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BMC Primary Care Apr 2023Several preventive medications and supplements become inappropriate in the last phase of life due to increased risk of adverse events caused by changed pharmacokinetics,...
BACKGROUND
Several preventive medications and supplements become inappropriate in the last phase of life due to increased risk of adverse events caused by changed pharmacokinetics, drug-drug interactions, and changed care goals. Information on these preventive medication and supplements use in patients with a life-limiting illness in the home-care setting is limited. The primary aim of this study was to assess the use of four different groups of preventive drugs and supplements, which are inappropriate in adult patients with a life-limiting illness, living at home in the last year of life. The secondary aims were to assess reasons for discontinuing these drugs as documented in the general practitioners' patient file and whether these reasons affected the time between medication discontinuation and death.
METHODS
We performed a retrospective cohort study using the routine primary care database of the Julius General Practitioners' Network of the University Medical Centre Utrecht, a database consisting of routine care data from GPs from the city of Utrecht and its vicinity. Patients in the homecare setting with a life-limiting illness, diagnosed at least one year before death, were included. Descriptive analyses were used to describe the study population and the frequency of starting, using, and discontinuing medication and supplements in the last year of life.
RESULTS
A total of 458 of 666 included patients (69%) used at least one preventive drug in the last year of life. Vitamins were used by 36% of the patients, followed with 35% using cholesterol-lowering medication, 24% using calcium supplements and 9% using bisphosphonates. Bisphosphonates were discontinued by 70% of the users, calcium supplements by 61%, vitamins by 56% and cholesterol-lowering medication by 48% of the users, with a median interval between day of discontinuation and death of 119, 60, 110 and, 65 days, respectively. The median time between medication or supplement discontinuation and death was longest in patients with side effects and who had medication reviews.
CONCLUSION
Many patients in their last phase of life in the home-care setting use inappropriate medication and supplements. Timely medication review may contribute to optimise medication use in the last year of life.
Topics: Adult; Humans; Retrospective Studies; Family Practice; Diphosphonates; Vitamins; Cholesterol
PubMed: 37061665
DOI: 10.1186/s12875-023-02049-x -
Nutrients Apr 2023Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and... (Review)
Review
Aging is a multi-faceted process caused by the accumulation of cellular damage over time, associated with a gradual reduction of physiological activities in cells and organs. This degeneration results in a reduced ability to adapt to homeostasis perturbations and an increased incidence of illnesses such as cognitive decline, neurodegenerative and cardiovascular diseases, cancer, diabetes, and skeletal muscle pathologies. Key features of aging include a chronic low-grade inflammation state and a decrease of the autophagic process. The Mediterranean diet has been associated with longevity and ability to counteract the onset of age-related disorders. Extra virgin olive oil, a fundamental component of this diet, contains bioactive polyphenolic compounds as hydroxytyrosol (HTyr) and oleuropein (OLE), known for their antioxidant, anti-inflammatory, and neuroprotective properties. This review is focused on brain, skeletal muscle, and gut microbiota, as these systems are known to interact at several levels. After the description of the chemistry and pharmacokinetics of HTyr and OLE, we summarize studies reporting their effects in in vivo and in vitro models of neurodegenerative diseases of the central/peripheral nervous system, adult neurogenesis and depression, senescence and lifespan, and age-related skeletal muscle disorders, as well as their impact on the composition of the gut microbiota.
Topics: Gastrointestinal Microbiome; Olive Oil; Muscle, Skeletal
PubMed: 37049607
DOI: 10.3390/nu15071767 -
Frontiers in Veterinary Science 2023"Meningoencephalomyelitis of unknown origin" (MUO)-a collective term for a group of clinically-indistinguishable (but pathologically distinct) autoimmune diseases of the... (Review)
Review
"Meningoencephalomyelitis of unknown origin" (MUO)-a collective term for a group of clinically-indistinguishable (but pathologically distinct) autoimmune diseases of the CNS-has become increasingly commonly recognized throughout the world. In the 1960s-1980s the focus was primarily on the pathological description of these conditions and, largely anecdotally, their response to glucocorticoids. The subsequent availability of magnetic resonance imaging for companion animals led to a focus on imaging characteristics and response of MUO to various immunosuppressive medications. Previous reviews have not found clear evidence of superiority of any specific treatment regimen. Here, we review outcomes in a further 671 dogs treated with various combinations of glucocorticoids and immunosuppressive drugs and reported since 2009, aiming to determine whether recommendations can be drawn from the material published during more recent decades. We observe that: (i) there is more complete information on outcome of MUO-affected dogs solely receiving glucocorticoids and these reports provide evidence to undermine the dogma that MUO inevitably requires treatment with glucocorticoids an immunosuppressive drug; (ii) there is far more information on the pharmacokinetics of cytarabine delivered by a variety of routes, revealing that previous dosing and duration of administration in dogs with MUO may not have been optimal; and, (iii) there is a large number of cases that could be available for entry into multi-institutional randomized controlled trials. Finally, we suggest new research avenues that might aid future clinical trials in MUO through improved understanding of etiological triggers and individual patterns of immune response, such as the impact of the gut microbiome, the potential of CSF flow cytometry, and the establishment of robust clinical scores for evaluation of treatment success.
PubMed: 37008358
DOI: 10.3389/fvets.2023.1114798 -
Pharmaceuticals (Basel, Switzerland) Mar 2023Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study...
Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study presents a descriptive analysis of adverse reactions (ADRs) attributed to DOAC dosage errors (overdose, underdose, and improper dose). The analysis was performed based on the Individual Case Safety Reports from the EudraVigilance (EV) database. Results show that data reported for rivaroxaban, apixaban, edoxaban, and dabigatran are mostly regarding underdosing (51.56%) compared to overdosing (18.54%). The most dosage error reports were identified for rivaroxaban (54.02%), followed by apixaban (33.61%). Dabigatran and edoxaban had similar percentages (6.26% and 6.11%, respectively) regarding dosage error reports. Since coagulation issues can become life-threatening events, and factors such as advanced age and renal failure can influence the pharmacokinetics of drugs, the correct usage of DOACs is of utmost importance for the management and prevention of venous thromboembolism. Thus, the collaboration and the complementarity of knowledge of physicians and pharmacists may offer a reliable solution for DOAC dose management and improve patient care.
PubMed: 36986554
DOI: 10.3390/ph16030455 -
PloS One 2023Local production of generic medicines in developing countries has a critical role to meet public health needs by ensuring the availability of essential medicines and...
Health professionals' perceptions on local production and bioequivalence study of generic medicines: A cross-sectional survey of physicians and pharmacy professionals in Addis Ababa, Ethiopia.
Local production of generic medicines in developing countries has a critical role to meet public health needs by ensuring the availability of essential medicines and providing patients' relief from the burden of unaffordable medical bills. Compliance with bioequivalence (BE) requirements increase the quality and competitiveness of generic drugs regardless of the source. In this regard, a regional BE center has been established in Addis Ababa, Ethiopia to serve the needs of Ethiopia and neighbouring countries. The present study aimed to assess the knowledge and perceptions of health professionals working in Addis Ababa regarding local production and BE studies of generic medicines. A cross-sectional survey was employed and physician participants working at public hospitals and pharmacists from various practice settings were selected using convenient sampling technique. Data was collected using self-administered structured questionnaire. Descriptive statistics was used to summarize the data and multinomial logistic regression analyses was used to assess predictors of health professionals' perception towards the source of drugs. Statistically significant association was declared at p-value < 0.05. A total of 416 participants responded and 272 (65.4%) of them were male. Nearly half of the study participants (n = 194) preferred the imported products. Compared to physicians, participants with diploma (AOR = 0.40; 95%CI: 0.18-0.91, p = 0.028) and bachelor degree and above holders (AOR = 0.32; 95%CI: 0.15-0.68, p = 0.003) in pharmacy were more likely to prefer locally produced products. Participants who practiced in pharmaceutical industries (AOR = 0.40, 95%CI: 0.22-0.77, p = 0.006) preferred locally manufactured products as compared to those practicing in the hospital. While a majority (321, 77.2%) believed in the advantages of doing BE studies locally, only 106 (25.5%) recognized that local pharmaceutical manufacturers did not implement BE studies for their generic products and lack of enforcement by the national regulatory body was raised as a reason for not conducting BE studies by most of the participants (67.9%). The present study revealed a modest preference by physicians and pharmacy professionals towards locally produced products. Majority of participants supported the idea of doing BE studies locally. However, manufacturers and regulators should devise ways to increase health professionals' confidence in local products. Strengthening local BE study capacity is also highly recommended.
Topics: Humans; Male; Female; Cross-Sectional Studies; Ethiopia; Drugs, Generic; Therapeutic Equivalency; Physicians; Pharmacy
PubMed: 36972261
DOI: 10.1371/journal.pone.0281665 -
Molecules (Basel, Switzerland) Mar 2023Chlorin e6 (Ce6) is among the most used sensitizers in photodynamic (PDT) and sonodynamic (SDT) therapy; its low solubility in water, however, hampers its clinical...
Chlorin e6 (Ce6) is among the most used sensitizers in photodynamic (PDT) and sonodynamic (SDT) therapy; its low solubility in water, however, hampers its clinical exploitation. Ce6 has a strong tendency to aggregate in physiological environments, reducing its performance as a photo/sono-sensitizer, as well as yielding poor pharmacokinetic and pharmacodynamic properties. The interaction of Ce6 with human serum albumin (HSA) (i) governs its biodistribution and (ii) can be used to improve its water solubility by encapsulation. Here, using ensemble docking and microsecond molecular dynamics simulations, we identified the two Ce6 binding pockets in HSA, i.e., the Sudlow I site and the heme binding pocket, providing an atomistic description of the binding. Comparing the photophysical and photosensitizing properties of Ce6@HSA with respect to the same properties regarding the free Ce6, it was observed that (i) a red-shift occurred in both the absorption and emission spectra, (ii) a maintaining of the fluorescence quantum yield and an increase of the excited state lifetime was detected, and (iii) a switch from the type II to the type I mechanism in a reactive oxygen species (ROS) production, upon irradiation, took place.
Topics: Humans; Serum Albumin, Human; Photosensitizing Agents; Tissue Distribution; Porphyrins; Chlorophyllides; Photochemotherapy; Cell Line, Tumor
PubMed: 36903592
DOI: 10.3390/molecules28052348 -
Scientific Reports Feb 2023The need for more efficient drug delivery strategies with ultraprecision and control over the release of drugs has led to the growth of more sophisticated drug-releasing...
The need for more efficient drug delivery strategies with ultraprecision and control over the release of drugs has led to the growth of more sophisticated drug-releasing systems as a promising alternative to conventional clinical therapies. This new seed of strategies has explored an encouraging property to overcome the inherent problems of traditional therapies. One of the major challenges for any drug delivery system is the introduction of a complete view of the delivery system. In this article, we intend to elucidate the theoretical proof of concept of the electrosynthesis ATN@DNA core-shell like structure as a model system. Therefore, we present a fractal kinetic model (non-exponential model) taking into consideration the concept of time-dependent diffusion coefficient, which was developed using a numerical method with the help of COMSOL Multiphysics. In addition to that, we present here a general fractional kinetic model in sense of the tempered fractional operator, which leads to better characterized memory properties of the release process. Also, the fractional model is compared with the fractal kinetic model and both offer a good description of drug release processes that present anomalous kinetics. The solutions of the fractal and fractional kinetic models are also fitted successfully with our real-release results.
Topics: Atenolol; Drug Delivery Systems; Drug Liberation; Pharmaceutical Preparations; Models, Biological
PubMed: 36813844
DOI: 10.1038/s41598-023-29774-8 -
ADMET & DMPK 2023Increased plasma concentrations of a variety of cellular enzymes (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, amylase, etc.) are commonly...
Increased plasma concentrations of a variety of cellular enzymes (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, amylase, etc.) are commonly used as routine screening tests for a range of conditions. An increased concentration usually is assumed to result from an increased rate of delivery to the plasma. Factors such as decreased metabolism or excretion or altered extravascular distribution usually are ignored. As a prelude to a detailed analysis of all the factors producing altered plasma enzyme levels, we have reviewed the relevant literature describing the pharmacokinetics (PK) of 13 of the commonly measured plasma proteins and developed a PK model that provides a simple physiological description of all the data. Our model starts with the general 3-compartment, 6-parameter system previously developed for albumin and interprets the fluxes in terms of unidirectional sieved protein convectional volume flows from the plasma to the two tissue compartments and equal lymph flows returning to the plasma. This greatly constrains the model such that each protein is characterized by only two adjustable parameters (plasma clearance and sieving factor). In addition to accurately fitting the plasma kinetics, the model can accurately describe the tissue and lymph protein PK. For example, it can describe the thoracic duct lymph protein concentration following an intravenous infusion or the plasma concentration following a subcutaneous tissue injection. This simple model provides a satisfactory framework for the PK of 12 of the 13 proteins investigated. The glycoprotein intestinal alkaline phosphatase is the exception, requiring the addition of a liver recycling compartment involving the asialoglycoprotein receptor.
PubMed: 36778906
DOI: 10.5599/admet.1570 -
Pharmacology Research & Perspectives Feb 2023This study assessed the safety, tolerability, and pharmacokinetics of single and multiple oral doses of DA-8010, a muscarinic M receptor antagonist, in healthy subjects.... (Randomized Controlled Trial)
Randomized Controlled Trial
This study assessed the safety, tolerability, and pharmacokinetics of single and multiple oral doses of DA-8010, a muscarinic M receptor antagonist, in healthy subjects. This was a randomized, double-blind, placebo-controlled, ascending single (Part A: 1, 2.5, 5, 20, and 40 mg QD fasted and 10 mg QD fasted and fed) and multiple doses (Part B: 5, 10, and 20 mg QD from Days 1 to 7 fasted), sequential-group study. Safety data were analyzed descriptively, time to maximum plasma concentration (t ) nonparametrically, and pharmacokinetic parameters using power and mixed models and ANOVA. Of 109 subjects randomized (Part A = 69 and Part B = 40; each part consisted a female group), 31 (44.9%) in Part A and 29 (72.5%) in Part B experienced treatment-emergent adverse events (TEAEs) in a dose-related manner. Common drug-related TEAEs in Part A and B were dizziness (8.7% and 15.0%), headache (5.8% and 12.5%) and blurred vision (8.7% and 20%). One male (20 mg) and one female (10 mg) from Part B discontinued the study due to a confusional state, and nausea and vomiting. Irrespective of sex, DA-8010 was steadily absorbed following single and multiple doses in the fasted state with increased systemic exposure in a dose-proportional manner with maximum plasma concentration occurring at a median t between 4.0 and 6.0 h. A high-fat meal increased systemic exposure. DA-8010 was safe, well tolerated, and well absorbed at lower doses and moderately tolerated at higher doses without any notable effects of food and sex.
Topics: Humans; Male; Female; Healthy Volunteers; Administration, Oral; Area Under Curve; Dizziness
PubMed: 36734627
DOI: 10.1002/prp2.1040 -
Frontiers in Oncology 2022Pembrolizumab is a well-tolerated biologic agent with a potentially stable and durable anti-tumor response. Unfortunately, discontinuation of therapy can occur as a...
BACKGROUND
Pembrolizumab is a well-tolerated biologic agent with a potentially stable and durable anti-tumor response. Unfortunately, discontinuation of therapy can occur as a consequence of immune-related adverse effects (irAEs). These irAEs appear independent of dose and exposure. However, such irAEs might also result from pembrolizumab's highly specific mechanism of action and current dosing regimens. However, the currently available pharmacokinetic (PK) and pharmacodynamic (PD) data to reassess dosing strategies are insufficient.To highlight the importance of additional PK/PD studies, we present a case describing the complexity of pembrolizumab's PK/PD after a single 200 mg pembrolizumab dose in a treatment-naive patient with non-small cell lung cancer (NSCLC).
CASE DESCRIPTION
A 72-year-old man with stage IV NSCLC presented hepatotoxic symptoms 19 days after receiving the first 200 mg pembrolizumab dose. Hence, pembrolizumab therapy was paused, and prednisolone therapy was initiated, which successfully inhibited the toxic effect of pembrolizumab. However, repeated flare-ups due to prednisolone tapering suggest that the toxic effect of pembrolizumab outlasts the presence of pembrolizumab in the bloodstream. This further suggests that the T-cell-mediated immune response outlasts the programmed cell death protein 1 (PD-1) receptor occupancy by pembrolizumab, which challenges the need for the current fixed-interval strategies and their stop criteria.Furthermore, a validated ELISA quantified pembrolizumab levels in 15 samples within 123 days after administration. A shift in the pembrolizumab clearance rate was evident ensuing day 77 (0.6 µg/mL) after administration. Pembrolizumab levels up to day 77 (9.1-0.6 µg/mL) strongly exhibited a linear, first-order clearance (R = 0.991), whereas after day 77, an accelerated non-linear clearance was observed. This transition from a linear to non-linear clearance was most likely a result of full target receptor saturation to non-full target receptor saturation, in which the added effect of target-mediated drug disposition occurs. This suggests that pembrolizumab's targets were fully saturated at levels above 0.6 µg/mL, which is 43 to 61 times lower than the steady-state trough levels (C) of the currently registered fixed-dosing regimens (3-5).
PubMed: 36713570
DOI: 10.3389/fonc.2022.960116