scholarly journals Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy

2019 ◽  
Vol 2 (2) ◽  
pp. 38
Author(s):  
Santosh Kumar Sreevatsav Adiraju ◽  
Kiran Shekar ◽  
Peter Tesar ◽  
Rishendran Naidoo ◽  
Ivan Rapchuk ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Laparoscopic Cholecystectomy ◽  
Observational Study ◽  
Extracorporeal Circulation ◽  
Control Group ◽  
Open Label ◽  
Cyp Enzymes ◽  
Post Surgery ◽  
The Impact

Pharmacokinetic alterations of medications administered during surgeries involving cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been reported. The impact of CPB on the cytochrome P450 (CYP) enzymes’ activity is the key factor. The metabolic rates of caffeine, dextromethorphan, midazolam, omeprazole, and Losartan to the CYP-specific metabolites are validated measures of in vivo CYP 1A2, 2D6, 3A4, 2C19, and 2C9 activities, respectively. The study aim is to assess the activities of major CYPs in patients on extracorporeal circulation (EC). This is a pilot, prospective, open-label, observational study in patients undergoing surgery using EC and patients undergoing laparoscopic cholecystectomy as a control group. CYP activities will be measured on the day, and 1–2 days pre-surgery/3–4 days post-surgery (cardiac surgery and Laparoscopic cholecystectomy) and 1–2 days after starting ECMO, 1–2 weeks after starting ECMO, and 1–2 days after discontinuation from ECMO. Aforementioned CYP substrates will be administered to the patient and blood samples will be collected at 0, 1, 2, 4, and 6 h post-dose. Major CYP enzymes’ activities will be compared in each participant on the day, and before/after surgery. The CYP activities will be compared in three study groups to investigate the impact of CYPs on EC.

Investigating the Impact of Cognitive Training for Individuals With Bothersome Tinnitus: A Randomized Controlled Trial

2021 ◽  
pp. 019459982199474
Author(s):  
Maggie Xing ◽  
Dorina Kallogjeri ◽  
Jay F. Piccirillo
Keyword(s):  
Randomized Controlled Trial ◽  
Cognitive Training ◽  
Mixed Model ◽  
Controlled Trial ◽  
Intervention Group ◽  
Control Group ◽  
Functional Index ◽  
Open Label ◽  
Randomized Controlled ◽  
The Impact

Objective To evaluate the effectiveness of cognitive training in improving tinnitus bother and to identify predictors of patient response. Study Design Prospective open-label randomized controlled trial. Setting Online. Methods Participants were adults with subjective idiopathic nonpulsatile tinnitus causing significant tinnitus-related distress. The intervention group trained by using auditory-intensive exercises for 20 minutes per day, 5 days per week, for 8 weeks. The active control group trained on the same schedule with non–auditory intensive games. Surveys were completed at baseline, 8 weeks, and 12 weeks. Results A total of 64 participants completed the study. The median age was 63 years (range, 25-69) in the intervention group and 61 years (34-68) in the control group. Mixed model analysis revealed that within-subject change in Tinnitus Functional Index in the intervention group was not different than the control group, with marginal mean differences (95% CI): 0.24 (–11.20 to 10.7) and 2.17 (–8.50 to 12.83) at 8 weeks and 2.33 (–8.6 to 13.3) and 3.36 (–7.91 to 14.6) at 12 weeks, respectively. When the 2 study groups were compared, the control group had higher Tinnitus Functional Index scores than the intervention group by 10.5 points at baseline (95% CI, –0.92 to 29.89), 8.1 at 8 weeks (95% CI, –3.27 to 19.42), and 9.4 at 12 weeks (95% CI, –2.45 to 21.34). Conclusion Auditory-intensive cognitive training was not associated with changes in self-reported tinnitus bother. Given the potential for neuroplasticity to affect tinnitus, we believe that future studies on cognitive training for tinnitus remain relevant.

scholarly journals The Effect of Chronic Iloperidone Treatment on Cytochrome P450 Expression and Activity in the Rat Liver: Involvement of Neuroendocrine Mechanisms

2021 ◽  
Vol 22 (16) ◽  
pp. 8447
Author(s):  
Przemysław J. Danek ◽  
Wojciech Kuban ◽  
Władysława A. Daniel
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Combined Treatment ◽  
Pharmacological Therapy ◽  
Mental Wellbeing ◽  
Cyp Enzymes ◽  
P450 Expression ◽  
Male Wistar Rats ◽  
Expression And Activity

In order to achieve a desired therapeutic effect in schizophrenia patients and to maintain their mental wellbeing, pharmacological therapy needs to be continued for a long time, usually from the onset of symptoms and for the rest of the patients’ lives. The aim of our present research is to find out the in vivo effect of chronic treatment with atypical neuroleptic iloperidone on the expression and activity of cytochrome P450 (CYP) in rat liver. Male Wistar rats received a once-daily intraperitoneal injection of iloperidone (1 mg/kg) for a period of two weeks. Twenty-four hours after the last dose, livers were excised to study cytochrome P450 expression (mRNA and protein) and activity, pituitaries were isolated to determine growth hormone-releasing hormone (GHRH), and blood was collected for measuring serum concentrations of hormones and interleukin. The results showed a broad spectrum of changes in the expression and activity of liver CYP enzymes, which are important for drug metabolism (CYP1A, CYP2B, CYP2C, and CYP3A) and xenobiotic toxicity (CYP2E1). Iloperidone decreased the expression and activity of CYP1A2, CP2B1/2, CYP2C11, and CYP3A1/2 enzymes but increased that of CYP2E1. The CYP2C6 enzyme remained unchanged. At the same time, the level of GHRH, GH, and corticosterone decreased while that of T3 increased, with no changes in IL-2 and IL-6. The presented results indicate neuroendocrine regulation of the investigated CYP enzymes during chronic iloperidone treatment and suggest a possibility of pharmacokinetic/metabolic interactions produced by the neuroleptic during prolonged combined treatment with drugs that are substrates of iloperidone-affected CYP enzymes.

scholarly journals Effects of Vitrification on the Blastocyst Gene Expression Profile in a Porcine Model

2021 ◽  
Vol 22 (3) ◽  
pp. 1222
Author(s):  
Cristina Cuello ◽  
Cristina A. Martinez ◽  
Josep M. Cambra ◽  
Inmaculada Parrilla ◽  
Heriberto Rodriguez-Martinez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Analysis ◽  
Survival Rates ◽  
Control Group ◽  
P Value ◽  
Transcriptome Profile ◽  
Embryo Viability ◽  
The Impact

This study was designed to investigate the impact of vitrification on the transcriptome profile of blastocysts using a porcine (Sus scrofa) model and a microarray approach. Blastocysts were collected from weaned sows (n = 13). A total of 60 blastocysts were vitrified (treatment group). After warming, vitrified embryos were cultured in vitro for 24 h. Non-vitrified blastocysts (n = 40) were used as controls. After the in vitro culture period, the embryo viability was morphologically assessed. A total of 30 viable embryos per group (three pools of 10 from 4 different donors each) were subjected to gene expression analysis. A fold change cut-off of ±1.5 and a restrictive threshold at p-value < 0.05 were used to distinguish differentially expressed genes (DEGs). The survival rates of vitrified/warmed blastocysts were similar to those of the control (nearly 100%, n.s.). A total of 205 (112 upregulated and 93 downregulated) were identified in the vitrified blastocysts compared to the control group. The vitrification/warming impact was moderate, and it was mainly related to the pathways of cell cycle, cellular senescence, gap junction, and signaling for TFGβ, p53, Fox, and MAPK. In conclusion, vitrification modified the transcriptome of in vivo-derived porcine blastocysts, resulting in minor gene expression changes.

scholarly journals Altered Expression Levels of MMP1, MMP9, MMP12, TIMP1, and IL-1βas a Risk Factor for the Elevated IOP and Optic Nerve Head Damage in the Primary Open-Angle Glaucoma Patients

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Lukasz Markiewicz ◽  
Dariusz Pytel ◽  
Bartosz Mucha ◽  
Katarzyna Szymanek ◽  
Jerzy Szaflik ◽  
...  
Keyword(s):  
Risk Factor ◽  
Aqueous Humor ◽  
Open Angle Glaucoma ◽  
Luciferase Assay ◽  
Control Group ◽  
Promoter Regions ◽  
Altered Expression ◽  
Expression Levels ◽  
The Impact

The aim of presented work was to analyze the impact of particular polymorphic changes in the promoter regions of the -1607 1G/2GMMP1, -1562 C/TMMP9, -82 A/GMMP12, -511 C/TIL-1β, and 372 T/CTIMP1genes on their expression level in POAG patients. Blood and aqueous humor samples acquired from 50 patients with POAG and 50 control subjects were used for QPCR and protein levels analysis by ELISA.In vivopromoter activity assays were carried on HTM cells using dual luciferase assay. All studied subjects underwent ophthalmic examination, including BCVA, intraocular pressure, slit-lamp examination, gonioscopy, HRT, and OCT scans. Patients with POAG are characterized by an increased mRNA expression ofMMP1,MMP9,MMP12, andIL-1βgenes as compared to the control group (P<0.001). Aqueous humor acquired from patients with POAG displayed increased protein expression of MMP1, MMP9, MMP12, and IL-1βcompared to the control group (P<0.001). Allele -1607 1G ofMMP1gene possesses only 42,91% of the -1607 2G allele transcriptional activity and allele -1562 C ofMMP9gene possesses only 21,86% of the -1562 T allele. Increased expression levels of metalloproteinases can be considered as a risk factor for the development of POAG.

Impact of Medicaid expansion on pancreatic cancer care: A difference-in-difference analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18567-e18567
Author(s):  
Ahmad Hamad ◽  
Mariam Eskander ◽  
Yaming Li ◽  
Oindrila Bhattacharyya ◽  
James L Fisher ◽  
...  
Keyword(s):  
Low Income ◽  
Early Stage ◽  
Ductal Adenocarcinoma ◽  
Control Group ◽  
Medicaid Expansion ◽  
Difference In Difference ◽  
Post Surgery ◽  
Number Of Patients ◽  
The Impact ◽  
Expansion Period

e18567 Background: The Affordable Care Act (ACA) increased insurance coverage for low-income individuals, which should potentially lead to better access to care and improved oncological outcomes. This study seeks to evaluate the impact of Medicaid expansion (ME) on care for pancreatic ductal adenocarcinoma (PDAC). Methods: Patients who were uninsured or on Medicaid and diagnosed with PDAC between 2004 and 2017 were queried from the National Cancer Database (NCDB). Two different expansion cohorts were included: early expansion states and 2014 expansion states. For early expansion states, the time period of pre-expansion was 2004-2009 and post-expansion was 2010-2017. As for the 2014 expansion states, the pre-expansion period was from 2004-2013 and post-expansion period was from 2014-2017. Patients in non-expansion states formed the control group. A difference-in-difference (DID) analysis was used to assess the association of ME with stage of diagnosis, treatment and survival for each expansion cohort. Results: In both early and January 2014 expansion states, there was an increase in overall Medicaid coverage (Early: DID = 0.29, 2014: DID = 0.37; P < 0.001), in particular for non-Hispanic Black and Hispanic Black patients (Non-Hispanic Black: Early: DID = 0.11, 2014: DID = 0.11; P < 0.001, Hispanic-Black: 2014: DID = 0.20; P = 0.003). There were no differences in early stage diagnosis (Early: DID = 0.02, 2014: DID = -0.02; P > 0.05). There was an increase in the number of patients receiving surgery (Early: DID = 0.05; P = 0.001, 2014: DID = 0.03; P = 0.029) but no difference in time to surgery among patients receiving surgery upfront (Early: DID = 1.75, 2014: DID = 0.38; P > 0.05). There was no difference in 30-day readmission post-surgery (Early: DID = 0.003; 2014: DID = -0.00007; P > 0.05) or 90-day mortality (Early: DID = -0.007, 2014: DID = -0.035; P > 0.05). Moreover, there was no difference in receipt of chemotherapy (Early: DID = 0.01, 2014: DID = 0.005; P > 0.05) or time to chemotherapy for patients receiving neoadjuvant chemotherapy (Early: Early: DID = 9.62, 2014: DID = 0.01; P > 0.05). Finally, there was no difference in receipt of palliative care among stage IV patients in both cohorts (Early: DID = -0.004, 2014: DID = 0.004; P > 0.05). Conclusions: This study suggests that after ME, PDAC patients were more likely to be insured and had increased access to surgical care. Future, studies should evaluate the implications of improved surgical access on clinical outcomes such as mortality.

scholarly journals Perioperative rifaximin is not associated with enhanced functional and volumetric recovery after major liver resection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jan Bednarsch ◽  
Zoltan Czigany ◽  
Sven H. Loosen ◽  
Lara Heij ◽  
Lorenz Ruckgaber ◽  
...  
Keyword(s):  
Liver Function ◽  
Primary Endpoint ◽  
Major Hepatectomy ◽  
Controlled Trial ◽  
Liver Volume ◽  
Relative Increase ◽  
Control Group ◽  
Open Label ◽  
Significant Difference ◽  
The Impact

AbstractThe objective of this randomized controlled trial (RCT) was to assess the impact of rifaximin on the course of liver function, liver regeneration and volumetric recovery in patients undergoing major hepatectomy. The ARROW trial was an investigator initiated, single-center, open-label, phase 3 RCT with two parallel treatment groups, conducted at our hepatobiliary center from 03/2016 to 07/2020. Patients undergoing major hepatectomy were eligible and randomly assigned 1:1 to receive oral rifaximin (550 mg twice daily for 7–10 or 14–21 days in case of portal vein embolization preoperatively and 7 days postoperatively) versus no intervention. Primary endpoint was the relative increase in postoperative liver function measured by LiMAx from postoperative day (POD) 4 to 7. Secondary endpoint were the course of liver function and liver volume during the study period as well as postoperative morbidity and mortality. Between 2016 and 2020, 45 patients were randomized and 35 patients (16 individuals in the rifaximin and 19 individuals in the control group) were eligible for per-protocol analysis. The study was prematurely terminated following interim analysis, due to the unlikelihood of reaching a significant primary endpoint. The median relative increase in liver function from POD 4 to POD 7 was 27% in the rifaximin group and 41% in the control group (p = 0.399). Further, no significant difference was found in terms of any other endpoints of functional liver- and volume regeneration or perioperative surgical complications following the application of rifaximin versus no intervention. Perioperative application of rifaximin has no effect on functional or volumetric regeneration after major hepatectomy (NCT02555293; EudraCT 2013-004644-28).

scholarly journals Conditionally Essential Amino Acid Supplementation Reduces Postoperative Muscle Wasting in Orthopedic Trauma Patients

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1135-1135
Author(s):  
Aspen Miller ◽  
Nathan Hendrickson ◽  
John Davison ◽  
Erin Wilson ◽  
Natalie Glass ◽  
...  
Keyword(s):  
Amino Acids ◽  
Muscle Wasting ◽  
Fat Free Mass ◽  
Nutrition Status ◽  
Control Group ◽  
Trauma Patients ◽  
Complication Rates ◽  
Metabolic Demand ◽  
Post Surgery ◽  
The Impact

Abstract Objectives Increased metabolic demand and inadequate oral intake after musculoskeletal trauma results in catabolic skeletal muscle wasting, which limits potential for functional recovery after injury. This study compared standard perioperative nutrition and oral supplementation with conditionally essential amino acids (CEAA) on changes in lean body mass after operative fixation of acute fractures. Methods Patients sustaining operative pelvis and extremity fractures presenting to a Level 1 trauma center were prospectively enrolled in a single blinded-randomized clinical trial. Demographics, injury classification, and comorbidities were collected at baseline. Fat Free Mass (FFM) was measured within 72 hours of surgery using A-Mode Ultrasound. Patients were randomly chosen to receive standard nutrition (Control) or standard nutrition plus an oral supplement (CEAA) containing 14 g of amino acids to be taken 2x daily for 2 weeks. FFM was re-assessed at 6 weeks and 3 months post-surgery. Statistical analysis was performed comparing Least Squared Mean FFM (P &lt; .05). Results 222 subjects (Control: 112, CEAA: 120) were included in this analysis. There were no differences in age, gender, BMI, or baseline FFM between Control and CEAA subjects (all P &gt; .05). Median supplement compliance was 22/28 servings (78.6%, sd ± 36.9%). At 6 weeks, average change in FFM among Controls was −1.28 kg (P = .004) and -.56 kg among CEAA (P = .19). Changes were not significant between groups (P = .23). At 12 weeks, there were non-significant changes in FFM from baseline in both groups (Controls: -.02 kg P = .96, CEAA: +.36 kg P = .44). From 6–12 weeks, FFM changes were + 1.26 kg (P = .012) and + .91 kg (P = .06) respectively. Conclusions Patients randomized to standard nutrition had significant FFM loss compared to those receiving additional CEAA supplementation 6 weeks after surgery. At 12 weeks, the control group decreased FFM further from baseline while the CEAA group mostly recovered their loss. Although 12-week FFM changes were not significant, results indicate CEAA supplementation prevents FFM loss in the acute post-operative phase. Further investigation is needed to compare FFM changes, clinical outcomes, complication rates, and the impact of baseline nutrition status. Funding Sources American Academy of Orthopaedic Surgeons, Board of Specialty Societies Quality and Patient Safety Action Fund.

scholarly journals Retrospective observational study of the impact on emergency admission of telehealth at scale delivered in community care in Liverpool, UK

BMJ Open ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. e028981
Author(s):  
Cees van Berkel ◽  
Peter Almond ◽  
Carol Hughes ◽  
Maurice Smith ◽  
Dave Horsfield ◽  
...  
Keyword(s):  
Observational Study ◽  
Subgroup Analysis ◽  
Intervention Group ◽  
Average Treatment Effect ◽  
Retrospective Observational Study ◽  
Control Group ◽  
Chronic Obstructive ◽  
Emergency Admissions ◽  
Percentage Decrease ◽  
The Impact

ObjectiveTo assess the effect of a real world, ongoing telehealth service on the use of secondary healthcare.DesignA retrospective observational study with anonymous matched controls.SettingPrimary and community healthcare. Patients were recruited over 4 years in 89 general practices in Liverpool, UK and remotely managed by a dedicated clinical team in Liverpool Community Health.Participants5154 patients with chronic obstructive pulmonary disease, heart failure or diabetes were enrolled in the programme, of whom 3562 satisfied the inclusion criteria of this study.InterventionAt least 9 weeks of telehealth including vital sign collection, questionnaires, education, support and informal coaching by clinical staff.Primary outcomeReduction in the number of emergency admissions in the 12 months after start, compared with the year before start. Secondary subgroup analysis to improve future targeting and personalisation of the service.ResultThe average number of emergency admissions for the intervention group at baseline is 0.35, 95% CI 0.32 to 0.38. The differential decrease in emergency admissions in the intervention group in comparison with the control group, the average treatment effect, is 0.08, 95 CI 0.05 to 0.11, corresponding to an average percentage decrease of 22.7%. In subgroup analysis, a score is calculated that can be used prospectively to predict individual benefit from the intervention. Patients with an above median score (37%) are predicted average reduction in emergency admissions of 0.15, 95% CI 0.09 to 0.2, corresponding to a percentage decrease in admissions of 25.3%.ConclusionThe telehealth intervention has a positive impact across a wide cohort of patients with different diseases. Prospective scoring of patients and allocation to targeted telehealth interventions is likely to improve the effectiveness and efficiency of the service.

scholarly journals Generic Vancomycin Enriches Resistant Subpopulations of Staphylococcus aureus after Exposure in a Neutropenic Mouse Thigh Infection Model

2011 ◽  
Vol 56 (1) ◽  
pp. 243-247 ◽  
Author(s):  
Carlos A. Rodriguez ◽  
Maria Agudelo ◽  
Andres F. Zuluaga ◽  
Omar Vesga
Keyword(s):  
Staphylococcus Aureus ◽  
Population Analysis ◽  
Recovery Process ◽  
Control Group ◽  
Infection Model ◽  
Content Type ◽  
Sterile Saline ◽  
Generic Products ◽  
The Impact

ABSTRACTPrevious studies have shown that “bioequivalent” generic products of vancomycin are less effectivein vivoagainstStaphylococcus aureusthan the innovator compound. Considering that suboptimal bactericidal effect has been associated with emergence of resistance, we aimed to assessin vivothe impact of exposure to innovator and generic products of vancomycin onS. aureussusceptibility. A clinical methicillin-resistantS. aureus(MRSA) strain from a liver transplant patient with persistent bacteremia was used for which MIC, minimum bactericidal concentration (MBC), and autolytic properties were determined. Susceptibility was also assessed by determining a population analysis profile (PAP) with vancomycin concentrations from 0 to 5 mg/liter. ICR neutropenic mice were inoculated in each thigh with ∼7.0 log10CFU. Treatment with the different vancomycin products (innovator and three generics; 1,200 mg/kg of body weight/day every 3 h) started 2 h later while the control group received sterile saline. After 24 h, mice were euthanized, and the thigh homogenates were plated. Recovered colonies were reinoculated to new groups of animals, and the exposure-recovery process was repeated until 12 cycles were completed. The evolution of resistance was assessed by PAP after cycles 5, 10, 11, and 12. The initial isolate displayed reduced autolysis and higher resistance frequencies thanS. aureusATCC 29213 but without vancomycin-intermediateS. aureus(VISA) subpopulations. After 12 cycles, innovator vancomycin had significantly reduced resistant subpopulations at 1, 2, and 3 mg/liter, while the generic products had enriched them progressively by orders of magnitude. The great capacity of generic vancomycin to select for less susceptible organisms raises concerns about the role of therapeutic inequivalence of any antimicrobial on the epidemiology of resistance worldwide.

scholarly journals Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A

2008 ◽  
Vol 53 (2) ◽  
pp. 541-551 ◽  
Author(s):  
Seongwook Jeong ◽  
Phuong D. Nguyen ◽  
Zeruesenay Desta
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Competitive Inhibitor ◽  
Major Effect ◽  
Cyp Enzymes ◽  
Human Cytochrome ◽  
Vitro Analysis ◽  
In Vitro Analysis

ABSTRACT Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 μM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 μM voriconazole). Further detailed experiments with HLMs showed that voriconazole is a potent competitive inhibitor of CYP2B6 (Ki < 0.5), CYP2C9 (Ki = 2.79 μM), and CYP2C19 (Ki = 5.1 μM). The inhibition of CYP3A by voriconazole was explained by noncompetitive (Ki = 2.97 μM) and competitive (Ki = 0.66 μM) modes of inhibition. Prediction of the in vivo interaction of voriconazole from these in vitro data suggests that voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.

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