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1.
Remo Holanda de Mendonça Furtado Robert Patrick Giugliano Celia Maria Cassaro Strunz Cyrillo Cavalheiro Filho José Antonio Franchini Ramires Roberto Kalil Filho Pedro Alves Lemos Neto Alexandre Costa Pereira Tânia Rúbia Rocha Beatriz Tonon Freire Elbio Antonio D’Amico José Carlos Nicolau 《Am J Cardiovasc Drugs》2016,16(4):275-284
Background
Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine.Objectives
Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine.Methods
We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12? (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA).Results
We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance (p = 0.07, 95 % confidence interval [CI] ?1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p = 0.04).Conclusions
Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel.Clinical Trial Registration
NCT01896557.2.
Rationale
Cocaine-induced changes in D2 receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D3 receptors is less clear.Objectives
To characterize the effects of repeated cocaine administration on the sensitivity of rats to D2- and D3-mediated behaviors, as well as the binding properties of ventral striatal D2-like and D3 receptors.Methods
Pramipexole was used to assess the sensitivity of rats to D3/D2 agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D2-like and D3 receptors (24 h and 42 days) were also evaluated.Results
Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h–42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose–response curve. Cocaine treatment also decreased B max and K d for D2-like receptors and increased D3 receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists.Conclusions
These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D3 and D2 receptors, with enhancements of D3-mediated behavioral effects observed within 72 h and enhancements of D2-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D3 receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.3.
4.
Catherine Guittet Maria Manso Ingrid Burton Luc-André Granier Frédéric Marçon 《Pharmaceutical research》2017,34(9):1840-1848
Purpose
The objective of this study was to assess the bioavailability and the sedative effect of a single-dose administration of an innovative oral solution of midazolam containing γ-cyclodextrins (ADV6209).Methods
A bioavailability study with a standard two-sequences, two-periods, and crossover design was conducted. Subjects randomly received 15 mg of ADV6209 by oral route followed by 5 mg of the reference drug (midazolam hydrochloride intravenous solution (Hypnovel®, Roche) by intravenous route or vice versa. Blood samples were drawn at different time points to measure midazolam and its metabolite α-hydroxymidazolam concentrations. Non-compartmental pharmacokinetic methods were used to calculate main pharmacokinetic parameters and absolute bioavailability.Results
Caucasian healthy subjects (n = 12) were included in the study. ADV6209 had a bioavailability of 39.6%. The oral elimination half-life with ADV6209 was slightly shorter than with the reference i.v. form (2.66 h versus 2.99 h). The sedative effect was observed 27.5 ± 15.5 min after oral administration for a duration of 48.5 ± 35.4 min. Double peak phenomenon was observed in 5 patients.Conclusions
Cyclodextrins have little impact on midazolam oral bioavailability and the pharmacokinetics parameters of midazolam formulation ADV6209 are close to those reported previously.5.
Introduction
Arginine vasopressin-stimulated reabsorption of urea occurs in the collecting duct via increased expression of the urea transporter.Objective
The aim of this study was to evaluate whether the blood urea nitrogen/creatinine (BUN/Cr) ratio is useful for predicting tolvaptan response in patients with decompensated heart failure (HF).Methods
Among 71 consecutive patients with HF who received oral tolvaptan between 2010 and 2014, we retrospectively studied 33 patients with decompensated HF without any mechanical circulatory assistance or inotropic support who had already been treated with loop diuretics. A responder to tolvaptan was defined as an individual who experienced a ≥30 % increase in their respective 24-h urine volume.Results
Among the 33 patients, 21 met the criteria of a responder. The area under the receiver operating characteristic curves of BUN/Cr and BUN were 0.790 and 0.714, respectively, and the respective cut-off values for responders to tolvaptan were 23.8 and 49.0. BUN/Cr and BUN retained their significant relationships with the responder status (odds ratio for BUN/Cr >23.8: 20.9; 95 % confidence interval [CI] 2.7–531.1; p = 0.002; odds ratio for BUN ≥49: 7.7; 95 % CI 1.4–65.8; p = 0.02).Conclusion
Our results suggest that high BUN/Cr may be a predictor of response to tolvaptan in decompensated HF patients. A prospective study with a large sample size is required to confirm this preliminary finding.6.
Purpose
Curcumin is very well established as a chemo-therapeutic, chemo-preventive and chemo-sensitizing agent in diverse disease conditions. As the isolated pure form has poor solubility and pharmacokinetic problems, therefore it is encapsulated in to several nano-formulations to improve its bioavailability. Here in the current study, we aim to compare different nano-formulations of curcumin for their chemo-sensitizing activity in doxorubicin (DOX) resistant K562 cells.Methods
Four different curcumin formulations were prepared namely DMSO assisted curcumin nano-dispersion (CurD, 260 nm), liposomal curcumin (CurL, 165 nm), MPEG-PCL micellar curcumin (CurM, 18 nm) and cyclodextrin encapsulated curcumin (CurN, 37 nm). The formulations were subjected to particle characterizations (size, zeta potential, release studies), followed by biological assays such as cellular uptake, P-gp inhibitory activity and reversal of DOX resistance by co-treatment with DOX.Results
Curcumin uptake in K562N and K562R cells was mildly reduced when treated with CurL and CurM, while for CurD and CurN the uptake remained equivalent. However, CurL retained P-gp inhibitory activity of curcumin and with a considerable chemo-sensitizing effect but CurM showed no P-gp inhibitory activity. CurN retained above biological activities, but requires a secondary carrier under in vivo conditions.Conclusions
From the results, CurM was found to be most suitable for solubilization of curcumin where as CurL can be considered as most suitable nano-formulation for reversal of DOX resistance.7.
Michela Blain Alexander Garrard Robert Poppenga Betty Chen Matthew Valento Melissa Halliday Gittinger 《Journal of medical toxicology》2017,13(3):259-262
Introduction
Monensin is a veterinary antibiotic with a narrow therapeutic window that has led to lethal intoxication in many animal species. Only two prior cases of human toxicity have been reported, both fatal. We present the first case of survival from severe toxicity following monensin ingestion.Case
A 58-year-old man presented with 8 days of vomiting and abdominal pain. Due to delusions of central nervous system toxoplasmosis, he ingested 300 mg of monensin. His laboratory studies revealed severe rhabdomyolysis without renal dysfunction. Total creatine kinase (CK) peaked above 100,000 U/L. His CK decreased to 5192 U/L after 15 days of aggressive hydration and sodium bicarbonate therapy. His ejection fraction on echocardiogram decreased from 69 to 56%.Discussion
Reports on acute clinical effects after human exposure to monensin are limited. Ingestion is known to cause skeletal and cardiac muscle rhabdomyolysis and necrosis. Animal studies demonstrate that monensin’s toxicity is due to increases in intracellular sodium concentrations and Ca2+ release. To date, no effective antidotal treatment has been described.Conclusions
Monensin is a veterinary medication not approved for human use by the US Food and Drug Administration. Though poorly studied in humans, this case demonstrates the severe harm that may occur following ingestion.8.
9.
Eduardo Celia Palma Nelson Guardiola Meinhardt Airton Tetelbom Stein Isabela Heineck Maria Isabel Fischer BibianaVerlindo de Araújo Teresa Dalla Costa 《Pharmaceutical research》2018,35(6):116
Purpose
To determine the efficacious cefazolin prophylactic dose for bariatric surgery using free subcutaneous concentrations accessed by microdialysis after 2 g or 3 g i.v. bolus dosing to morbidly obese women and POPPK modeling.Methods
A POPPK model with variable plasma and subcutaneous tissue protein binding was developed to simultaneously describe plasma and tissue data sets. The outcomes was predicted for common surgical site infection (SSI) bacteria over 3, 4, 5 and 6 h periods postdose, as probability of target attainment (PTA) using Monte Carlo simulation.Results
CFZ 2 g warrant up to 5 h SSI prophylaxis for bacteria with MICs ≤1 mg/L such as Escherichia coli and Staphylococcus aureus. For species such as Klebsiella pneumoniae, which present MIC distribution frequency of 2 mg/L, the maintenance of PTA?≥?90% occurs with a 3 g dose for surgeries lasting up to 5 h, and 2 g dose provide an adequate response up to 4 h (PTA of 89%).Conclusions
Effectiveness of CFZ 2 g is similar to 3 g against bacteria with a MIC up to 2 mg/L, especially if the surgery does not last for more than 4 h.10.
Aim and objective
6-hydroxy dopamine (6-OHDA) is a neurotoxin which on intranigral administration produces severe nigrostriatal damage with motor and cognitive deficit in animals. Curcumin (CMN) in combination with bioenhancer piperine (PP) in 6-hydroxydopamine-induced Parkinsonian rats was used to investigate the antioxidant, neuromodulatory and neuroprotective mechanisms.Materials and methods
Hemi-Parkinson’s rat model was developed with intranigral infusion of 6-OHDA (8 μg/2 μl, once, unilaterally), treatment with CMN (25 and 50 mg/kg) and combination of PP (2.5 mg/kg) with CMN (25 mg/kg) was given daily for 21 days starting from the 7th day after 6-OHDA infusion. The behavioral (locomotor, grip strength, and narrow beam walk) parameters were studied on weekly basis. On 22nd day, isolated brain preparations were subjected to biochemical (lipid peroxidation, glutathione, and nitrite), neuroinflammatory (IL-1β, IL-6, and TNF- α), and neurochemical (DA, NE, 5- HT, GABA, Glutamate, DOPAC, HVA, and 5-HIAA) analysis.Results
Oral administration of CMN had significantly prevented behavioral, neuroinflammatory, and neurochemical changes and preserved the antioxidant potential of the nigrostriatum in rats treated with 6-OHDA.Conclusion
In the present study, PP and CMN had afforded a better neuroprotective effect compared to alone treatment on behavior, biochemical, neuroinflammatory, and neurochemical parameters in rats.11.
Pankaj K. Singh Anil K. Jaiswal Vivek K. Pawar Kavit Raval Animesh Kumar Himangsu K. Bora Anuradha Dube Manish K. Chourasia 《Pharmaceutical research》2018,35(3):60
Purpose
To fabricate, characterize and evaluate 3-O-sn-Phosphatidyl-L-serine (PhoS) anchored PLGA nanoparticles for macrophage targeted therapeutic intervention of VL.Materials and Methods
PLGA-AmpB NPs were prepared by well-established nanoprecipitation method and decorated with Phos by thin film hydration method. Physico-chemical characterization of the formulation was done by Zetasizer nano ZS and atomic force microscopy.Results
The optimized formulation (particle size, 157.3?±?4.64 nm; zeta potential, ? 42.51?±?2.11 mV; encapsulation efficiency, ~98%) showed initial rapid release up to 8 h followed by sustained release until 72 h. PhoS generated ‘eat-me’ signal driven augmented macrophage uptake, significant increase in in-vitro (with ~82% parasite inhibition) and in-vivo antileishmanial activity with preferential accumulation in macrophage rich organs liver and spleen were found. Excellent hemo-compatibility justified safety profile of developed formulation in comparison to commercial formulations.Conclusion
The developed PhoS-PLGA-AmpB NPs have improved efficacy, and necessary stability which promisingly put itself as a better alternative to available commercial formulations for optimized treatment of VL.12.
Naoki Itoh Eiichi Yamamoto Tomofumi Santa Takashi Funatsu Masaru Kato 《Pharmaceutical research》2016,33(6):1440-1446
Purpose
Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.Methods
We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome? and DOXIL?).Results
These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.Conclusions
The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.13.
Thuy Vu Peiming Ma Jiyun Sunny Chen Jan de Hoon Anne Van Hecken Lucy Yan Liviawati Sutjandra Wu Lisa Hamilton Gabriel Vargas 《Pharmaceutical research》2017,34(9):1784-1795
Purpose
Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects.Methods
Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated.Results
Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87–91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF.Conclusions
Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.14.
The effects of chronic versus acute desipramine on nicotine withdrawal and nicotine self-administration in the rat 总被引:1,自引:1,他引:0
Rationale
Nicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence.Objectives
The aim of this work was to evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats.Materials and methods
A rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic mini pumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via mini pump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing mini pumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure.Results
Acute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding.Conclusions
The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal and may alter the rewarding effects of nicotine and food.15.
Aim
A preliminary evaluation of mobile phone technology for repeated independent remote data capture using the mobile phone-based m-WOMAC® NRS 3.1 Index.Methods
Following orientation to the m-WOMAC® Index, and initial completion in the office, patients took the phones home and independently completed the Index on four subsequent occasions over 12 days, sending their data each time to a server in USA.Results
Three men and nine women with hip (n = 2) and knee (n = 10) OA successfully completed the m-WOMAC® Index on each occasion. Average time to completing the Index at termination was 4.8 min. The majority of patients rated logging on/opening the application, completing the m-WOMAC® Index on the phone, and sending data as very easy (10–11/12), and were very confident (11/12) in continuing to use the phone to report their symptoms.Conclusions
These data support the feasibility of repeated independent remote data capture using the m-WOMAC® NRS3.1 Index.16.
Jesper Østergaard Emil Meng-Lund Susan Weng Larsen Claus Larsen Karsten Petersson James Lenke Henrik Jensen 《Pharmaceutical research》2010,27(12):2614-2623
Purpose
This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.Methods
The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.Results
Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.Conclusion
Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.17.
Sriwiriyajan S Mahatthanatrakul W Ridtitid W Jaruratanasirikul S 《European journal of clinical pharmacology》2007,63(5):479-483
Objective
To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients.Methods
Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16.Results
Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. Cmax and AUC0?24 were significantly decreased by 44 and 72%, respectively. The T ½ was significantly shorter by 58%.Conclusion
Efavirenz has a strong inducing effect on the metabolism of ketoconazole.18.
Stephanie M. Davis Derek Reichel Younsoo Bae Keith R. Pennypacker 《Pharmaceutical research》2018,35(1):6
Purpose
To synthesize and assess the in vitro biological activity of nanoparticles containing leukemia inhibitory factor (LIF). These NanoLIF particles are designed to prolong the neuroprotective and anti-inflammatory actions of LIF in future preclinical studies of ischemic stroke.Methods
LIF was packaged in nanoparticles made of poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) polymer to form LIF-loaded nanoparticles (NanoLIF). The surface of NanoLIF was also modified with the CD11b antibody (CD11b-NanoLIF) targeting activated peripheral macrophages to increase cytokine delivery to inflammatory macrophages. ELISA was used to quantify bioactive cytokine inside and releasing from NanoLIF. NanoLIF biological activity was measured using the M1 murine leukemia cell proliferation assay.Results
NanoLIF and CD11b-NanoLIF had diameters of approximately 30 nm, neutral surface charge, and physicochemical stability retaining biological activity of the cytokine during incubation at 25°C for 12 h. NanoLIF particles released LIF relatively fast from 0 to 6 h after incubation at 37°C followed by slow release from 24 to 72 h according to a two-phase exponential decay model. NanoLIF and CD11b-NanoLIF significantly decreased M1 cell proliferation over 72 h compared to free LIF.Conclusions
NanoLIF and CD11b-NanoLIF preserved the metabolic stability and biological activity of LIF in vitro. These results are promising to improve the therapeutic potential of LIF in treating neurodegenerative and inflammatory diseases.19.
Catiúscia P. Oliveira Willian A. Prado Vladimir Lavayen Sabrina L. Büttenbender Aline Beckenkamp Bruna S. Martins Diogo S. Lüdtke Leandra F. Campo Fabiano S. Rodembusch Andréia Buffon Adalberto PessoaJr Silvia S. Guterres Adriana R. Pohlmann 《Pharmaceutical research》2017,34(2):438-452
Purpose
This study was conducted a promising approach to surface functionalization developed for lipid-core nanocapsules and the merit to pursue new strategies to treat solid tumors.Methods
Bromelain-functionalized multiple-wall lipid-core nanocapsules (Bro-MLNC-Zn) were produced by self-assembling following three steps of interfacial reactions. Physicochemical and structural characteristics, in vitro proteolytic activity (casein substrate) and antiproliferative activity (breast cancer cells, MCF-7) were determined.Results
Bro-MLNC-Zn had z-average diameter of 135 nm and zeta potential of +23 mV. The complex is formed by a Zn-N chemical bond and a chelate with hydroxyl and carboxyl groups. Bromelain complexed at the nanocapsule surface maintained its proteolytic activity and showed anti-proliferative effect against human breast cancer cells (MCF-7) (72.6?±?1.2% at 1.250 μg mL?1 and 65.5?±?5.5% at 0.625 μg mL?1). Comparing Bro-MLNC-Zn and bromelain solution, the former needed a dose 160-folds lower than the latter for a similar effect. Tripan blue dye assay corroborated the results.Conclusions
The surface functionalization approach produced an innovative formulation having a much higher anti-proliferative effect than the bromelain solution, even though both in vitro proteolytic activity were similar, opening up a great opportunity for further studies in nanomedicine.20.
Anselm Wong Kathy Mac Anders Aneman Jeffrey Wong Betty S. Chan 《Journal of medical toxicology》2016,12(1):130-133