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1.
Tippawan Siritientong Apichai Angspatt Juthamas Ratanavaraporn Pornanong Aramwit 《Pharmaceutical research》2014,31(1):104-116
Purpose
An ethyl alcohol-precipitated silk sericin/PVA scaffold that controlled the release of silk sericin was previously developed and applied for the treatment of full-thickness wounds in rats and demonstrated efficient healing. In this study, we aimed to further evaluate the clinical potential of this scaffold, hereafter called “silk sericin-releasing wound dressing”, for the treatment of split-thickness skin graft donor sites by comparison with the clinically available wound dressing known as “Bactigras®”.Methods
In vitro characterization and in vivo evaluation for safety of the wound dressings were performed. A clinical trial of the wound dressings was conducted according to standard protocols.Results
The sericin released from the wound dressing was not toxic to HaCat human keratinocytes. A peel test indicated that the silk sericin-releasing wound dressing was less adhesive than Bactigras®, potentially reducing trauma and the risk of repeated injury upon removal. There was no evidence of skin irritation upon treatment with either wound dressing. When tested in patients with split-thickness skin graft donor sites, the wounds treated with the silk sericin-releasing wound dressing exhibited complete healing at 12?±?5.0 days, whereas those treated with Bactigras® were completely healed at 14?±?5.2 days (p?=?1.99?×?10?4). In addition, treatment with the silk sericin-releasing wound dressing significantly reduced pain compared with Bactigras® particularly during the first 4 postoperative days (p?=?2.70?×?10?5 on day 1).Conclusion
We introduce this novel silk sericin-releasing wound dressing as an alternative treatment for split-thickness skin graft donor sites. 相似文献2.
Purpose
To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug cefadroxil.Methods
The effective permeability (P eff ) of cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of cefadroxil were also examined after oral gavage.Results
The P eff (cm/s) of cefadroxil in wild-type mice was 0.49?×?10?4 in duodenum, 0.80?×?10?4 in jejunum, 0.88?×?10?4 in ileum and 0.064?×?10?4 in colon. The P eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003?×?10?4, 0.090?×?10?4, 0.042?×?10?4 and 0.032?×?10?4, respectively. Jejunal uptake of cefadroxil was saturable (Km?=?2–4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of cefadroxil after oral dosing.Conclusions
The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of cefadroxil as well as its enhanced oral drug performance. 相似文献3.
Euitae Kim Oliver D. Howes Federico E. Turkheimer Bo-Hyung Kim Jae Min Jeong Ji Who Kim Jae Sung Lee In-Jin Jang Sang-Goo Shin Shitij Kapur Jun Soo Kwon 《Psychopharmacology》2013,227(2):221-229
Rationale
The effects of aripiprazole on cognitive function are obscure, possibly due to the difficulty in disentangling the specific effects on cognitive function from effects secondary to the improvement of other schizophrenic symptoms. This prompts the necessity of using an intermediate biomarker relating the drug effect on the brain to change in cognitive function.Objectives
To explore the effect of aripiprazole on cognitive function, we measured changes in frontal metabolism as an intermediate biomarker and sought to determine its relationship with D2 receptor occupancy and changes in working memory.Methods
Fifteen healthy male volunteers participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride and [18?F]FDG were conducted 1 day before and 2 days after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [18?F]FDG scan.Results
The mean (±SD) D2 receptor occupancies were 22.2?±?16.0 % in the 2 mg group, 35.5?±?3.6 % in the 5 mg group, 63.2?±?9.9 % in the 10 mg group and 72.8?±?2.1 % in the 30 mg group. The frontal metabolism was significantly decreased after the administration of aripiprazole (t?=?2.705, df?=?14, p?=?0.017). Greater striatal D2 receptor occupancy was related to greater decrease in frontal metabolism (r?=??0.659, p?=?0.010), and greater reduction in frontal metabolism was associated with longer reaction times (r?=??0.597, p?=?0.019) under the greatest task load.Conclusions
Aripiprazole can affect cognitive function and alter frontal metabolic function. The changes in these functions are linked to greater D2 receptor occupancy. This suggests that it may be important to find the lowest effective dose of aripiprazole in order to prevent adverse cognitive effects. 相似文献4.
Zhang Q Bal-dit-Sollier C Drouet L Simoneau G Alvarez JC Pruvot S Aubourg R Berge N Bergmann JF Mouly S Mahé I 《European journal of clinical pharmacology》2011,67(3):309-314
Purpose
We investigated whether acetaminophen, given at 2?g/day and 3?g/day might potentiate the anticoagulant effect of warfarin.Methods
Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2?g/day or 3?g/day) or placebo.Results
The mean maximal INR increase was 0.70?±?0.49 and 0.67?±?0.62 in patients receiving acetaminophen at 2?g/day and 3?g/day, respectively (P?=?0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R 2?=?0.36, P?0.0001), factor VII (R 2?=?0.46, P?0.0001) and a maximal increase in acetaminophen plasma concentrations (R 2?=?0.563, P?0.0001).Conclusion
Acetaminophen, at 2?g/day or 3?g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting. 相似文献5.
Rashmin B. Patel Mrunali R. Patel Kashayap K. Bhatt Bharat G. Patel 《Journal of pharmaceutical innovation》2013,8(3):195-204
Purpose
This paper describes formulation considerations and in vitro evaluation of a microemulsion drug delivery system designed for intranasal administration of Paliperidone.Methods
Drug-loaded microemulsions were successfully prepared by a water titration. Prepared formulations were subjected to physicochemical characterization, and evaluated for in vitro diffusion, nasal cilio toxicity, and in vitro mucoadhesion.Results
The microemulsion, containing 4 % oleic acid, 30 % surfactant mixture of [Labrasol/Cremophor RH 40 (1:1)]/[Transcutol P] (3:1) and 66 % (wt/wt) aqueous phase, that displayed a 99.93 % optical transparency, globule sizes of 20.01?±?1.28 nm, and a polydispersity index of 0.117?±?0.034 was selected for the incorporation of polyelectrolytic polymer (polycarbophil) as the mucoadhesive component. The mucoadhesive microemulsion formulation of Paliperidone that contains 0.5 % by weight of polycarbophil displayed higher in vitro mucoadhesive potential (18.0?±?2.5 min) and diffusion coefficient (3.83?×?10?6?±?0.019?×?10?6) than microemulsion. Also, they were found to be free from nasal ciliotoxicity and had stability for 6 months.Conclusion
The in vitro studies demonstrated the potential of developing mucoadhesive microemulsion formulation for intranasal delivery of Paliperidone. 相似文献6.
Mahtab Asadabadi Mohammad-Reza Mohammadi Ahmad Ghanizadeh Amirhossein Modabbernia Mandana Ashrafi Elmira Hassanzadeh Saeedeh Forghani Shahin Akhondzadeh 《Psychopharmacology》2013,225(1):51-59
Rational
Autism is associated with activation of the inflammatory response system.Objective
This study aims to assess the efficacy of a cyclooxygenase-2 inhibitor, celecoxib, as adjunctive therapy in the treatment of autismMethods
In a 10-week randomized double-blind placebo-controlled study, 40 outpatient children with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision clinical diagnosis of autism were randomly allocated to celecoxib plus risperidone or placebo plus risperidone. The dose of risperidone and celecoxib were titrated up to 3 and 300 mg/day, respectively. Patients were assessed at baseline and after 2, 4, 6, and 10 weeks of starting medication using the Aberrant Behavior Checklist-Community (ABC-C) Rating Scale. Primary outcome measure was the change in irritability subscale of ABC-C.Results
Significant time?×?treatment interaction was observed for Irritability (F (1.658, 63.021)?=?13.580, P?<?0.001), Lethargy/Social Withdrawal (F (1.948, 74.032)?=?16.811, P?<?0.001), and Stereotypic Behavior (F(1.742, 66.198)?=?12.104, P?<?0.001), but not for Hyperactivity/Noncompliance (F (2.564, 97.424)?=?1.469, P?=?0.232), and Inappropriate Speech subscales (F (1.607, 61.075)?=?0.173, P?=?0.794). By week 10, patients in the celecoxib group showed significantly greater improvement in the Irritability (P?<?0.001), Lethargy/Social Withdrawal (P?<?0.001), and Stereotypic Behavior (P?<?0.00) but not in Hyperactivity/Noncompliance (P?=?0.202) and Inappropriate Speech (P?=?0.802) subscales than the placebo group. Complete response was achieved by four (20 %) patients in the placebo group and 11 (55 %) patients in the celecoxib group (χ 2 (1)?=?5.227, P?=?0.022). Frequency of side effects was similar between the two groups.Conclusions
Combination of risperidone and celecoxib was superior to risperidone alone in treating irritability, social withdrawal, and stereotypy of children with autism. (Registration, www.irct.ir; IRCT138711091556N2) 相似文献7.
Impaired social behavior in chicks exposed to sodium valproate during the last week of embryogenesis
Hideo Nishigori Keisuke Kagami Ai Takahashi Yu Tezuka Atsushi Sanbe Hidekazu Nishigori 《Psychopharmacology》2013,227(3):393-402
Rationale and objectives
To evaluate direct exposure to sodium valproate (VPA) during embryogenesis, we administered VPA to chick embryos and examined their social behaviors after hatching.Methods and results
Embryos treated with VPA (35 μmol/egg) on day 14 were similar to controls for hatching date (day 21) and hatchlings' abilities, such as motor, imprinting, and surface righting. However, these VPA chicks on posthatching day 3 scored significantly low in the chick's social separation stress (SSS) test as follows. Aggregation test evaluated the speed of four chicks, individually isolated by a cardboard in a box, to aggregate upon removal of the cardboards. Belongingness test evaluated the speed of a chick isolated at a corner to join the group of three chicks placed at the opposite corner. Vocalization test for each chick was performed in an isolated corner by using a sound level meter. The results demonstrated that compared with controls, VPA chicks were significantly slow in aggregation (12.7?±?2.5 s vs. 2.9?±?0.9 s, p?=?0.006) and belongingness (3.6?±?0.28 s/40 cm vs. 2.6?±?0.14 s/40 cm, P?=?0.003) and weak in vocalization (13.4?±?2.8 dB/30 s vs. 26.7?±?1.3 dB/30 s, P?=?0.001), respectively. Weight of cerebellum of VAP chick was 15 % lighter than controls (P?=?0.004).Conclusions
Chick embryos exposed to VPA during the last week of embryogenesis had impaired social behaviors in spite of normal mortar and imprinting ability. The present method will be a useful animal model for assessing the effects of environment during embryogenesis on social behaviors in later life. 相似文献8.
J. Martínez-Clemente R. López-Arnau M. Carbó D. Pubill J. Camarasa E. Escubedo 《Psychopharmacology》2013,229(2):295-306
Rationale
Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.Objective
The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model.Methods
Mephedrone was administered to male Sprague–Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized using LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180–240 min.Results
Mephedrone plasma concentrations after i.v. administration fit a two-compartment model (α?=?10.23 h?1, β?=?1.86 h?1). After oral administration, peak mephedrone concentrations were achieved between 0.5 and 1 h and declined to undetectable levels at 9 h. The absolute bioavailability of mephedrone was about 10 % and the percentage of mephedrone protein binding was 21.59?±?3.67 %. We have identified five phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85?±?0.08. Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic–pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect.Conclusions
We suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude, and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity. 相似文献9.
Shu-Ting Ren Yi-Ran Liao Xiao-Ning Kang Yi-Ping Li Hui Zhang Hong Ai Qiang Sun Jing Jing Xing-Hua Zhao Li-Fang Tan Xin-Liang Shen Bing Wang 《Pharmaceutical research》2013,30(6):1574-1585
Purpose
To develop a novel docetaxel (DOC)-loaded lipid microbubbles (MBs) for achieving target therapy and overcoming the poor water-solubility drawback of DOC.Methods
A novel DOC-loaded microbubble (DOC + MB) was prepared by lyophilization and the physicochemical properties including ultrasound contrast imaging of the liver were measured. The anti-tumor effect of the DOC + MBs combined with low-frequency ultrasound (LFUS; 0.8Hz, 2.56 W/cm2, 50% cycle duty) on the DLD-1 cancer cell line was examined using an MTT assay.Results
The physicochemical properties of the two tested formats of DOC + MBs (1.0 mg and 1.6 mg) was shown: concentration, (6.74?±?0.02)?×?108 bubbles/mL and (8.27?±?0.15)?×?108 bubbles/mL; mean size, 3.296?±?0.004 μm and 3.387?±?0.005 μm; pH value, 6.67?±?0.11 and 6.56?±?0.05; release rate, 3.41% and 12.50%; Zeta potential, ?37.95?±?7.84 mV and ?44.35?±?8.70 mV; and encapsulation efficiency, 54.9?±?6.21% and 46.3?±?5.69%, respectively. Compared with SonoVue, the DOC + MBs similarly enhanced the echo signal of the liver imaging. The anti-tumor effect of the DOC + MBs/LFUS group was significantly better than that of DOC alone and that of the normal MBs/LFUS groups.Conclusions
The self-made DOC + MBs have potential as a new ultrasound contrast agent and drug-loaded microbubble, and can obviously enhance the antitumor effect of DOC under LFUS exposure. 相似文献10.
Purpose
This study employed a mouse model to evaluate the effects of diabetic nephropathy on the pharmacokinetics of 8C2, a murine monoclonal antibody (mAb).Methods
Streptozotocin (STZ) was administered to mice to induce diabetic nephropathy (125 mg/kg/day?×?2). Mice were grouped (n?=?8–10) based on time after STZ-treatment (control, 1, 2, 3, 4, or 6 weeks), and injected intravenously with 10 mg/kg 8C2. Blood samples were collected up to 7 days, and 8C2 plasma concentrations were determined via immunoassay. Inulin clearance and urinary albumin excretion rate (UAE) were determined to assess renal function.Results
UAE, inulin clearance, and 8C2 clearance increased significantly following STZ. Comparing control and 6 week STZ-treatment groups, UAE and inulin clearance increased from 25.7?±?3.3 to 99.3?±?13.7 μg/day, and from 421?±?31 to 584?±?78 μl/min. 8C2 clearance increased from 121?±?12.5 to 228?±?61 μl/hr/kg (p?<?0.01). 8C2 clearance was highly correlated with UAE (r2: 0.731). Inclusion of UAE as a covariate in population modeling explained significant residual variability in 8C2 clearance.Conclusions
The clearance of 8C2 increased significantly in STZ-treated mice. Population pharmacokinetic modeling suggests that UAE has potential for use in predicting mAb clearance in subjects with diabetic nephropathy, possibly assisting in the individualization of mAb dosing. 相似文献11.
Moumita Sarkar Gideon Koren Sanjog Kalra Angela Ying Carlo Smorlesi Marco De Santis Orna Diav-Citrin Meytal Avgil Sharon Voyer Lavigne Matti Berkovich Adrienne Einarson 《European journal of clinical pharmacology》2009,65(12):1259-1264
Background
Montelukast (Singulair) is a selective leukotriene receptor antagonist (LTRA) indicated for the maintenance treatment of asthma. Currently, there are limited prospective, comparative studies in the literature examining the safety of montelukast use in pregnancy.Objectives
The primary objective of this study was to determine whether exposure to montelukast during pregnancy increases the rate of major malformations above the 1–3% baseline risk or the rate of other adverse effects.Methods
Pregnant women taking montelukast were enrolled in the study from six teratogen information services around the world. These women were compared to two other groups of women: (1) disease-matched, who used inhalers for a similar indication and (2) women not diagnosed with asthma and not exposed to any known teratogens. The primary outcome was major malformations and secondary endpoints included spontaneous abortion, fetal distress, gestational age at birth and birth weight.Results
Out of 180 montelukast-exposed pregnancies, there were 160 live births including three sets of twins, 20 spontaneous abortions, 2 elective abortions and 1 major malformation reported. The mean birth weight was lower (3,214?±?685 g) compared to controls [3,356?±?657 (disease-matched) and 3,424?±?551 (exposed to non-teratogens), P?=?0.038] and the gestational age was shorter [37.8?±?3.1 weeks (montelukast) and 37.6?±?4.4 (disease-matched) versus 39.3?±?2.4 weeks (exposed to non-teratogens), P?=?0.045]. About 25% of the newborns had fetal distress, a higher rate than controls (P?=?0.007). However, upon sub-analysis of women who continued the drug until delivery, only birth-weight difference (304 g) remained significant.Conclusions
Montelukast does not appear to increase the baseline rate of major malformations. The lower birth weight in both asthma groups is most likely associated with the severity of the maternal condition. 相似文献12.
Susanne Kossatz Robert Ludwig Heidi Dähring Volker Ettelt Gabriella Rimkus Marzia Marciello Gorka Salas Vijay Patel Francisco J. Teran Ingrid Hilger 《Pharmaceutical research》2014,31(12):3274-3288
Purpose
Tumor cells can be effectively inactivated by heating mediated by magnetic nanoparticles. However, optimized nanomaterials to supply thermal stress inside the tumor remain to be identified. The present study investigates the therapeutic effects of magnetic hyperthermia induced by superparamagnetic iron oxide nanoparticles on breast (MDA-MB-231) and pancreatic cancer (BxPC-3) xenografts in mice in vivo.Methods
Superparamagnetic iron oxide nanoparticles, synthesized either via an aqueous (MF66; average core size 12 nm) or an organic route (OD15; average core size 15 nm) are analyzed in terms of their specific absorption rate (SAR), cell uptake and their effectivity in in vivo hyperthermia treatment.Results
Exceptionally high SAR values ranging from 658?±?53 W*gFe ?1 for OD15 up to 900?±?22 W*gFe ?1 for MF66 were determined in an alternating magnetic field (AMF, H?=?15.4 kA*m?1 (19 mT), f?=?435 kHz). Conversion of SAR values into system-independent intrinsic loss power (ILP, 6.4?±?0.5 nH*m2*kg?1 (OD15) and 8.7?±?0.2 nH*m2*kg?1 (MF66)) confirmed the markedly high heating potential compared to recently published data. Magnetic hyperthermia after intratumoral nanoparticle injection results in dramatically reduced tumor volume in both cancer models, although the applied temperature dosages measured as CEM43T90 (cumulative equivalent minutes at 43°C) are only between 1 and 24 min. Histological analysis of magnetic hyperthermia treated tumor tissue exhibit alterations in cell viability (apoptosis and necrosis) and show a decreased cell proliferation.Conclusions
Concluding, the studied magnetic nanoparticles lead to extensive cell death in human tumor xenografts and are considered suitable platforms for future hyperthermic studies. 相似文献13.
Andre C. Felicio Tais S. Moriyama Clecio Godeiro-Junior Ming C. Shih Marcelo Q. Hoexter Vanderci Borges Sonia M. A. Silva Edson Amaro-Junior Luiz A. F. Andrade Henrique B. Ferraz Rodrigo A. Bressan 《Psychopharmacology》2010,211(1):27-31
Rationale
Depression is a frequent non-motor symptom in Parkinson’s disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is not clear since clinical matching was inappropriate and DAT reduction could be attributed to PD severity.Objectives
To further examine the role of DAT in PD depression, this study compared thoroughly matched depressed vs. non-depressed PD patients (ndPD).Materials and methods
Twenty PD patients (n?=?10 ndPD; n?=?10 dPD) matched for age and disease severity were submitted to brain SPECT imaging with [99mTc]-TRODAT-1, a DAT radioligand. DAT-binding potential was calculated using regions of interest bilaterally drawn in the striatum, caudate, and putamen. Depression was defined according to Beck Depression Inventory (BDI; cut-off >18).Results
Mean BDI scores were higher in dPD (25.0?±?5.6) than in ndPD patients (8.0?±?1.9, p?<?0.0001). DAT density was greater on dPD especially in the left caudate (dPD 0.87?±?0.19 vs. ndDP 0.69?±?0.18, p?=?0.02) and right putamen (dPD 0.37?±?0.07 vs. ndPD 0.28?±?0.13, p?=?0.03) than in ndPD patients.Conclusion
Our results suggest that in vivo DAT density is increased in dPD patients as compared to ndPD, suggesting that DAT is implicated in the pathophysiology of PD depression. 相似文献14.
In this investigation, we test the hypothesis that treatment with sorafenib, an anti-angiogenic agent, decreases tumor vascularization and, consequently, hinders the delivery of monoclonal antibodies (mAb) to xenograft tumors. Severe combined immunodeficiency mice bearing carcinoembryonic antigen (CEA) expressing tumor xenografts were divided into control and sorafenib-treated groups. Sorafenib was administered to the latter group at 50 mg/kg IP every 48 h, starting 4 days post-tumor implantation. When tumors attained a size of 200–300 mm3, mice were evaluated for (a) tumor microvessel density (using immunohistochemical analysis), (b) tumor macromolecular extravasation (using Evans Blue Dye (EBD)), (c) pharmacokinetics of an anti-CEA mAb, T84.66, following an intravenous dose of 10 mg/kg, and (d) intra-tumoral spatial distribution of T84.66 (using autoradiography). Sorafenib treatment resulted in a substantial reduction in tumor growth rate, a visible reduction in tumor microvessel density, and in a 46.4% decrease in EBD extravasation in tumor tissue (p?<?0.0455). For control and treated mice, no significant difference was found for the area under the mAb plasma concentration-time curve (AUC(0–7d): 1.67?×?103?±?1.28?×?102 vs. 1.76?×?103?±?1.75?×?102 nM?×?day, p?=?0.51). However, tumor AUC(0–7d) was reduced by 40.8% in sorafenib-treated mice relative to that observed in control mice (5.61?×?102?±?4.27?×?101 vs. 9.48?×?102?±?5.61?×?101 nM?×?day, p?<?0.001). Sorafenib therapy was also found to markedly alter mAb tumor spatial distribution. The results collectively suggest that sorafenib treatment causes a significant reduction in mAb delivery to, and distribution within, solid tumors. 相似文献
15.
Yuichiro Imamura Nobuyuki Murayama Noriko Okudaira Atsushi Kurihara Katsuhisa Inoue Hiroaki Yuasa Takashi Izumi Hiroyuki Kusuhara Yuichi Sugiyama 《Pharmaceutical research》2013,30(2):447-457
Purpose
To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6β-hydroxycortisol, an endogenous probe of hepatic CYP3A4 activity, in healthy subjects.Methods
The effect of DX-619 on CYP3A4 was examined in human liver microsomes. The apparent formation and renal clearance of 6β-hydroxycortisol (CL6β?OHF and CLrenal,6β?OHF, respectively) were determined in placebo- and DX-619-treated subjects. 6β-hydroxycortisol uptake was determined in HEK293 cells expressing OAT1, OAT3, OCT2, MATE1, and MATE2-K.Results
DX-619 was a mechanism-based inhibitor of CYP3A4, with KI and kinact of 67.9?±?7.3 μmol/l and 0.0730?±?0.0033 min?1, respectively. Pharmacokinetic simulation suggested in vivo relevance of CYP3A4 inhibition by DX-619. CL6β?OHF and CLrenal,6β?OHF were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo (P?<?0.05). 6β-hydroxycortisol was a substrate of OAT3 (Km?=?183?±?25 μmol/l), OCT2, MATE1, and MATE2-K. Maximum unbound concentration of DX-619 (9.1?±?0.4 μmol/l) was above Ki of DX-619 for MATE1 (4.32?±?0.79 μmol/l).Conclusions
DX-619 caused a moderate inhibition of hepatic CYP3A4-mediated formation and significant inhibition of MATE-mediated efflux of 6β-hydroxycortisol into urine. Caution is needed in applying CL6β?OHF as an index of hepatic CYP3A4 activity without evaluating CLrenal,6β?OHF. 相似文献16.
Rationale
Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression.Objectives
This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect.Methods
Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats.Results
Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max?=?141?±?13 %) and simultaneously decreased NA in the PFC (Emax?=??46?±?7 %). In the local presence into the LC of the α2-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (Emax?=?157?±?25 %) and PFC (Emax?=?175?±?24 %). Local citalopram (0.1–100 μM) into the LC induced NA increase in the LC (Emax?=?210?±?25 %) and decrease in the PFC (Emax?=??38?±?9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT3 receptor antagonist MDL72222 (1 μM) but not the 5-HT1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (Emax?=?158?±?26 %). Local citalopram into the PFC enhanced NA (Emax?=?376?±?18 %) in the area, which was prevented by MDL72222.Conclusions
The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT3 receptors and somatodendritic α2-adrenoceptors in the LC play an important role in the global effect of SSRIs. 相似文献17.
Yuko Shimamoto Tsuyoshi Fukuda Shinjiro Tominari Kyoko Fukumoto Kazuyuki Ueno Min Dong Kazuhiko Tanaka Takuma Shirasaka Katsuya Komori 《European journal of clinical pharmacology》2013,69(3):449-457
Purpose
Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent.Methods
After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator.Results
Patients with an LVEF of?<40 % (16 patients) or those with an LVEF of ≥ 40 %? and <60 % (40 %?≤?LVEF?<?60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of?≥60 % (53 patients) (2.29?±?0.95 or 2.79?±?0.99 vs. 3.50?±?1.04 L/h; p?<?0.001 or p?<?0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of?<40 % (r?=?0.828) and 40 %?≤?LVEF?<?60 % (r?=?0.773), but also with an LVEF in patients with a CLcr of?<60 mL/min (r?=?0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r 2?=?0.649).Conclusions
Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF. 相似文献18.
Thien Le Mercedes Xia Min Jia Nathan Sarkar Jerry Chen He Li Gary H. Wynn Robert J. Ursano Kwang H. Choi 《Psychopharmacology》2014,231(23):4569-4577
Rationale
Although chronic use of opiates can induce physical dependence and addiction, individual differences contributing to these symptoms are largely unknown.Objectives
Using intravenous morphine self-administration (MSA), we investigated whether individual differences in drug intake are associated with weight change, acoustic startle reflex (ASR), pre-pulse inhibition (PPI), and drug seeking during spontaneous withdrawal.Methods
Male Sprague-Dawley rats self-administered morphine (0.5 mg/kg/infusion) or saline for 3 weeks (4–6 h/day, 5 days/week) and drug intake and body weight were monitored daily. The ASR and the PPI (baseline, 1 day and 1 week) and drug seeking (1 week) were measured during spontaneous withdrawal.Results
Morphine animals did not gain weight (101 %?±?0.69), while the control animals did (115 %?±?1.06) after 3 weeks of self-administration. The ASR and the PPI were not significantly different between morphine and saline animals in 1-day or 1-week withdrawal. However, individual differences in initial (first 10 min), but not total (4–6 h), morphine intake of the daily sessions were positively correlated with weight change (r?=?0.437, p?=?0.037) and drug seeking (r?=?0.424, p?=?0.035) while inversely correlated with the ASR (r?=??0.544, p?=?0.005) in 1-week withdrawal from chronic morphine.Conclusions
A subgroup of animals that self-administered a larger amount of morphine at the beginning of the daily sessions exhibited subsequent weight gain, reduced ASR, and enhanced drug seeking in morphine withdrawal. Thus, individual differences in initial morphine intake may reveal a novel behavioral phenotype in opioid addiction. 相似文献19.
Michael Poyurovsky Camil Fuchs Artashez Pashinian Adva Levi Ronit Weizman Abraham Weizman 《Psychopharmacology》2013,226(3):615-622
Rationale
Combination treatment with reboxetine, a selective norepinephrine reuptake inhibitor, and betahistine, a histamine H1 receptor agonist/H3 antagonist, was developed to produce complementary action in CNS pathways regulating appetite and body weight. In the present placebo-controlled study, we evaluated whether a reboxetine–betahistine combination attenuates olanzapine-induced weight gain in schizophrenia patients.Method
Forty-three inpatients with DSM-IV schizophrenic disorder participated in a randomized double-blind study. Reboxetine (4 mg/day) with betahistine (48 mg/day) (N?=?29) or placebo (N?=?14) was co-administered with olanzapine (10 mg/day) for 6 weeks. Mental status was assessed at baseline and endpoint with relevant rating scales. Intention-to-treat method was used for statistical analysis.Results
Seven patients in the study group and four in the placebo group discontinued the trial. At the end of the trial, patients in the olanzapine/reboxetine + betahistine group gained significantly less weight than those in the olanzapine/placebo group [2.02?±?2.37 and 4.77?±?3.16 kg, respectively; t?=?2. 89, degrees of freedom (df)?=?41, p?=?0.006]. The weight-attenuating effect of this combination was twofold larger than the weight-attenuating effect previously demonstrated with reboxetine alone. Significantly fewer patients in the study group than in the comparison group increased their initial weight by >7 %, the cutoff for clinically significant weight gain [3/29 (10.3 %) and 6/14 (42.9 %), respectively; χ 2?=?6.03, df?=?1, p?=?0.014]. The reboxetine–betahistine combination was safe and well tolerated.Conclusions
Reboxetine–betahistine combination produces a clinically meaningful attenuation of olanzapine-induced weight gain. These results justify direct comparison between the reboxetine–betahistine combination and reboxetine alone. 相似文献20.
Fancy C. Thomas Kunal Taskar Vinay Rudraraju Satyanarayana Goda Helen R. Thorsheim Julie A. Gaasch Rajendar K. Mittapalli Diane Palmieri Patricia S. Steeg Paul R. Lockman Quentin R. Smith 《Pharmaceutical research》2009,26(11):2486-2494