共查询到20条相似文献,搜索用时 46 毫秒
1.
Mitsushige Sugimoto Naohito Shirai Masafumi Nishino Chise Kodaira Takahiro Uotani Shu Sahara Hitomi Ichikawa Takuma Kagami Ken Sugimoto Takahisa Furuta 《European journal of clinical pharmacology》2014,70(9):1073-1078
Introduction
The aim of therapeutic regimens using proton pump inhibitors (PPIs) in patients with acid-related diseases is to potently inhibit acid secretion for the full 24 h. However, optimum treatment is still unclear because the pharmacodynamics of PPIs differ among CYP2C19 genotypes and most of the previous studies have had loss of sample power.Methods
Using pH monitoring, we compared acid inhibition at standard dosage of omeprazole (20 mg, 50 times), lansoprazole (30 mg, 68 times), and rabeprazole (10 mg, 65 times) in Helicobacter pylori-negative healthy young Japanese volunteers.Results
Median pH with rabeprazole was 5.4 (3.3–7.5), which was significantly greater than with either omeprazole [4.4 (2.1–7.3)] or lansoprazole [4.8 (3.5–6.4)] (both P?0.05). Median 24-h pH differed among the different CYP2C19 genotypes in all three PPIs. In CYP2C19 extensive metabolizers (EMs), the genotype that is refractory to PPI treatment, median pH with omeprazole, lansoprazole, and rabeprazole was 3.8 (2.1–4.4), 4.5 (3.5–5.3) and 4.8 (3.3–7.5), respectively.Discussion
Treatment with the selected PPIs at their standard dosages had difficulty maintaining acid inhibition for a full 24 h, especially in CYP2C19 EM. However, rabeprazole has the merit of less influence of CYP2C19 genotype compared with the other PPIs. 相似文献2.
3.
Fang Wu Lu Gaohua Ping Zhao Masoud Jamei Shiew-Mei Huang Edward D. Bashaw Sue-Chih Lee 《Pharmaceutical research》2014,31(8):1919-1929
Purpose
The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug.Methods
By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur.Results
The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively.Conclusions
PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole. 相似文献4.
Chua D Chu E Lo A Lo M Pataky F Tang L Bains A 《The Canadian journal of hospital pharmacy》2012,65(2):98-102
Background
Medication discrepancies may occur on admission, transfer, or discharge from hospital. Therapeutic interchange within a drug class is a common practice in hospitals, and orders for specific proton pump inhibitors (PPIs) are often substituted with the hospital’s formulary PPI through therapeutic interchange protocols. Rabeprazole is the PPI on the formulary of the British Columbia PharmaCare program. However, different PPIs may appear on the formularies of the province’s hospitals. This misalignment and use of therapeutic interchange may lead to increased rates of medication discrepancies at the time of discharge.Objective
To evaluate the effect of formulary misalignment for PPIs between St Paul’s Hospital in Vancouver and the British Columbia PharmaCare program and use of therapeutic interchange on the occurrence of medication discrepancies at discharge.Methods
A cohort chart review was performed to compare discharge discrepancy rates for PPI orders between 2 periods: June 2006 to June 2008, when the same PPI appeared on the hospital and provincial formularies, and July 2008 to July 2010, when the designated PPIs differed between the hospital and provincial formularies. Data for the first study period were used to establish the baseline discharge discrepancy rate, and data for the later period represented the discharge discrepancy rate in the presence of misalignment between the hospital and PharmaCare formularies.Results
The discharge discrepancy rate for PPIs was 27.3% (24/88) when the 2 formularies were aligned and 49.1% (81/165) when the formularies were misaligned. This represents an absolute increase of 21.8 percentage points in the risk of discharge discrepancies (95% confidence interval 9.8–33.9 percentage points; p < 0.001) when the hospital and provincial formularies were misaligned and the hospital’s therapeutic interchange protocol was used.Conclusions
Misalignment between the PPIs specified in the hospital and provincial formularies, combined with use of therapeutic interchange, was associated with a significant increase in medication discrepancies at discharge. 相似文献5.
Stephanie Dodd Sivacharan Kollipara Manuel Sanchez-Felix Hyungchul Kim Qingshuo Meng Stefania Beato Tycho Heimbach 《Journal of pharmaceutical sciences》2019,108(1):87-101
Advances in understanding of human disease have prompted the U.S. Food and Drug Administration to classify certain molecules as “break-through therapies,” providing an accelerated review that may potentially enhance the quality of patient lives. With this designation come compressed timelines to develop drug products, which are not only suitable for clinic trials but can also be approved and brought to the market rapidly. Early risk identification for decreased oral absorption due to drug-drug interactions with proton pump inhibitors (PPIs) or acid-reducing agents (ARAs) is paramount to an effective drug product development strategy. An early ARA/PPI drug-drug interaction (DDI) risk identification strategy has been developed using physiologically based absorption modeling that readily integrates ADMET predictor generated in silico estimates or measured in vitro solubility, permeability, and ionization constants. Observed or predicted pH-solubility profile data along with pKas and drug dosing parameters were used to calculate a fraction of drug absorbed ratio in absence and presence of ARAs/PPIs. An integrated physiologically based pharmacokinetic absorption model using GastroPlus? with pKa values fitted to measured pH-solubility profile data along with measured permeability data correctly identified the observed ARA/PPI DDI for 78% (16/22) of the clinical studies. Formulation strategies for compounds with an anticipated pH-mediated DDI risk are presented. 相似文献
6.
Nadine Petrovsky Ulrich Ettinger Henrik Kessler Rainald Mössner Steffen Wolfsgruber Norbert Dahmen Wolfgang Maier Michael Wagner Boris B. Quednow 《Psychopharmacology》2013,229(1):31-40
Rationale
Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence.Objectives
We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI.Methods
We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured.Results
Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation.Conclusions
The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior. 相似文献7.
Neal R. Swerdlow Paul D. Shilling Michelle Breier Ryan S. Trim Gregory A. Light Richard Saint Marie 《Psychopharmacology》2012,224(3):349-362
Rationale
Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague?CDawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia.Objectives
After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH).Methods
Startle and PPI were assessed in SD and LE rats administered d-amphetamine (0 vs. 4.5?mg/kg, sc). Two weeks later, brain tissue was processed for comt, nrg1, grid2, and csnk1e expression; blood comt expression was also tested.Results
Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE?>?SD expression in most genes and regions, and female?>?male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120?ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30?ms PPI and startle magnitude correlated significantly with VH nrg1 and blood comt expression.Conclusions
Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia. 相似文献8.
Kenneth Grant Noor Al-Adhami June Tordoff Jocelyn Livesey Gil Barbezat David Reith 《International journal of clinical pharmacy》2006,28(4):189-193
Objectives
To evaluate the appropriateness of initiation of proton pump inhibitor (PPI) treatment in hospital, the quality of discharge information, and any association with continued treatment in the community.Method
Survey of all inpatients newly initiated on a PPI in June–August 2003. Assessment of appropriateness of therapy and completeness of discharge information; assessment of continuation of PPI therapy in the community after 6 months.Results
Thirty-five of 58 patients (60%) were considered appropriately commenced on PPI treatment. Less than 25% of patients discharged on a PPI had discharge information recommending duration of treatment or review. In the “appropriate” group 30 patients (86%) were discharged on omeprazole, and 13/21 (62%) evaluable patients remained on this at 6 months. In the “inappropriate” group 15 (65%) were discharged on omeprazole, and 10/14 (71%) evaluable patients remained on this at 6 months. Older patients remained on omeprazole for a longer duration but appropriateness of commencement did not influence the duration of treatment. Dose titration was attempted for 10 (29%) patients including three from the “inappropriate” group.Conclusion
Care should be taken to commence PPIs only when clinically indicated. Discharge information to GPs, especially recommendations for duration of treatment and/or dose titration, requires improvement. 相似文献9.
David J. Drobes David A. MacQueen Melissa D. Blank Michael E. Saladin Robert J. Malcolm 《Psychopharmacology》2013,229(2):285-294
Rationale
The reinforcing properties of nicotine may be, in part, derived from its ability to enhance certain forms of cognitive processing. Several animal and human studies have shown that nicotine increases prepulse inhibition (PPI) of the startle reflex. However, it remains unclear whether these effects are related to smoking susceptibility.Objectives
The current study examined the effects of intravenously delivered nicotine on PPI in smokers and non-smokers, as well as its association with a quantitative index of familial smoking.Methods
The sample consisted of 30 non-smokers and 16 smokers, who completed an initial assessment, followed on a separate day by a laboratory assessment of PPI prior to and following each of two intravenous nicotine infusions. Separate doses were used in smoker and non-smoker samples.Results
Analyses indicated that both nicotine infusions acutely enhanced PPI among non-smokers, and this enhancement was positively related to the degree of smoking among first and second-degree relatives. Smokers also displayed PPI enhancement after receiving the first infusion, but this effect was unrelated to familial smoking.Conclusions
These data suggest that the PPI paradigm may have utility as an endophenotype for cognitive processes which contribute to smoking risk. 相似文献10.
11.
Linney S Fernandes T Einarson T Sengar A Walker JH Mills A 《The Canadian journal of hospital pharmacy》2010,63(1):31-37
Background:
The use of proton pump inhibitors (PPIs) has been implicated as a potential contributor to the development of Clostridium difficile–associated disease (CDAD) because of the ability of these drugs to substantially reduce the bactericidal effect of gastric acid. This study focused on the impact of PPIs, among other known risk factors, during an outbreak of CDAD in a hospital setting.Objectives:
The primary objective was to determine whether there was an association between current use of a PPI and the CDAD outbreak. Secondary objectives were to evaluate any correlations between the CDAD outbreak and past use of PPIs, use of antibiotics, diabetes mellitus, enteral feeding, cancer, gastrointestinal surgery, inflammatory bowel disease, and previous care or residence in an institutional setting.Methods:
A retrospective case–control study was conducted. One hundred and fifty cases of hospital-acquired Clostridium difficile were identified. Patients were individually matched to controls for age, sex, date of admission to hospital, and hospital unit. The groups were compared with respect to each exposure.Results:
Eight case patients could not be matched with suitable controls. Therefore, data from 142 cases and 142 controls were analyzed. There was no association between current use of a PPI and the CDAD outbreak (odds ratio [OR] 1.0, 95% confidence interval [CI] 0.99–1.01). Similarly, there was no correlation between the CDAD outbreak and diabetes, enteral feeding, cancer, gastrointestinal surgery, inflammatory bowel disease, or previous care or residence in an institution. However, the development of CDAD was positively associated with use of antibiotics within the 30 days preceding the infection (OR 12.0, 95% CI 4.0–35.7) and with past use of a PPI (OR 2.4, 95% CI 1.4–4.3).Conclusions:
The development of CDAD during a hospital outbreak was associated with use of antibiotics and with past, not current, use of PPIs. 相似文献12.
Takahisa Furuta Takayuki Iwaki Kazuo Umemura 《British journal of clinical pharmacology》2010,70(3):383-392
AIMS
The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.METHODS
Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a ‘low responder’. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.RESULTS
In rapid metabolizers (RMs, *1/*1, n = 15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n = 24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became ‘low-responders’ when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.CONCLUSIONS
The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs. 相似文献13.
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14.
Kate Chitty Matthew A. Albrecht Kyran Graham Chantelle Kerr Joseph W. Y. Lee Rajan Iyyalol Mathew T. Martin-Iverson 《Psychopharmacology》2014,231(11):2327-2337
Rationale
Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects.Objectives
The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli.Methods
A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES50) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity.Results
Dexamphetamine increased the threshold and ES50 of the response to pulse-alone trials in both sexes and reduced R MAX exclusively in females. Dexamphetamine modestly increased PPI of the R MAX across both attention conditions. PPI of R MAX was reduced during the ATTEND condition compared to the IGNORE condition.Conclusions
Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia. 相似文献15.
16.
Motoyasu Yamashita Yasufumi Sakakibara F. Scott Hall Yohtaro Numachi Sumiko Yoshida Hideaki Kobayashi Osamu Uchiumi George R. Uhl Yoshiyuki Kasahara Ichiro Sora 《Psychopharmacology》2013,227(4):741-749
Rationale
Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes.Objectives
Impulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating.Results
DAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice.Conclusion
These results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice. 相似文献17.
《Expert opinion on drug discovery》2013,8(9):1123-1143
Background: The discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor at present in Phase I clinical trials for cancer, is described. Emphasis is placed on the specific hurdles overcome throughout the discovery process that relate to the nature of the targeted protein–protein interaction (PPI). Objective/methods: This review draws on observations from the experience of discovering ABT-263 and discusses them within the framework of the larger issue of discovering drugs targeting PPIs. Issues discussed include the ‘hot spot’ paradigm, hit and lead generation, serum protein binding, structure-based design, and in particular, hydrophobicity and molecular size and their relation to pharmacokinetic/pharmacodynamic properties. Results/conclusion: Approaches to understanding obstacles thought of as being specifically attached to PPIs, and existing techniques to combat these obstacles, were very helpful in overcoming them. The example of ABT-263 provides evidence that the larger family of PPI targets is more tractable than may have been thought. 相似文献
18.
19.
T. N. Douma M. J. Millan D. Boulay G. Griebel P. M. Verdouw K. G. Westphal B. Olivier L. Groenink 《Psychopharmacology》2014,231(7):1289-1303
Rationale
As enhanced corticotropin-releasing factor (CRF) transmission is associated with induction of sensorimotor gating deficits, CRF1 receptor antagonists may reverse disrupted prepulse inhibition (PPI), an operational measure of sensorimotor gating.Objectives
To determine the effects of CRF1 receptor antagonists in pharmacological models of disrupted PPI and to determine if long-term elevated central CRF levels alter sensitivity towards PPI disrupting drugs.Methods
CP154,526 (10–40 mg/kg), SSR125543 (3–30 mg/kg) and DMP695 (40 mg/kg) were tested on PPI disruption provoked by d-amphetamine (2.5, 3 mg/kg), ketamine (5, 30 mg/kg) and MK801 (0.2, 0.5 mg/kg) in Wistar rats, C57Bl/6J and CD1 mice, and on spontaneously low PPI in Iffa Credo rats and DBA/2J mice. PPI-disrupting effects of d-amphetamine (2.5–5 mg/kg) and MK801 (0.3–1 mg/kg) were examined in CRF-overexpressing (CRFtg) mice, which display PPI deficits. Finally, we determined the influence of CP154,526 on d-amphetamine-induced dopamine outflow in nucleus accumbens and prefrontal cortex of CRFtg mice using in vivo microdialysis.Results
No CRF1?antagonists improved PPI deficits in any test. CRFtg mice showed blunted PPI disruption in response to MK801, but not d-amphetamine. Further, d-amphetamine-induced dopamine release was less pronounced in CRFtg versus wild-type mice, a response normalized by pretreatment with CP154,526.Conclusion
The inability of CRF1 receptor antagonists to block pharmacological disruption of sensorimotor gating suggests that the involvement of CRF1 receptors in the modulation of dopaminergic and glutamatergic neurotransmission relevant for sensory gating is limited. Furthermore, the alterations observed in CRFtg mice support the notion that long-term elevated central CRF levels induce changes in these neurotransmitter systems. 相似文献20.