共查询到20条相似文献,搜索用时 31 毫秒
1.
Anne Orgle Sordi Flavio Pechansky Felix Henrique Paim Kessler Flávio Kapczinski Bianca Pfaffenseller Carolina Gubert Bianca Wollenhaupt de Aguiar Joana Correa de Magalhães Narvaez Felipe Ornell Lisia von Diemen 《Psychopharmacology》2014,231(20):4031-4039
Rationale
An important goal of addiction research is to discover neurobiological markers that could predict the severity of addiction and help to determine appropriate treatment. Brain-derived neurotrophic factor (BDNF) and thiobarbituric acid reactive substances (TBARS) are being related to cerebral plasticity and impairment caused by substance abuse.Objectives
This study aims to evaluate alteration of TBARS and BDNF levels among crack cocaine users during early drug withdrawal and its relationship to severity of drug use.Methods
Forty-nine adults crack cocaine users were recruited at a public psychiatric hospital with a specialized addiction treatment unit. Blood sample was collected at intake and discharge for the analysis of TBARS and BDNF measures. Information about drug use was assessed by the Addiction Severity Index 6th Version (ASI-6). Detailed information about crack cocaine use was obtained through the “Profile of the crack cocaine user.” Severity of crack use was estimated using information from age of first crack use, years of crack use, and crack rocks used in the previous 30 days.Results
There is a positive correlation between TBARS levels and severity of crack cocaine use (R?=?0.304, p?=?0.04) and a negative correlation between BDNF and severity of crack cocaine use (R?=??0.359, p?=?0.01) at discharge. Also, we found an inverse correlation between TBARS and BDNF levels (R?=??0.294, p?=?0.004) at discharge.Conclusions
Our findings suggest that BDNF and TBARS could be possible markers for the severity of drug use. Further studies may show how those markers could be related to staging, prognosis, and treatment in crack cocaine dependence. 相似文献2.
Rationale
Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized.Objective
To characterize changes in decision making caused by acute pharmacological stress, the effects of yohimbine (an α2-adrenergic antagonist) were examined in a delay discounting task. Noradrenergic contributions to decision making were further characterized by examining the effects of propranolol (a β antagonist), prazosin (an α1 antagonist), and guanfacine (an α2 agonist).Methods
Sprague–Dawley rats were administered drugs prior to performance on a delay discounting task, in which the delay preceding the large reward increased within each session (ascending delays). To dissociate drug-induced changes in delay sensitivity from behavioral inflexibility, drug effects were subsequently tested in a modified version of the discounting task, in which the delay preceding the large reward decreased within each session (descending delays).Results
Yohimbine increased choice of the large reward when tested with ascending delays but decreased choice of the same large reward when tested with descending delays, suggesting that drug effects could be attributed to perseverative choice of the lever preferred at the beginning of the session. Propranolol increased choice of the large reward when tested with ascending delays. Prazosin and guanfacine had no effect on reward choice.Conclusions
The stress-like effects of yohimbine administration may impair decision making by causing inflexible, perseverative behavior. 相似文献3.
Christine E. Marx Jimmy Lee Mythily Subramaniam Attilio Rapisarda Dianne C. T. Bautista Edwin Chan Jason D. Kilts Robert W. Buchanan Eu Pui Wai Swapna Verma Kang Sim Jayaraman Hariram Rajesh Jacob Richard S. E. Keefe Siow Ann Chong 《Psychopharmacology》2014,231(17):3647-3662
Rationale
Preclinical and clinical data suggest that pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids.Objective
The objective of this study is to conduct a randomized controlled trial of adjunctive pregnenolone in schizophrenia.Methods
Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment—Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized.Results
No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n?=?56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n?=?55), p?=?0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p?0.001). Serum pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s?=?0.497, p?0.042, n?=?17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated.Conclusions
Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia. 相似文献4.
Jolyce Bourgeois Monique M. Elseviers Luc Van Bortel Mirko Petrovic Robert H. Vander Stichele 《European journal of clinical pharmacology》2014,70(10):1251-1260
Purpose
Guidelines discourage chronic benzodiazepines and related Z drugs (BZD/Zs) for sleep problems. However, prevalence among nursing home residents remains high. Discontinuing these drugs is widely recommended but seems difficult to implement. The aim of our study was to evaluate the overall feasibility in the nursing home, in terms of willingness towards discontinuation and success rate at 8 months, together with the impact on withdrawal symptoms, change in sleep quality, quality of life and medication use.Methods
In a convenience sample of five nursing homes (823 residents), we included cognitively competent residents with chronic BZD/Z use for insomnia. We investigated sleep quality [with Pittsburgh Sleep Quality Index (PSQI)], quality of life (EQ-5D) and withdrawal symptoms [Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)]. Success rate was analysed with survival analysis.Results
Of the 135 eligible residents, both general physician (GP) and resident were willing to initiate discontinuation in 38 residents. Reasons for refusing to initiate discontinuation among GPs was the unmotivated patient and among residents the reluctance towards change. At 8 months, 66.0 % were successful discontinuers, with the subjective PSQI component evolving favourably (p?=?0.013) and a decreasing number of midnight awakenings (p?=?0.041). In the relapse group (n?=?13), the quality of life decreased (p?=?0.012), with mainly an increase of problems with activities and pain/discomfort. In both groups, the withdrawal symptoms, functionality and medication use did not change.Conclusion
Discontinuation of chronic BZD/Z use is feasible in the nursing home setting without noticeable withdrawal symptoms, without a switch in medication use, without detrimental effect on quality of life and with a positive effect on the self-perceived sleep quality. 相似文献5.
Antonio Molina-Carballo Fuensanta Justicia-Martínez Francisco Moreno-Madrid Isabel Cubero-Millán Irene Machado-Casas Laura Moreno-García Josefa León Juan-de-Dios Luna-del-Castillo José Uberos Antonio Muñoz-Hoyos 《Psychopharmacology》2014,231(17):3635-3645
Rationale
Attention deficit with hyperactivity disorder is a neurodevelopmental disorder associated with alterations in the prefrontal cortex via dopaminergic and noradrenergic neurotransmission. Neurosteroids (e.g. allopregnanolone and dehydroepiandrosterone) modulate the release of multiple neurotransmitters.Objective
This study aims to determine the baseline concentrations and daily variations in allopregnanolone and dehydroepiandrosterone in children with attention deficit hyperactivity disorder (ADHD) and to determine the effect of chronic administration of methylphenidate on clinical symptoms and on the concentrations of these two neurosteroids.Methods
We included 148 children aged 5 to 14 years, subdivided into two groups: ADHD group (n?=?107, with a diagnosis of ADHD (DSM-IV-TR criteria), further classified in subtypes by an “attention deficit and hyperactivity scale” and subgroups by the “Children’s Depression Inventory”) and a control group (n?=?41). The clinical workup included blood samples that were drawn at 20:00 and 09:00 hours, at inclusion in both groups, and after 4.61?±?2.29 months of treatment only in the ADHD group, for measurements for allopregnanolone and dehydroepiandrosterone. Factorial analysis, adjusted for age and gender, was performed by using Stata 12.0.Results
Methylphenidate induced the doubling of allopregnanolone levels in the predominantly inattentive ADHD patients without depressive symptoms (27.26?±?12.90 vs. 12.67?±?6.22 ng/ml, morning values). Although without statistical differences, baseline dehydroepiandrosterone levels were higher and slightly increased after methylphenidate in the ADHD subtype with depressive symptoms (7.74?±?11.46 vs. 6.18?±?5.99 ng/ml, in the morning), opposite to the lower baseline levels, and further decrease after methylphenidate in the inattentive subtype with depressive symptoms.Conclusions
Different neurosteroids may have different baseline concentrations and differential responses to methylphenidate treatment as a function of ADHD subtype and subgroup. These differential responses may be a clinical marker of ADHD subtype and/or co-morbidities. 相似文献6.
Yunzhe Ma Wenqian Tao Shelly J. Krebs William F. Sutton Nancy L. Haigwood Harvinder S. Gill 《Pharmaceutical research》2014,31(9):2393-2403
Purpose
The objective of this study is to evaluate the feasibility of using coated microneedles to deliver vaccines into the oral cavity to induce systemic and mucosal immune responses.Method
Microneedles were coated with sulforhodamine, ovalbumin and two HIV antigens. Coated microneedles were inserted into the inner lower lip and dorsal surface of the tongue of rabbits. Histology was used to confirm microneedle insertion, and systemic and mucosal immune responses were characterized by measuring antigen-specific immunoglobulin G (IgG) in serum and immunoglobulin A (IgA) in saliva, respectively.Results
Histological evaluation of tissues shows that coated microneedles can penetrate the lip and tongue to deliver coatings. Using ovalbumin as a model antigen it was found that the lip and the tongue are equally immunogenic sites for vaccination. Importantly, both sites also induced a significant (p?0.05) secretory IgA in saliva compared to pre-immune saliva. Microneedle-based oral cavity vaccination was also compared to the intramuscular route using two HIV antigens, a virus-like particle and a DNA vaccine. Microneedle-based delivery to the oral cavity and the intramuscular route exhibited similar (p?>?0.05) yet significant (p?0.05) levels of antigen-specific IgG in serum. However, only the microneedle-based oral cavity vaccination group stimulated a significantly higher (p?0.05) antigen-specific IgA response in saliva, but not intramuscular injection.Conclusion
In conclusion, this study provides a novel method using microneedles to induce systemic IgG and secretory IgA in saliva, and could offer a versatile technique for oral mucosal vaccination. Figure? 相似文献
7.
Ameera X. Patel Sam R. Miller Pradeep J. Nathan Ponmani Kanakaraj Antonella Napolitano Philip Lawrence Annelize Koch Edward T. Bullmore 《Psychopharmacology》2014,231(19):3817-3828
Rationale
The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress.Objectives/methods
Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18–45 years; BMI 19.0–25.9 kg/m2), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans.Results
Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p?0.003), the peak electromyography (p?0.0001) and galvanic skin response (GSR, p?=?0.04) to acoustic startle, the resting GSR (p?=?0.01), and increased appetite following ITT (p?0.0005). SB-649868 pre-treatment produced no significant results.Conclusion
We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity. 相似文献8.
9.
T. L. Putt Stephen B. Duffull J. B. W. Schollum R. J. Walker 《European journal of clinical pharmacology》2014,70(10):1221-1226
Purpose
Dose modification in renal impairment has traditionally been based on changes in estimated glomerular filtration rate (eGFR; estimated by creatinine clearance). However, many drugs are eliminated by tubular anionic and cationic transport where changes in eGFR may not necessarily reflect changes in tubular function. This study investigated the relationship between GFR and renal tubular function with reference to drug handling by using accepted drug probes.Methods
Three drug probes, 51Cr-EDTA, fluconazole, and pindolol, were administered to patients who had varying degrees of renal impairment. Blood sampling, assays, and a pharmacokinetic analysis were performed for all drug probes and endogenous urate. Measured GFR (51Cr-EDTA clearance; mGFR) was compared to tubular anionic transport (urate clearance), tubular reabsorption (fluconazole clearance), and tubular cationic transport (S-pindolol clearance).Results
A moderately strong association was demonstrated between the measured isotopic GFR and creatinine clearance (R2?=?0.78). A moderate positive correlation was found between mGFR and proximal tubular anion transport and reabsorption (R2?=?0.40–0.44, p?0.0001). In contrast, cationic secretion correlated poorly with mGFR (R2?=?0.11, p?=?0.036).Conclusions
Given that drug dosing schedules utilise eGFR values as the basis for modifying drug dosing, our results would suggest that a recommendation of a dose reduction according to eGFR alone should be treated with caution. 相似文献10.
Sarah Cargnin Michele Viana Grazia Sances Marika Bianchi Natascia Ghiotto Cristina Tassorelli Giuseppe Nappi Pier Luigi Canonico Armando A. Genazzani Salvatore Terrazzino 《European journal of clinical pharmacology》2014,70(10):1195-1202
Purpose
No information is currently available on genetic determinants of short-term response to drug withdrawal in medication overuse headache (MOH). In the present study, we aimed to evaluate the role of 14 polymorphisms in 8 candidate genes potentially relevant for drug addiction (OPRM1, DRD2, DBH, COMT, BDNF, SLC6A4, 5HT2A, and SLC1A2) as predictors for detoxification outcome of MOH patients at 2 months of follow-up.Methods
Genotyping was conducted by PCR, PCR-RFLP analysis, or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. The association between gene variants and risk of unsuccessful detoxification was evaluated by univariate and multivariate logistic regression analyses.Results
One hundred and eight MOH patients with effective drug withdrawal therapy and 65 MOH patients with unsuccessful detoxification were available for the analysis. In the multivariable logistic regression analysis, triptan overuse (odds ratio (OR) 0.271, 95 % confidence interval (CI) 0.083–0.890, P?=?0.031) and TT genotype carriage of DRD2 NcoI (OR 0.115, 95 % CI 0.014–0.982, P?=?0.048) emerged as independent predictors for unsuccessful detoxification. In addition, carriers of at least four of the six top-ranked gene variants (P?0.10) were found at higher odds for unsuccessful detoxification than patients with ≤3 high-risk genotypes (OR 3.40, 95 % CI 1.65–7.01, P?=?0.001).Conclusion
This exploratory study suggests that DRD2 NcoI may be a genetic determinant of detoxification outcome in MOH patients. Our findings also show that an approach based on the combination of multiple genetic markers could be clinically useful for identification of MOH patients at higher risk for unsuccessful detoxification. 相似文献11.
Rationale
Hypothalamic-pituitary-adrenal (HPA) axis hormones have neuroactive metabolites with receptor activity similar to ethanol.Objectives
The present study related HPA hormones in naïve monkeys to ethanol self-administration.Methods
Morning plasma adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone (DOC), aldosterone, and dehydroepiandrosterone-sulfate (DHEA-S) were measured longitudinally in male rhesus macaques (Macaca mulatta) induced to drink ethanol followed by access to ethanol (4 %?w/v, in water) and water 22 h/day for 12 months.Results
During ethanol access, DOC increased among non-heavy (average intake over 12 months ≤3.0 g/kg/day, n?=?23) but not among heavy drinkers (>3.0 g/kg/day, n?=?9); aldosterone was greater among heavy drinkers after 6 months. The ratio of DOC/aldosterone decreased only among heavy drinkers after 6 or12 months of ethanol self-administration. ACTH only correlated significantly with DHEA-S, the ratio of cortisol/DHEA-S and DOC after the onset of ethanol access, the former two just in heavy drinkers. Baseline hormones did not predict subsequent ethanol intake over 12 months, but baseline DOC correlated with average blood-ethanol concentrations (BECs), among all monkeys and heavy drinkers as a group. During ethanol access, aldosterone and DOC correlated and tended to correlate, respectively, with 12-month average ethanol intake.Conclusions
Ethanol self-administration lowered ACTH and selectively altered its adrenocortical regulation. Mineralocorticoids may compensate for adrenocortical adaptation among heavy drinkers and balance fluid homeostasis. As DOC was uniquely predictive of future BEC and not water intake, to the exclusion of aldosterone, GABAergic neuroactive metabolites of DOC may be risk factors for binge drinking to intoxication. 相似文献12.
Kyra J. Barnes Andrew Rowland Thomas M. Polasek John O. Miners 《European journal of clinical pharmacology》2014,70(9):1097-1106
Objective
To investigate the potential inhibitory effects of uremic toxins on the major human hepatic drug-metabolising cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes in vitro.Methods
Benzyl alcohol, p-cresol, indoxyl sulfate, hippuric acid and a combination of the four uremic toxins were co-incubated with human liver microsomes and selective probe substrates for the major human drug-metabolising CYP and UGT enzymes. The percentage of enzyme inhibition was calculated by measuring the rates of probe metabolite formation in the absence and presence of the uremic toxins. Kinetics studies were conducted to evaluate the K i values and mechanism(s) of the inhibition of CYP2E1, CYP3A4, UGT1A1 and UGT1A9 by p-cresol.Results
The individual uremic toxins inhibited CYP and UGT enzymes to a variable extent. p-Cresol was the most potent individual inhibitor, producing >50 % inhibition of CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7 at a concentration of 100 μM. The greatest inhibition was observed with UGT1A9. p-Cresol was shown to be an uncompetitive inhibitor of UGT1A9, with unbound K i values of 9.1 and 2.5 μM in the absence and presence of bovine serum albumin (BSA), respectively. K i values for p-cresol inhibition of human liver microsomal CYP2E1, CYP3A4 and UGT1A1 ranged from 43 to 89 μM. A combination of the four uremic toxins produced >50 % decreases in the activities of CYP1A2, CYP2C9, CYP2E1, CYP3A4, UGT1A1, UGT1A9 and UGT2B7.Conclusions
Uremic toxins may contribute to decreases in drug hepatic clearance in individuals with kidney disease by inhibition of hepatic drug-metabolising enzymes. 相似文献13.
Sabra S. Inslicht Anne Richards Erin Madden Madhu N. Rao Aoife O’Donovan Lisa S. Talbot Evelyn Rucker Thomas J. Metzler Richard L. Hauger Thomas C. Neylan 《Psychopharmacology》2014,231(17):3581-3595
Rationale
Mechanisms contributing to sex differences in the regulation of acute stress responsivity and their effect on the increased incidence of posttraumatic stress disorder (PTSD) in women are poorly understood. The reproductive hormone, progesterone, through conversion to allopregnanolone (ALLO), suppresses the hypothalamic pituitary adrenal (HPA) axis and has potent anxiolytic effects. The potential that progesterone and allopregnanolone reactivity modulate HPA axis responses and account for sex differences in PTSD has not been previously examined.Objective
The present study examined the effects of sex and PTSD on adrenocorticotropic hormone (ACTH), progesterone, and allopregnanolone responses to metyrapone and whether progesterone and allopregnanolone reactivity could affect the ACTH response in PTSD.Methods
Healthy medication-free male and premenopausal follicular phase female participants with chronic PTSD (n?=?43; 49 % female) and controls (n?=?42; 50 % female) completed an overnight metyrapone challenge and ACTH, progesterone, and allopregnanolone were obtained by repeated blood sampling.Results
The increase in ACTH response to metyrapone was higher in PTSD subjects compared to controls and in women compared to men. Contrary to our initial prediction of an inverse relationship, progesterone and allopregnanolone were positively associated with ACTH. Progesterone and allopregnanolone partially mediated the relationship between PTSD and ACTH.Conclusions
Our findings of increased ACTH to metyrapone in PTSD and in women may reflect heightened hypothalamic CRF hypersecretion. Progesterone and allopregnanolone partially mediated the ACTH response in PTSD. Further characterizing sex differences in these processes will advance our understanding of the pathophysiology of PTSD, and may ultimately lead to better-targeted, more effective treatment. 相似文献14.
Deborah Ducasse Laurent Boyer Pierre Michel Anderson Loundou Alexandra Macgregor Jean-Arthur Micoulaud-Franchi Philippe Courtet Mocrane Abbar Marion Leboyer Guillaume Fond 《Psychopharmacology》2014,231(18):3765-3770
Rationale and objective
The relationship between clinically effective antipsychotic drugs in obsessive–compulsive disorders (OCD) and binding affinities to cloned dopamine and serotonin receptor subtypes was analyzed in an effort to clarify the contribution of individual receptor subtypes to medication response.Methods
Meta-analysis was used to update previous meta-analyses of effectiveness data of add-on antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) in OCD. Twelve previously analyzed randomized controlled trials (RCTs) and one new RCT were included. We performed a metaregression using a mixed-effect model to examine the association between antipsychotic’s effectiveness and receptor affinity.Results
A total of 5 treatment arms obtained from 13 RCTs (431 patients) were included in our study. The results of our metaregression showed a significant association between D2 and D3 dopamine receptor affinities and effectiveness in OCD (respectively, slope?=??0.36, p?=?0.01; and slope?=??0.50, p?=?0.01) whereas other dopamine receptors and serotonin receptors were not significantly associated.Conclusions
These observations suggest that increasing D2 and D3 dopamine receptor binding affinities enhances antipsychotics’ effectiveness in obsessive–compulsive disorders. 相似文献15.
Jie Zheng Yu Wan Abdelbary Elhissi Zhirong Zhang Xun Sun 《Pharmaceutical research》2014,31(8):2220-2233
Purpose
To develop a tumor-targeted drug delivery system based on solid lipid nanoparticles (SLNs) conjugated with the enzymatically cleavable polyethylene glycol (PEG).Methods
SLNs loaded with paclitaxel (PTX) were prepared using the film ultrasonication method, followed by conjugation with a PEGylated peptide (Pp) that can specifically interact with matrix metalloproteinases (MMPs) that is over-expressed by tumor cells. The physicochemical characteristics of the Pp-PTX-SLNs were studied and the in vitro drug release, cytotoxicity and cell uptake of the formulations were investigated. Furthermore, using an animal model, the pharmacokinetic properties, biodistribution and anti-tumor activity of this system were evaluated.Results
The resulting Pp-PTX-SLNs penetrated through tumor cells via facilitated uptake mediated by MMPs. The uncleavable Pp’-PTX-SLNs showed a lower cell uptake efficiency, compared with the Pp-PTX-SLNs. In a tumor-bearing mice model, Pp-PTX-SLNs accumulated to a greater extent at the tumor location, persisted longer in blood circulation, and showed lower toxicity than did PTX-SLNs or Taxol®. Most importantly, the mice treated with Pp-PTX-SLNs survived longer than the groups treated with Pp’-PTX-SLNs, PTX-SLNs or Taxol®.Conclusions
These results suggest that Pp-PTX-SLNs hold promise as a new strategy for paclitaxel chemotherapy, and that Pp-SLNs can be a useful nanocarrier for other chemotherapeutic drugs. FigureShielding the SLN with PEG2000-Gly-Pro-Leu-Gly-Ile-Ala-Gly-Gln-Cys prolongs its circulation time in blood. Cleavage of the PEG chain by tumor-secreted MMPs leads to paclitaxel uptake by target tumor cells. This SLN modification offers a new strategy for paclitaxel chemotherapy. 相似文献
16.
Rationale
Stress, a powerful precipitant of drug seeking during abstinence, may also accelerate the return to pathological patterns of intake after initial instances of drug reuse.Objective
To explore the effect of stress on a learning process underlying relapse, this study assessed the effect of yohimbine on reacquisition of oxycodone seeking.Methods
One hundred thirty-two male Sprague?CDawley rats underwent place conditioning with oxycodone (2?mg/kg, SC; ×6?days), extinction (vehicle?×?6?days), and reconditioning with 0, 0.25, 2, or 5?mg/kg oxycodone (2?days). Yohimbine (0, 2.5, or 5?mg/kg, IP) was administered 30?min prior to reconditioning.Results
Pretreatment with 2.5?mg/kg yohimbine increased, while 5?mg/kg yohimbine decreased, reacquisition of oxycodone-induced place preference. A follow-up study (n?=?30) further indicated that the effect of yohimbine was specific to reacquisition.Conclusion
The observation that yohimbine can enhance reacquisition of oxycodone seeking supports the hypothesis that stress can facilitate learning processes involved in the unfolding of relapse. 相似文献17.
Eric W. Fish Buddy J. Whitman Jeff F. DiBerto J. Elliott Robinson A. Leslie Morrow C. J. Malanga 《Psychopharmacology》2014,231(17):3415-3423
Rationale
The neuroactive steroid (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP, allopregnanolone) has effects on reward-related behaviors in mice and rats that suggest that it may activate brain reward circuits. Intracranial self-stimulation (ICSS) is an operant behavioral technique that detects changes in the sensitivity of brain reward circuitry following drug administration.Objective
To examine the effects of the neuroactive steroid allopregnanolone on ICSS and to compare these effects to those of cocaine.Methods
Male C57BL/6J mice implanted with stimulating electrodes implanted into the medial forebrain bundle responded for reinforcement by electrical stimulation (brain stimulation reward (BSR)). Mice received cocaine (n?=?11, 3.0–30.0 mg/kg, intraperitoneal (i.p.)) or the neuroactive steroid allopregnanolone (n?=?11, 3.0–17.0 mg/kg, i.p.). BSR thresholds (θ 0) and maximum (MAX) operant response rates after drug treatments were compared to those after vehicle injections.Results
Cocaine and allopregnanolone dose dependently lowered BSR thresholds relative to vehicle injections. Cocaine was maximally effective (80 % reduction) in the second 15 min following the 30 mg/kg dose, while allopregnanolone was maximally effective (30 % reduction) 15–45 min after the 17 mg/kg dose. Neither drug had significant effects on MAX response rates.Conclusions
The effects of allopregnanolone on BSR thresholds are consistent with the previously reported effects of benzodiazepines and alcohol, suggesting that positive modulation of GABAA receptors can facilitate reward-related behaviors in C57BL/6J mice. 相似文献18.
Jyun-Lin Lee Chia-Wen Lo Claude Inserra Jean-Christophe Béra Wen-Shiang Chen 《Pharmaceutical research》2014,31(9):2354-2366
Purpose
Polyethylenimine (PEI), a cationic polymer, has been shown to aggregate plasmid DNA and facilitate its internalization. It has also been shown that combining ultrasound (US) with PEI could enhance and prolong in vitro and in vivo transgene expression. However, the role US in the enhancement of PEI uptake is poorly understood. This study investigates the impact of US on PEI-mediated gene transfection.Methods
Specific endocytosis pathway siRNA, including clathrin HC siRNA, caveolin-1 siRNA and protein kinase C-delta (PKC-δ) siRNA, are used to block the corresponding endocytosis pathways prior to the transfection of luciferase DNA/PEI polyplexes to cultured cells by 1-MHz pulsed US with ultrasound contrast agent SonoVue®.Results
Transgene expression was found not to be enhanced by US treatment in the presence of the PKC-δ siRNA. We further demonstrated that PKC-δ protein could be enhanced at 6 h after US exposure. Moreover, intracellular calcium levels were found to be significantly increased at 3 h after US exposure, while transgene expressions were significantly reduced in the presence of calcium channel blockers both in vitro and in vivo.Conclusions
Our results suggest that US enhanced PEI-mediated gene transfection specifically by increasing PKC-δ related fluid phase endocytosis, which was induced by increasing the intracellular calcium levels. 相似文献19.
Muhammad R. Haque Dong Yun Lee Cheol-Hee Ahn Jee-Heon Jeong Youngro Byun 《Pharmaceutical research》2014,31(9):2453-2462
Purpose
The purpose of this study was to investigate the effect of locally delivered pancreatic islet with liposomal clodronate (Clodrosome®) as an immunoprotection agent for the treatment of type 1 diabetes.Method
The bio-distribution of liposomal clodronate in matrigel was checked by imaging analyzer. To verify the therapeutic efficacy of locally delivered islet with liposomal clodronate using injectable hydrogel, four groups of islet transplanted mice (n?=?6 in each group) were prepared: 1) the islet group, 2) the islet-Clodrosome group, 3) the islet-Matrigel group, and 4) the islet-Matrigel-Clodrosome group. Immune cell migration and activation, and pro-inflammatory cytokine secretion was evaluated by immunohistochemistry staining and ELISA assay.Results
Cy5.5 labeled liposomes remained in the matrigel for over 7 days. The median survival time of transplanted islets (Islet-Matrigel-Clodrosome group) was significantly increased (>60 days), compared to other groups. Locally delivered liposomal clodronate in matrigel effectively inhibited the activation of macrophages, immune cell migration and activation, and pro-inflammatory cytokine secretion from macrophages.Conclusions
Locally co-delivered pancreatic islets and liposomal clodronate using injectable hydrogel effectively cured type 1 diabetes. Especially, the inhibition of macrophage attack in the early stage after local delivery of islets was very important for the successful long-term survival of delivered islets. 相似文献20.
Rick Morrison Tyson Belz Saleh K. Ihmaid Jasim M. A. Al-Rawi Michael J. Angove 《Medicinal chemistry research》2014,23(11):4680-4691
The 2-morpholino-substituted-benzoxazines 7a and 7b were used in the synthesis of 2-morpholino-di-O-benzyl, O-pyridin-2yl, 3-yl and 4yl-methoxy)-1,3-benzoxazines 8a–8d, and N-(2-morpholino-4-oxo-4H-benz[e][1,3]oxazin-7-yl)-N-(pyridin-2-and-3-ylmethyl)acetamides 8e and 8f. The DNA-dependent protein kinase (DNA-PK) and phosphatidylinositol 3-kinase (PI3K) α, β, γ, and δ isoforms were studied for the new compounds 8a–8f and PI3K for the 18 previously synthesized compounds 9–26. The most active DNA-PK inhibitors were the 2-morpholino-O-substituted linear or angular naphthoxazine compounds 18–20 and 21–22 which showed potent and selective DNA-PK activity (IC50 from 0.01 to 2.43 µM) over PI3K. 8-(2-(4-Methylpiperazin-1-yl)ethoxy)-2-morpholino compound 13, and 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy) compound 25 showed selective DNA-PK inhibition. 2-morpholino-8-substituted-benzoxazine 9 (8-ph) and 10–12 (8-(pyridine-2-, 3-, or 4-ylmethoxy) showed high-to-moderate inhibition of PI3K and DNA-PK. A similar pattern for DNA-PK nonselectivity over PI3K was observed for compounds with 7,8-O-bis-substituted 8a, 8c, and 8d. No DNA-PK selectivity over PI3K was observed regardless whether the substitution was phenyl, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, and pyridin-4-ylmethoxy. 相似文献