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1.
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: |
2.
3.
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: |
4.
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: |
5.
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: |
6.
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: |
7.
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: |
8.
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: |
9.
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: |
10.
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: |
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12.
The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value 下载免费PDF全文
Andreas Svennebring 《Drug development research》2016,77(1):3-11
Preclinical Research |
13.
Barbara Wilhelm Renate Kellert Rainer Schnell Holger Lüdtke Orlando Petrini 《Psychopharmacology》2009,205(4):679-688
Aims An objective physiological test was used to investigate the hangover effect, its time course and dose relationship compared
to placebo and an herbal relaxant.
Methods Pupillographic Sleepiness Test as an objective measurement, Stanford Sleepiness Scale (SSS) and visual analogue scales (VAS)
were used. Study design included: (a) randomised, double-blind, double-dummy, placebo-controlled crossover trial; (b) double-blind,
placebo-controlled, randomised study. Primary end point was the Pupillary Unrest Index (lnPUI).
Results Oxazepam 10 mg did not increase PUI. In the VAS and SSS, there was no increase in sleepiness after the three treatment periods.
Neither 10 nor 30 mg oxazepam caused sedation in healthy volunteers. Subjective and objective sleepiness measures correlated
significantly.
Discussion The lack of sedative effects after vespertine intake of oxazepam (10/30 mg) seems to be relevant with respect to product safety.
With regard to the subjective perception at 30 mg, fatigue rather than sleepiness may be the underlying reason.
相似文献
Barbara WilhelmEmail: |
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15.
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: |
16.
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: |
17.
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: |
18.
19.
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: |
20.
Zhi‐Hao Shi Nian‐Guang Li Qian‐Ping Shi Hao‐Tang Yu‐Ping Tang 《Drug development research》2012,73(6):317-324
Strategy, Management and Health Policy |
Preclinical Research |