Lean body mass and total body weight versus body surface area as determinant of docetaxel pharmacokinetics and toxicity

Aim: In our study we examined whether anthropometric and body composition parameters, i.e. body surface area (BSA), lean body mass (LBM) and total body weight (TBW), are correlated with docetaxel clearance and exposure. In addition, LBM, TBW and a fixed dose were compared to BSA as dosing parameters for dose individualisation of docetaxel. Methods: Thirty-six patients affected by breast or castration-resistant prostate carcinoma receiving docetaxel chemotherapy entered the study. LBM was measured by a Dual Energy Xray Absorptiometry (DEXA) scanner before treatment. Blood samples were collected up to 180 minutes after dosing to analyse docetaxel concentrations and to determine individual pharmacokinetic (PK) parameters. Results: No significant correlations were found between the docetaxel pharmacokinetic parameters clearance and volume of distribution and the anthropometric and body composition variables BSA, LBM and TBW. AUC was significantly but poorly correlated with BSA (r=0.452 [p=0.016]) and with TBW (r=0.476 (p=0.011]). The Mean Absolute Percentage Error and Mean Error of simulated dosing based on LBM and fixed dosing ME were not significant different compared to BSA. For TBW, only the MAPE of dosing was significant higher compared to BSA (24.1 vs. 17.1, P=0.001). Conclusion: There is no correlations between docetaxel pharmacokinetics and the anthropometric and body composition variables BSA, LBM and TBW. Dose individualisation of docetaxel based on LBM or TBW or fixed dosing cannot be recommended over BSA based dosing.

Piecing together human adult comparative pharmacokinetic trials and rodent studies: What happens to drug clearance in obesity?

In many comparative trials examining the effects of adult obesity on pharmacokinetics of drugs, conclusions were made based on values that were either not adjusted to total body weight or adjusted to non-obese body mass (e.g., ideal or lean body weight). In many cases these values were higher in the obese subjects. We have reviewed the data from comparative human trials, and it is apparent that in examining clearance normalization to total body weight (as typically done in studies involving pediatric obese patients), the clearances are often reduced in the obese. We have also reviewed the results of experimental obese versus non-obese rodent models. Those studies have mostly found that the systemic exposures to the same dose per body weight are increased, with obesity-related decreases in clearance. Furthermore, the expression of a number of important drug metabolizing enzymes are reduced in the experimental obese state. There is also evidence that obesity causes increases in the measured mass of eliminating organs such as liver and kidney. Human clearance normalized to total body weight appears to better reflect the underlying changes reported in the expression of protein and functional activity of drug clearance mechanisms.

Evaluation of 2’-Fucosyllactose and Bifidobacterium longum Subspecies infantis on Growth, Organ Weights, and Intestinal Development of Piglets

Human milk is rich in oligosaccharides that influence intestinal development and serve as prebiotics for the infant gut microbiota. Probiotics and 2’-fucosyllactose (2’-FL) added individually to infant formula have been shown to influence infant development, but less is known about the effects of their synbiotic administration. Herein, the impact of formula supplementation with 2’-fucosyllactose (2’-FL) and Bifidobacterium longum subsp. infantis Bi-26 (Bi-26), or 2’-FL + Bi-26 on weight gain, organ weights, and intestinal development in piglets was investigated. Two-day-old piglets (n = 53) were randomized in a 2 × 2 design to be fed a commercial milk replacer ad libitum without (CON) or with 1.0 g/L 2’-FL. Piglets in each diet were further randomized to receive either glycerol stock alone or Bi-26 (109 CFU) orally once daily. Body weights and food intake were monitored from postnatal day (PND) 2 to 33/34. On PND 34/35, animals were euthanized and intestine, liver and brain weights were assessed. Intestinal samples were collected for morphological analyses and measurement of disaccharidase activity. Dry matter of cecum and colon contents and Bifidobacterium longum subsp. infantis abundance by RT-PCR were also measured. All diets were well tolerated, and formula intake did not differ among the treatment groups. Daily body weights were affected by 2’-FL, Bi-26, and day, but no interaction was observed. There was a trend (p = 0.075) for greater total body weight gain in CON versus all other groups. Jejunal and ascending colon histomorphology were unaffected by treatment; however, there were main effects of 2’-FL to increase (p = 0.040) and Bi-26 to decrease (p = 0.001) ileal crypt depth. The addition of 2’-FL and/or Bi-26 to milk replacer supported piglet growth with no detrimental effects on body and organ weights, or intestinal structure and function.

EFFECT OF FINE PARTICULATE MATTER EXPOSURE ON TRIGGERING DEPRESSIVE-LIKE RESPONSE AND TOTAL BODY WEIGHT IN C57BL/6J MICE

Objective: To study the effect of fine particulate matter exposure in instigating depressive-like response and total body weight changes in C57BL/6J mice. Study Design: Laboratory-based experimental study. Place and Duration of Study: Anatomy Department, Army Medical College, Rawalpindi, in collaboration with the Military Hospital, Rawalpindi and the National Institute of Health (NIH), Islamabad, from Jun to Sep 2020. Methodology: Thirty male and female C57BL/6 mice, 8 weeks of age, weighing 37 ± 2 gm were obtained from NIH, Islamabad. They were retained in separate cages in the animal house of NIH under standard laboratory conditions. The animals were divided into two groups, 15 mice in each group (8 males and 7 females) Group A was marked as control, received regular diet and water ad libitum. Group B (experimental group) received dynamic inhalation of 3 mg/m³ fine particles (soot) through air circulation for 6h/d for 12 weeks, in a plastic cabin measuring 2x2x2 feet fitted with two small fans for evenly distribution of PM. The initial and final weight of animals was recorded, and a tail suspension test was performed to assessdepression in form of immobility. Result: The experimental group after exposure to fine particulate matter showed decreased activity and behavioural deficits with p-value <0.001 and loss in total body weight as compared to the control group with a p-value <0.001. Conclusion: Fine particulate matter has a significant effect on behaviour and cognition. It also causes a decrease in the total body weight of animals due to stress and agitation.

Switching to a Bictegravir Single Tablet Regimen in Elderly People Living with HIV-1: Data Analysis from the BICTEL Cohort

Bictegravir/emtricitabine/tenofovir alafenamide fumarate (BIC/FTC/TAF) is a recommended once-daily single tablet regimen for the treatment of people living with HIV-1 (PLWH). We aimed to assess efficacy, safety and tolerability of BIC/FTC/TAF among PLWH, with a specific focus on people older than 55 years. Thus, we recruited an observational retrospective real-life cohort including all PLWH who underwent a therapeutic switch to BIC/FTC/TAF, independently from the provenience treatment regimen. After 48 weeks of follow-up, 147 PLWH were included and 93 were older than 55 years. PLWH with HIV-RNA < 37 copies/mL increased from 140 to 146 (p < 0.033). Among the overall population, we observed an increase in CD4+ T cells count by 30.1% (p-value < 0.001), in CD8+ T cells count by 7.1% (p-value = 0.004) and in CD4+/CD8+ ratio by 21.5% (p-value < 0.001). Lipidic profile was characterized by decreasing total cholesterol/HDL ratio by 8% (p-value < 0.001) and LDL by 6.8% (p-value = 0.007). Total body weight increased by 1.8% (p-value = 0.014) and BMI by 4.2% (p-value < 0.001), even remaining within the healthy range. Hepatic and renal profile were not altered by the switch, nor were adverse events and/or discontinuations events detected. In conclusion, BIC/FTC/TAF is effective, safe and well tolerated in real life and among PLWH older than 55.

Discovery of the First in Class 9-N-Berberine Derivative as Hypoglycemic Agent with Extra-Strong Action

Berberine is well known for its ability to reduce the blood glucose level, but its high effective dose and poor bioavailability limits its use. In this work we synthesized a new derivative of berberine, 9-(hexylamino)-2,3-methylenedioxy-10-methoxyprotoberberine chloride (SHE-196), and analyzed the profile of its hypoglycemic effects. Biological tests have shown that the substance has a very pronounced hypoglycemic activity due to increased insulin sensitivity after single and multiple dosing. In obese type 2 diabetes mellitus (T2DM) mice, it was characterized by improved glucose tolerance, decreased fasting insulin levels and sensitivity, decreased total body weight and interscapular fat mass, and increased interscapular brown fat activity. All these effects were also confirmed histologically, where a decrease in fatty degeneration of the liver, an improvement in the condition of the islets of Langerhans and a decrease in the size of fat droplets in brown adipose tissue were found. Our results indicate that 9-(hexylamino)-2,3-methylenedioxy-10-methoxyprotoberberine chloride could be the first in a new series of therapeutic agents for the treatment of diabetes mellitus.

Developing a Reference Database for Typical Body and Organ Growth of the Artificially Reared Pig as a Biomedical Research Model

Objectives: The pig is a common model utilized to support substantiation of novel bioactive components in infant formula. However, reference ranges for outcomes to determine safety are unclear. Our objective was to use historical data to objectively define typical body and organ growth metrics of the domesticated pig in research.Methods: Twenty-two studies were compiled to assess typical growth of body and organ weights in young pigs. Metadata were organized to include milk replacer sources, bioactive components, sex, breed, source of herd, feeding regimen, and rearing environment. A combination of statistical models including simple linear regression and linear mixed effect models were used to assess typical growth patterns.Results: Over 18,000 data points from 786 animals were available. In general, minimal differences in the growth of pigs who were male and female, artificially- or sow-reared, or fed ad libitum- or by scheduled-feeding, were observed in the first 30 days of life (P &gt; 0.05). A weight-for-age chart from reference pigs was developed to compare body weights of pigs demonstrating growth characterized as accelerated, typical, reduced, and failure to thrive to illustrate effects of dietary interventions. Distributions of relative brain, liver, and intestine weights (as % of total body weight) were similar between rearing environments and sexes. An alternative bivariate level approach was utilized for the analysis of organ weights. This approach revealed significant biologically-relevant insights into how deficient diets can affect organ weight that a univariate level assessment of weight distribution was unable to detect.Conclusions: Ultimately, these data can be used to better interpret whether bioactive ingredients tested in the pig model affect growth and development within typical reference values for pigs in the first 30 days of life.

Passive longitudinal weight and cardiopulmonary monitoring in the home bed

Home health monitoring has the potential to improve outpatient management of chronic cardiopulmonary diseases such as heart failure. However, it is often limited by the need for adherence to self-measurement, charging and self-application of wearables, or usage of apps. Here, we describe a non-contact, adherence-independent sensor, that when placed beneath the legs of a patient’s home bed, longitudinally monitors total body weight, detailed respiratory signals, and ballistocardiograms for months, without requiring any active patient participation. Accompanying algorithms separate weight and respiratory signals when the bed is shared by a partner or a pet. Validation studies demonstrate quantitative equivalence to commercial sensors during overnight sleep studies. The feasibility of detecting obstructive and central apneas, cardiopulmonary coupling, and the hemodynamic consequences of non-sustained ventricular tachycardia is also established. Real-world durability is demonstrated by 3 months of in-home monitoring in an example patient with heart failure and ischemic cardiomyopathy as he recovers from coronary artery bypass grafting surgery. BedScales is the first sensor to measure adherence-independent total body weight as well as longitudinal cardiopulmonary physiology. As such, it has the potential to create a multidimensional picture of chronic disease, learn signatures of impending hospitalization, and enable optimization of care in the home.