only a slight induction of IFN-γ was measured after DNA delivery, which is probably induced by the CpG mediated response. Conclusion  Taken together our data highlight that linear polyethylenimine is a delivery reagent of choice for nucleic acid therapeutics.

Organoprotection and cytoprotection of histamine differ in rats

Aims  The aim of the present study was to compare the organoprotective (in vivo) and cytoprotective (in vitro) effects of histamine. Methods  In vivo, gastric mucosal damage was produced by intragastric (ig) administration of 1 ml 96% ethanol (EtOH) in Sprague-Dawley rats. The animals were sacrificed 1 h after EtOH administration, when the gastric mucosal damage was measured. Histamine was given subcutaneously (sc) 30 min before administration of EtOH with and without PGI₂Na (5 μg/kg sc). Gastric acid secretion was also measured 1 h after pylorus ligation in control (saline-), histamine- and PGI₂-treated animals. The affinity, intrinsic activity curves and the values of pD₂ and pA₂ were determined in EtOH-treated and in PGI₂-treated animals. For the in-vitro studies, a mixed population of rat gastric mucosal cells was isolated by pronase digestion. Cells were preincubated for 60 min with histamine (10^♪−8-10⁻⁶ mol/L) with or without PGI₂Na (10⁻⁴ mol/L). At the end of this incubation period, cells were treated with 15% EtOH with or without 10⁻⁶-10³ mol/L indomethacin (IND) for 5 min. Cell viability was tested by trypan blue exclusion test and succinic dehydrogenase activity. Results  

Safety of an injection with a mixture of extracts from Herba Artemisiae annuae, Fructus Gardeniae and Flos Lonicerae

Objective This study aimed to evaluate the safety for an injection with a mixture of extracts from Herba Artemisiae annuae, Fructus Gardeniae and Flos Lonicerae and to determine the risk factors that may affect its adverse drug reactions. Methods A drug-oriented prospective observational study was performed. Physicians filled in clinical observation forms with detailed information of the patients including general information, drug information, therapeutic effects and adverse drug events. The adverse drug reaction factors were analyzed by both mono-factor and multiple-factor logistic regression methods. Results From April to July 2007, we collected 12,427 observation forms from 46 hospitals in Jiangsu Province of China. Among the 11,707 observation forms we analyzed, 8,074 patients were children younger than 14 years old (69%). Among 51 reported adverse drug events, 45 cases were adverse drug reactions. The total adverse drug reaction incidence of the injection was 0.38%. While most adverse drug reactions were previously known (e.g., rash, pruritus, vomiting and diarrhea), we observed three new ADR symptoms: shiver, phlebitis and anhelation. All the adverse drug reactions were controlled very well through the follow-up therapy, and none of them was life threatening. The mono-factor analysis showed that adverse drug reactions of the injection were significantly correlated with total medication dose (P = 0.0049) and combination medication (P = 0.0143), especially with antimicrobial drugs (P = 0.0079) and macrolides (P = 0.0017). The multiple factor analysis confirmed these results: medication dosage and combination medication had a crucial impact on adverse drug reactions of the injection; the risk was increased by 24.8% (the estimated value of relative risk was 1.248, 95% confidence interval: 1.054–1.479) and 89% (1.890, 1.001–3.566), respectively. Conclusion The total adverse drug reaction incidence of the injection was 0.38% and lower than we expected. Moreover, we observed three new adverse drug reactions, none of which was severe.

Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding

Background and objectives  The idea that nucleus accumbens (Acb) dopamine transmission contributes to the neural mediation of reward, at least in a general sense, has achieved wide acceptance. Nevertheless, debate remains over the precise nature of dopamine’s role in reward and even over the nature of reward itself. In the present article, evidence is reviewed from studies of food intake, feeding microstructure, instrumental responding for food reinforcement, and dopamine efflux associated with feeding, which suggests that reward processing in the Acb is best understood as an interaction among distinct processes coded by discrete neurotransmitter systems. Results  In agreement with several theories of Acb dopamine function, it is proposed here that allocation of motor effort in seeking food or food-associated conditioned stimuli can be dissociated from computations relevant to the hedonic evaluation of food during the consummatory act. The former appears to depend upon Acb dopamine transmission and the latter upon striatal opioid peptide release. Moreover, dopamine transmission may play a role in ‘stamping in’ associations between motor acts and goal attainment and perhaps also neural representations corresponding to rewarding outcomes. Finally, evidence is reviewed that amino acid transmission specifically in the Acb shell acts as a central ‘circuit breaker’ to flexibly enable or terminate the consummatory act, via descending connections to hypothalamic feeding control systems. Conclusions  The heuristic framework outlined above may help explain why dopamine-compromising manipulations that strongly diminish instrumental goal-seeking behaviors leave consummatory activity relatively unaffected.

Accurate Potentiometric Determination of Lipid Membrane–Water Partition Coefficients and Apparent Dissociation Constants of Ionizable Drugs: Electrostatic Corrections

Purpose  Potentiometric lipid membrane–water partition coefficient studies neglect electrostatic interactions to date; this leads to incorrect results. We herein show how to account properly for such interactions in potentiometric data analysis. Materials and Methods  We conducted potentiometric titration experiments to determine lipid membrane–water partition coefficients of four illustrative drugs, bupivacaine, diclofenac, ketoprofen and terbinafine. We then analyzed the results conventionally and with an improved analytical approach that considers Coulombic electrostatic interactions. Results  The new analytical approach delivers robust partition coefficient values. In contrast, the conventional data analysis yields apparent partition coefficients of the ionized drug forms that depend on experimental conditions (mainly the lipid-drug ratio and the bulk ionic strength). This is due to changing electrostatic effects originating either from bound drug and/or lipid charges. A membrane comprising 10 mol-% mono-charged molecules in a 150 mM (monovalent) electrolyte solution yields results that differ by a factor of 4 from uncharged membranes results. Conclusion  Allowance for the Coulombic electrostatic interactions is a prerequisite for accurate and reliable determination of lipid membrane–water partition coefficients of ionizable drugs from potentiometric titration data. The same conclusion applies to all analytical methods involving drug binding to a surface.

A neurocomputational account of catalepsy sensitization induced by D2 receptor blockade in rats: context dependency,extinction, and renewal

Rationale  Repeated haloperidol treatment in rodents results in a day-to-day intensification of catalepsy (i.e., sensitization). Prior experiments suggest that this sensitization is context-dependent and resistant to extinction training. Objectives  The aim of this study was to provide a neurobiological mechanistic explanation for these findings. Materials and methods  We use a neurocomputational model of the basal ganglia and simulate two alternative models based on the reward prediction error and novelty hypotheses of dopamine function. We also conducted a behavioral rat experiment to adjudicate between these models. Twenty male Sprague–Dawley rats were challenged with 0.25 mg/kg haloperidol across multiple days and were subsequently tested in either a familiar or novel context. Results  Simulation results show that catalepsy sensitization, and its context dependency, can be explained by “NoGo” learning via simulated D2 receptor antagonism in striatopallidal neurons, leading to increasingly slowed response latencies. The model further exhibits a non-extinguishable component of catalepsy sensitization due to latent NoGo representations that are prevented from being expressed, and therefore from being unlearned, during extinction. In the rat experiment, context dependency effects were not dependent on the novelty of the context, ruling out the novelty model’s account of context dependency. Conclusions  Simulations lend insight into potential complex mechanisms leading to context-dependent catalepsy sensitization, extinction, and renewal. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study

Rationale  Bifeprunox is a partial dopamine agonist with a unique receptor-binding profile and potential antipsychotic properties. Objectives  The current study evaluated the efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia. Materials and methods  In this 6-week, double-blind, placebo-controlled study, 589 patients were randomly assigned to once-daily treatment with bifeprunox 5, 10, or 20 mg, placebo, or risperidone 6 mg. Efficacy was assessed by changes in symptom rating scales [Positive and Negative Syndrome Scale (PANSS) total and subscale scores; PANSS-derived BPRS scores; Clinical Global Impression—Severity (CGI—S) and Clinical Global Impression—Improvement (CGI—I) scores]. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms (EPS), laboratory values, electrocardiograms, prolactin levels, and weight. Results  Compared with placebo, bifeprunox 20 mg produced a statistically significantly greater reduction from baseline to last assessment in the primary efficacy variable (PANSS total score; effect size = −0.339), as well as most secondary efficacy measures. No statistically significant differences in efficacy were seen with lower doses of bifeprunox. The most common treatment-emergent adverse events (TEAEs) noted with bifeprunox were gastrointestinal; no clear dose-related trend in the incidence of any TEAE was observed in the bifeprunox groups. Compared to placebo, treatment with bifeprunox led to small but statistically significant decreases in weight and prolactin levels. EPS were comparable between bifeprunox and placebo. The active reference in this study, risperidone 6 mg, showed statistically significant differences from placebo for the primary efficacy parameter (effect size = −0.628) and all secondary efficacy parameters. Conclusions  These data suggest that 20 mg of bifeprunox may be efficacious in improving symptoms in patients with an acute exacerbation of schizophrenia. Bifeprunox appeared to be safe and well tolerated by patients in this 6-week study.

The botanical origin of kratom (<Emphasis Type="Italic">Mitragyna speciosa</Emphasis>; Rubiaceae) available as abused drugs in the Japanese markets

Kratom is the leaves of Mitragyna speciosa (Rubiaceae). Recently, kratom has been sold in street shops or on the Internet in Japan for the purpose of abuse due to its opium-like effects. In this study, we investigated the botanical origin of the commercial kratom products using the internal transcribed spacer (ITS) sequence analysis of rDNA in preparation for future regulation of this product. In addition, a previously reported method to authenticate the plant, utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to the same products in order to estimate the method’s accuracy and utility. The ITS sequence analysis of the commercial kratoms revealed that most of them were derived from M. speciosa or closely related plants, while the others were made from the same tribe plant as M. speciosa. The reported PCR-RFLP method could clearly distinguish kratoms from the other psychoactive plants available in the Japanese markets and also from related plants. The authentication method is considered to be useful for the practical regulation of the plant due to its wide range of application, high accuracy and simplicity. Electronic supplementary material  The online version of this article () contains supplementary material, which is available to authorized users.