Impact of starting BMI and degree of weight loss on changes in appetite-regulating hormones during diet-induced weight loss.

OBJECTIVE: The aim of this study was to determine whether the hormone changes following weight loss are proportional to the degree of weight loss and to starting BMI. METHODS: A very low-energy diet was used to achieve 15% weight loss. Fasting and postprandial gut hormones and leptin were measured during a meal test at baseline and at 5% (1%), 10% (2%), and 15% (2.5%) weight loss. Linear mixed-effects models were used to analyze hormone changes. RESULTS: From baseline to 5% weight loss, decreases were seen in fasting concentrations of leptin (-8.25 ng/mL; p < 0.001), amylin (-21.3 pg/mL; p < 0.001), and glucagon-like peptide 1 (-59.55 pg/mL; p < 0.001). There was a small further reduction in leptin between 5% and 15% weight loss (-1.88 ng/mL; p = 0.019) but not in glucagon-like peptide 1 and amylin. Fasting ghrelin showed a significant increase at 10% weight loss (41.64 pg/mL; p = 0.002), with a nonsignificant increase from 10% to 15% loss (26.03 pg/mL; p = 0.065). Postprandial changes in hormone levels were variable. There was no correlation between baseline weight and the degree of hormone changes. CONCLUSIONS: The majority of changes in fasting gut hormones and leptin occurred in early weight loss, with minor further changes up to 15% weight loss. Starting weight did not affect the degree of hormone change.

Pharmacokinetics and safety of inhaled ivermectin in mice as a potential COVID-19 treatment.

Pharmacokinetic limitations associated with oral ivermectin may limit its success as a potential COVID-19 treatment based on in vitro experiments which demonstrate antiviral efficacy against SARS-CoV-2 at high concentrations. Targeted delivery to the lungs is a practical way to overcome these limitations and ensure the presence of a therapeutic concentration of the drug in a clinically critical site of viral pathology. In this study, the pharmacokinetics (PK) and safety of inhaled dry powders of ivermectin with lactose were investigated in healthy mice. Female BALB/c mice received ivermectin formulation by intratracheal administration at high (3.15 mg/kg) or low doses (2.04 mg/kg). Plasma, bronchoalveolar lavage fluid (BALF), lung, kidney, liver, and spleen were collected at predetermined time points up to 48 h and analyzed for PK. Histological evaluation of lungs was used to examine the safety of the formulation. Inhalation delivery of ivermectin formulation showed improved pharmacokinetic performance as it avoided protein binding encountered in systemic delivery and maintained a high exposure above the in vitro antiviral concentration in the respiratory tract for at least 24 h. The local toxicity was mild with less than 20% of the lung showing histological damage at 24 h, which resolved to 10% by 48 h.

Preparation and Characterization of Inhalable Ivermectin Powders as a Potential COVID-19 Therapy.

Background: Ivermectin has received worldwide attention as a potential COVID-19 treatment after showing antiviral activity against SARS-CoV-2 in vitro. However, the pharmacokinetic limitations associated with oral administration have been postulated as limiting factors to its bioavailability and efficacy. These limitations can be overcome by targeted delivery to the lungs. In this study, inhalable dry powders of ivermectin and lactose crystals were prepared and characterized for the potential treatment of COVID-19. Methods: Ivermectin was co-spray dried with lactose monohydrate crystals and conditioned by storage at two different relative humidity points (43% and 58% RH) for a week. The in vitro dispersion performance of the stored powders was examined using a medium-high resistance Osmohaler connecting to a next-generation impactor at 60 L/min flow rate. The solid-state characteristics including particle size distribution and morphology, crystallinity, and moisture sorption profiles of raw and spray-dried ivermectin samples were assessed by laser diffraction, scanning electron microscopy, Raman spectroscopy, X-ray powder diffraction, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption. Results: All the freshly spray-dried formulation (T0) and the conditioned samples could achieve the anticipated therapeutic dose with fine particle dose of 300 µg, FPFrecovered of 70%, and FPFemitted of 83%. In addition, the formulations showed a similar volume median diameter of 4.3 µm and span of 1.9. The spray-dried formulations were stable even after conditioning and exposing to different RH points as ivermectin remained amorphous with predominantly crystalline lactose. Conclusion: An inhalable and stable dry powder of ivermectin and lactose crystals was successfully formulated. This powder inhaler ivermectin candidate therapy appears to be able to deliver doses that could be safe and effective to treat the SARS-COV-2 infection. Further development of this therapy is warranted.

The relationship between commencement of continuous renal replacement therapy and urine output, fluid balance, mean arterial pressure and vasopressor dose.

Background and objectives: The effect of initiating continuous renal replacement therapy (CRRT) on urine output, fluid balance and mean arterial pressure (MAP) in adult intensive care unit (ICU) patients is unclear. We aimed to evaluate the impact of CRRT on urine output, MAP, vasopressor requirements and fluid balance, and to identify factors affecting urine output during CRRT. Design: Retrospective cohort study using data from existing databases and CRRT machines. Setting: Medical and surgical ICUs at a single university-associated centre. Participants: Patients undergoing CRRT between 2015 and 2018. Main outcome measures: Hourly urine output, fluid balance, MAP and vasopressor dose 24 hours before and after CRRT commencement. Missing values were estimated via Kaplan smoothing univariate time-series imputation. Mixed linear modelling was performed with noradrenaline equivalent dose and urine output as outcomes. Results: In 215 patients, CRRT initiation was associated with a reduction in urine output. Multivariate analysis confirmed an immediate urine output decrease (-0.092 mL/kg/h; 95% confidence interval [CI], -0.150 to -0.034 mL/kg/h) and subsequent progressive urine output decline (effect estimate, -0.01 mL/kg/h; 95% CI, -0.02 to -0.01 mL/kg/h). Age and greater vasopressor dose were associated with lower post-CRRT urine output. Higher MAP and lower rates of net ultrafiltration were associated with higher post-CRRT urine output. With MAP unchanged, vasopressor dose increased in the 24 hours before CRRT, then plateaued and declined in the 24 hours thereafter (effect estimate, -0.004 µg/kg/ min per hour; 95% CI, -0.005 to -0.004 µg/kg/min per hour). Fluid balance remained positive but declined towards neutrality following CRRT implementation. Conclusions: CRRT was associated with decreased urine output despite a gradual decline in vasopressor and a positive fluid balance. The mechanisms behind the reduction in urine output associated with commencement of CRRT requires further investigation.

Venous thromboembolism prophylaxis and related outcomes in patients with traumatic brain injury and prolonged intensive care unit stay.

Objective: Traumatic brain injury (TBI) patients with prolonged intensive care unit (ICU) stay are at risk of secondary intracranial haemorrhage (ICH) and venous thromboembolism (VTE). We aimed to study VTE prophylaxis, secondary ICH, and VTE prevalence and outcomes in this population. Design: Retrospective observational study. Setting: Level 1 trauma centre ICU. Patients: One hundred TBI patients receiving prolonged ICU treatment (≥ 7 days). Interventions: We collected data from medical records, pathology and radiology systems, and hospital and ICU admission databases. We analysed patient characteristics, interventions, episodes and types of secondary ICH and VTE, and timing and dosage of VTE prophylaxis. Results: Data from the 100 patients in our study showed that early use of compression stockings and pneumatic calf compression was common (75% and 91% in the first 3 days, respectively). VTE chemoprophylaxis, however, was only used in 14% of patients by Day 3 and > 50% by Day 10. We observed VTE in 12 patients (10 as pulmonary embolism), essentially all after Day 6. Radiologically confirmed secondary ICH occurred in 43% of patients despite normal coagulation. However, 72% of ICH events (42/58) were radiologically mild, and the median time of onset of ICH was Day 1, when only 3% of patients were on chemical prophylaxis. Moreover, 82% of secondary ICH events (48/58) occurred in the first 3 days, with no severe ICH thereafter. Conclusions: In TBI patients receiving prolonged ICU treatment, early chemical VTE prophylaxis was uncommon. Early secondary ICH was common and mostly radiologically mild, whereas later secondary ICH was essentially absent. In contrast, early VTE was essentially absent, whereas later VTE was relatively common. Earlier chemical VTE prophylaxis and/or ultrasound screening in this population appears logical.