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Drug Delivery Dec 2023Amphotericin B (AmB) is regarded as a first-line therapy against life-threatening invasive fungal infections. Due to its poor oral bioavailability, AmB is restricted to... (Review)
Review
Amphotericin B (AmB) is regarded as a first-line therapy against life-threatening invasive fungal infections. Due to its poor oral bioavailability, AmB is restricted to intravenous administration in clinical practice. As science continues to move forward, two lipid-based formulations are successfully developed for oral AmB administration, currently undergoing phase I clinical trials. Encouragingly, lipid-AmB conjugates with emulsions also exhibit a better bioavailability, which may be another strategy to design oral AmB formulation in clinical practice. Thus, this review mainly focused on the two lipid-based formulations in clinical trials, and discussed the potential perspectives of AmB-lipid conjugation-loaded nanocochleates and emulsions.
Topics: Amphotericin B; Antifungal Agents; Emulsions; Administration, Oral; Anti-Bacterial Agents; Macrolides; Lipids
PubMed: 36601799
DOI: 10.1080/10717544.2022.2161671 -
Journal of Pharmacy & Pharmaceutical... 2018Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic... (Review)
Review
Clearance concepts were introduced into the pharmacokinetics discipline in the 1970s and since then have played a major role in characterization of the pharmacokinetic behavior of drugs. These concepts are based on the relationship between organ extraction ratio or clearance and physiologic parameters such as the organ blood flow and the intrinsic capability of the eliminating organ to remove the free (unbound) drug from the body. Several theoretical models have been developed, which define these relationships and may be used to predict the effects of changes in the physiological parameters on various pharmacokinetic parameters of drugs, such as drug clearance. In this communication, the fundamentals of the two most widely used models of hepatic metabolism, namely the well-stirred (venous equilibrium) and parallel-tube (sinusoidal perfusion) models, are reviewed. Additionally, the assumptions inherent to these models and the differences between them in terms of their predictive behavior are discussed. The effects of changes in the physiologic determinants of clearance on the blood concentration-time profiles of drugs with low and high extraction ratio are also presented using numerical examples. Lastly, interesting and unusual examples from the literature are provided where these concepts have been applied beyond their widely known applications. These examples include estimation of the oral bioavailability of drugs in the absence of otherwise needed intravenous data, differentiation between the role of liver and gut in the first-pass loss of drugs, and distinction between the incomplete absorption and first-pass metabolism in the gastrointestinal tract after the oral administration of drugs. It is concluded that the clearance concepts are a powerful tool in explaining the pharmacokinetics of drugs and predicting the changes in their blood concentration-time courses when the underlying physiologic parameters are altered due to age, disease states, or drug interactions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Administration, Oral; Animals; Biological Availability; Humans; Pharmaceutical Preparations
PubMed: 30041730
DOI: 10.18433/jpps29896 -
Journal of Nuclear Medicine : Official... Apr 2020Intravenous access is difficult in some patients referred for F-FDG PET imaging. Extravasation at the injection site and accumulation in central catheters can lead to... (Clinical Trial)
Clinical Trial
Intravenous access is difficult in some patients referred for F-FDG PET imaging. Extravasation at the injection site and accumulation in central catheters can lead to limited tumor F-FDG uptake, erroneous quantitation, and significant image artifacts. In this study, we compared the human biodistribution and dosimetry for F-FDG after oral and intravenous administrations sequentially in the same subjects to ascertain the dosimetry and potential suitability of orally administered F-FDG as an alternative to intravenous administration. We also compared our detailed intravenous F-FDG dosimetry with older dosimetry data. Nine healthy volunteers (6 male and 3 female; aged 19-32 y) underwent PET/CT imaging after oral and intravenous administration of F-FDG. Identical preparation and imaging protocols (except administration route) were used for oral and intravenous studies. During each imaging session, 9 whole-body PET scans were obtained at 5, 10, 20, 30, 40, 50, 60, 120, and 240 min after F-FDG administration (370 ± 16 MBq). Source organ contours drawn using CT were overlaid onto registered PET images to extract time-activity curves. Time-integrated activity coefficients derived from time-activity curves were given as input to OLINDA/EXM for dose calculations. Blood uptake after orally administered F-FDG peaked at 45-50 min after ingestion. The oral-to-intravenous ratios of F-FDG uptake for major organs at 45 min were 1.07 ± 0.24 for blood, 0.94 ± 0.39 for heart wall, 0.47 ± 0.12 for brain, 1.25 ± 0.18 for liver, and 0.84 ± 0.24 for kidneys. The highest organ-absorbed doses (μGy/MBq) after oral F-FDG administration were observed for urinary bladder (75.9 ± 17.2), stomach (48.4 ± 14.3), and brain (29.4 ± 5.1), and the effective dose was significantly higher (20%) than after intravenous administration ( = 0.002). F-FDG has excellent bioavailability after oral administration, but peak organ activities occur later than after intravenous injection. These data suggest PET at 2 h after oral F-FDG administration should yield images that are comparable in biodistribution to conventional clinical images acquired 1 h after injection. Oral F-FDG is a palatable alternative to intravenous F-FDG when venous access is problematic.
Topics: Administration, Intravenous; Administration, Oral; Adult; Female; Fluorodeoxyglucose F18; Healthy Volunteers; Humans; Male; Radiometry; Young Adult
PubMed: 31628217
DOI: 10.2967/jnumed.119.233288 -
Frontiers in Public Health 2023Correct medicine dosing is an important component in the safe and effective delivery of medicines, particularly for the pediatric population. However, there is a...
BACKGROUND
Correct medicine dosing is an important component in the safe and effective delivery of medicines, particularly for the pediatric population. However, there is a scarcity of public campaigns on the correct administration and choice of dosing aids for oral liquid dosage form in many countries, leading to medicine safety issues and therapeutic failures.
METHODS
The study targeted the assessment of the knowledge and practice of university students. It utilizes pre- and post-intervention surveys administered through google forms as a survey tool during online zoom and in-person sessions. The intervention included a short video presentation detailing the selection and use of medicine spoons and other aids for the administration of oral liquid dosage. The Fischer Exact test was used to assess the pre- and post-test shift of responses.
RESULTS
Nine-degree programs were engaged in the activity, and 108 students attended this health awareness activity after obtaining formal consent. A significant decline (CI = 95%, -value < 0.05) in the choice of selecting tablespoon and a shift to a low-volume spoon, as well as rejection of an entire variety of household spoons, were observed. A significant improvement in the correct naming of spoons, the meaning of the abbreviation "tsp," and the correct volume of a standard teaspoon were also observed with a -value of <0.001.
CONCLUSION
A deficit in the knowledge of the proper use of measuring devices for oral liquid medicines in the educated population was observed, which can be enhanced through simple tools like short video presentations and awareness seminars.
Topics: Humans; Child; Medication Errors; Administration, Oral; Pharmaceutical Preparations; Surveys and Questionnaires; Students
PubMed: 36891337
DOI: 10.3389/fpubh.2023.1084667 -
Archives of Disease in Childhood Feb 1984
Topics: Administration, Oral; Diarrhea, Infantile; Fluid Therapy; Glucose; Humans; Infant; Infant, Newborn; Sucrose; World Health Organization
PubMed: 6703773
DOI: 10.1136/adc.59.2.99 -
BMJ (Clinical Research Ed.) Feb 2007Standardised dosing can improve the safety of prescribing
Standardised dosing can improve the safety of prescribing
Topics: Administration, Oral; Antineoplastic Agents; Humans; Medication Errors
PubMed: 17322214
DOI: 10.1136/bmj.39128.449317.BE -
ALTEX 2019The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data... (Review)
Review
The replacement of animals in acute systemic toxicity testing remains a considerable challenge. Only animal data are currently accepted by regulators, including data generated by reduction and refinement methods. The development of Integrated Approaches to Testing and Assessment (IATA) is hampered by an insufficient understanding of the numerous toxicity pathways that lead to acute systemic toxicity. Therefore, central to our work has been the collection and evaluation of the mechanistic information on eight organs identified as relevant for acute systemic toxicity (nervous system, cardiovascular system, liver, kidney, lung, blood, gastrointestinal system and immune system). While the nervous and cardiovascular systems are the most frequent targets, no clear relationship emerged between specific mechanisms of target organ toxicity and the level (category) of toxicity. From a list of 114 chemicals with acute oral in vivo and in vitro data, 98 were identified with target organ specific effects, of which 93% were predicted as acutely toxic by the 3T3 neutral red uptake cytotoxicity assay and 6% as non-toxic. This analysis will help to prioritise the development of adverse outcome pathways for acute oral toxicity, which will support the assessment of chemicals using mechanistically informed IATA.
Topics: Administration, Oral; Animal Testing Alternatives; Animals; Cell Survival; Drug-Related Side Effects and Adverse Reactions; Toxicity Tests, Acute
PubMed: 30015985
DOI: 10.14573/altex.1805181 -
Ugeskrift For Laeger Nov 2020During the latest decades, the efficacy and safety of an early switch from intravenous to oral antibiotics has been the topic of several investigations. In this review,... (Review)
Review
During the latest decades, the efficacy and safety of an early switch from intravenous to oral antibiotics has been the topic of several investigations. In this review, we summarise the results of studies, which have shown that it is safe to treat mild infections with oral antibiotics only. For more severe infections, three days of intravenous antibiotics followed by oral antibiotics is typically sufficient. There are several benefits of early switch therapy including easier administration and lower expenses. The most frequently prescribed intravenous antibiotics have oral formulations or oral alternatives with a high bioavailability.
Topics: Administration, Intravenous; Administration, Oral; Anti-Bacterial Agents; Humans
PubMed: 33269686
DOI: No ID Found -
Drug Delivery and Translational Research Apr 2021Lipid-based nanocarriers have gained much interest as carriers of drugs with poor oral bioavailability because of their remarkable advantages like low toxicity,... (Review)
Review
Lipid-based nanocarriers have gained much interest as carriers of drugs with poor oral bioavailability because of their remarkable advantages like low toxicity, affordable scale-up manufacture, strong biocompatibility or high drug loading efficiency. The potential of these nanocarriers lies in their ability to improve the gastrointestinal stability, solubility and permeability of their cargo drugs. However, achieving efficient oral drug delivery through lipid-based nanocarriers is a challenging task, since they encounter multiple physicochemical barriers along the gastrointestinal tract, e.g. the gastric acidic content, the intestinal mucus layer or the enzymatic degradation, that they must surmount to reach their target. These limitations may be turned into opportunities through a rational design of lipid-based nanocarriers. For that purpose, this review focuses on the main challenges of the oral route indicating the strategies undertaken for lipid-based nanocarriers in order to overcome them. Understanding their shortcomings and identifying their strengths will determine the future clinical success of lipid-based nanocarriers.
Topics: Administration, Oral; Biological Availability; Drug Carriers; Drug Delivery Systems; Lipids; Nanoparticles
PubMed: 33528830
DOI: 10.1007/s13346-021-00908-7 -
Clinical Drug Investigation Aug 2023Tolebrutinib is a covalent inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be...
BACKGROUND AND OBJECTIVE
Tolebrutinib is a covalent inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be major drivers of inflammation in multiple sclerosis. This excretion balance and metabolism study evaluated the metabolite profile of tolebrutinib in healthy male volunteers.
METHODS
Six healthy volunteers received a 60-mg oral dose of [C]-tolebrutinib, and metabolite profiling of C-labeled metabolites was performed using a combination of liquid chromatography, mass spectrometry, and radioactivity assay methods.
RESULTS
Tolebrutinib was rapidly and completely absorbed from the gastrointestinal tract, followed by rapid and extensive metabolism. Excretion via feces was the major elimination pathway of the administered radioactivity (78%). Tolebrutinib was highly metabolized, with 19 metabolites identified in human plasma. Phase 1 biotransformations were primarily responsible for the circulating metabolites in plasma. Seven metabolites that achieved exposure in plasma similar to or higher than the parent compound were characterized biochemically for inhibition of Bruton's tyrosine kinase activity. Metabolite M8 exceeded the exposure threshold of 10% (18%) of the total radioactivity but had little if any pharmacological activity. Metabolite M2 (4% of circulating radioactivity) retained the ability to irreversibly and potently inhibit Bruton's tyrosine kinase in vitro, similar to the parent compound. Tolebrutinib and metabolite M2 had short (3.5-h) half-lives but durable pharmacodynamic effects as expected for an irreversible antagonist.
CONCLUSIONS
Tolebrutinib was extensively metabolized to multiple metabolites. The hydroxylated metabolite M2 demonstrated similar inhibitory potency toward Bruton's tyrosine kinase as the parent compound. Both tolebrutinib and metabolite M2 likely contributed to pharmacological activity in vivo.
Topics: Humans; Male; Agammaglobulinaemia Tyrosine Kinase; Administration, Oral; Feces; Protein Kinase Inhibitors; Chromatography, Liquid
PubMed: 37642857
DOI: 10.1007/s40261-023-01296-1