scholarly journals Possible inhibitory effects of terbinafine on aripiprazole metabolism: Two case reports

2021 ◽  
Vol 11 (5) ◽  
pp. 297-300
Author(s):  
Ian R. McGrane ◽  
Tori J. Lindbloom ◽  
Robert C. Munjal
Keyword(s):  
Claims Data ◽  
Case Reports ◽  
Therapeutic Drug ◽  
Inhibitory Effects ◽  
Probability Scale ◽  
Drug Concentrations ◽  
Serum Trough ◽  
Related Drug ◽  
State Concentration ◽  
Interaction Probability

Abstract Aripiprazole, an atypical antipsychotic, is a metabolic substrate for cytochrome P450 (CYP)3A4 and 2D6. Terbinafine, an antifungal agent used for onychomycosis, is a CYP2D6 inhibitor and could theoretically reduce the metabolism of aripiprazole. However, there are no published reports describing this interaction. We present 2 female patients hospitalized in a psychiatric unit who were both taking aripiprazole 15 mg daily and terbinafine 250 mg daily prior to admission. The first patient was a 58-year-old female who was prescribed aripiprazole and terbinafine concomitantly for approximately 5 months prior to admission. A commercial pharmacogenetic testing platform classified this patient as a normal metabolizer for CYP3A4 and 2D6. The first patient's serum trough aripiprazole concentration at steady-state concentration (Css) was 207.5 ng/mL. The second patient was a 43-year-old female who was taking aripiprazole and terbinafine concomitantly for approximately 2 weeks prior to admission who had a Css aripiprazole concentration of 278.9 ng/mL. Aripiprazole has a wide therapeutic range (100 to 350 ng/mL) and a reference dose-related drug concentration of 11.7 (mean) ± 5.6 (SD) ng/mL/mg/d. Our patients had Css aripiprazole concentrations 18% and 59% higher than guideline-supported dose-related drug concentrations. Through the use of therapeutic drug monitoring, pharmacogenetic data, electronic pharmaceutical claims data, and the Drug Interaction Probability Scale, we suggest terbinafine possibly increases aripiprazole concentrations 18% to 59%. Further reports are needed to confirm these findings prior to using this information in clinical practice.

Topical Bimatoprost Insert for Primary Open-Angle Glaucoma and Ocular Hypertension Treatment - A Phase II Controlled Study

2021 ◽  
Vol 18 ◽  
Author(s):  
Francine Rubião ◽  
Alan Cezar Faria Araújo ◽  
João Bernardo Sancio ◽  
Bárbara Silva Nogueira ◽  
Juçara Ribeiro Franca ◽  
...  
Keyword(s):  
Ocular Hypertension ◽  
Primary Open Angle Glaucoma ◽  
Open Angle Glaucoma ◽  
T Test ◽  
Controlled Study ◽  
Therapeutic Drug ◽  
Eye Drops ◽  
Open Angle ◽  
Drug Concentrations

Background: The most common treatment for primary open-angle glaucoma (POAG) is the daily use of eye drops. Sustained-release drug delivery systems have been developed to improve patient adherence by achieving prolonged therapeutic drug concentrations in ocular target tissues while limiting systemic exposure. The purpose of this study is to compare the efficacy and safety of bimatoprost inserts with bimatoprost eye drops in patients with POAG and ocular hypertension (OH). Methods: We include OH and POAG patients aged between 40 and 75 years-old. Both OH and POAG patients had intraocular pressure (IOP) greater than 21 and ≤30 mmHg at 9:00 am without glaucoma medication and normal biomicroscopy. Five normal patients with IOP≤14 mmHg constitute the control group. A chitosan-based insert of bimatoprost was placed at the upper conjunctival fornix of the right eye. In the left eye, patients used one drop of LumiganTM daily at 10:00 pm. For statistical analysis, we used a two-way analysis of variance (ANOVA), Student t-test, and paired t-test. Results: Sixteen POAG and 13 OH patients with a mean age of 61 years were assessed. In both eyes, IOP reduction was similar during three weeks of follow-up (19.5±2.2 mmHg and 16.9±3.1 mmHg), insert, and eye drop, respectively; P=0.165). The percentage of IOP reduction in the third week was 30% for insert and 35% for eye drops (P=0.165). No intolerance or discomfort with the insert was reported. Among the research participants, 58% preferred the use of the insert while 25% preferred eye drops, and 17% reported no preference. Conclusions: Bimatoprost-loaded inserts showed similar efficacy to daily bimatoprost eye drops during three weeks of follow up, without major side effects. This might suggest a possible change in the daily therapeutic regimen for the treatment of POAG and OH.

scholarly journals A156 SERUM TUMOUR NECROSIS FACTOR-α ANTAGONIST DRUG CONCENTRATIONS IN PATIENTS WITH PYODERMA GANGRENOSUM ASSOSCIATED WITH INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 162-163
Author(s):  
M Mikail ◽  
A Wilson
Keyword(s):  
Inflammatory Bowel Disease ◽  
Pyoderma Gangrenosum ◽  
Bowel Disease ◽  
Complete Resolution ◽  
Therapeutic Drug ◽  
Drug Concentrations ◽  
Median Serum ◽  
Inflammatory Bowel ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background The utility of therapeutic drug monitoring for guiding the dosing of tumor necrosis factor-α antagonists (TNFAs) in luminal inflammatory bowel disease (IBD) is well-established and well-accepted. TNFAs, specifically infliximab and adalimumab, have become integral to the management of the rare, neutrophilic dermatosis, pyoderma gangrenosum (PG) in IBD. Little is known regarding the target serum TNFA concentrations to guide dosing to achieve resolution of PG in IBD. Aims To describe the serum TNFA concentrations (infliximab or adalimumab) associated with the resolution of PG lesions in patients with IBD. Methods Patients with IBD and associated PG treated with one of infliximab or adalimumab (collectively known as TNFAs) seen at two academic hospitals affiliated with Western University were identified. Serum TNFA concentrations were assessed at the time of PG treatment. Results Nine patients were identified. All patients had IBD-associated PG. Seven patients were treated with infliximab and 2 patients were treated with adalimumab. All patients received standard dosing. Eight patients had complete resolution of their PG, while one had near complete resolution at the time of last follow-up. A median serum infliximab concentration of 3.00 (IQR, 3.52) µg/ml at week 14 and a median serum adalimumab concentration of 2.02 (IQR, 0.98) µg/ml at week 12 were seen at the time of PG treatment. Conclusions Herein, we report low serum TNFA concentrations despite PG healing in a cohort of IBD patients. This is lower than what is in patients for successful TNFA treatment in luminal and fistulising IBD. Funding Agencies NoneNone.

Pharmacokinetics of culture-directed antibiotics for the treatment of peritonitis in automated peritoneal dialysis: A systematic narrative review

2021 ◽  
Vol 41 (3) ◽  
pp. 261-272
Author(s):  
Chau Wei Ling ◽  
Kamal Sud ◽  
Connie Van ◽  
Syed Tabish Razi Zaidi ◽  
Rahul P. Patel ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Case Reports ◽  
Plasma Concentrations ◽  
Case Series ◽  
Therapeutic Drug ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Automated Peritoneal Dialysis ◽  
Final Study ◽  
Drug Plasma

The objectives of this study were to provide a summary of the pharmacokinetic data of some intraperitoneal (IP) antibiotics that could be used for both empirical and culture-directed therapy, as per the ISPD recommendations, and examine factors to consider when using IP antibiotics for the management of automated peritoneal dialysis (APD)-associated peritonitis. A literature search of PubMed, EMBASE, Scopus, MEDLINE and Google Scholar for articles published between 1998 and 2020 was conducted. To be eligible, articles had to describe the use of antibiotics via the IP route in adult patients ≥18 years old on APD in the context of pharmacokinetic studies or case reports/series. Articles describing the use of IP antibiotics that had been recently reviewed (cefazolin, vancomycin, gentamicin and ceftazidime) or administered for non-APD-associated peritonitis were excluded. A total of 1119 articles were identified, of which 983 abstracts were screened. Seventy-three full-text articles were assessed for eligibility. Eight records were included in the final study. Three reports had pharmacokinetic data in patients on APD without peritonitis. Each of cefepime 15 mg/kg IP, meropenem 0.5 g IP and fosfomycin 4 g IP given in single doses achieved drug plasma concentrations above the minimum inhibitory concentration for treating the susceptible organisms. The remaining five records were case series or reports in patients on APD with peritonitis. While pharmacokinetic data support intermittent cefepime 15 mg/kg IP daily, only meropenem 0.5 g IP and fosfomycin 4 g IP are likely to be effective if given in APD exchanges with dwell times of 15 h. Higher doses may be required in APD with shorter dwell times. Information on therapeutic efficacy was derived from case reports/series in individual patients and without therapeutic drug monitoring. Until more pharmacokinetic data are available on these antibiotics, it would be prudent to shift patients who develop peritonitis on APD to continuous ambulatory peritoneal dialysis, where pharmacokinetic information is more readily available.

scholarly journals Simultaneous quantitation of five triazole anti-fungal agents by paper spray-mass spectrometry

2020 ◽  
Vol 58 (5) ◽  
pp. 836-846 ◽  
Author(s):  
Christine L. Skaggs ◽  
Greta J. Ren ◽  
El Taher M. Elgierari ◽  
Lillian R. Sturmer ◽  
Run Z. Shi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Therapeutic Drug ◽  
Reference Laboratory ◽  
Triple Quadrupole Mass Spectrometer ◽  
Limit Of Quantification ◽  
Paper Spray ◽  
Calibration Curves ◽  
Drug Concentrations ◽  
Limit Of Quantitation ◽  
Anti Fungal

AbstractBackgroundInvasive fungal disease is a life-threatening condition that can be challenging to treat due to pathogen resistance, drug toxicity, and therapeutic failure secondary to suboptimal drug concentrations. Frequent therapeutic drug monitoring (TDM) is required for some anti-fungal agents to overcome these issues. Unfortunately, TDM at the institutional level is difficult, and samples are often sent to a commercial reference laboratory for analysis. To address this gap, the first paper spray-mass spectrometry assay for the simultaneous quantitation of five triazoles was developed.MethodsCalibration curves for fluconazole, posaconazole, itraconazole, hydroxyitraconazole, and voriconazole were created utilizing plasma-based calibrants and four stable isotopic internal standards. No sample preparation was needed. Plasma samples were spotted on a paper substrate in pre-manufactured plastic cartridges, and the dried plasma spots were analyzed directly utilizing paper spray-mass spectrometry (paper spray MS/MS). All experiments were performed on a Thermo Scientific TSQ Vantage triple quadrupole mass spectrometer.ResultsThe calibration curves for the five anti-fungal agents showed good linearity (R2 = 0.98–1.00). The measured assay ranges (lower limit of quantification [LLOQ]–upper limit of quantitation [ULOQ]) for fluconazole, posaconazole, itraconazole, hydroxyitraconazole, and voriconazole were 0.5–50 μg/mL, 0.1–10 μg/mL, 0.1–10 μg/mL, 0.1–10 μg/mL, and 0.1–10 μg/mL, respectively. The inter- and intra-day accuracy and precision were less than 25% over the respective ranges.ConclusionsWe developed the first rapid paper spray-MS/MS assay for simultaneous quantitation of five triazole anti-fungal agents in plasma. The method may be a powerful tool for near-point-of-care TDM aimed at improving patient care by reducing the turnaround time and for use in clinical research.

scholarly journals Rapid point-of-care anti-infliximab antibodies detection in clinical practice: comparison with ELISA and potential for improving therapeutic drug monitoring in IBD patients

2021 ◽  
Vol 14 ◽  
pp. 175628482199990
Author(s):  
Sonia Facchin ◽  
Andrea Buda ◽  
Romilda Cardin ◽  
Nada Agbariah ◽  
Fabiana Zingone ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Point Of Care ◽  
Drug Clearance ◽  
Elisa Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Therapeutic Drug ◽  
Drug Concentrations ◽  
Inflammatory Bowel

Anti-drug antibodies can interfere with the activity of anti-tumor necrosis factor (TNF) agents by increasing drug clearance via direct neutralization. The presence of anti-drug antibodies is clinically relevant when trough drug concentrations are undetectable or sub-therapeutic. However, traditional immunoassay is not easily and rapidly accessible, making the translation of the results into treatment adjustment difficult. The availability of a point-of-care (POC) test for therapeutic drug monitoring (TDM) might represent an important step forward for improving the management of inflammatory bowel disease (IBD) patients in clinical practice. In this pilot study, we compared the results obtained with POC tests with those obtained by enzyme-linked immunosorbent assay (ELISA) in a group of IBD patients treated with Infliximab (IFX). We showed that POC test can reliably detect presence of antibody-to-IFX with 100% of specificity and 76% sensitivity, in strong agreement with the ELISA test ( k-coefficient = 0.84).

Immunosuppressant quantification in intravenous microdialysate – towards novel quasi-continuous therapeutic drug monitoring in transplanted patients

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Susanne Weber ◽  
Sara Tombelli ◽  
Ambra Giannetti ◽  
Cosimo Trono ◽  
Mark O’Connell ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Real Time ◽  
Drug Monitoring ◽  
Time Course ◽  
Drug Dosage ◽  
Immunosuppressive Drug ◽  
Therapeutic Drug ◽  
Continuous Sampling ◽  
Real Time Analysis ◽  
Drug Concentrations

AbstractObjectivesTherapeutic drug monitoring (TDM) plays a crucial role in personalized medicine. It helps clinicians to tailor drug dosage for optimized therapy through understanding the underlying complex pharmacokinetics and pharmacodynamics. Conventional, non-continuous TDM fails to provide real-time information, which is particularly important for the initial phase of immunosuppressant therapy, e.g., with cyclosporine (CsA) and mycophenolic acid (MPA).MethodsWe analyzed the time course over 8 h of total and free of immunosuppressive drug (CsA and MPA) concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 16 kidney transplant patients. Besides repeated blood sampling, intravenous microdialysis was used for continuous sampling. Free drug concentrations were determined from ultracentrifuged EDTA-plasma (UC) and compared with the drug concentrations in the respective microdialysate (µD). µDs were additionally analyzed for free CsA using a novel immunosensor chip integrated into a fluorescence detection platform. The potential of microdialysis coupled with an optical immunosensor for the TDM of immunosuppressants was assessed.ResultsUsing LC-MS/MS, the free concentrations of CsA (fCsA) and MPA (fMPA) were detectable and the time courses of total and free CsA comparable. fCsA and fMPA and area-under-the-curves (AUCs) in µDs correlated well with those determined in UCs (r≥0.79 and r≥0.88, respectively). Moreover, fCsA in µDs measured with the immunosensor correlated clearly with those determined by LC-MS/MS (r=0.82).ConclusionsThe new microdialysis-supported immunosensor allows real-time analysis of immunosuppressants and tailor-made dosing according to the AUC concept. It readily lends itself to future applications as minimally invasive and continuous near-patient TDM.

scholarly journals SCIDOT-18. NANOTHERAPEUTICS FOR NEUROSURGICALLY-APPLIED DRUG DELIVERY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi275-vi275
Author(s):  
Catherine Vasey ◽  
Vincenzo Taresco ◽  
Stuart Smith ◽  
Cameron Alexander ◽  
Ruman Rahman
Keyword(s):  
Drug Delivery ◽  
Ex Vivo ◽  
Drug Formulation ◽  
Local Drug Delivery ◽  
Resection Margins ◽  
Therapeutic Drug ◽  
Tumour Resection ◽  
Combination Drug ◽  
Drug Encapsulation ◽  
Drug Concentrations

Abstract Design and implementation of innovative local drug delivery systems (DDS) may overcome current limitations in GBM treatment, such as the lack of therapeutic drug concentrations reaching residual GBM cells following surgery. Here we describe a novel DDS which utilises a bespoke mechanically engineered spray device, designed for safe surgical use, to deliver a mucoadhesive hydrogel containing chemotherapeutic nanoparticles (NPs) into the tumour resection margins. The overall aim is to spray a NP and polymer solution onto the resection cavity and potentially increase penetration of anti-cancer drugs within the 2 cm reoccurrence zone beyond the infiltrative margin. The mucoadhesive gel of choice, pectin, is currently used in other in vivo applications; however we have repurposed this for the brain. Pectin is biocompatible with GBM and human astrocyte cells in vitro and showed neither toxicity nor inflammation for up to 2 weeks upon orthotopic brain injection. Pectin is biodegradable in artificial CSF and is capable of being sprayed from the engineered device. A panel of polymeric, oil-based and polymer-coated NPs have been developed and optimised to maximise drug encapsulation of etoposide and olaparib as proof-of-concept for combination drug delivery. Etoposide/olaparib was chosen due to cytotoxicity from 5 GBM cell lines, including primary lines isolated from the invasive tumour margin (Mean IC50 of 1.1 µM and 8.3 µM respectively). The optimal NP/drug formulation (based on drug encapsulation, spray capability and bio-adhesiveness) will ultimately be assessed for tolerability and efficacy using orthotopic allograft and xenograft high-grade glioma models, including measurement of penetration of drug/nanoparticle in ex vivo murine and porcine brain using novel hybrid time-of-flight/Orbitrap TM secondary ion mass spectrometer (orbiSIMS) technology.

scholarly journals Zidovudine-Mediated Autophagy Inhibition Enhances Mitochondrial Toxicity in Muscle Cells

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
H. Lin ◽  
M. V. Stankov ◽  
J. Hegermann ◽  
R. Budida ◽  
D. Panayotova-Dimitrova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cell Viability ◽  
Therapeutic Drug ◽  
Ros Generation ◽  
Mtor Inhibition ◽  
Membrane Hyperpolarization ◽  
Thymidine Analogue ◽  
Drug Concentrations ◽  
Mitochondrial Functions ◽  
The Impact

ABSTRACT Nucleoside reverse transcriptase inhibitors (NRTI), such as zidovudine (AZT), are constituents of HIV-1 therapy and are used for the prevention of mother-to-child transmission. Prolonged thymidine analogue exposure has been associated with mitochondrial toxicities to heart, liver, and skeletal muscle. We hypothesized that the thymidine analogue AZT might interfere with autophagy in myocytes, a lysosomal degradation pathway implicated in the regulation of mitochondrial recycling, cell survival, and the pathogenesis of myodegenerative diseases. The impact of AZT and lamivudine (3TC) on C2C12 myocyte autophagy was studied using various methods based on LC3-green fluorescent protein overexpression or LC3 staining in combination with Western blotting, flow cytometry, and confocal and electron microscopy. Lysosomal and mitochondrial functions were studied using appropriate staining for lysosomal mass, acidity, cathepsin activity, as well as mitochondrial mass and membrane potential in combination with flow cytometry and confocal microscopy. AZT, but not 3TC, exerted a significant dose- and time-dependent inhibitory effect on late stages of autophagosome maturation, which was reversible upon mTOR inhibition. Inhibition of late autophagy at therapeutic drug concentrations led to dysfunctional mitochondrial accumulation with membrane hyperpolarization and increased reactive oxygen species (ROS) generation and, ultimately, compromised cell viability. These AZT effects could be readily replicated by pharmacological and genetic inhibition of myocyte autophagy and, most importantly, could be rescued by pharmacological stimulation of autophagolysosomal biogenesis. Our data suggest that the thymidine analogue AZT inhibits autophagy in myocytes, which in turn leads to the accumulation of dysfunctional mitochondria with increased ROS generation and compromised cell viability. This novel mechanism could contribute to our understanding of the long-term side effects of antiviral agents.

scholarly journals P467 Can induction and maintenance serum vedolizumab levels predict long-term clinical outcome in inflammatory bowel disease (IBD)?

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S413-S414 ◽  
Author(s):  
C Miller ◽  
H Morgan ◽  
A Steel ◽  
M Wahed
Keyword(s):  
Clinical Outcome ◽  
Clinical Remission ◽  
Statistical Significance ◽  
Therapeutic Drug ◽  
Fisher Exact Test ◽  
Positive Outcomes ◽  
Mayo Score ◽  
Serum Trough

Abstract Background Vedolizumab (VDZ) is an established IBD therapy, however, the role of therapeutic drug levels (TDM) is not fully established.1 Our aim was to assess whether week 6 and maintenance serum trough VDZ levels predict the clinical outcome at week 52. Methods A retrospective review of patients with Crohn’s disease (CD) or ulcerative colitis (UC) on VDZ was performed. Twenty-one IBD patients with serum VDZ trough level monitoring between January 2016 and December 2017 were identified. All patients received VDZ induction and maintenance as per standard protocol. Patients were excluded if complete dataset of VDZ levels was not available. Clinical remission was defined as a partial Mayo score < 2 for patients with UC or a Harvey–Bradshaw index (HBI) score < 4 for those with CD. A trough VDZ level ≥ 27 μg/ml cut-off was used to evaluate remission outcomes for both induction and average maintenance VDZ levels. Statistically, analysis was carried out using the Fisher exact test. Key demographics are 57% CD, 43% UC; Baseline HBI score: 11; Baseline Partial Mayo score: 9; Concurrent Immunomodulator: 55% Results: ( 1) Week 6 induction levels: At week 52, 69% of patients were in clinical remission. Those patients in remission had a higher mean and median trough VDZ levels (Figure A). When the induction serum trough VDZ level ≥ 27 μg/ml 30% more patients were in clinical remission at week 52, although this failed to reach statistical significance (p = 0.40) (Figure C). (2) Average maintenance VDZ levels: At week 52, 63% of patients were in clinical remission. Those patients in remission had a higher mean and median average maintenance trough VDZ levels (Figure B). When the average maintenance trough VDZ level was ≥ 27 μg/ml 17% more patients were in clinical remission, this failed to reach statistical significance (p = .0.39) (Figure D). Conclusion High levels of clinical remission in both CD and UC were seen. In our study, we could use a similar cut-off for induction trough VDZ levels to those used in the literature that correlated with positive outcomes.1 Although the observed levels used to predict remission did not reach statistical significance, this may represent a type 2 error in view of the small numbers of patient. Furthermore, it was not possible to assess whether there is a difference between CD and UC. For maintenance levels, our cut-off of 27 μg/ml was higher than that used in the literature that correlated with positive outcomes.1 Our data suggest there is some correlation between trough VDZ levels for both induction and average maintenance levels and long-term clinical remission. Our induction cut-off was similar to currently available data associated with positive outcomes.1 Further studies are required to fully establish the role of TDM. References

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