Dosing of neuromuscular blocking agents in patients with obesity: A narrative review

There is no consensus on which weight clinicians should use for weight-based dosing of neuromuscular blocking agents (NMBAs), as exemplified by differing or absent recommendations in clinical practice guidelines. The purpose of this paper is to review studies that evaluated various size descriptors for weight-based dosing of succinylcholine and non-depolarising NMBAs, and to provide recommendations for the descriptors of choice for the weight-based dosing of these agents in patients with obesity. All of the studies conducted to date involving depolarising and non-depolarising NMBAs in patients with obesity have assessed single doses or short-term infusions conducted in perioperative settings. Recognising that any final dosing regimen must take into account patient-specific considerations, the available evidence suggests that actual body weight is the size descriptor of choice for weight-based dosing of succinylcholine and that ideal body weight, or an adjusted (or lean) body weight, is the size descriptor of choice for weight-based dosing of non-depolarising NMBAs.

Assessment of Kidney Function in Patients With Extreme Obesity: A Narrative Review

Objectives: To discuss the evidence and caveats associated with estimated and measured creatinine clearance (eClCr and mClCr) and glomerular filtration rate (eGFR and mGFR) assessments of kidney function in patients with more extreme forms of obesity. Data Sources: PubMed (1976 to mid-May 2020) was used, with bibliographies of retrieved articles searched for additional articles. Study Selection and Data Extraction: Articles using gold standard mGFR to evaluate eClCr, mClCr, and eGFR assessments of kidney function in patients with more extreme forms of obesity were included. Data Synthesis: The overestimation of GFR by mClCr is well established, but mClCr is an alternative to mGFR assessments for determining medication dosing in patients with extremes of body size or muscle mass, or in patients receiving narrow therapeutic index medications when eGFR is likely to be inaccurate. The vast majority of studies comparing eGFR assessments with gold standard indicators of kidney function were attempts to validate eGFR equations for diagnosing and staging chronic kidney disease (CKD). Relevance to Patient Care and Clinical Practice: For dosing medications in patients with stable kidney function and extreme obesity, a deindexed 4-variable Modification of Diet in Renal Disease or CKD Epidemiology Collaboration equation is an alternative to Cockcroft-Gault. Consistent use of the same equation by provider and between providers within any given setting is of paramount importance. Conclusions: In patients with extreme obesity and stable kidney function, eClCr or eGFR using deindexed values provides estimates of function for dosing adjustments of medications with elimination by the kidneys, but more research is needed with respect to the best size descriptor to use with estimating equations.

P072 Evaluation of dosing strategies of anti-TNFα monoclonal antibodies using pharmacokinetic modelling and simulation

Background Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn’s disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration–time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110% and CV ≈80%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52–71%), being the highest for LBW-adjusted dosing. Conclusion By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66% vs. 71%, respectively). References

TSD Algorithm to Design CA Based Expert System for Pipelining to Stop Urban Flood

Flood is a frequent disaster disturbing the daily life and sometimes found deadly. Out of all kind of floods, urban flood is avoidable through quick exit of drainage. Urban flood starts water logging that can be eliminated by efficient pipeline structure. A dedicated drainage pipeline structure may facilitate better during urban flood. A Cellular Automata is a theoretical computer science tool used to solve complex problems as well as to design structures. In these days, applications of CA continuously increasing, out of which an application of designing a flood avoidance drainage mechanism using CA based structure presented in this paper. To generate knowledge for an expert system to design a flood free city in initial stage of development of a city this paper presents a structure for maximum way of exit. This structure including tanks connected at every corner to minimize the dependency on ground water and reuse the rainwater. In order to avoid flood, minimum size of tanks has been calculated by proposed Tank Size Descriptor (TSD) algorithm with the help of actual rainfall data. With the help of TSD algorithm any expert system of civil engineering will be able to suggest a design of a flood free city using hexagonal shapes within the cellular automata.

Maturity Status Does Not Exert Effects on Aerobic Fitness in Soccer Players After Appropriate Normalization for Body Size

The present study investigated the effects of pubertal status on peak oxygen uptake (VO2peak), respiratory compensation point (RCP), and ventilatory threshold (VT) in young soccer players using different body size descriptors. Seventy-nine soccer players (14 prepubescent, 38 pubescent and 27 postpubescent) participated in this study. A maximal exercise test was performed to determine the VO2peak, RCP, and VT. Ultrasonography was used to measure lower limb muscle volume (LLMV). LLMV (mL-b) was rated as the most effective body size descriptor to normalize VO2peak (mLO2•mL-0.43•min-1), RCP (mLO2•mL-0.48•min-1), and VT (mLO2•mL-0.40•min-1). The values of VO2peak, RCP, and VT relative to allometric exponents derived by LLMV were similar among groups (p > .05; 0.025 < η2 < 0.059) when the effect of chronological age was controlled. Allometric VO2peak, RCP, and VT values were: 100.1 ± 7.9, 107.5 ± 9.6, and 108.0 ± 10.3 mLO2.mL-0.43•min-1; 51.8 ± 5.3, 54.8 ± 4.7, and 57.3 ± 5.8 mLO2•mL-0.48•min-1; and 75.7 ± 7.1, 79.4 ± 7.0, and 80.9 ± 8.3 mLO2•mL-0.40•min-1 for prepubertal, pubertal, and postpubertal groups, respectively. Maturity status showed no positive effect on VO2peak, RCP, and VT when the data were properly normalized by LLMV in young soccer players. Allometric normalization using muscle volume as a body size descriptor should be used to compare aerobic fitness between soccer players heterogeneous in chronological age, maturity status, and body size.

Exploring structure indenture for some Schiff bases as anti-Salmonella typhi drugs: A QSAR Approach

There are many drugs available in the market for treating typhoid infection, but the emergence of multi-drug resistant strain of Salmonella typhi (S.typhi) has necessitated the exploration and development of newer structural moiety of Schiff bases as anti-S. typhi agents owing to their enormous inhibitory activity against this bacterium. In this present study, a Genetic function approximation (GFA) QSAR analysis of some selected Schiff bases with anti-S. typhi activity was performed using OD,1D, 2D and 3D descriptors resulting in the generation of three statistically significant models from which an octa-parametric model was selected as the most robust model with R2 = 0.8589, R2adj = 0.8155, Q2 = 0.7437,R2 - Q2 = 0.1152, r2 r02 / r2 =0.00, r2 r02 / r2 = 0.0263, K = 1.0E-7, K = 0.1969. The optimization model hinted the dominant influence of the size descriptor ETA-Eta-B (Branching index EtaB relative to molecular size) on the observed anti-S.typhi activity of Schiff bases. It is envisaged that the QSAR results identified in this study will offer important structural insight into designing novel anti-S.typhi drugs from Schiff bases.