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1.
Franck Maschino Caroline Hurault-Delarue Leila Chebbane Vincent Fabry Jean Louis Montastruc Haleh Bagheri 《European journal of clinical pharmacology》2012,68(11):1557-1560
Aim
The aim of the present study was to investigate bleeding adverse drug reactions (ADRs) in patients exposed to serotonin reuptake inhibitors (SRI) plus antiplatelet agents using the French Pharmacovigilance Database (FPVDB) regarding the controversial data in the literature.Methods
The case/non-case method was used to measure the association between bleedings and exposure to SRIs plus antiplatelet agents versus antiplatelet drugs alone.Results
Over 3?years, a total of 1,977 spontaneous reports of ADRs were collected with antiplatelet drugs, and antiplatelet agents plus SRIs in patients aged over 50?years, of which 1,331 (67.3?%) concerned bleeding. Multivariate logistic regression analysis failed to show any significant association [adjusted ROR?=?0.8 (0.5–1.2)].Conclusion
The data did not demonstrate any significant association between bleeding ADRs and exposure to SRI + antiplatelet agents versus antiplatelets alone. Considering other conflicting results, this risk should be kept in mind by physicians when treating patients with several risk factors. 相似文献2.
Carmen C. Franz Carole Hildbrand Christa Born Sabin Egger Alexandra E. Rätz Bravo Stephan Krähenbühl 《European journal of clinical pharmacology》2013,69(8):1565-1573
Aim and background
To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.Methods
This was a cross-sectional retrospective study assessing the dose adequacy of drug treatment of 400 cirrhotic patients at hospital admission based on the authors’ own previous studies and standard literature. The prevalence of total and preventable ADRs and of hospitalizations due to preventable ADRs was determined.Results
Of all 1653 drugs prescribed (median 4 per patient), 336 (20 %) drugs were inadequately dosed in 184 patients. Overall, 210 ADRs (78 % preventable) occurred in 120 patients. Sixty-nine ADRs (33 % of all ADRs) were associated with inadequate drug dosing in 46 patients, of which 68 % were preventable. Nonsteroidal anti-inflammatory drugs and psycholeptics in particular frequently caused preventable ADRs associated with inadequate drug dosing. Inadequate drug dosing was more frequently associated with ADRs than adequate drug dosing, and patients receiving inadequately dosed drugs were more frequently admitted to the hospital due to ADRs. Hospitalization of patients receiving inadequately dosed drugs that caused preventable ADRs resulted in 94 additional hospital days.Conclusion
In this retrospective study, inadequate drug dosing was associated with an increased frequency of ADRs, hospital admissions and hospital days in cirrhotic patients. We therefore conclude that the careful dosing of critical drugs is important in patients with liver cirrhosis. 相似文献3.
E. Dehours V. Bounes H. Bagheri B. Vallé J. L. Ducassé J. L. Montastruc 《European journal of clinical pharmacology》2014,70(7):881-887
Purpose
The purpose of this study is to assess the incidence of adverse drug reactions (ADR) leading to call an emergency medical dispatching centre.Methods
A prospective, observational, monocentric clinical study performed over a 2-year period (2011–2012) in a French prehospital emergency dispatching centre, the Service d'Aide Médicale Urgente (SAMU) covering 1,156,000 inhabitants. All adult patients (age?≥?18) who called for any cause were included. We created an electronic trigger ‘iatrogenic event’ implemented by the dispatching physician for each suspected case of ADR, then we completed the analyses of all the cases with a chief complain represented in more than 1 % of the triggered cases. The primary outcome variable was the occurrence of any possible ADR. We then used the French method of causal relationship assessment.Results
The SAMU dispatched 339,915 calls during the study. In total, 1,467 ADRs were identified, representing 0.95 % (CI 95 % 0.90–1.00 %) of cases. ADRs were as serious (SADR) in 51.06 % (CI 95 % 48.45–53.67 %) of cases. The major ADR observed was haemorrhage, (42.81 % (CI 95 % 40.62–45.00 %), n?=?628) followed by allergy, hypoglycaemia, vomiting, dizziness and drowsiness. The class of drugs most frequently involved was antithrombotic (43.69 % (CI 95 % 41.45–45.93 %), n?=?641), followed by insulin (17.98 % (CI 95 %:17.06–18.90 %), n?=?264).Conclusions
Emergency calls concerning ADRs were estimated as 9/1,000, and one out of two is serious. 相似文献4.
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Linda Härmark Eugène van Puijenbroek Kees van Grootheest 《European journal of clinical pharmacology》2013,69(2):209-215
Purpose
Duloxetine (Cymbalta®) is a serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitor indicated for the treatment of depression, diabetic peripheral neuropathic pain and general anxiety disorder. The aim of this study is to gain insight in the user and safety profile of duloxetine in daily practice, reported by patients via a web-based intensive monitoring system during their first 6 months of use.Methods
First-time users of duloxetine were identified through the first dispensing signal in the pharmacy. Patient demographics and information about drug use and adverse drug reactions, ADRs, were collected through electronic questionnaires sent 2 and 6 weeks, 3 and 6 months after the start of duloxetine administration. ADRs were quantified and signal detection was performed on a case by case basis.Results
Three hundred and ninety-eight patients registered for the study; 69.1 % were female. Depression was the main indication. Three hundred and three patients (76.1 %) filled in at least one questionnaire and 78.9 % of these reported an ADR. Serious ADRs were reported by 4 patients. Three new signals were identified, amenorrhea, shock-like paraesthesias and micturition problems.Conclusions
Web-based intensive monitoring is an observational prospective cohort study mirroring the use and ADRs of duloxetine in daily practice. This study indicates that duloxetine is a relatively safe drug as used by patients for six months in daily practice, but the aforementioned signals need to be evaluated in more detail. 相似文献8.
Ben D. Snyder Andrew Rowland Thomas M. Polasek John O. Miners Matthew P. Doogue 《European journal of clinical pharmacology》2014,70(9):1115-1122
Objective
To evaluate felodipine as a potential perpetrator of pharmacokinetic drug-drug interactions (PK-DDIs) involving cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp).Methods
Felodipine extended-release 10 mg was administered daily to six healthy subjects for 7 days (days 1–7). Subjects were administered a modified Inje cocktail comprising the selective probe substrates caffeine 100 mg (CYP1A2), losartan 25 mg (CYP2C9), omeprazole 20 mg (CYP2C19), dextromethorphan 30 mg (CYP2D6), midazolam 2 mg (CYP3A) and digoxin 250 μg (P-gp) on day 0 (prior to felodipine exposure) and day 7 (after felodipine exposure). Plasma samples were collected over 24 h and drug concentrations measured by UPLC-MS/MS.Results
The geometric means of the area under the plasma concentration–time curve ratios (probe AUC after felodipine exposure/probe AUC prior to felodipine exposure) and 95 % confidence intervals for each probe were: caffeine 0.91 (0.64–1.30), losartan 1.05 (0.95–1.15), omeprazole 1.17 (0.78–1.76), dextromethorphan 1.46 (1.00–2.12), midazolam 1.23 (0.99–1.52) and digoxin 1.01 (0.89–1.15).Conclusion
Felodipine may be a weak in vivo inhibitor of CYP3A and CYP2D6 but is unlikely to act as a significant perpetrator of PK-DDIs. 相似文献9.
Rationale
The cAMP-dependent protein kinase A (PKA) signaling transduction pathway has been shown to play an important role in the modulation of several ethanol-induced behaviors. Different studies have demonstrated intracellular calcium (Ca2+)-dependent activation of the PKA cascade after ethanol administration. Thus, the cAMP cascade mediator Ca2+-dependent calmodulin (CaM) has been strongly implicated in the central effects of ethanol.Objectives
In this study, we assessed the role of the CaM inhibitor W7 on ethanol-induced stimulation, ethanol intake, and ethanol-induced activation of PKA.Methods
Swiss mice were pretreated with W7 (0–10 mg/kg) 30 min before ethanol (0–3.75 g/kg) administration. Immediately, animals were placed during 20 min in an open-field chamber. Ethanol (10 %, v/v) intake in 2 h was assessed using a limited access paradigm. Experiments with caffeine (0–15 mg/kg), cocaine (0–4 mg/kg), and saccharine (0.1 %, w/v) were designed to compare their results to those obtained with ethanol. Western blot was assayed 45 min after ethanol administration.Results
Results showed that pretreatment with W7, reduced selectively in a dose-dependent fashion ethanol-induced locomotor stimulation and ethanol intake. The ethanol-induced activation of PKA was also prevented by W7 administration.Conclusions
These results demonstrate that CaM inhibition resulted in a selective reduction of ethanol-stimulating effects and ethanol intake. The PKA activation induced by ethanol was blocked after the CaM blockade with W7. These results provide further evidence of the key role of cellular Ca2+-dependent pathways on the central effects of ethanol. 相似文献10.
Jesse S. Rodriguez Colin S. Cunningham Fernando B. Moura Pauline Ondachi F. Ivy Carroll Lance R. McMahon 《Psychopharmacology》2014,231(23):4455-4466
Rationale
Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential.Objective
This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2′-fluoro-3′-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2′-fluorodeschloroepibatidine (RTI-7527-36), and 3′-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76).Methods
Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature.Results
In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12?ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine?>?RTI-7527-36?>?nicotine?>?RTI-7527-102?>?varenicline?=?cytisine?=?RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β-erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine.Conclusions
The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2-subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists. 相似文献11.
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12.
Motoki Kubo Toru Miyoshi Tomonari Kimura Yoko Noda Kunihisa Kohno Kazufumi Nakamura Hiroshi Morita Hiroshi Ito 《Am J Cardiovasc Drugs》2014,14(5):387-392
Background
Residual risk of cardiovascular disease from increased small dense low-density lipoprotein (sdLDL)-cholesterol levels and low n-3 polyunsaturated fatty acid (PUFA) levels is a considerable therapeutic issue. The purpose of this study was to evaluate the effect of ezetimibe as an add-on to statins and supplemental eicosapentaenoic acid (EPA) on sdLDL cholesterol and absorption of EPA in patients with coronary artery disease.Methods
The study population consisted of ten male patients who were concurrently receiving statins and EPA 1,800 mg/day. Serum lipids and PUFAs, including EPA and arachidonic acid, were measured in blood samples collected before ezetimibe (baseline), 4 weeks after starting 10-mg/day ezetimibe, and 4 weeks after discontinuing ezetimibe.Results
Ezetimibe significantly decreased sdLDL-cholesterol levels after 4 weeks of treatment (baseline 35 ± 13 mg/dl; treatment 27 ± 9 mg/dl), but the levels returned to baseline after discontinuation of ezetimibe (37 ± 13 mg/dl). The concentration of EPA did not significantly change during the study.Conclusion
Ezetimibe shows great promise as an add-on therapy to statins to reduce sdLDL-cholesterol-related residual risk of cardiovascular disease without affecting absorption of supplemental EPA in patients with coronary artery disease. 相似文献13.
Miguel Molina-Hernández N. Patricia Téllez-Alcántara Jorge I. Olivera-López M. Teresa Jaramillo 《Psychopharmacology》2014,231(17):3343-3350
Rationale
There is a significant delay in the clinical response of antidepressant drugs, and antidepressant treatments produce side effects.Objective
We examined the relationship between 17β-estradiol and topiramate in ovariectomized Wistar rats submitted to the forced swimming test (FST).Methods
Topiramate was administered alone or combined with 17β-estradiol to ovariectomized rats submitted to the FST.Results
Topiramate (20 mg/kg, P?0.05; 30 mg/kg, P?0.05) reduced immobility by increasing swimming; these effects were antagonized by finasteride (50 mg/kg). In interaction experiments, topiramate (10 mg/kg) plus 17β-estradiol (5 micrograms per rat; P?0.05) reduced immobility by increasing swimming behavior. Besides, 17β-estradiol (2.5 micrograms per rat) shortened the onset of the antidepressant-like effects of topiramate (P?0.05). In the open field test, topiramate alone or combined with 17β-estradiol (P?0.05) reduced locomotion.Conclusions
Topiramate alone or combined with 17β-estradiol produced antidepressant-like actions; and 17β-estradiol shortened the onset of the antidepressant-like effects of topiramate. 相似文献14.
Emmanuelle Faye Emmanuelle Bondon-Guitton Pascale Olivier-Abbal Jean-Louis Montastruc 《European journal of clinical pharmacology》2013,69(10):1819-1826
Purpose
Our aim was to describe all serious cutaneous adverse drug reactions (ADRs) spontaneously reported in France for all oral protein kinase inhibitors, their characteristics and whether they were labeled (reported in the Summary of Product Characteristics) or not.Methods
We performed a retrospective observational study in the French PharmacoVigilance Database, selecting for analysis serious cutaneous reactions of patients due to treatment with oral protein kinase inhibitors (erlotinib, gefitinib, imatinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, everolimus) between 1 January 2008 and 31 December 31 2010.Results
Ninety-four patients suffered from 115 serious cutaneous reactions due to oral protein kinase inhibitors. Serious cutaneous reactions more frequently reported were maculo-papular rash (mostly with imatinib), followed by hand–foot syndrome (specifically with sorafenib) and papulopustular rash (particularly with erlotinib). Patients were mostly males (63 %) with a mean age of 62.6?±?15.4 years. Drug withdrawal was observed in 73.1 % of cases because of these cutaneous reactions. Delay of occurrence of the ADR varied from 11.5 to 58.5 days. Unlabeled serious reactions were found (17.4 %), including skin ulceration, vasculitis or purpura with sorafenib or sunitinib and drug rash with eosinophilia and systemic symptoms with imatinib.Conclusion
Some of the serious ADRs spontaneously reported with oral protein kinase inhibitors are labeled and commonly reported in the literature, but others occur only rarely and unlabeled. In our study, most serious ADRs occurred in males within the 2 first months of treatment and were responsible for the withdrawal of therapy with protein kinase inhibitors. 相似文献15.
Joseph P. Schacht Raymond F. Anton Patrick K. Randall Xingbao Li Scott Henderson Hugh Myrick 《Psychopharmacology》2014,231(18):3799-3807
Rationale
The α4β2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas.Objectives
This pilot study tested varenicline’s effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals.Methods
Thirty-five such individuals (mean age?=?30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC).Results
Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas.Conclusions
These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption. 相似文献16.
Samuel V. Mussi Rupa Sawant Federico Perche Mônica C. Oliveira Ricardo B. Azevedo Lucas A. M. Ferreira Vladimir P. Torchilin 《Pharmaceutical research》2014,31(8):1882-1892
Purpose
To develop a nanostructured lipid carrier (NLC) co-loaded with doxorubicin and docosahexaenoic acid (DHA) and to evaluate its potential to overcome drug resistance and to increase antitumoral effect in MCF-7/Adr cancer cell line.Methods
The NLC was prepared by a hot homogenization method and characterized for size, zeta potential, entrapment efficiency (EE) and drug loading (DL). Drug release was evaluated by dialysis in complete DMEM, and NLC aggregation was assayed in the presence of serum. The cytotoxicity of formulations, doxorubicin uptake or penetration were evaluated in MCF-7 and MCF-7/Adr as monolayer or spheroid models.Results
The formulation had a size of about 80 nm, negative zeta potential, EE of 99%, DL of 31 mg/g, a controlled drug release in DMEM and no particles aggregation in presence of serum. The NLC loaded with doxorubicin and DHA showed the same activity as free drugs against MCF-7 but a stronger activity against MCF-7/Adr cells. In monolayer model, the doxorubicin uptake as free and encapsulated form was similar in MCF-7 but higher for the encapsulated drug in MCF-7/Adr, suggesting a bypassing of P-glycoprotein bomb efflux. For spheroids, the NLC loaded with doxorubicin and DHA showed a prominent cytotoxicity and a greater penetration of doxorubicin.Conclusions
These findings suggest that the co-encapsulation of doxorubicin and DHA in NLC enhances the cytotoxicity and overcomes the doxorubicin resistance in MCF-7/Adr. Figure? 相似文献
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Matea Nikolac Perkovic Gordana Nedic Erjavec Maja Zivkovic Marina Sagud Suzana Uzun Alma Mihaljevic-Peles Oliver Kozumplik Dorotea Muck-Seler Nela Pivac 《Psychopharmacology》2014,231(18):3757-3764
Rationale
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a major role in neurogenesis and neuroplasticity, and in the modulation of several neurotransmitter systems including the dopaminergic system. There are mixed reports about the association between the BDNF Val66Met polymorphism, schizophrenia, and treatment response to antipsychotic drugs.Objectives
The present study evaluated the association of the BDNF Val66Met polymorphism with treatment response to atypical antipsychotic olanzapine in schizophrenia and the possible predictive value of the BDNF Val66Met genotype status in treatment response to antipsychotic medication.Methods
The study included 590 ethnically homogenous Caucasian patients with schizophrenia (diagnosed using the SCID), 40.2?±?12.0 years old, treated with olanzapine monotherapy (10–20 mg/day), or with other antipsychotics such as risperidone (3–6 mg/day), clozapine (100–500 mg/day), haloperidol (3–115 mg/day), fluphenazine (4–25 mg/day), and quetiapine (50–800 mg/day). Patients were subdivided into responders and non-responders according to a 50 % reduction in the Positive and Negative Syndrome Scale (PANSS) total and subscale scores after 8 weeks of treatment.Results
The results, corrected for possible effects of gender and age, showed a significant association between the BDNF Val66Met polymorphism and treatment response to olanzapine in patients. The Val/Val genotype was observed more frequently in treatment responders to olanzapine, and this genotype was associated with an improvement in clinical symptoms.Conclusions
Our results suggest that BDNF Val66Met variants might influence the response to 8 weeks of monotherapy with olanzapine, in a relatively large sample of patients with schizophrenia. 相似文献18.
19.
Taugourdeau-Raymond S Rouby F Default A Jean-Pastor MJ;French Network of Pharmacovigilance Centers 《European journal of clinical pharmacology》2012,68(7):1103-1107
Purpose
Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor, is widely used in association with standard chemotherapy in metastatic cancer. Well tolerated, bevacizumab is sometimes associated with serious adverse drug reactions (ADRs). The objective of this study is to describe the profile of ADRs related to bevacizumab and reported to the French Pharmacovigilance system.Method
All serious cases of ADRs associated with bevacizumab recorded in the French Pharmacovigilance database up to November 31, 2010 were identified and analyzed, focusing on patient information, drug exposure, and characteristics of the ADRs. Categorical variables were compared using the chi-square test when appropriate.Results
A total of 351 serious cases involving 626 ADRs were recorded in the database during the study interval. The most frequent ADRs reported involved the gastrointestinal system (21.9%). The most frequent ADRs included gastrointestinal perforation (4.8%), thromboembolic events (4.0%), pulmonary embolism (3.2%), hypertension (2.7%), gastrointestinal hemorrhage (2.7%), and cerebral hemorrhage or vascular accident (2.6%). The median duration of bevacizumab exposure was four cycles (range 1–30) when ADRs occurred. In 18 cases of death directly caused by ADRs, 50% occurred after only one cycle. In cases of disability, 40% of ADRs were neurologic: neuropathy, paralysis, and paresis.Conclusion
To the best of our knowledge, this is the first analysis of bevacizumab safety profile using data collected in a national pharmacovigilance database. Our study confirms the frequency and seriousness of gastrointestinal, thromboembolic, and hemorrhage events with bevacizumab use and provides a picture of the bevacizumab safety profile in daily medical practice, despite intrinsic limitations. 相似文献20.
Antoniette M. Maldonado-Devincci Matthew C. Beattie Danielle H. Morrow Raechel E. McKinley Jason B. Cook Todd K. O’Buckley A. Leslie Morrow 《Psychopharmacology》2014,231(17):3281-3292