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Pharmaceuticals (Basel, Switzerland) Jun 2024This study aims to improve the solubility and dissolution rate of alectinib (ALB), a tyrosine kinase inhibitor commonly used for treating non-small-cell carcinoma...
Evaluation of Solubility, Dissolution Rate, and Oral Bioavailability of β-Cyclodextrin and Hydroxypropyl β-Cyclodextrin as Inclusion Complexes of the Tyrosine Kinase Inhibitor, Alectinib.
This study aims to improve the solubility and dissolution rate of alectinib (ALB), a tyrosine kinase inhibitor commonly used for treating non-small-cell carcinoma (NSCLC). Given ALB's low solubility and bioavailability, complexation with β-cyclodextrin (βCD) and hydroxy propyl β-cyclodextrin (HPβCD) was evaluated. Some of the different preparation methods used with varying ALB-to-CD ratios led to the formation of complexes that were characterized using Fourier-Transform Infrared (FTIR) techniques and Differential Scanning Calorimetry (DSC) to prove complex formation. The encapsulation efficiency was also determined. The simulations were carried out for ALB's interactions with βCD and HPβCD. This study identified the most soluble complex (ALB-HPβCD; 1:2 ratio) and evaluated its dissolution. The bioavailability of the ALB-HPβCD complex was evaluated in Wistar rats relative to free ALB. Pharmacokinetic profiles revealed increased Cmax (240 ± 26.95 ng/mL to 474 ± 50.07 ng/mL) and AUC0-48 (5946.75 ± 265 ng.h/mL to 10520 ± 310 ng.h/mL) with no change in the elimination rate constant. In conclusion, the complexation of ALB-HPβCD manages to increase in vitro solubility, the dissolution rate, and oral bioavailability, providing a favorable approach to improving ALB administration.
PubMed: 38931404
DOI: 10.3390/ph17060737 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination,...
Lipophilicity is one of the principal parameters that describe the pharmacokinetic behavior of a drug, including its absorption, distribution, metabolism, elimination, and toxicity. In this study, the lipophilicity and other physicochemical, pharmacokinetic, and toxicity properties that affect the bioavailability of newly synthesized dialkylaminoalkyldiquinothiazine hybrids as potential drug candidates are presented. The lipophilicity, as R, was determined experimentally by the RP-TLC method using RP18 plates and acetone-TRIS buffer (pH 7.4) as the mobile phase. The chromatographic parameters of lipophilicity were compared to computationally calculated partition coefficients obtained by various types of programs such as iLOGP, XLOGP3, WLOGP, MLOGP, SILCOS-IT, LogP, logP, and milogP. In addition, the selected ADMET parameters were determined in silico using the SwissADME and pkCSM platforms and correlated with the experimental lipophilicity descriptors. The results of the lipophilicity study confirm that the applied algorithms can be useful for the rapid prediction of logP values during the first stage of study of the examined drug candidates. Of all the algorithms used, the biggest similarity to the chromatographic value (R) for certain compounds was seen with iLogP. It was found that both the SwissADME and pkCSM web tools are good sources of a wide range of ADMET parameters that describe the pharmacokinetic profiles of the studied compounds and can be fast and low-cost tools in the evaluation of examined drug candidates during the early stages of the development process.
PubMed: 38931392
DOI: 10.3390/ph17060725 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant...
Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant challenge in its utilization as an effective treatment for managing Parkinson's disease (PD). The utilization of lipid nanoparticles can be a promising approach to overcome the limitations of BCR bioavailability. The aim of the research work was to develop and evaluate bromocriptine-loaded solid lipid nanoparticles (BCR-SLN) and bromocriptine-loaded nanostructured lipid carriers (BCR-NLC) employing the Box-Behnken design (BBD). BCR-SLNs and BCR-NLCs were developed using the high-pressure homogenization method. The prepared nanoparticles were characterized for particle size (PS), polydispersity index (PDI), and entrapment efficiency (EE). In vitro drug release, cytotoxicity studies, in vivo plasma pharmacokinetic, and brain distribution studies evaluated the optimized lipid nanoparticles. The optimized BCR-SLN had a PS of 219.21 ± 1.3 nm, PDI of 0.22 ± 0.02, and EE of 72.2 ± 0.5. The PS, PDI, and EE of optimized BCR-NLC formulation were found to be 182.87 ± 2.2, 0.16 ± 0.004, and 83.57 ± 1.8, respectively. The in vitro release profile of BCR-SLN and BCR-NLC showed a biphasic pattern, immediate release, and then trailed due to the sustained release. Furthermore, a pharmacokinetic study indicated that both the optimized BCR-SLN and BCR-NLC formulations improve the plasma and brain bioavailability of the drug compared to the BCR solution. Based on the research findings, it can be concluded that the BCR-loaded lipid nanoparticles could be a promising carrier by enhancing the BBB penetration of the drug and helping in the improvement of the bioavailability and therapeutic efficacy of BCR in the management of PD.
PubMed: 38931387
DOI: 10.3390/ph17060720 -
Pharmaceuticals (Basel, Switzerland) May 2024Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some...
BACKGROUND
Amiodarone is an anti-arrhythmic drug that has extensive tissue distribution and substantial storage in the fat tissue. Different studies have described some implications of body fat composition in its pharmacokinetics and pharmacodynamics. However, no clinical studies have described its implications for clinical efficacy.
METHODS
We studied 878 patients with persistent atrial fibrillation (AF) treated with a regimen of amiodarone and referred to electrical cardioversion (ECV), included prospectively in two Spanish registries. We analyzed the influence of body mass index (BMI), as well as overweight and obesity, in the efficacy of amiodarone for achieving pharmacologic cardioversion to sinus rhythm (SR) before ECV.
RESULTS
A total of 185 patients (21.1%) reverted to SR before ECV. Patients who reverted to SR had a lower BMI than those who did not revert (27.45 ± 4.36 kg/m vs. 29.11 ± 4.09 kg/m; < 0.001). We observed a progressively lower probability of reverting to SR in overweight and obese patients (normal weight 28.3%, overweight 21.3%, obesity 13.1%; < 0.001). In the logistic regression, BMI (kg/m) adjusted for other related variables remained as the main factor inversely related to reversion to SR (OR = 0.904 × kg/m); CI 75% 0.864-0.946).
CONCLUSIONS
We observed a negative relationship between an increased BMI and the efficacy of amiodarone for reversion to SR, suggesting a negative clinical impact of excess body fat in its efficacy.
PubMed: 38931360
DOI: 10.3390/ph17060693 -
Pharmaceuticals (Basel, Switzerland) May 2024The purpose of this paper was to investigate the anti-inflammatory and anti-angiogenic activities of sulfated polysaccharide from (PCT) using carrageenan (CARR)-induced...
The purpose of this paper was to investigate the anti-inflammatory and anti-angiogenic activities of sulfated polysaccharide from (PCT) using carrageenan (CARR)-induced paw edema in a rat model and anti-vasculogenic activity on a chorioallantoic membrane assay (CAM) model. Based on in vitro tests of anti-radical, total antioxidant, and reducing power activities, PCT presents a real interest via its antioxidant activity and ability to scavenge radical species. The in vivo pharmacological tests suggest that PCT possesses anti-inflammatory action by reducing paw edema and leukocyte migration, maintaining the redox equilibrium, and stabilizing the cellular level of several pro-/antioxidant system markers. It could significantly decrease the malondialdehyde levels and increase superoxide dismutase, glutathione peroxidase, and glutathione activities in local paw edema and erythrocytes during the acute inflammatory reaction of CARR. PCT pretreatment was effective against DNA alterations in the blood lymphocytes of inflamed rats and reduced the hematological alteration by restoring blood parameters to normal levels. The anti-angiogenic activity results revealed that CAM neovascularization, defined as the formation of new vessel numbers and branching patterns, was decreased by PCT in a dose-dependent manner, which supported the in silico bioavailability and pharmacokinetic findings. These results indicated the therapeutic effects of polysaccharides from and their possible use as anti-proliferative molecules based on their antioxidant, anti-inflammatory, and anti-angiogenic activities.
PubMed: 38931340
DOI: 10.3390/ph17060672 -
Pharmaceuticals (Basel, Switzerland) May 2024Dasatinib is one of the tyrosine kinase inhibitors. The main use of these agents is inhibition of cancerous cell proliferation. The therapeutic importance of tyrosine...
BACKGROUND AND OBJECTIVES
Dasatinib is one of the tyrosine kinase inhibitors. The main use of these agents is inhibition of cancerous cell proliferation. The therapeutic importance of tyrosine kinase inhibitors raises the necessity of many types of investigations, especially the pharmacokinetic analysis of these drugs in humans. This analysis, along with other investigations and clinical research, will contribute to the overall knowledge of the drug. This study focused on the population pharmacokinetics of dasatinib. The objective of the study was to investigate the sources of the variability of dasatinib in a population pharmacokinetics study in healthy participants.
METHODS
We utilized 4180 plasma observations from 110 subjects who were administered SPRYCEL on two separate occasions under fasting conditions; data from 20% of the subjects (22 subjects) were extracted for the purpose of internal model evaluation and data from 88 subjects were used in modeling. The model was evaluated by visual predictive check of three different datasets. A two-compartmental model with first order absorption and transit compartment was considered the simplest base model to describe the data based on the corrected Bayesian information criterion evaluation. Covariates were tested through conditional sampling for the stepwise approach-screening procedure in Monolix 2020R1 version. Conditional sampling for the stepwise approach was used to include the correlated covariates within the base model in the forward inclusion step and then to eliminate them backwardly to ensure that the key covariates were kept in the model at the final stage.
RESULTS
The effect of body mass index on the absorption rate constant was considered as significant covariate in the final established model. Visual predictive check for simulations, 20% of the original dataset (internal dataset) and an external dataset demonstrated the appropriateness of the final model.
CONCLUSIONS
Population pharmacokinetic modeling was performed to describe dasatinib pharmacokinetics in healthy subjects. Body mass index was considered as a factor that might be used in the future along with studies on patients to adjust the dosing regimens.
KEY POINTS
Dasatinib is classified as a highly variable drug; this variability was demonstrated in the study by the effect of body mass index on the absorption rate constant.
PubMed: 38931339
DOI: 10.3390/ph17060671 -
Pharmaceuticals (Basel, Switzerland) May 2024The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population...
AIMS
The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile.
METHODS
Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges.
RESULTS
A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CL), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM.
CONCLUSIONS
We found that qCRP, CRRT, CL, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.
PubMed: 38931333
DOI: 10.3390/ph17060665 -
Nutrients Jun 2024Abnormal glucose homeostasis is associated with metabolic syndromes including cardiovascular diseases, hypertension, type 2 diabetes mellitus, and obesity, highlighting... (Review)
Review
Abnormal glucose homeostasis is associated with metabolic syndromes including cardiovascular diseases, hypertension, type 2 diabetes mellitus, and obesity, highlighting the significance of maintaining a balanced glucose level for optimal biological function. This highlights the importance of maintaining normal glucose levels for proper biological functioning. Sulforaphane (SFN), the primary bioactive compound in broccoli from the Cruciferae or Brassicaceae family, has been shown to enhance glucose homeostasis effectively while exhibiting low cytotoxicity. This paper assesses the impact of SFN on glucose homeostasis , , and human trials, as well as the molecular mechanisms that drive its regulatory effects. New strategies have been proposed to enhance the bioavailability and targeted delivery of SFN in order to overcome inherent instability. The manuscript also covers the safety evaluations of SFN that have been documented for its production and utilization. Hence, a deeper understanding of the favorable influence and mechanism of SFN on glucose homeostasis, coupled with the fact that SFN is abundant in the human daily diet, may ultimately offer theoretical evidence to support its potential use in the food and pharmaceutical industries.
Topics: Isothiocyanates; Humans; Sulfoxides; Homeostasis; Animals; Glucose; Brassica; Blood Glucose; Biological Availability
PubMed: 38931232
DOI: 10.3390/nu16121877 -
Nutrients Jun 2024Cardiovascular diseases (CVD) are the leading cause of death worldwide, influenced by the interaction of factors, including age, sex, genetic conditions,...
Cardiovascular diseases (CVD) are the leading cause of death worldwide, influenced by the interaction of factors, including age, sex, genetic conditions, overweight/obesity, hypertension, an abnormal lipid profile, vitamin deficiencies, diabetes, and psychological factors. This study aimed to assess the relationships between psychosocial and nutritional factors in a group of 61 patients with CVD (i.e., atherosclerosis, hypertension, ischemic heart disease, and myocardial infarction) and their possible impact on the course of the disease. The plasma concentrations of vitamins A, E, D, and β-carotene were determined using validated HPLC-MS/MS, while the lipid profile was analyzed enzymatically. Psychosocial factors and nutritional behaviors were assessed using author-designed questionnaires. Over 50% of patients had 25-OH-D3 and retinol deficiencies, while >85% of patients exhibited significant deficiencies in α-tocopherol and β-carotene. The lipid profile showed no specific relationship with any particular CVD. Dietary behavior minimally impacted biochemical parameters except for higher β-carotene concentrations in the group with higher fruit and vegetable intake. The negative impact of the CVD on selected parameters of quality of life was noticed. To increase the effectiveness of the prevention and treatment of CVD, the need for interdisciplinary cooperation observed between doctors, psychologists, and specialists in human nutrition seems to be justified.
Topics: Humans; Female; Male; Middle Aged; Cardiovascular Diseases; Aged; Vitamins; Nutritional Status; beta Carotene; Quality of Life; Adult; Vitamin A; Feeding Behavior; Diet; Lipids; Vitamin E
PubMed: 38931221
DOI: 10.3390/nu16121866 -
Plants (Basel, Switzerland) Jun 2024Petitgrain essential oil (PGEO) is derived from the water distillation process on mandarin () leaves. The chemical constituents of PGEO were analyzed by gas...
Petitgrain essential oil (PGEO) is derived from the water distillation process on mandarin () leaves. The chemical constituents of PGEO were analyzed by gas chromatography/mass spectrometry (GC/MS) method which revealed the presence of six compounds (100%). The major peaks were for methyl-N-methyl anthranilate (89.93%) and γ-terpinene (6.25%). Over 19 days, zebrafish (Tubingen strain) received PGEO (25, 150, and 300 μL/L) before induction of cognitive impairment with scopolamine immersion (SCOP, 100 μM). Anxiety-like behavior and memory of the zebrafish were assessed by a novel tank diving test (NTT), Y-maze test, and novel object recognition test (NOR). Additionally, the activity of acetylcholinesterase (AChE) and the extent of the brain's oxidative stress were explored. In conjunction, in silico forecasts were used to determine the pharmacokinetic properties of the principal compounds discovered in PGEO, employing platforms such as SwissADME, Molininspiration, and pKCSM. The findings provided evidence that PGEO possesses the capability to enhance memory by AChE inhibition, alleviate SCOP-induced anxiety during behavioral tasks, and diminish brain oxidative stress.
PubMed: 38931080
DOI: 10.3390/plants13121648