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Journal of Clinical Medicine Apr 2024Patients with cystic fibrosis (CF) commonly experience pulmonary exacerbations, and it is recommended by the TOPIC study to treat this with tobramycin at a dose of 10...
Patients with cystic fibrosis (CF) commonly experience pulmonary exacerbations, and it is recommended by the TOPIC study to treat this with tobramycin at a dose of 10 mg/kg once daily. The aim of this study was to evaluate the target attainment of the current dosing regimen. A single-center retrospective cohort study of child and adult patients with CF who received tobramycin between 2019 and 2022 was conducted. Descriptive statistics and linear mixed models were used to assess target attainment for tobramycin. In total, 25 patients (53 courses), of which 10 were children (12 courses) and 15 were adults (41 courses), were included. Those 25 patients all received 10 mg/kg/day. The tobramycin peak concentrations were supratherapeutic in 82.9% and therapeutic in 100.0% of adults and children, respectively. The trough concentrations were outside the target range in 0% and 5.1% of children and adults, respectively. We found lower tobramycin concentrations with the same dose in children compared to adults. This study illustrates the need to validate dosing advice in a real-world setting, as supratherapeutic concentrations of tobramycin were prevalent in adults with CF.
PubMed: 38731170
DOI: 10.3390/jcm13092641 -
Biomedicine & Pharmacotherapy =... May 2024The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit...
The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity. Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety. Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation. In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively. Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method. Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers. For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.
PubMed: 38713939
DOI: 10.1016/j.biopha.2024.116686 -
Journal of the American College of... Jun 2024Phenobarbital (PB) is a long-acting GABA A-agonist with favorable pharmacokinetics (long half-life and duration of effect) that allows effective treatment of alcohol...
OBJECTIVES
Phenobarbital (PB) is a long-acting GABA A-agonist with favorable pharmacokinetics (long half-life and duration of effect) that allows effective treatment of alcohol withdrawal (AW) after administration of a single loading dose. Current evidence suggests that in the setting of AW, PB administration may be associated with decreased hospital admissions and hospital length of stay. The aim of this study was to evaluate the safety outcomes of AW patients who were treated and discharged from the emergency department (ED) after receiving PB for AW.
METHODS
This retrospective chart review included a convenience sample of 33 AW patients who presented to four EDs within an 18-month span. Descriptive statistics (frequencies and percentages) were used to describe demographics, distribution of resources and referrals, and the safety outcomes of PB administration for low-risk AW patients. Patients were selected for inclusion in consultation with a medical toxicologist, treated with PB, and discharged from the ED. Electronic medical records were utilized to gather information on the patient cohort.
RESULTS
All patients were treated with at least a single loading dose of 5‒10 mg/kg (ideal body weight) of intravenous or per os PB during their ED stay. Only one patient had an unanticipated event after discharge, which was related to driving against advice. Two additional patients had ED revisits for recurrent alcohol use within 72 h, and 16 patients had recurrent alcohol use within 30 days. All 33 patients were provided with resources for linkage to treatment. None required hospital admission.
CONCLUSION
ED PB "load and go" may be a safe, effective AW treatment that could help treat AW, facilitate linkage to specific rehabilitation treatments, and decrease hospital admissions.
PubMed: 38707981
DOI: 10.1002/emp2.13178 -
BMC Medical Research Methodology Apr 2024This retrospective analysis aimed to comprehensively review the design and regulatory aspects of bioequivalence trials submitted to the Saudi Food and Drug Authority...
BACKGROUND
This retrospective analysis aimed to comprehensively review the design and regulatory aspects of bioequivalence trials submitted to the Saudi Food and Drug Authority (SFDA) since 2017.
METHODS
This was a retrospective, comprehensive analysis study. The Data extracted from the SFDA bioequivalence assessment reports were analyzed for reviewing the overall design and regulatory aspects of the successful bioequivalence trials, exploring the impact of the coefficient of variation of within-subject variability (CVw) on some design aspects, and providing an in-depth assessment of bioequivalence trial submissions that were deemed insufficient in demonstrating bioequivalence.
RESULTS
A total of 590 bioequivalence trials were included of which 521 demonstrated bioequivalence (440 single active pharmaceutical ingredients [APIs] and 81 fixed combinations). Most of the successful trials were for cardiovascular drugs (84 out of 521 [16.1%]), and the 2 × 2 crossover design was used in 455 (87.3%) trials. The sample size tended to increase with the increase in the CVw in trials of single APIs. Biopharmaceutics Classification System Class II and IV drugs accounted for the majority of highly variable drugs (58 out of 82 [70.7%]) in the study. Most of the 51 rejected trials were rejected due to concerns related to the study center (n = 21 [41.2%]).
CONCLUSION
This comprehensive analysis provides valuable insights into the regulatory and design aspects of bioequivalence trials and can inform future research and assist in identifying opportunities for improvement in conducting bioequivalence trials in Saudi Arabia.
Topics: Humans; Therapeutic Equivalency; Drugs, Generic; Saudi Arabia; Retrospective Studies; Sample Size
PubMed: 38580928
DOI: 10.1186/s12874-024-02207-4 -
The Journal of Infection Mar 2024Interest in phages as adjunctive therapy to treat difficult infections has grown in the last decade. However, phage dosing and delivery for orthopedic infections have... (Review)
Review
OBJECTIVES
Interest in phages as adjunctive therapy to treat difficult infections has grown in the last decade. However, phage dosing and delivery for orthopedic infections have not been systematically summarized.
METHODS
Following PRISMA-ScR guidelines, we conducted a SCOPING review through September 1st, 2023, of MEDLINE, Embase, Web of Science Core Collection, and Cochrane Central.
RESULTS
In total, 77 studies were included, of which 19 (24.7%) were in vitro studies, 17 (22.1%) were animal studies, and 41 (53.2%) were studies in humans. A total of 137 contemporary patients receiving phage therapy are described.
CONCLUSIONS
Direct phage delivery remains the most studied form of phage therapy, notably in prosthetic joint infections, osteomyelitis, and diabetic foot ulcers. Available evidence describing phage therapy in humans suggests favorable outcomes for orthopedic infections, though this evidence is composed largely of low-level descriptive studies. Several phage delivery devices have been described, though a lack of comparative and in-human evidence limits their therapeutic application. Limitations to the use of phage therapy for orthopedic infections that need to be overcome include a lack of understanding related to optimal dosing and phage pharmacokinetics, bacterial heterogeneity in an infection episode, and phage therapy toxicity.
Topics: Animals; Humans; Phage Therapy; Bacteria; Osteomyelitis; Arthritis, Infectious; Bacterial Infections
PubMed: 38373574
DOI: 10.1016/j.jinf.2024.106125 -
Frontiers in Pharmacology 2024Kaixinsan (KXS) is a noteworthy classical prescription, which consists of four Chinese medicinal herbs, namely Polygalae Radix, Ginseng Radix et Rhizoma, Poria, and... (Review)
Review
Kaixinsan (KXS) is a noteworthy classical prescription, which consists of four Chinese medicinal herbs, namely Polygalae Radix, Ginseng Radix et Rhizoma, Poria, and Acori Tatarinowii Rhizoma. KXS was initially documented in the Chinese ancient book Beiji Qianjin Yaofang written by Sun Simiao of the Tang Dynasty in 652 A.D. As a traditional Chinese medicine (TCM) prescription, it functions to nourish the heart and replenish Qi, calm the heart tranquilize the mind, and excrete dampness. Originally used to treat amnesia, it is now also effective in memory decline and applied to depression. Although there remains an abundance of literature investigating KXS from multiple aspects, few reviews summarize the features and research, which impedes better exploration and exploitation of KXS. This article intends to comprehensively analyze and summarize up-to-date information concerning the chemical constituents, pharmacology, pharmacokinetics, clinical applications, and safety of KXS based on the scientific literature, as well as to examine possible scientific gaps in current research and tackle issues in the next step. The chemical constituents of KXS primarily consist of saponins, xanthones, oligosaccharide esters, triterpenoids, volatile oils, and flavonoids. Of these, saponins are the predominant active ingredients, and increasing evidence has indicated that they exert therapeutic properties against mental disease. Pharmacokinetic research has illustrated that the crucial exposed substances in rat plasma after KXS administration are ginsenoside Re (GRe), ginsenoside Rb1 (GRb1), and polygalaxanthone III (POL). This article provides additional descriptions of the safety. In this review, current issues are highlighted to guide further comprehensive research of KXS and other classical prescriptions.
PubMed: 38362144
DOI: 10.3389/fphar.2024.1338024 -
Drug Metabolism and Disposition: the... Feb 2024Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and academic research. The use of PBPK models is...
Physiologically based pharmacokinetic (PBPK) models of small molecules have become mainstream in drug development and academic research. The use of PBPK models is continuously expanding with the majority of work now focusing on predictions of drug-drug interactions, drug-disease interactions, and changes in drug disposition across lifespan. Recently, publications that use PBPK modeling to predict drug disposition during pregnancy and in organ impairment have increased reflecting the advances in incorporating diverse physiological changes into the models. Due to the expanding computational power and diversity of modeling platforms available, the complexity of PBPK models has also increased. Academic efforts have provided clear advances in better capturing human physiology in PBPK models and incorporating more complex mathematical concepts into PBPK models. Examples of such advances include the segregated gut model with a series gut compartments allowing modeling of physiological blood flow distribution within an organ and zonation of metabolic enzymes, and series compartment liver models allowing simulations of hepatic clearance for high extraction drugs. Despite these advances in academic research, the progress in assessing model quality and defining model acceptance criteria based on the intended use of the models has not kept pace. This review suggests that awareness of the need for predefined criteria for model acceptance has increased but many manuscripts still lack description of scientific justification and/or rationale for chosen acceptance criteria. As artificial intelligence and machine learning approaches become more broadly accepted, these tools offer promise for development of comprehensive assessment for existing observed data and analysis of model performance. PBPK modeling has become a mainstream application in academic literature and is broadly used for predictions, analysis and evaluation of pharmacokinetic data. Many significant advances have been made in developing advanced PBPK models that better capture human physiology but oftentimes sufficient justification for the chosen model acceptance criterion and model structure is still missing. This review provides a summary of the current landscape of PBPK applications used and highlights the needs for advancing PBPK modeling science and training in academia.
PubMed: 38326033
DOI: 10.1124/dmd.123.000960 -
PloS One 2024Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine... (Clinical Trial)
Clinical Trial
Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine administered by an enema has not been clarified in Chinese population. We conducted an open-label study to assess the PK and safety profiles of mesalazine in 11 healthy Chinese subjects after receiving mesalazine enema (1 g/100 mL) once daily for 7 consecutive days. Blood and urine samples were collected for assay of mesalazine and N-acetyl mesalazine by liquid chromatography-tandem mass spectrometry. The PK and safety data were summarized using descriptive statistics. The mean (standard deviation) maximum plasma concentration (Cmax), area under plasma drug concentration-time curve from time 0 to the last measurable plasma concentration time point (AUC0-t) and elimination half-life (t1/2) of mesalazine were 1007.64 (369.00) ng/mL, 9608.59 (3533.08) h·ng/mL and 3.33 (1.99) h, respectively after the first dose administration. In multiple-dose study, the estimated accumulation factor of mesalazine was 1.09. The cumulative urinary excretion rate of parent and major metabolite of mesalazine was 27.77%. After the last doe administration, 2.21% of the administered dose was excreted as mesalazine and 24.47% as N-acetyl mesalazine in urine within 24 h. Overall, 9 adverse events (AEs) were reported in 4 of the 11 subjects (36.4%), including oral ulcer, toothache, upper respiratory tract infection (1 each) and laboratory abnormalities (6 cases). All AEs were mild and recovered spontaneously without treatment, and were not considered as related to mesalazine. Mesalazine enema (1 g/100 mL) was safe and well tolerated in healthy Chinese subjects. These findings support further clinical trials in Chinese patients. Trial registration: This trial was registered to Chinese Clinical Trial Registry (ChiCTR) at https://www.chictr.org.cn (registration number: ChiCTR2300073148).
Topics: Humans; Administration, Oral; Area Under Curve; China; Chromatography, Liquid; Dose-Response Relationship, Drug; Healthy Volunteers; Mesalamine; Tandem Mass Spectrometry
PubMed: 38306390
DOI: 10.1371/journal.pone.0296940 -
Molecular Biology Reports Feb 2024Vascular diseases are the underlying pathology in many life-threatening illnesses. Human cellular and molecular mechanisms involved in angiogenesis are complex and... (Review)
Review
Vascular diseases are the underlying pathology in many life-threatening illnesses. Human cellular and molecular mechanisms involved in angiogenesis are complex and difficult to study in current 2D in vitro and in vivo animal models. Engineered 3D in vitro models that incorporate human pluripotent stem cell (hPSC) derived endothelial cells (ECs) and supportive biomaterials within a dynamic microfluidic platform provide a less expensive, more controlled, and reproducible platform to better study angiogenic processes in response to external chemical or physical stimulus. Current studies to develop 3D in vitro angiogenesis models aim to establish single-source systems by incorporating hPSC-ECs into biomimetic extracellular matrices (ECM) and microfluidic devices to create a patient-specific, physiologically relevant platform that facilitates preclinical study of endothelial cell-ECM interactions, vascular disease pathology, and drug treatment pharmacokinetics. This review provides a detailed description of the current methods used for the directed differentiation of human stem cells to endothelial cells and their use in engineered 3D in vitro angiogenesis models that have been developed within the last 10 years.
Topics: Animals; Humans; Endothelial Cells; Drug Evaluation, Preclinical; Angiogenesis; Pluripotent Stem Cells; Neovascularization, Physiologic; Cell Differentiation
PubMed: 38302762
DOI: 10.1007/s11033-023-09048-2 -
Heliyon Jan 2024Primaquine is metabolized by the cytochrome P450-2D6 enzyme (CYP2D6) to an active primaquine-5,6-orthoquinone (POQ). No relationships of polymorphisms with the...
OBJECTIVES
Primaquine is metabolized by the cytochrome P450-2D6 enzyme (CYP2D6) to an active primaquine-5,6-orthoquinone (POQ). No relationships of polymorphisms with the pharmacokinetics of primaquine and POQ were reported in the Thai population.
METHODS
We evaluated the genetic distribution of in 345 Thai army populations together with the pharmacokinetic profiles of primaquine and POQ in plasma and urine (n = 44, descriptive data are presented in median (range)). All dose-related pharmacokinetic parameters were normalized by primaquine dose per body weight before statistical analysis.
RESULTS
was the allele observed with the highest frequency (56.62%) corresponding to (32.94%) and (27.94%) genotypes. intermediate metabolizers ( IM) were found in 44.41% of the cohort and had an increase in the cumulative amount of primaquine excreted (CAE) in urine compared to normal metabolizers of ( NM); ( IM vs. NM: 2444 (1697-3564) vs. 1757 (1092-2185) μg/mg/kg, p = 0.039), a reduction in urine CAE of POQ ( IM vs NM: 115 (46-297) vs. 318 (92-498) μg/mg/kg, p = 0.047) and a reduction in the POQ/primaquine CAE ratio in urine ( IM vs. NM: 0.06 (0.01-0.11) vs. 0.16 (0.06-0.26), p = 0.009). No significant differences were found in the pharmacokinetic profiles of plasma primaquine and POQ.
CONCLUSIONS
The polymorphisms influenced the changes in primaquine and POQ that were noticeable in the urine, supporting the role of the gene testing before drug administration.
PubMed: 38293439
DOI: 10.1016/j.heliyon.2024.e24351