Liposomal Artificial Red Blood Cell-Based Carbon Monoxide Donor Is a Potent Renoprotectant against Cisplatin-Induced Acute Kidney Injury

Cisplatin (CDDP) is an essential anti-tumor agent for chemotherapeutic regimens against various types of cancer. However, the progression of nephrotoxicity, which is the main adverse effect of CDDP, leads to discontinuation of CDDP chemotherapy. Therefore, development of a renoprotectant against CDDP-induced nephrotoxicity is crucial. Here, the potential of a carbon monoxide (CO)-loaded hemoglobin-vesicle (CO-HbV) as a renoprotectant for CDDP-induced nephrotoxicity was evaluated for its renoprotective effects against CDDP-induced nephrotoxicity, inhibitory effects on the anti-tumor activity of CDDP, and anti-tumor activity. In healthy mice, after pretreatment with either saline, HbV, or CO-HbV prior to CDDP administration, only the CO-HbV pretreatment group ameliorated the progression of CDDP-induced nephrotoxicity by suppressing apoptosis via caspase-3. In experiments using B16-F10 melanoma cells, the half-maximal inhibitory concentration of CDDP decreased with co-incubation with CO-HbV, owing to the anti-tumor activity of CO. CO-HbV pretreatment had no impact on the anti-tumor activity of CDDP in B16-F10 melanoma cell-bearing mice, which was consistent with the results of the cell experiment. Furthermore, CO-HbV pretreatment improved body growth and survival rates. In conclusion, CO-HbV pretreatment is a potent renoprotectant for CDDP-induced nephrotoxicity, allowing treatment with CDDP to be conducted without failure of cancer treatment.

Right Ventricular Function during Trastuzumab Therapy for Breast Cancer

PurposeCardiotoxicity (CDT) is the main adverse effect related to trastuzumab (TTZ) use, and the role of the right ventricle (RV) in this context is not clear. We aimed to evaluate the longitudinal changes in RV function during TTZ therapy and to determine the differences in RV function associated with subclinical CDT.MethodsPatients with breast cancer underwent echocardiograms at the beginning of TTZ treatment (Ex 1) and every 3 months during the first year (Ex 2, 3, 4). Subclinical CDT was defined as ≥ 12% relative reduction of left ventricle global longitudinal strain (LV GLS).ResultsTwenty-five women (52.1 ± 13.1 y-o) were included. We found a decrease in LV ejection fraction between the first and fourth exams and the LV GLS gradually decreased during follow-up (Ex1: -20.6 ± 2.0; Ex2: -19.4 ± 2.1; Ex3: -19.2 ± 1.8; Ex4: -19.0 ± 2.1, all p < 0.05). RV GLS changed from baseline to 3 month and to 6 month (Ex1: -23.9% ± 1.6; Ex2: -22.5% ± 2.1; Ex3: -22.5% ± 2.3, all p < 0.05), and the RV Fractional Area Change was lower in the third exam (Ex1: 44.3% ± 6.6 vs Ex3: 39.9% ± 6.0, p = 0.004). We found subclinical CDT in 13 patients (52%); changes in RV parameters had the same pattern of changing in the group with and without subclinical CDT.ConclusionIn this sample, the RV function decreased during TTZ therapy and the decrease was not associated to the observed LV cardiotoxicity.

A randomized double-blind pilot study comparing cetirizine with diphenhydramine in the prevention of paclitaxel-associated infusion-related reactions.

e24080 Background: Cetirizine is a less sedative alternative to diphenhydramine for the prevention of infusion-related reactions (IRR) to paclitaxel. However, there is no prospective data to support its use in this context. In this study, we conducted a feasibility study for a future definitive non-inferiority trial comparing cetirizine with diphenhydramine as premedication to prevent paclitaxel-related IRR. Methods: This was a single center randomized double-blind parallel-group prospective pilot study. Participants were paclitaxel-naive cancer patients scheduled to start paclitaxel chemotherapy, alone or in combination. They were assigned to receive either intravenous diphenhydramine 50 mg + oral placebo (diphenhydramine group) or intravenous placebo + oral cetirizine 10 mg (cetirizine group) for their first two paclitaxel treatments. To assess the feasibility of a larger study, the percentage of eligible patients completing a first paclitaxel treatment and the recruitment rate were calculated. IRR events were documented. Change in drowsiness compared with baseline was assessed using the Stanford Sleepiness Scale (SSS). Results: Among 37 eligible patients, 27 were recruited and randomized (control 13; intervention 14) and 25 completed the study. The recruitment rate was 4.8 participants/month, meeting the primary feasibility target of 4 participants per month. One participant had an IRR (cetirizine group, CTCAE grade 2) and no unexpected serious adverse events occurred. Drowsiness was the main adverse effect associated with the premedication. The increase in drowsiness compared to baseline (ΔSSS) was greater in the diphenhydramine group compared to the cetirizine group (median ΔSSS 2 (IQR 3.25) vs median ΔSSS 0 (IQR 1), p < 0.01) when measured one hour after the administration of the premedication. Patient self-assessed moderate or intense discomfort caused by drowsiness was exclusively reported in the diphenhydramine group, by 4 out of 13 participants. Conclusions: The trial methods were feasible in terms of recruitment rate, retention and patient safety. IRR were infrequent and a larger trial is warranted to confirm non-inferiority for IRR prevention. Cetirizine was significantly less sedating than diphenhydramine when administered as premedication to prevent paclitaxel-associated IRR. Clinical trial information: NCT04237090. [Table: see text]

Dosimetry Analysis in Non-brain Tissues During TMS Exposure of Broca’s and M1 Areas

For human protection, the internal electric field is used as a dosimetric quantity for electromagnetic fields lower than 5–10 MHz. According to international standards, in this frequency range, electrostimulation is the main adverse effect against which protection is needed. One of the topics to be investigated is the quantification of the internal electric field threshold levels of perception and pain. Pain has been reported as a side effect during transcranial magnetic stimulation (TMS), especially during stimulation of the Broca’s (speech) area of the brain. In this study, we designed an experiment to conduct a dosimetry analysis to quantify the internal electric field corresponding to perception and pain thresholds when targeting the Broca’s and M1 areas from magnetic stimulator exposure. Dosimetry analysis was conducted using a multi-scale analysis in an individualized head model to investigate electrostimulation in an axonal model. The main finding is that the stimulation on the primary motor cortex has higher perception and pain thresholds when compared to Broca’s area. Also, TMS-induced electric field applied to Broca’s area exhibited dependence on the coil orientation at lower electric field threshold which was found to be related to the location and thickness of pain fibers. The derived dosimetry quantities provide a scientific rationale for the development of human protection guidelines and the estimation of possible side effects of magnetic stimulation in clinical applications.

Sedative effects of acepromazine in combination with nalbuphine or butorphanol, intramuscularly or intravenously, in healthy cats: a randomized, blinded clinical trial

Objectives The aim of this study was to compare the sedative effects in cats administered acepromazine–nalbuphine and acepromazine–butorphanol, intramuscularly (IM) and intravenously (IV), and the occurrence of adverse cardiorespiratory effects. Methods Forty-six cats were randomly divided into four groups and administered acepromazine (0.05 mg/kg) combined with nalbuphine (0.5 mg/kg) or butorphanol (0.4 mg/kg), IV (ACP-NALIV and ACP-BUTIV groups, respectively) or IM (ACP-NALIM and ACP-BUTIM groups, respectively). Sedation scores, ease of intravenous catheter placement (simple descriptive scale [SDS] scores), physiologic variables, venous blood gases and the propofol dose required for anesthetic induction were recorded. Results Mild sedation was observed in all groups approximately 30 mins after treatment administration (timepoint T1, prior to propofol administration). Sedation scores at T1 increased above baseline in all groups ( P <0.05), but no significant difference was observed among groups. Dynamic interactive visual analogue scale sedation scores (range 0–100 mm) recorded at T1 were (median [interquartile range]): ACP-NALIM, 12 (10–12); ACP-NALIV, 11 (6–16); ACP-BUTIM, 11 (7–14); and ACP-BUTIV, 12 (7–19). Overall, SDS scores did not change from baseline at T1 and there was no significant difference among groups. The propofol dose did not differ among groups. Blood gases remained within the reference intervals for cats. Significant decreases from baseline were detected for all groups in systolic arterial pressure (SAP). Mean ± SD values at T1 were (mmHg): ACP-NALIM, 108 ± 13; ACP-NALIV, 102 ± 10; ACP-BUTIM, 97 ± 13; and ACP-BUTIV, 98 ± 21. Arterial hypotension (SAP <90 mmHg) was recorded at T1 in 0/11, 1/13, 4/11 and 5/11 cats in groups ACP-NALIM, ACP-NALIV, ACP-BUTIM and ACP-BUTIV, respectively, and was further exacerbated after the induction of anesthesia with propofol. Conclusions and relevance In healthy cats administered acepromazine–nalbuphine and acepromazine–butorphanol, IM and IV, the degree of sedation was mild regardless of the protocol and the route of administration. The main adverse effect observed was a reduction in arterial blood pressure.

The Potential Benefits of Renal Replacement Therapy in Combination with a Hemadsorption Column in Critically Ill Patients with Acute on Chronic Liver Failure

Background. Acute on chronic liver failure (AoCLF) represents a life-threatening complication of liver cirrhosis with high mortality if patients cannot be bridged to emergency liver transplantation. The aim of this study was to assess clinical and paraclinical effects of renal replacement therapy (RRT) in combination with a hemadsorption column in patients with AoCLF. Methods. Patients were included in the study after Intensive Care Unit (ICU) admission and RRT in combination with CytoSorb® was started for three consecutive sessions. Clinical and paraclinical data were recorded before the first session and after the end of the third session. 28-days mortality was also noted. Results. Fourteen patients were included in the final data analysis. The use of CytoSorb® was associated with a decrease in bilirubin levels (p = 0.03) and creatinine (p = 0.02) and an increase in urine output (p = 0.02). Although we observed a significant decrease in platelet count (p = 0.05), no haemorrhagic complications were noted. C-Reactive Protein significantly decreased after the therapy (p = 0.05), but we did not observe a similar decrease in leucocyte count (p = 0.87) or procalcitonin levels (p = 0.18). Seven patients underwent emergency liver transplantation and survival was 100% in this group. Conclusion. The use of CytoSorb® was associated with an improvement in liver and renal functions and a decrease in C - Reactive Protein. Thrombocytopenia represents the main adverse effect of the therapy, but no haemorrhagic complications were recorded. In patients that could be bridged to liver transplantation, survival was 100%. Trial registration number: NCT04511507

Ameliorative effect of Cubeba Officinalis dried fruits against Tacrolimus induced nephrotoxicity in Wistar albino rats

Cubeba Officinalis is traditionally effective in the treatment of various kidney ailments, and the main adverse effect of tacrolimus is nephrotoxicity. There is no documented evidence about the ameliorative potential of Cubeba Officinalis in tacrolimus induced nephrotoxicity. The main endeavor of the study was to determine the nephroprotective activity of ethanolic extract of Cubeba Officinalis dried fruits against tacrolimus induced nephrotoxicity in Wistar albino rats. The Cubeba Officinalis dried fruits were collected from the local market, and Male albino rats weighing 200-250 g were used for the study. The dose of is lower 200mg/kg, higher dose 400 mg/kg of test drug (EECO) was used, and silymarin is used as the standard at the dose of 20 mg/kg. The animals were divided into five groups, six animals each, which is started prior to oral administration of tacrolimus and continued with the fourteen days tacrolimus treatment. After the whole period of study, the rats were sacrificed, and histopathological studies and biochemical estimations were carried out. The BUN values were decreased from 33.60±3.84 in nephrotoxic rats to 28.27±2.48 (200mg/kg) and 20.70±0.81 (400mg/kg),creatinine levels from 1.645±0.21 to 0.926±0.19 (200mg/kg) and 0.638±0.07(400 mg/kg),uric acid levels from 1.822±0.249 to 1.092±0.306 (200 mg/kg) and 0.806±0.181 (400 mg/kg) sodium, potassium and chloride levels from 1.607± 0.091, 2.548± 0.293 and 259.8±6.42 to 1.302± 0.169 , 1.023±0.174 and 134.7±9.138 (200mg/kg of EECO) and 0.586±0.092 , 0.831±0.174 and 130.2±2.29 (400mg/kg of EECO). The Ethanolic extract of cubeba officinalis was found to be effective in treating the nephrotoxicity in tacrolimus induced nephrotoxicity.

New Drugs, Old Toxicities: Pneumonitis Related to Palbociclib – A Case Report

Background: Palbociclib is a specific inhibitor of cyclin-dependent kinases 4 and 6 that is approved for the treatment of advanced or metastatic breast cancer patients. Despite a good toxicity profile in pivotal trials, where asymptomatic neutropenia was the main adverse effect, its wider use in clinical practice may show less prevalent but serious toxicities. Case Presentation: Here, we describe a case of pneumonitis due to palbocicblib. A 57-year-old female with breast cancer with bone metastasis presented dyspnea at rest 3 months after beginning treatment with palbociclib and letrozole. Palbociclib-induced pneumonitis was considered the most probable cause after ruling out all alternatives, and the patient was successfully treated with steroids and showed complete remission. Conclusions: In summary, we present a well-documented case report of pneumonitis related to palbociclib. However, the mechanism of toxicity is still unknown, and there are as yet no reliable biomarkers to predict toxicity with cyclin-dependent kinase 4/6 inhibitors. In this case report, we alert physicians about new drugs that can provoke old toxicities.

Design of a Repellent Against Aedes aegypti (Diptera: Culicidae) Using in silico Simulations With AaegOBP1 Protein

Skin irritation has been reported to be the main adverse effect of excessive use of N,N-diethyl-m-toluamide (DEET) and ethyl 3-acetyl(butyl)amino (IR3535) commercial repellents. Therefore, there is an interest in alternatives of natural origin such as essential oils (EOs) and major compounds, which have repellent effects but have no contraindications. The main purpose of the present study was to identify the repellent effect of selected terpenes on Aedes aegypti Linnaeus, 1762 (Diptera: Culicidae) by in silico analysis based on their affinity with the odorant protein AaegOBP1. The protein-metabolite interactions in 20 terpenes were analyzed using the SwissDock tool. Terpenes presenting the highest affinity compared with commercial repellents were selected to evaluate repellent activity at concentrations 0.1, 10, and 25% against Ae. aegypti. Different periods (0–2, 2–15, 15–60 min) were evaluated with DEET as a positive control. The toxicity of terpenes was verified through Osiris and Molinspiration Cheminformatics Software, and cytotoxicity assays in Vero and HepaRG cells were performed using the MTT method. Two formulations were prepared with polyethylene glycol to evaluate skin long-lasting in vivo assay. The results showed four terpenes: geranyl acetate, nerolidol, α-bisabolol, and nerol, with affinity to AaegOBP1 comparable with DEET and IR3535. Geranyl acetate, nerolidol, and their mixtures showed no cytotoxicity and protection percentages close to 100% during the test at concentrations 10 and 25%. Long-lasting assays with geranyl acetate and nerolidol formulate showed 3 h as maximum protection time with 100% protection percentage. These metabolites and their mixtures are candidates to repellent formulations with times and protection percentages similar to DEET.