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Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model-informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine-treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: "low" (demographic), "medium" (demographic and environmental interaction), and "high" (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R

Dosing guidance for children with obesity is often unknown despite the fact that nearly 20% of US children are classified as obese. Enoxaparin, a commonly prescribed low-molecular-weight heparin, is dosed based on body weight irrespective of obesity status to achieve maximum concentration within a narrow therapeutic or prophylactic target range. However, whether children with and without obesity experience equivalent enoxaparin exposure remains unclear. To address this clinical question, 2,825 anti-activated factor X (anti-Xa) surrogate concentrations were collected from the electronic health records of 596 children, including those with obesity. Using linear mixed-effects regression models, we observed that 4-hour anti-Xa concentrations were statistically significantly different in children with and without obesity, even for children with the same absolute dose (P = 0.004). To further mechanistically explore obesity-associated differences in anti-Xa concentration, a pediatric physiologically-based pharmacokinetic (PBPK) model was developed in adults, and then scaled to children with and without obesity. This PBPK model incorporated binding of enoxaparin to antithrombin to form anti-Xa and elimination via heparinase-mediated metabolism and glomerular filtration. Following scaling, the PBPK model predicted real-world pediatric concentrations well, with an average fold error (standard deviation of the fold error) of 0.82 (0.23) and 0.87 (0.26) in children with and without obesity, respectively. PBPK model simulations revealed that children with obesity have at most 20% higher 4-hour anti-Xa concentrations under recommended, total body weight-based dosing compared to children without obesity owing to reduced weight-normalized clearance. Enoxaparin exposure was better matched across age groups and obesity status using fat-free mass weight-based dosing.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

OBJECTIVE The aim of this systematic review and meta-analysis was to determine if a combination of analgesics conveys any significant clinical benefit over paracetamol alone in managing acute musculoskeletal injuries. METHODS Two reviewers independently searched MEDLINE (via PubMed), EMBASE and Cochrane electronic databases. Randomised controlled trials comparing paracetamol with paracetamol plus other oral analgesics in managing acute musculoskeletal injuries (e.g. sprains, contusions) were identified. Outcomes were reduction in pain score, adverse events and need for additional analgesia. Studies were critiqued using the Cochrane Risk of Bias Assessment Tool and data analysed using RevMAN meta-analysis software. RESULTS Six studies were included (n = 1254). No paediatric studies were identified. Five studies compared paracetamol to paracetamol plus NSAID. One study also included an opioid in the combination group. There was no clinically important difference between groups for reduction in pain score in the first 2 h, 24 h or 72 h. At 2 h the mean difference in reduction in pain score at rest on 100 mm VAS was 0.72 mm (-1.36, 2.79), P = 0.5. On activity it was -1.79 mm (-4.08, 0.49), P = 0.12. The risk of adverse events in ED was -0.00 (-0.04, 0.03). More patients receiving combination therapy required additional analgesia in the first 2 h: -0.03 (-0.06, -0.01), P = 0.01. CONCLUSION Paracetamol monotherapy is a reasonable first-line analgesic for acute musculoskeletal injuries as combining additional oral agents does not result in any significant additional analgesic effect.

Syndrome Coronavirus 2 (SARS-CoV-2) has led to remarkable efforts by the scientific communities internationally to identify potential pharmacological treatments through the rapid initiation of clinical trials of novel and/or re-purposed regulatory authorityapproved therapies. We greatly welcome the significant global effort to safely expedite trials. However, we are concerned that many studies have not been of high quality to generate clinically meaningful data to enable effective translation to clinical practice. Identifying the “right” drug (or drug combinations) is only the first step. Applying core clinical pharmacology principles at all stages of research will help identify the right dose, the right patient, and the right treatment protocol. We hope that by setting out the principles outlined in this statement, efforts to find a safe and efficacious treatment for COVID-19 will have the best chance of success.

To investigate external factors that trigger manic and hypomanic relapses and how this is associated with personality and clinical outcome measured as number of affective episodes over a seven-year period.This is a prospective cohort study of 204 meticulously characterized Swedish bipolar disorder patients. Personality was evaluated at baseline using the Swedish universities Scales of Personality in 170 patients, and 90 patients were followed up after approximately seven years in order to evaluate clinical outcomes.We found that 44% of the patients reported trigger factors, including sleep disturbance, work or family related issues, medication, and illicit drug use. There were no significant differences in any of the personality traits when comparing the 74 patients that reported triggers with the 90 patients that did not. At seven-year follow-up, there was no difference between the groups in number of affective episodes (depressive, hypomanic, manic or mixed), involuntary commitments, suicide attempts, or self-harm incidents since baseline.Around 40% of the patients reported external triggers for manic and hypomanic episodes. However, this was neither associated with personality traits nor number of affective episodes at seven-year follow-up.Around 40% of all bipolar disorder patients reported trigger factors for manic or hypomanic episodes. Reporting trigger factors was not associated with personality Reporting trigger factors was not associated with outcomes over a seven-year period. Limitations Patients had on average long duration of illness and may be less sensitive to external stressors than persons with recent onset. Trigger factors were identified retrospectively, and may thus be prone to recall bias. The number of affective episodes might be a too crude outcome measure as most subjects had not suffered any affective episodes at follow-up.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DKD is glomeru- lar basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease (MCD). According to fundamental transport physiological principles, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C. Twenty- nine patients with a kidney biopsy diagnosis of either DKD (n = 17) or MCD (n = 12) were retrospectively included in the study. GBM thickness was measured at 20 sepa- rate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport. The mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/ eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (p < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine- ratio (Pearson's r = −0.61, p < 0.01). Two-pore modeling predicted a eGFRcystatin C/ eGFRcreatinine-ratio of 78% in DKD. We provide clinical and theoretical evidence sug- gesting that thickening of the glomerular filter, increasing the diffusion length of cys- tatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DKD. (Less)

Angiotensin II (Ang II) induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor, Ang II elicits Ca2+ influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La3+ salts have been shown to block TRPC channels in vitro, and we therefore tested their potential effect on Ang II‐induced glomerular hyperpermeability. Anesthetized male Sprague‐Dawley rats were infused with Ang II (80 ng kg–1 min–1) alone, or together with clemizole or low‐dose La3+ (activates TRPC5, blocks TRPC6) or high‐dose La3+ (blocks both TRPC5 and TRPC6). Plasma and urine samples were taken during baseline and at 5 min after the start of the infusions and analyzed by high‐performance size‐exclusion chromatography for determination of glomerular sieving coefficients for Ficoll 10–80 Å (1–8 nm). Ang II infusion evoked glomerular hyperpermeability to large Ficolls (50–80 Å), which was ameliorated by clemizole, having no significant effect on glomerular filtration rate (GFR) or Ang II‐mediated increase in mean arterial pressure (ΔMAP). In contrast, high‐ and low‐dose La3+ significantly lowered ΔMAP and reduced Ang II‐induced hyperpermeability. Combined, clemizole and low‐dose La3+ were less effective at ameliorating Ang II‐induced glomerular hyperpermeability than low‐dose La3+ alone. In conclusion, our data show that both clemizole and La3+ are effective against Ang II‐induced glomerular hyperpermeability, with differential effects on blood pressure. Further research using more specific blockers of TRPC5 and TRPC6 should be performed to reveal the underlying mechanisms.

During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based meta-analysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.

Introduction Pemphigus vulgaris (PV) is a relatively rare, potentially life-threatening autoimmune disease that, in most cases, has an unknown etiology. Medications for hypertension have been linked to the onset and exacerbation of PV-like symptoms. The diagnosis of medication-related PV can be challenging because it has an identical appearance to the clinical and histologic appearance of idiopathic PV and cases may not resolve after discontinuation of the drug. Case presentation We present a case of an elderly patient with gingival and cutaneous erosions, who underwent several medical and dental consultations without an appropriate diagnosis. After biopsy and a thorough review of her medical history, metoprolol was suspected as the offending agent. After consulting with her cardiologist, metoprolol was discontinued, and a complete resolution of all lesions resulted. Conclusions To our knowledge, the current case is the first reported case of metoprolol-induced PV in the English-language literature. As such, it highlights the potential of medication involvement in some immune-mediated diseases. Because the oral mucosa is often the first site of involvement in PV, knowledge of drug-related PV is crucial in the diagnosis, treatment, and management of dental patients.

Antioxidant activity (AOA ) and phytochemical content of Moringa oleifera Lam leaves were determined as a function of their age and extraction solvent. Fresh Moringa leaves aged 30, 45, and 60 days were harvested and extracted with three solvents; methanol, ethanol, and water. AOA of leaf extracts was measured using radical scavenging assays (DPPH , ABTS , antiperoxide activity [APA ]) and reducing assays (FRAP and total antioxidant capacity [TAC ]), and these were correlated with total polyphenols (TPC ), total flavonoids (TFC ), and chlorophyll contents of leaves. Significant variability (p < 0.05) in TPC and AOA of Moringa leaf extracts was observed with age and extraction solvent as well as their interaction. TPC and TFC increased with maturity, except in aqueous extract. The 60‐day‐old leaves showed highest TPC , TFC , and tocopherol contents with highest DPPH activity. On their part, 30‐day‐old leaves recorded better vitamin C, chlorophyll, and carotenoids with highest ABTS activity and APA . Methanol was best extraction solvent for TPC (4.6 g GAE /100 g DM ) while ethanol was for flavonoids (1.8 g CE /100 g DM ). Ethanol extracts exhibited the highest DPPH activity (53.3%–71.1%), while both ethanolic and methanolic extracts had similar and higher ABTS + activity (3.83–3.86 g AAE /100 g DM ). Strong positive correlations (r ≥ 0.8; p < 0.05) were observed between chlorophyll content and DPPH , ABTS , and APA , suggesting that chlorophyll was the major contributor to AOA . TAC was highest in aqueous solvent. Free radical scavenging activity in Moringa leaves is positively correlated to chlorophyll, TFC , and TPC while reducing power is positively correlated to chlorophyll and TPC . AOA of fresh Moringa leaf extract is a function of its phytochemical content and is influenced by both the age of the leaves and the extraction solvent used. Methanolic and ethanolic extracts of 45‐day‐old Moringa leaves exhibited best antioxidant potentials.