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The cochlea’s inaccessibility and complex nature provide significant challenges to delivering drugs and other agents uniformly, safely and efficiently, along the entire cochlear spiral. Large drug concentration gradients are formed along the cochlea when drugs are administered to the middle ear. This undermines the major goal of attaining therapeutic drug concentration windows along the whole cochlea. Here, utilizing a well-known physiological effect of salicylate, we demonstrate a proof of concept in which drug distribution along the entire cochlea is enhanced applying round window membrane low-frequency micro vibrations with a probe that only partially covers the round window. We provide evidence of enhanced drug influx into the cochlea and cochlear apical drug distribution without breaching cochlear boundaries. It is further suggested that ossicular functionality is not required for the effective drug distribution we report. The novel method of local drug delivery to the cochlea presented here could be implemented when ossicular functionality is absent or impeded and can be incorporated in clinically approved auditory protheses for patients who suffer with conductive, sensorineural or mixed hearing loss.

Comparison data regarding anti-tumor necrosis factor drug concentrations in inflammatory bowel disease (IBD) between the enzyme-linked immunosorbent assay (ELISA) and the homogenous mobility shift assay (HMSA) are scarce.1-3 As decisions in clinical practice depend on the thresholds that define a therapeutic drug concentration, it is important to determine if this varies based on the type of assay used for therapeutic drug monitoring.4 We recently showed a discrepancy between a commercially available ELISA and the HMSA for both infliximab and adalimumab concentrations in patients with IBD.5 Based on the results of the study, Prometheus Laboratories (San Diego, CA) initiated a comprehensive review of their HMSA assays and found that there was an upward drift for both infliximab (from December 2017 to May 2019) and adalimumab (from August 2017 to May 2019), including when our study was performed. Prometheus Laboratories corrected the errant values and reported the revised drug concentrations to physicians (Supplementary Methods). We aimed to compare the corrected infliximab and adalimumab concentrations with the original ELISA values.

Introduction Tacrolimus (TAC) is the mainstay immunosuppressant for renal transplantation. A narrow therapeutic index, multiple drug interactions, and interindividual variability in pharmacokinetics make it obligatory to monitor therapeutic drug levels. The Multidrug resistance gene 1 (MDR1) and CYP3A5 gene polymorphism may blend to achieve the optimal level. The optimal dose as per body weight is difficult to single out in the early posttransplantation period. In this study, we aimed to analyze the melding effect of both gene polymorphisms and to elicit the dose depending on the combination of genetic single nucleotide polymorphisms (SNPs) in northern Indian transplant recipients, for whom data are limited. Methods The daily TAC dose, weight-adjusted doses (mg/kg per day), TAC trough blood concentration (average of at least 3 levels), dose normalized with a corresponding dose using TAC concentration/weight-adjusted dose ratio (ng/ml per mg/kg per day) of 248 patients were recorded. All recipients were genotyped for the SNPs of CYP3A5 at intron 3 A6986G (the *3 or *1 allele), MDR1 at exons 12 (C1236T), 21 (G2677A/T), and 26 (C3435T). We analyzed the blending effect of mutant SNPs of the MDR gene and CYP3A5 for optimized TAC levels. Results Among CYP3A5 genotypic variants, the dose-adjusted TAC level was significantly lower, and the TAC dose required to achieve the target level was significantly higher, in CYP3A5*1*1 (expressor) than that of CYP3A5*1*3 and CYP3A5*3*3. Of the MDR1 gene SNPs, only the G2677T/A homozygous mutant was significantly associated with TAC level, and it was strongly correlated with P-gp expression.The daily TAC dose requirement was highest with a combination of CYP3A5*1*1 and homozygous mutant TT+AA genotype of G2677T/A, and was lowest with CYP3A5*3*3 and wild-type GG of the G2677T/A genotype. Conclusion Both CYP gene and MDR1 gene polymorphism affect TAC dose requirements, and there is a need to look for both in an individual to achieve the target trough concentration.

Vancomycin therapy has long been individualized through concentration monitoring. Because the therapeutic drug concentration monitoring (TDM) service is not available in all hospitals, ways to predict its area under the curve (AUC) using estimated creatinine clearance (CLcr) without drug concentration have been sought. More than 80% of vancomycin is eliminated via renal excretion and its clearance (CL) is known to be approximately 50-80% of measured glomerular filtration rate (GFR) [1]. Thus, an equation describing linear relationship between vancomycin clearance (CL) and CLcr may be used to predict vancomycin AUC without measuring its concentration.

Microdialysis sampling was used for the determination of the protein binding and the free therapeutic drug concentration of drugs in plasma in vitro . Several drugs with varying extent of protein binding and for which the plasma monitoring is important were studied. To mimic the in vivo situation, an artificial blood vessel was constructed and filled with spiked plasma circulating at the flow rate of human blood at 37°C. The microdialysis probe (16 mm membrane length, 20000 MW cut off) was placed in the vessel and perfused with 0.9% NACl at 5 μl min −1 . Dialysates were collected every 10 min and were analysed by reversed-phase LC with UV detection. The free concentration of the drug was calculated by correcting the concentration in the dialysate for the recovery of the probe, which was also determined in the artificial blood vessel after the experiment. The data confirm that microdialysis is a valid alternative technique for the determination of protein binding or free therapeutic plasma concentration of drugs on a comparative basis. Reference to literature values indicates that the results of the proposed method correspond reasonably well with accepted values.

The past 15 years have been marked by a great increase in knowledge about the time course and magnitude of absorption, distribution, biotransformation and elimination of drugs in normal volunteers and in patients with disease. Combined with knowledge of the time course and magnitude of drug effects, we can plan dose schedules, initiate treatment and in many instances follow it by monitoring therapeutic drug concentration to optimize drug efficacy and prevent or reduce drug toxicity.

Rational dosing of anaesthetic drugs derives from an understanding of both the pharmacokinetics and dynamics of the compound in use1. This knowledge can be applied to develop strategies to achieve a required therapeutic drug concentration. The pharmacokinetics of intravenous drugs can be described by a polyexponential function2: $$ Cp(t) = \sum\limits_{i = 1}^n {c_i .e^{ - \lambda it} } $$

A patient receiving a standard dose of imipramine developed a drug-induced delirium. Her plasma antidepressant level was in the low therapeutic range. Thus, tricyclic-induced delirium may in some cases be an idiosyncratic phenomenon unrelated to plasma drug concentration.