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1.
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.
相似文献
Daniel E. CaseyEmail: |
2.
This paper discusses the development of engineering controls and automation strategy required to practically implement a Control
Strategy within a Quality by Design environment. It describes the relationship to the ISPE PQLI Control Strategy model, and
covers operating philosophy, record keeping, data management, and alarm strategy. Engineering and automation controls may
include measurement technologies for equipment parameters (off-line, at-line, in-line or on-line), univariate or multivariate
process models and control models, engineering or plant procedural controls and automation systems. Concepts from ANSI/ISA
S95 standards are applied.
相似文献
Stephen Tyler (Corresponding author)Email: |
3.
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.
相似文献
Scott H. KollinsEmail: |
4.
5.
This study evaluated the health of the marine ecosystem in Lavaca Bay, Texas using the Eastern oyster (Crassostrea virginica) as the sentinel species. Lavaca Bay has a history of having gradients of concentrations of pollutants present with some
areas containing concentrations high enough to pose a threat to marine ecosystem health. The Comet assay was used to evaluate
for the presence of genotoxic response in oyster hematocytes. Bayesian geostatistical analysis was then used to determine
if the DNA damage in oyster hematocytes was spatially oriented and to develop continuous surface maps of the risk of DNA damage
in this sentinel species. Results indicated that proximity to industrial facilities increased the locational risk of genotoxicity
in this species.
相似文献
Wesley Bissett Jr.Email: |
6.
This paper describes progress made by the Criticality Task Team within the ISPE PQLI initiative. It aims to provide a concise,
coherent, and universal approach for determining criticality for parameters, material attributes, conditions, and quality
attributes. The work also clarifies the risk based distinctions governing the assignment of criticality to provide consistency
and facilitate the adoption and implementation of Quality by Design (QbD) principles in the development of pharmaceutical
manufacturing processes. The application of the concept of criticality presented in this paper aligns with the principles
of ICH Q8, Q9 and Q10 guidelines.
相似文献
Tom SchultzEmail: |
7.
William A. Corrigall 《Psychopharmacology》2009,206(1):23-37
Background The hypocretin/orexin system has been implicated in arousal mechanisms, sleep, and sleep disorders, including narcolepsy,
and more recently in drug addiction. Theoretically, hypocretin (hcrt) mechanisms appear to be potential substrates for nicotine
addiction: arousal and attentional mechanisms influence use and withdrawal symptoms, and hcrt systems overlap anatomically
with a number of brain regions associated with nicotine addiction.
Objective This review summarizes the studies that have examined hcrt mechanisms in the effects of nicotine and describes hcrt innervation
of, and effects in, several brain regions implicated in nicotine addiction. The review speculates on the possible mechanisms
by which hcrt may contribute to nicotine addiction in these regions, with the objective of encouraging research in this area.
Results In a small literature, both experimenter-administered and self-administered nicotine have been shown to elicit or depend on
hcrt signaling. However, although untested in experimental designs, there is compelling evidence that hcrt mechanisms in the
ventral tegmental area, the pontine region, thalamocortical circuits, the prefrontal cortex, and the amygdala could have a
broad influence on nicotine addiction.
Conclusions Evidence reviewed leads to the conclusion that hcrt mechanisms could mediate several dimensions of nicotine addiction, including
a multi-faceted regulation of mesocorticolimbic dopaminergic function, but beyond dopaminergic mechanisms, hcrt could influence
nicotine use and relapse during abstinence through broadly based arousal/attentional effects. These speculative ideas need
to be examined experimentally; the potential gains are a more thorough understanding of the pathophysiology of nicotine addiction,
and the discovery of novel targets for the development of pharmacotherapeutics.
相似文献
William A. CorrigallEmail: |
8.
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.
相似文献
Michael J. Frank (Corresponding author)Email: |
9.
Takuro Maruyama Ahmed Abbaskhan Muhammad Iqbal Choudhary Yoshisuke Tsuda Yukihiro Goda Michel Farille Jean-Pierre Reduron 《Journal of natural medicines》2009,63(3):248-253
In the course of our study on the traditional medicines and foodstuffs used in Pakistan, we investigated the origin of Indian
celery by using the analysis of the internal transcribed spacer (ITS) sequence of nuclear rDNA and a phytochemical approach.
We found that the source plant of the Indian celery containing coumarin derivatives such as seselin (1), bergapten (2) and isopimpinellin (3) was not common celery, Apium graveolens. Our results suggest the source plant is Seseli diffusum even though Indian workers reported that A. graveolens seeds contain the aforementioned compounds. In addition, a market survey of the Indian celery in Pakistan and related countries
revealed that the Indian celery seeds in Pakistani markets are mainly composed of three species which have been confused in
rural markets.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
相似文献
Takuro MaruyamaEmail: |
10.
This paper gives an overview of progress made by the ISPE PQLI initiative - a global industry-led initiative aimed at facilitating
the implementation of ICH Q8, Q9, and ultimately Q10 guidance. Through this initiative ISPE is spearheading the effort to
help industry begin to define areas where they will be able to provide the technical framework for the implementation of key
elements of Quality by Design (QbD) - a systematic approach to development that begins with predefined objectives and emphasizes
product and process understanding based on sound science and quality risk management. Three topic areas, Design Space, Criticality,
and Control Strategy were selected for specific focus and discussion, and this paper gives an overview of progress in these
three areas.
相似文献
Roger NosalEmail: |
11.
Bissett W Smith R Adams LG Field R Moyer W Phillips T Scott HM Thompson JA 《Ecotoxicology (London, England)》2009,18(1):87-93
This study, performed at the behest of ranchers living and working down-prevailing wind from industrial facilities located
in Calhoun County, Texas investigated locational risks to ecosystem health associated with proximity to specific industrial
complexes. Concerns expressed were for potential genotoxicity in cattle resulting from the release of complex chemical mixtures.
The Comet Assay and flow cytometric evaluation of variations in DNA content were utilized to evaluate DNA damage. Bayesian
geo-statistical analysis revealed the presence of important spatial processes. The Comet assay’s optical density provided
a strong indication of increased damage down-prevailing wind from the industrial complexes. Results indicated that proximity
to and location down-prevailing winds from industrial facilities increased the locational risk of genotoxicity in this sentinel
species.
相似文献
Wesley Bissett Jr.Email: |
12.
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.
相似文献
Gregor Cevc (Corresponding author)Email: |
13.
Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding 总被引:9,自引:6,他引:3
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.
相似文献
Brian A. BaldoEmail: |
14.
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.
相似文献
Anne-Laure Bolcato-BelleminEmail: |
15.
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.
相似文献
Michael S. McCloskeyEmail: |
16.
Takuro Maruyama Maiko Kawamura Ruri Kikura-Hanajiri Hiromitsu Takayama Yukihiro Goda 《Journal of natural medicines》2009,63(3):340-344
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.
相似文献
Yukihiro GodaEmail: |
17.
Pär Matsson Jenny M. Pedersen Ulf Norinder Christel A. S. Bergström Per Artursson 《Pharmaceutical research》2009,26(8):1816-1831
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.
相似文献
Per ArturssonEmail: |
18.
Background Stimuli from the terminal phase of smoke or drug intake are paired with drug effect but have surprisingly low cue reactivity.
Smoking terminal stimuli were compared to cues under conditions of different perceived smoke intake to probe whether (1) terminal
stimuli are only weak cues, (2) any effect is an artifact of rigid test conditions, and (3) terminal stimuli have a unique
function during the intake ritual.
Materials and methods Nonabstinent, healthy smokers were tested in three experiments with one-session, within-subject cue reactivity tests. Smoking
terminal stimuli and cues were compared using pictures depicting events after completion (END) and before start of smoke inhalation
(BEGIN). Test pictures were presented alone and in combination with no-go symbols (from no-smoking signs) or with extra cues
to decrease and to increase perceived smoke availability, respectively. Measured were subjective effects and affect modulation
of the startle reflex.
Results END stimuli relative to BEGIN stimuli evoked less subjective craving and pleasure but more arousal. A no-go stimulus, which
reduced reports of intention to smoke, reduced the reactivity to BEGIN but only marginally affected responses to END stimuli.
This was confirmed with different sets of test pictures and using tests with the startle response. An extra cue did not affect
reactivity to a BEGIN stimulus but increased craving and pleasure to the END stimulus, although not to the level of BEGIN
stimuli alone.
Conclusions This first systematic study of terminal stimuli found their effects to be robust and have test generality. They are probably
not weak cues but evoke reactivity, which may oppose reactivity of cues. They may signal poor availability of drug. Methodological,
clinical, and theoretical implications were noted.
相似文献
Ronald F. MuchaEmail: |
19.
S. Body T. H. C. Cheung C. L. Hampson F. S. den Boon G. Bezzina K. C. F. Fone C. M. Bradshaw E. Szabadi 《Psychopharmacology》2009,203(3):547-559
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-HT2A 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-HT2A receptors, may play a ‘permissive’ role in dopamine release.
相似文献
S. BodyEmail: |