A cross-sectional study in critically ill patients affected by COVID-19 in an intensive care unit: would Acinetobacter baumannii resistant to carbapenems be the biggest villain?

AIM: to describe cases of infection of Acinetobacter baumannii (A. baumannii) in critically ill patients affected by COVID-19, admitted to an intensive care unit (ICU), using dexamethasone. METHODOLOGY: cross-sectional study conducted on patients admitted to the intensive care unit COVID-19 survey among hospitalized patients from November 2020 to March 2021. SETTING: large hospital, reference for caring for patients with COVID-19 in Bahia (Brazil). PATIENTS: a convenience sample of 22 patients admitted to the COVID ICU signed the consent form agreeing to participate in the study. Three patients were excluded for having decided to participate without signing the form. RESULTS: of the 22 patients listed, 45 % (10) had blood infection or mechanical ventilation-associated pneumonia by A. baumannii in blood cultures and/or tracheal aspirate secretion. We observed that there is a moderate correlation between the length of stay and infection by A. baumannii (Spearman's ρ; 0.592; p-value<0.005) and a strong correlation between the number of days on mechanical ventilation and infection by these bacteria (Spearman's ρ; 0.740; p-value<0.001). This percentage is higher than the value of 0.62 % of infection by A. baumannii in this ICU in the same period of the year before COVID-19 (p-value<0.0001). CONCLUSIONS: hospitals that receive patients with COVID-19 may be vulnerable to outbreaks of multi-drug resistant organisms, such as A. baumannii . It is worth reflecting on the care and operational practices in handling these patients, especially in isolation and restriction measures for those from other nosocomial areas.

Coumarins from Rutaceae: Chemical diversity and biological activities.

Rutaceae is a family expressed by approximately 2100 species distributed in 154 genera widespread in tropical and temperate regions of Australasia, America, and South Africa. Substantial species of this family are employed as folk medicines. The literature describes the Rutaceae family as a great source of natural and bioactive compounds like terpenoids, flavonoids, and, especially, coumarins. To data, 655 coumarins were isolated and identified from Rutaceae in the past twelve years and, most of them, showed different biological and pharmacological activities. There are studies with coumarins from Rutaceae indicating that these compounds showed activity against cancer, inflammation, infectious diseases, and in the treatment of endocrinal and gastrointestinal conditions. Although coumarins are considered versatile bioactive molecules, until the present, there is no compiled information about coumarins from the Rutaceae family demonstrating the potency of these compounds in all dimensions and chemical similarities among the genera. The present review covers the relevant studies dealing with isolation of Rutaceae coumarins from 2010 until 2022 and outlines the current data on pharmacological activities these coumpounds. Additionally, the chemical disposition and similarity among Rutaceae genera are also statistically discussed employing PCA and HCA methods.

A pilot study of chemotherapy combinations in rats: Focus on mammary cancer treatment in female dogs.

The use of combined chemotherapy is an essential alternative in treating breast cancer. However, knowledge of the pharmacokinetics of drugs is necessary to obtain maximum efficiency of the protocol and reduce adverse reactions. This study suggests for the first time the effect of the association of carboplatin with ivermectin and carboplatin with cyclophosphamide. This investigation was performed with 36 healthy Wistar rats, divided into four groups: group control, carboplatin (C), carboplatin preceded by ivermectin (C + IV), and carboplatin associated with cyclophosphamide (C + CI). Plasma concentrations quantification was performed using the High-Performance Liquid Chromatographic (HPLC) equipment with an Ultraviolet (UV) detector at eight different time points. Then, the animal was euthanized and necropsied. The bioanalytical method was validated for the two matrices (dogs and rats' plasma), with full validation in female dogs and partial validation in rats, as recommended by the EMA. In both matrices, the method was linear and reproducible. Here, we show the results in female rats' plasma. When comparing the experimental rats' groups (C; C + IV, and C + CI), there is a tendency to increase the bioavailability of carboplatin when used in association, a slight increase for C + IV and more evident to the C + CI group with an AUC rise higher than 2-fold (AUC0-∞ = 2983.61 for C; 4459.06 for C + CI; 7064.68 for C + CI min·mg·mL-1). The blood count, biochemistry profile, and histopathology of the organs revealed only alterations inherent to the metabolic effects of the drugs used. The carboplatin association with ivermectin appeared safe for this pilot group. We believe the carboplatin dose can be maintained without risk to the patient. However, in the carboplatin association with cyclophosphamide, a slight reduction in carboplatin's amount is suggested, seeking to avoid increased effects due to cyclophosphamide. Thus, studies with a more significant number per group must confirm the relevance of this pilot study.

Hecogenin and its derivates: A pharmacology review.

Despite the several uses of drugs from natural compounds in the pharmaceutical industry, new molecules have been discovered and associated with pharmacological activities over the years. Hecogenin, a steroidal saponin, has been the subject of several studies due to reports of pharmacological activities. This study combines the articles published to date that show the pharmacological activity and the mechanism of action of hecogenin, its acetate, and its derivates. This compilation shows that the compounds can act in different pathologies that affect many systems of the human body. They showed pharmacological properties in inflammation, mediating cytokines, cells, and environment. Also, it participated in tumoral processes by pathways like PPGARγ, ERK½, and MMP-2 and showed antimicrobial effects against organisms like Candida and Aedes aegypti's larvae. This review indicates that continuing studies with these molecules are essential once they have the potential to be a future drug.

Pharmacokinetic/Pharmacodynamic Modeling and Application in Antibacterial and Antifungal Pharmacotherapy: A Narrative Review.

Pharmacokinetics and pharmacodynamics are areas in pharmacology related to different themes in the pharmaceutical sciences, including therapeutic drug monitoring and different stages of drug development. Although the knowledge of these disciplines is essential, they have historically been treated separately. While pharmacokinetics was limited to describing the time course of plasma concentrations after administering a drug-dose, pharmacodynamics describes the intensity of the response to these concentrations. In the last decades, the concept of pharmacokinetic/pharmacodynamic modeling (PK/PD) emerged, which seeks to establish mathematical models to describe the complete time course of the dose-response relationship. The integration of these two fields has had applications in optimizing dose regimens in treating antibacterial and antifungals. The anti-infective PK/PD models predict the relationship between different dosing regimens and their pharmacological activity. The reviewed studies show that PK/PD modeling is an essential and efficient tool for a better understanding of the pharmacological activity of antibacterial and antifungal agents.

Population Pharmacokinetics of Magnesium Sulfate in Preeclampsia and Associated Factors.

BACKGROUND AND OBJECTIVE: The pharmacokinetic basis of magnesium sulphate (MgSO4) dosing regimens for preeclampsia (PE) prophylaxis and treatment is not clearly established. The aim of study is to develop a population pharmacokinetic (PK) model of MgSO4 in PE, and to determine key covariates having an effect in MgSO4 pharmacokinetics in preeclampsia (PE) and to determine key covariates having an effect in MgSO4 PK. METHODS: A prospective cohort study was conducted from June 2016 to February 2018 in patients with PE administered MgSO4 as a 4-g bolus followed by continuous infusion at a rate of 1 g/h. Serum magnesium concentrations were obtained before treatment administration and 2, 6, 12, and 18 h after the initial dose. The software Monolix was used to estimate population PK parameters of MgSO4 [clearance (CL), volume of distribution (V), half-life] and to develop a PK model with baseline patient demographic, clinical, and laboratory covariates. RESULTS: The study population consisted of 109 patients. The PK profile of MgSO4 was adequately described by a one-compartment PK model. The model estimate of the population CL was 1.38 L/h; for V, it was 13.3 L; and the baseline magnesium concentration was 0.77 mmol/L (1.87 mg/dL). The baseline body weight and serum creatinine statistically influenced MgSO4 CL and V, respectively. The model was parameterized as CL and V. CONCLUSION: The PK of MgSO4 in pregnant women with PE is significantly affected by creatinine and body weight. Pregnant women with PE and higher body weight have a higher V and, consequently, a lower elimination rate of MgSO4. Pregnant women with PE and a higher serum creatinine value show lower CL and, therefore, lower MgSO4 elimination rate.

Detection of allopurinol and oxypurinol in canine urine by HPLC/MS-MS: Focus on veterinary clinical pharmacokinetics.

Allopurinol is the most commonly used drug for the treatment of hyperuricemia in people, and in view of the risks of fatal hypersensitivity in patients with renal dysfunction, doses based on the glomerular filtration rate are proposed. In veterinary medicine, allopurinol is used in the treatment of canine leishmaniasis (CanL) caused by Leishmania infantum owing to the drug action of inhibiting the parasite's RNA synthesis. However, renal dysfunction frequently ensues from disease progression in dogs. The purpose of the present study was to standardize and validate a sensitive high-performance liquid chromatography-mass spectrometric (HPLC-MS/MS) method to determine the concentration of allopurinol and its active metabolite oxypurinol in canine urine for clinical pharmacokinetic investigation. Urine samples of eleven (11) dogs with naturally occurring CanL and in the maintenance phase of the treatment with alopurinol were used. For the chromatographic analysis of urine, the mobile phase consisted of a solution of 0.1 % formic acid (88 %) in 10 mM ammonium acetate. Separation of allopurinol and oxypurinol occurred in a flow of 0.8 mL/min on a C8 reverse phase column 5 µm, and acyclovir was the internal standard. The HPLC-MS/MS method was validated by reaching the limits of detection and quantification, reproducibility and linearity. The lower limit of quantification achieved by the method was 10 µg/mL for both allopurinol and oxypurinol. Calibration curves were prepared in blank urine added with allopurinol at concentrations of 10-1000 µg/mL, and oxypurinol at 10-200 µg/mL. Coefficients of variation of less than 15 % between intracurrent and intercurrent accuracy values were observed for both allopurinol and oxypurinol. Urine test samples remained stable after being subjected to freeze-thaw cycles and remaining at room temperature for 4 h. The method proved to be adequate to quantify allopurinol and oxypurinol in urine samples from dogs under treatment.

Incidence of Adverse Drug Reactions in High-Risk Pregnancy: A Prospective Cohort Study in Obstetric Intensive Care.

PURPOSE: To estimate the cumulative incidence of adverse drug reactions (ADRs) in women with high-risk pregnancy hospitalized in an obstetric intensive care unit, then to describe the medicines involved and to identify major risk factors. METHODS: From June 2016 to December 2017, patients admitted to the ICU with high-risk pregnancy were considered eligible in this observational, longitudinal, prospective study. Patients were investigated daily for the occurrence of ADRs through pharmaceutical anamnesis, active search in medical records and questioning of the health team. Suspected ADRs were classified according to Naranjo's algorithm. Written informed consent was obtained from all patients. Univariate and multivariate logistic regression were used to identify risk factors of ADR. RESULTS: The study population consisted of 607 high-risk pregnancies from 851 women admitted to the ICU, of whom 244 admitted for non-obstetric conditions, with an ICU stay less than 24 h or readmitted to the ICU were excluded. The mean age was 27.0 ± 7.5 years-old, mean gestational age was 33.8 ± 6.3 weeks. ADR were observed in 165 women (27.2%). No severe ADR was observed and 29.7% were of moderate severity. The most often implicated medicine was magnesium sulphate (25.2%) with 44.5% of patients administered that substance experiencing ADRs consisting of somnolence (68.6%), absent patellar reflex (21.6%) and hypotension (9.8%). Risk factors of ADR were blood pressure (adjusted odds-ratio (aOR) 1.02), haemoglobin level (aOR 1.21) and body temperature (aOR 0.71). CONCLUSIONS: ADRs affect about one third of high-risk pregnancies, mainly due to magnesium sulphate administrations. High blood pressure, lower body temperature, and high haemoglobin concentration on admission were associated with an increased risk of ADR.

Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution.

1. LASSBio-1736 ((E)-1-4(trifluoromethyl) benzylidene)-5-(2-4-dichlorozoyl) carbonylhydrazine) is proposed to be an oral cysteine protease leishmanicidal inhibitor. 2. This work aimed to investigate plasma pharmacokinetics, protein binding and tissue distribution of LASSBio-1736 in male Wistar rats. 3. LASSBio-1736 was administered to male Wistar rats at doses of 3.2 mg/kg intravenously and 12.6 mg/kg oral and intraperitoneal. The individual plasma-concentration profiles were determined by HPLC-UV and evaluated by non-compartmental and population pharmacokinetic analysis (Monolix 2016R1, Lixoft). Tissue distribution was evaluated after iv injection of 3.2 mg/kg drug by non-compartmental approach. 4. After intravenous administration, Vdss (1.79 L/kg), t ½ (23.1 h) and CLtot (56.1 mL/h/kg) were determined, and they were statistically similar (α =0.05) to oral and intraperitoneal pharmacokinetic parameters. The plasma profiles obtained after intravenous, oral and intraperitoneal administration of the compound were best fitted to a three-compartment and one-compartment open model with first-order absorption. 5. The intraperitoneal and oral bioavailability were around 40 and 15%, respectively. 6. Liver, spleen and skin tissues showed penetration of 340, 130 and 40%, respectively, with t ½ like plasma values. 7. LASSBio-1736 protein binding was 95 ± 2%. 8. The t ½, CLtot and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity.

Does the Anesthetic Urethane Influence the Pharmacokinetics of Antifungal Drugs? A Population Pharmacokinetic Investigation in Rats.

The aim of this paper was to analyze the impact of anesthesia induced by urethane on pharmacokinetics (PK) parameters of fluconazole (FCZ), mostly eliminated via renal excretion and voriconazole (VRC), eliminated mainly by hepatic metabolism. FCZ and VRC PK were investigated after administration of 10 mg/kg i.v. and 5 mg/kg i.v. doses to awake and urethane anesthetized Wistar rats (n = 6 per group), respectively. After dosing, blood samples were collected up to 18 h (FCZ) or 12 h (VRC) and the plasma data analysis was performed using the software MONOLIX v. 4.2.2. The population PK parameters and microconstants were determined by fitting plasma concentration-time profiles to two-compartment model for FCZ and three-compartment model for VRC. Fitting of FCZ plasma profiles after dosing to awake and anaesthetized animals resulted in a volume of distribution (V) of 9.3 and 8.1 L/kg, and k10 values of 0.12 and 0.14 h(-1) , respectively. VRC plasma profiles in awake and anaesthetized showed V 8.7 of and 7.6 L/kg, and k10 of 0.15 and 0.16 h(-1) , respectively. No statistical differences between plasma PK parameters and microconstants for the same drug in both animal conditions studied were observed (α = 0.05).

Role of microdialysis in pharmacokinetics and pharmacodynamics: current status and future directions.

Diagnostic and therapeutic decisions in medical practice are still generally based on blood concentrations of drugs and/or biomolecules despite the knowledge that biochemical events and pharmacological effects usually take place in tissue rather than in the bloodstream. Microdialysis is a semi-invasive technique that is able to measure concentrations of the free, active drug or endogenous compounds in almost all human tissues and organs. It is currently being used to monitor brain metabolic processes and quantify tissue biomarkers, and determine transdermal drug distribution and tissue pharmacokinetics, confirming its importance as a widely used sampling technique in clinical drug monitoring and drug development as well as therapy and disease follow-up, contributing to rationalizing drug dosing regimens and influencing the clinical decision-making process.

Comparison of fluconazole renal penetration levels in healthy and Candida albicans-infected Wistar rats.

The aims of this study were to evaluate free levels of fluconazole (FCZ) in the kidneys of healthy and Candida albicans-infected Wistar rats using microdialysis and to establish the relationship between free renal and total plasma levels under both conditions. Microdialysis recovery rates were determined in vitro by dialysis, and retrodialysis recovery rates were determined in vivo by retrodialysis. The recovery rate was around 50%, independent of the method, drug concentration, or condition (in vitro or in vivo) used. FCZ kidney penetration in healthy and infected rats was investigated after the administration of 10 mg/kg of body weight intravenously (i.v.) or 50 mg/kg orally (n = 6/group) and blood and microdialysate sample harvesting at predetermined time points up to 24 and 18 h, respectively. There were no statistical differences between the area under the free concentration-time curve (AUC(0-∞)) values in plasma and in tissue for either healthy or infected groups for the same dose regimen investigated. The antifungal tissue penetrations were similar for both doses and under all conditions investigated (ranging from 0.77 to 0.84). The unbound fraction of FCZ was concentration independent (86.0% ± 2.0%), allowing the prediction of free renal levels using pharmacokinetic parameters obtained from total plasma fitting. The results showed that free renal and free plasma levels are similar in healthy and systemically C. albicans-infected rats. Therefore, free plasma levels are a good surrogate to estimate free FCZ renal concentrations in systemic candidiasis and can be used to optimize dosing regimens for this drug.

Pre-clinical pharmacokinetics evaluation of an anticonvulsant candidate benzaldehyde semicarbazone free and included in beta-cyclodextrin.

The study aimed to investigate the pharmacokinetics and tissue distribution of the benzaldehyde semicarbazone (BS) a potential antiepileptic drug, administered as a free drug or complexed beta-cyclodextrin (BS/beta-CD). Free BS and BS/beta-CD were administered to male Wistar rats as a 10mg/kg intravenous bolus dose. For the oral route, 50mg/kg and 100mg/kg doses of the free drug and 50mg/kg of the complex were administrated and plasma concentrations were determinated by a validated HPLC-UV method. Individual profiles were evaluated by non-compartmental and compartmental analysis using Excel and Scientist, respectively. Free BS plasma protein binding was 34+/-5%. A one-compartmental model adequately described all the plasma profiles for both formulations. After intravenous (10mg/kg) and oral (50mg/kg) administration, the V(d) (1.6+/-0.5 and 2.2+/-0.8L/kg, respectively) and the Cl(tot) (1.4+/-0.5 and 1.8+/-0.5L/hkg, respectively) determinated for the BS/beta-CD complex were higher than those obtained for the free drug, but the t(1/2) (0.8+/-0.1h) was similar (p<0.05). The oral bioavailability of the BS/beta-CD complex (approximately 37%) was approximately 2-fold of the free BS ( approximately 20%). The higher drug brain penetration (2.8) after BS/beta-CD dosing and the longer mean residence time in this organ, regardless of the administration route, reveals that the complex may be a potential drug carrier for the central nervous system delivery of BS.