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PloS One 2024Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic...
Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.
Topics: Animals; Mice; Skin Absorption; Caffeine; Drug Compounding; Microfluidics; Administration, Cutaneous; Skin; Models, Theoretical
PubMed: 38603673
DOI: 10.1371/journal.pone.0299501 -
Journal of Clinical Medicine Feb 2024Coronavirus disease 2019 (COVID-19) can manifest with ocular symptoms. These symptoms can be divided into isolated events attributed to COVID-19, and those occurring in...
Coronavirus disease 2019 (COVID-19) can manifest with ocular symptoms. These symptoms can be divided into isolated events attributed to COVID-19, and those occurring in multisystem inflammatory syndrome in children (MIS-C), a newly diagnosed disease entity associated with COVID-19 infection. Currently, the literature lacks specific guidelines and treatment regimens for COVID-19 ocular symptoms, especially in children. The authors present the case of a 14-and-a-half-year-old boy with bilateral uveitis of the anterior and posterior segments along with vasculitis and optic neuritis associated with SARS-CoV-2 infection. The authors also perform an up-to-date review of all available publications on the treatment of post-COVID-19 uveitis in children described in the literature between 2020 and 2023. In the case described by the authors, the treatment involved a Depo-Medrol 40 mg/mL injection uder the Tenon capsule, with two subconjunctival injections of epinephrine, topical steroid therapy and non-steroidal anti-inflammatory drugs: dexamethasone 0.1%; diclofenac eye drops. In addition, acetylsalicylic acid (150 mg) and pentoxifylline (100 mg, orally) were administered throughout the course of the disease as well as up to 12 months after its termination, until a complete improvement in visual acuity and the withdrawal of ocular lesions were achieved. It can be assumed that this type of treatment is far more beneficial for pediatric patients, with an effect comparable to systemic steroid administration with a preserved improvement in retinal-vascular circulation, without exposing the child to systemic post-steroid complications.
PubMed: 38592169
DOI: 10.3390/jcm13051341 -
Heliyon Apr 2024The purpose of the current investigation was to conduct a detailed analysis of the chemical components and medicinal properties of the methanolic crude extract derived...
The purpose of the current investigation was to conduct a detailed analysis of the chemical components and medicinal properties of the methanolic crude extract derived from the leaves of Cassia fistula. This analysis was carried out using both experimental (in vivo) and computational (in silico) methods. Eleven chemicals were chromatographically isolated using GC-MS/MS, which utilizes a library of NIST and Wiley 2020 versions. FTIR analysis of the extract was performed to identify the functional group of the compounds. The glucose-lowering capacity, analgesic, and anti-diarrheal activities of methanolic crude extract were analyzed utilizing a well-known oral glucose tolerance test, tail immersion method, writhing assay, and castor oil-induced diarrheal mice methods, respectively. After 60 min, 120 min, and 180 min of loading the drugs, a significant reduction of blood glucose levels was examined (p < 0.05) in all the extracts of this plant (200 mg/kg, 400 mg/kg and 600 mg/kg) utilized in this research at a time-dependent manner. Similarly, all the crude extracts showed significant (p < 0.05) effects against pain centrally and peripherally compared to the standard drug morphine (2 mg/kg bw) and diclofenac sodium (50 mg/kg bw). Moreover, the methanol extract (400 mg/kg bw) manifested anti-diarrheal efficacy by inhibiting 72.0 % of the diarrheal episode in mice compared to the standard drug loperamide (inhibition = 80.0%). The results of the computational investigations corroborated existing in-vivo findings. Greater or close to equivalent binding affinity to the active binding sites of kappa opioid receptor, glucose transporter 3 (GLUT 3), and cyclooxygenase 2 was indicative of the potential anti-diarrheal, hypoglycemic, and analgesic characteristics of the isolated compounds (COX-2). Moreover, anticancer and antimicrobial potentiality was also found impressive through evaluation of binding affinity with epidermal growth factor receptor (EGFR) and dihydrofolate reductase (DHFR) receptors. Results from this study indicated that C. fistula might be a beneficial natural resource for treating diarrhea, hyperglycemia, and pain. However, additional research is required to conduct a comprehensive phytochemical screening and establish precise action mechanisms of the crude extract or the plant-derived compounds.
PubMed: 38590868
DOI: 10.1016/j.heliyon.2024.e28460 -
Synthetic and Systems Biotechnology Sep 2024Gene circuits allow cells to carry out complex functions such as the precise regulation of biological metabolic processes. In this study, we combined, in the yeast ,...
Gene circuits allow cells to carry out complex functions such as the precise regulation of biological metabolic processes. In this study, we combined, in the yeast , genetic regulatory elements with the enzymatic reactions of the human CYP2C9 and its redox partner CPR on luciferin substrates and diclofenac. cells were permeabilized and used as enzyme bags in order to host these metabolic reactions. We engineered three different (genetic)-enzymatic basic Boolean gates (YES, NOT, and N-IMPLY). In the YES and N-IMPLY gates, human CYP2C9 was expressed under the galactose-inducible promoter. The carbon monoxide releasing molecule CORM-401 was used as an input in the NOT and N-IMPLY gates to impair CYP2C9 activity through inhibition of the Fe- heme prosthetic group in the active site of the human enzyme. Our study provides a new approach in designing synthetic bio-circuits and optimizing experimental conditions to favor the heterologous expression of human drug metabolic enzymes over their endogenous counterparts. This new approach will help study precise metabolic attributes of human P450s.
PubMed: 38590712
DOI: 10.1016/j.synbio.2024.03.013 -
BMC Infectious Diseases Apr 2024Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive activation of the immune system, leading to hypercytokinemia and damage to...
BACKGROUND
Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive activation of the immune system, leading to hypercytokinemia and damage to multiple organs. We report a rare case of HLH with myopericarditis caused by Campylobacter infection.
CASE PRESENTATION
A 28-year-old male patient with a history of hypertension without medicine control presented at the hospital after a four-day fever, decreasing urine amount, rashes on his trunk and limbs, and other symptoms. He was admitted with a provisional diagnosis of atypical infection and allergic skin rash related to diclofenac. However, his condition deteriorated, and he developed shock, tachycardia, chest distress, and bilateral pleural effusion after admission. Further investigations revealed cardiogenic shock related to myopericarditis, and he was transferred to the ICU. In addition, a stool PCR panel subsequently revealed a positive result for Campylobacter. On day 6, he was diagnosed with HLH. Under Clarithromycin and dexamethasone infusion, leukocytosis, anemia and thrombocytopenia with cardiogenic shock status improved. Then, he was later discharged in stable condition.
CONCLUSIONS
HLH and myopericarditis caused by Campylobacter are very rare. Early detection of Campylobacter-induced HLH and multiple organ failure, as well as prompt use of antibiotics and immunosuppressants, can be helpful for prognosis.
Topics: Male; Humans; Adult; Lymphohistiocytosis, Hemophagocytic; Campylobacter; Shock, Cardiogenic; Anemia; Thrombocytopenia; Myocarditis
PubMed: 38589812
DOI: 10.1186/s12879-024-09128-z -
Cureus Mar 2024Intrauterine devices (IUDs) are considered a reliable contraceptive option for women, but they can come with side effects. There is a disconnect in standard guidelines... (Review)
Review
Intrauterine devices (IUDs) are considered a reliable contraceptive option for women, but they can come with side effects. There is a disconnect in standard guidelines for IUD insertion within and without the U.S. The objective of this review was to address a gap in the literature regarding official procedures for pain management during IUD implantation. This scoping review was initiated using keywords to extract relevant articles from multiple databases: U.S. National Library of Medicine National Institutes of Health (PubMed), MEDLINE (Ovid), and Excerpta Medica dataBASE (EMBASE, Ovid). Initially, 457 articles were identified and after a rigorous screening and selection process, 37 articles were chosen to be further assessed to ascertain if they met the study's inclusion criteria. Those 37 articles were further evaluated fully to check for relevancy. From that process, 19 articles were chosen for the review, and all passed quality assessment evaluations using the JB Appraisal Tools. To best address the research question, the data from the 19 articles were divided into three categories: 1) circumstantial factors, 2) non-pharmacological methods, and 3) pharmacological methods. Circumstantially, women with previous vaginal deliveries experienced the lowest pain during the procedure, and nulligravid (never pregnant) women experienced the most pain. Lower pain scores were reported by lactating women compared to non-lactating. Black women experienced the most anticipated pain compared to other races. Regarding non-pharmacological methods, different insertion techniques, tools, and the use of a cold compress were found to not affect the level of pain during IUD insertion. Lastly, it was shown that pharmacological methods such as lidocaine gel, lidocaine paracervical block, and lidocaine combined with either diclofenac or prilocaine decreased pain scores at different time stamps of the procedure. Also, oral ketorolac and a vaginal combination of misoprostol and dinoprostone helped reduce pain. Findings from this scoping review revealed a lack of uniformity across practices when performing IUD insertions, possibly due to differences in procedures across circumstantial factors, non-pharmacological methods, and pharmacological methods. More research is needed to investigate the intricacies of pain with IUD insertion. Moving forward, especially following a potential increase in the use of IUDs after the reversal of Roe v. Wade, establishing this gap may lead to a more refined standardized protocol to mitigate pain with IUD insertions.
PubMed: 38586685
DOI: 10.7759/cureus.55785 -
Journal of Medicine and Life Dec 2023The inappropriate use of analgesics and antibiotics is a widespread issue among dentists globally, leading to the risk of over-prescription that could negatively affect...
The inappropriate use of analgesics and antibiotics is a widespread issue among dentists globally, leading to the risk of over-prescription that could negatively affect patient health and quality of life. This study aimed to assess the prescribing patterns of analgesics and antibiotics by dentists in Kirkuk City, Iraq, focusing on their attitudes, knowledge levels, and practices regarding these medications. A cross-sectional survey was conducted among 280 dentists in Kirkuk City. The dentists were contacted via their work email addresses, and they responded to a survey. Descriptive statistics, including frequency analysis, were employed to evaluate the appropriateness of analgesic and antibiotic prescriptions for different dental conditions. The first-choice analgesic for 44.6% of dentists was mefenamic acid, followed by paracetamol (31.1%). Regarding antibiotic use, 56.8% of dentists in Kirkuk City reported using antibiotics for empirical and direct therapy. Other dentists (43.2%) revealed that they did not have enough information regarding antibiotic group preference in empirical therapy. 106 of the participants (37.85%) recommended the use of broad-spectrum antibiotics in the treatment of bacterial infections. However, most (45%) were unfamiliar with the group preferences in empirical therapy. Dentists in Kirkuk City showed variations in knowledge and awareness regarding using analgesics and antibiotics. This requires further education and training on proper analgesics and antibiotic stewardship guidelines.
Topics: Humans; Anti-Bacterial Agents; Cross-Sectional Studies; Iraq; Quality of Life; Practice Patterns, Dentists'; Analgesics; Prescriptions; Dentists
PubMed: 38585523
DOI: 10.25122/jml-2023-0405 -
Advanced Pharmaceutical Bulletin Mar 2024N-methyl-D-aspartate (NMDA) receptors that are expressed by T-cells modulate T-cell proliferation, cytotoxicity and cell migration toward chemokines. Several studies...
PURPOSE
N-methyl-D-aspartate (NMDA) receptors that are expressed by T-cells modulate T-cell proliferation, cytotoxicity and cell migration toward chemokines. Several studies have shown an anti-inflammatory effect of NMDA receptor antagonists. This study compares the effect of the noncompetitive low-affinity NMDA receptor antagonist N-(2-adamantyl)-hexamethyleneimine hydrochloride (hemantane) in a topical formulation (gel) with the cyclooxygenase (COX) inhibitor diclofenac in a topical formulation (gel) in rats with arthritis induced by Freund's Complete Adjuvant (FCA).
METHODS
On day 14 after an FCA injection into the left hind paw, rats with contralateral hind paw edema were selected for further investigation (29/65). They were treated with 5% hemantane gel or 1% diclofenac gel applied locally to hind paws daily for 2 weeks starting 14 days after the FCA injection. Rats with arthritis were examined hind paw edema, hyperalgesia, and motor deficits; their body weight and hematological parameters were recorded. The rats were euthanized on day 28, followed by histological examination of the ankle joint (HE stain).
RESULTS
Rats with arthritis exhibited hind paw inflammation and hyperalgesia, motor deficits, changes of hematological parameters, reduced weight gain and spleen hypertrophy. Histological examination of the ankle joint revealed degenerative-dystrophic lesions of the cartilaginous tissue, proliferative inflammation of the synovium, edema and lymphocytic/macrophage infiltration of periarticular tissues. Hemantane gel reduced hind paw edema, pain, motor deficits and histological signs of inflammation; its effect was comparable to diclofenac gel.
CONCLUSION
Hemantane gel alleviates FCA-induced arthritis in rats, and its effect is comparable to diclofenac gel.
PubMed: 38585463
DOI: 10.34172/apb.2024.002 -
Rheumatology International Jun 2024Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both...
Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic side effects. We, therefore, examined the risk of cardiovascular events associated with NSAID use in patients with gout. We conducted a nationwide, population-based case-crossover study of all Danes ≥ 18 years of age with first-time gout during 1997-2020, who experienced a cardiovascular event (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation/flutter, or cardiovascular death) (n = 59,150). The exposure was use of NSAIDs, overall and according to type (ibuprofen, naproxen, or diclofenac). We used the dates 300, 240, 180, and 120 before the outcome date as reference dates. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and cardiovascular events. NSAID use was overall associated with 12% decreased odds of a cardiovascular event (OR = 0.88, 95% CI: 0.85-0.91). This decreased odds ratio was observed for the use of ibuprofen (OR = 0.92, 95% CI: 0.88-0.97) and naproxen (OR = 0.85, 95% CI: 0.74-0.97), but not for the use of diclofenac (OR = 0.97, 95% CI: 0.90-1.05). Overall, use of NSAIDs was associated with decreased odds of all the individual components of the composite outcome. NSAIDs were not associated with an increased cardiovascular event rate when used in gout patients. Ibuprofen and naproxen appeared to have better cardiovascular risk profiles than diclofenac.
Topics: Humans; Anti-Inflammatory Agents, Non-Steroidal; Gout; Male; Female; Middle Aged; Cross-Over Studies; Aged; Denmark; Cardiovascular Diseases; Naproxen; Ibuprofen; Adult; Diclofenac
PubMed: 38581450
DOI: 10.1007/s00296-024-05584-7 -
Molecular Pharmacology May 2024Liver fatty acid binding protein 1 (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and...
Liver fatty acid binding protein 1 (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data are available for human FABP1 (hFABP1). FABP1 has a large binding pocket, and up to two fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses, native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1, and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (K = 0.2 M) and low (K > 10 M) affinity binding sites. Nine drugs bound to hFABP1 with equilibrium dissociation constant (K) values ranging from 1 to 20 M. None of the tested drugs completely displaced DAUDA from hFABP1, and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-hFABP1-diclofenac ternary complex was verified with native MS. Docking predicted diclofenac binding in the portal region of FABP1 with DAUDA in the binding cavity. The catalytic rate constant of diclofenac hydroxylation by CYP2C9 was decreased by ∼50% ( < 0.01) in the presence of FABP1. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 binding in the liver will alter drug metabolism and clearance. SIGNIFICANCE STATEMENT: Many commonly prescribed drugs bind fatty acid binding protein 1 (FABP1), forming ternary complexes with FABP1 and the fluorescent fatty acid 11-(dansylamino)undecanoic acid. These findings suggest that drugs will bind to apo-FABP1 and fatty acid-bound FABP1 in the human liver. The high expression of FABP1 in the liver, together with drug binding to FABP1, may alter drug disposition processes in vivo.
Topics: Fatty Acid-Binding Proteins; Humans; Diclofenac; Protein Binding; Cytochrome P-450 CYP2C9; Binding Sites; Liver; Oxidation-Reduction; Pharmaceutical Preparations
PubMed: 38580446
DOI: 10.1124/molpharm.124.000878