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Pharmacogenomics Aug 2023is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of...
is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of this testing to prevent SJS/TEN. A model was developed to compare three strategies: no screening, use allopurinol; screening; and no screening, use probenecid. A willingness-to-pay of three-times gross domestic product per capita was used. Compared with 'no screening, use allopurinol', 'screening' increased quality-adjusted life-years by 0.0069 with the incremental cost of Vietnam dong (VND) 14,283,633 (US$617), yielding an incremental cost-effectiveness ratio of VND 2,070,459,122 (US$89,398) per quality-adjusted life-year. Therefore, 'screening' was unlikely to be cost-effective under the current willingness-to-pay. Testing's cost-effectiveness may change with targeted high-risk patients, reimbursed febuxostat or lower probenecid prices. The implementation of nationwide testing before the use of allopurinol is not cost-effective, according to this analysis. This may be due to the lack of quality data on the effectiveness of testing and costing data in the Vietnamese population.
PubMed: 37706247
DOI: 10.2217/pgs-2023-0095 -
Phytomedicine : International Journal... Nov 2023The Qiji Shujiang granule (QJG) is a traditional Chinese drug widely used in treating PD patients. However, the potential mechanism of QJG in PD therapy is still unclear.
BACKGROUND
The Qiji Shujiang granule (QJG) is a traditional Chinese drug widely used in treating PD patients. However, the potential mechanism of QJG in PD therapy is still unclear.
PURPOSE
This study aims to examine the neuroprotective effects of QJG and the specific mechanism by which QJG alleviates MPTP/Probenecid-induced pyroptosis and offers an alternative for PD treatment.
STUDY DESIGN AND METHODS
We first employed network pharmacology along with molecular docking to identify potential molecular targets and pathways. Subsequently, we validated our findings of RNA-sequencing (RNA-seq) analysis and experiments in vivo and vitro. Lentiviral systems and inhibitors were used for experiments.
RESULTS
The protein-protein interactions (PPI) core genes network consists of NLRP3, CASP1 (caspase-1), TP53, and MAPK8. Pathway enrichment analysis revealed that inflammatory responses related to pyroptosis were significantly enriched. The molecular docking findings showed the highest degree of centrality regarding the top three bioactive compounds following the online database. RNA-seq analysis identified that NLRP3 inflammasome was significantly downregulated in the QJG group while it was significantly upregulated in the model group. Our findings revealed that QJG dose-dependently increased the total traveled distances, enhanced the dopaminergic neurons, and accelerated the restoration of the TH protein level, showing a good antioxidant capacity through increasing the SOD levels and decreasing MDA levels. QJG significantly reduced the expression levels of NLRP3, GSDMD-N, IL-1β, and caspase-1 in striatum tissue. Furthermore, the group treated with OE-NLRP3 decreased cell viability, increased ROS and MDA levels, and promoted NLRP3, GSDMD-N, and caspase-1, in addition to IL-1β expression levels. Furthermore, OE-NLRP3+QJG treatment significantly reversed the effect. In vivo experiments, QJG dose-dependently alleviated motor impairment by increasing the total traveled distances, rescued dopaminergic neurons, inhibited oxidative stress through increasing the SOD levels and decreasing MDA levels and suppressed NLRP3-mediated pyroptosis by reducing the expression levels of NLRP3, GSDMD-N, IL-1β, and caspase-1 in MPTP induced PD Mice. Moreover, in vitro experiments, the OE-NLRP3 treated group decreased cell viability, increased ROS and MDA levels, and promoted NLRP3, GSDMD-N, caspase-1, in addition to IL-1β expression levels. Furthermore, OE-NLRP3+QJG treatment significantly reversed the effect.
CONCLUSIONS
This study provides pharmacological support for the use of QJG in the treatment of PD. Herein, we concluded that QJG induced the alleviation of pyroptosis by inhibiting the NLRP3/caspase-1 pathway to exert a neuroprotective effect.
Topics: Humans; Animals; Mice; Caspase 1; Parkinson Disease; NLR Family, Pyrin Domain-Containing 3 Protein; Dopaminergic Neurons; Molecular Docking Simulation; Pyroptosis; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 37657208
DOI: 10.1016/j.phymed.2023.155019 -
Frontiers in Neuroscience 2023The subventricular zone (SVZ) is a brain region that contains neural stem cells and progenitor cells (NSCs/NPCs) from which new neurons and glial cells are formed during...
INTRODUCTION
The subventricular zone (SVZ) is a brain region that contains neural stem cells and progenitor cells (NSCs/NPCs) from which new neurons and glial cells are formed during adulthood in mammals. Recent data indicate that SVZ NSCs are the cell type that acquires the initial tumorigenic mutation in glioblastoma (GBM), the most aggressive form of malignant glioma. NSCs/NPCs of the SVZ present hemichannel activity whose function has not yet been fully elucidated. In this work, we aimed to analyze whether hemichannel-mediated communication affects proliferation of SVZ NPCs and GBM cells.
METHODS AND RESULTS
For that purpose, we used boldine, an alkaloid derived from the boldo tree (), that inhibits connexin and pannexin hemichannels, but without affecting gap junctional communication. Boldine treatment (50 μM) of rat SVZ NPCs grown as neurospheres effectively inhibited dye uptake through hemichannels and induced a significant reduction in neurosphere diameter and in bromodeoxyuridine (BrdU) incorporation. However, the differentiation pattern was not modified by the treatment. Experiments with specific blockers for hemichannels formed by connexin subunits (D4) or pannexin 1 (probenecid) revealed that probenecid, but not D4, produced a decrease in BrdU incorporation similar to that obtained with boldine. These results suggest that inhibition of pannexin 1 hemichannels could be partially responsible for the antiproliferative effect of boldine on SVZ NPCs. Analysis of the effect of boldine (25-600 μM) on different types of primary human GBM cells (GBM59, GBM96, and U87-MG) showed a concentration-dependent decrease in GBM cell growth. Boldine treatment also induced a significant inhibition of hemichannel activity in GBM cells.
DISCUSSION
Altogether, we provide evidence of an antimitotic action of boldine in SVZ NPCs and in GBM cells which may be due, at least in part, to its hemichannel blocking function. These results could be of relevance for future possible strategies in GBM aimed to suppress the proliferation of mutated NSCs or glioma stem cells that might remain in the brain after tumor resection.
PubMed: 37655012
DOI: 10.3389/fnins.2023.1211467 -
Drug Metabolism and Disposition: the... Nov 2023Urate transporter 1 (URAT1) is a transporter responsible for uric acid (UA) reabsorption by renal proximal tubules and a pharmacological target of uricosuric agents....
Urate transporter 1 (URAT1) is a transporter responsible for uric acid (UA) reabsorption by renal proximal tubules and a pharmacological target of uricosuric agents. Probenecid and benzbromarone have been used as uricosuric agents, while dotinurad was recently approved in Japan. Notably, the in vitro of dotinurad on URAT1 is not strong enough to explain its in vivo uricosuric effect estimated based on clinical unbound plasma concentrations, suggesting the presence of mechanisms other than competition with UA uptake at the extracellular domain of URAT1 (-inhibition). In this study, -inhibition was hypothesized as the mechanism underlying URAT1 inhibition by dotinurad, wherein intracellularly accumulated dotinurad inactivates URAT1. In URAT1-expressing Madin-Darby Canine Kidney-II cells and oocytes, pre-incubation with dotinurad potentiated the inhibitory effect more than co-incubation alone, but this effect was not observed with benzbromarone or probenecid. Under co-incubation, dotinurad inhibited UA uptake in a competitive manner (-inhibition). When we pre-injected dotinurad directly into oocytes and immediately measured [C]UA uptake without coincubation (only -inhibition), dotinurad noncompetitively inhibited UA uptake. URAT1 is an exchange transporter for UA and monocarboxylates such as nicotinic acid (NA). Pre-injected dotinurad and extracellular UA attenuated and facilitated efflux of [H]NA, respectively, whereas pre-injection of benzbromarone or probenecid did not affect it, suggesting that dotinurad exhibits -inhibition by attenuating URAT1-mediated efflux of monocarboxylates, which is a driving force for UA uptake by URAT1. Accordingly, dotinurad ameliorates URAT1-mediated UA reabsorption by both - and -inhibition, explaining its clinically stronger uricosuric effect than that estimated by the in vitro value. SIGNIFICANCE STATEMENT: The uricosuric agent dotinurad inhibits uric acid reabsorptive transporter (URAT) 1 with a clinical potency stronger than that estimated from obtained by in vitro URAT1 inhibition. This in vivo-in vitro discrepancy was explained by the -inhibition effect of dotinurad on URAT1. -inhibition was due to the attenuation of monocarboxylates efflux via URAT1, which is a driving force for URAT1-mediated exchange transport of uric acid. Overall, this is the first study to experimentally demonstrate -inhibition mechanism of URAT1.
PubMed: 37643882
DOI: 10.1124/dmd.123.001412 -
Journal of Pharmaceutical and... Oct 2023Furosemide (FUR) has been used in probe drugs cocktails for in vivo evaluation of the renal transporters OAT1 and OAT3 activities in studies of drug-drug interactions...
Determination of furosemide and its glucuronide metabolite in plasma, plasma ultrafiltrate and urine by HPLC-MS/MS with application to secretion and metabolite formation clearances in non-pregnant and pregnant women.
Furosemide (FUR) has been used in probe drugs cocktails for in vivo evaluation of the renal transporters OAT1 and OAT3 activities in studies of drug-drug interactions (generally using probenecid as an inhibitor) and drug-disease interactions. The objective of this study was to develop and validate methods for FUR and its glucuronide metabolite (FUR-GLU) analysis in plasma, plasma ultrafiltrate and urine for application in pharmacokinetics studies: a pilot drug-drug interaction study in pregnant women (n = 2), who received a single oral dose of FUR (40 mg) and in another occasion a single oral dose of probenecid (750 mg) before a single oral dose of FUR (40 mg), and in non-pregnant women participants (n = 12), who only received a single oral dose of FUR (40 mg). The samples preparation for FUR in 50 µL of plasma and plasma lysate were carried by acidified liquid-liquid extraction, while 50 µL of urine and 200 µL of plasma ultrafiltrate were simply diluted with the mobile phase. The methods presented linearities in the range of 0.50 - 2500 ng/mL of plasma and plasma lysate, 0.125 - 250 ng/mL of plasma ultrafiltrate, and 50 - 20,000 ng/mL of urine. FUR-GLU methods presented linearities in the range of 0.125 - 250 ng/mL of plasma ultrafiltrate and 50 - 20,000 ng/mL of urine. Precision and accuracy evaluations showed coefficients of variation and relative errors < 15%. In the pregnant women participants, the mean values of FUR CL CL CL and CL were all reduced when probenecid was administered with FUR (8.24 vs 2.89 L/h, 8.15 vs 2.80 L/h, 3.86 vs 1.75 L/h, 48.26 vs 22.10 L/h, respectively). Non-pregnant women presented similar values of FUR CL CL CL to the pregnant women who received FUR only. Finally, FUR fraction unbound (fu) resulted in values of approximately 1% in pregnant women and to 0.22% in non-pregnant women. These developed and validated methods for FUR and FUR-GLU quantification in multiple matrices can allow the further investigation of UGT1A9/1A1 and the fu when FUR is administered as an OAT 1 and 3 in vivo probe.
Topics: Female; Humans; Furosemide; Glucuronides; Chromatography, High Pressure Liquid; Probenecid; Tandem Mass Spectrometry
PubMed: 37634358
DOI: 10.1016/j.jpba.2023.115635 -
European Journal of Orthodontics Sep 2023Orthodontic mechanical force on the periodontal ligament induces extracellular adenosine triphosphate (ATP) release. However, mechanosensitive molecules have not been...
OBJECTIVES
Orthodontic mechanical force on the periodontal ligament induces extracellular adenosine triphosphate (ATP) release. However, mechanosensitive molecules have not been confirmed functionally in periodontal ligament cells. In the present study, we examined the roles of mechanosensitive PIEZO channels in the mechanically stimulated release of ATP in human periodontal ligament fibroblasts (HPdLFs).
MATERIALS AND METHODS
To examine PIEZO expression in HPdLFs, we performed reverse transcription-quantitative polymerase chain reaction, fluorescent immunostaining, and Ca2+ imaging. ATP concentrations were measured in culture medium after applications of the PIEZO1 agonist Yoda1 and compression force in a newly developed in vitro weight-loaded cell model (IVWLC) using balance weights and a 48-well plate. The mechanosensitive channel inhibitor GsMTx4 and the ATP-releasing route inhibitors clodronic acid, meclofenamic acid, and probenecid were used. To suppress PIEZO1 expression, short interference RNA (siRNA) treatment of the PIEZO1 gene was performed.
RESULTS
PIEZO1 mRNA was expressed more abundantly than PIEZO2 mRNA in HPdLFs. HPdLF cell bodies were immunoreactive to anti-PIEZO1 antibody. Yoda1 increased intracellular Ca2+ and extracellular ATP concentrations in a dose-dependent manner. ATP release was inhibited by GsMTx4 and inhibitors of ATP release routes. In the IVWLC, HPdLFs released ATP in response to compression force but not in response to hypoxic stimulation that was simultaneously applied to cells. Mechanically stimulated ATP release was inhibited by GsMTx4, inhibitors of ATP-releasing routes and siRNA treatment of PIEZO1.
CONCLUSIONS
PIEZO1 on the cell membranes of HPdLFs is activated by compression force and then induces ATP release via intracellular Ca2+-dependent exocytosis and ATP-permeable channels.
Topics: Humans; Calcium; Periodontal Ligament; Fibroblasts; Adenosine Triphosphate; RNA, Small Interfering
PubMed: 37632763
DOI: 10.1093/ejo/cjad052 -
Clinical Pharmacology and Therapeutics Dec 2023Monitoring endogenous biomarkers is increasingly used to evaluate transporter-mediated drug-drug interactions (DDIs) in early drug development and may be applied to...
Monitoring endogenous biomarkers is increasingly used to evaluate transporter-mediated drug-drug interactions (DDIs) in early drug development and may be applied to elucidate changes in transporter activity in disease. 4-pyridoxic acid (PDA) has been identified as the most sensitive plasma endogenous biomarker of renal organic anion transporters (OAT1/3). Increase in PDA baseline concentrations was observed after administration of probenecid, a strong clinical inhibitor of OAT1/3 and also in patients with chronic kidney disease (CKD). The aim of this study was to develop and verify a physiologically-based pharmacokinetic (PBPK) model of PDA, to predict the magnitude of probenecid DDI and predict the CKD-related changes in PDA baseline. The PBPK model for PDA was first developed in healthy population, building on from previous population pharmacokinetic modeling, and incorporating a mechanistic kidney model to consider OAT1/3-mediated renal secretion. Probenecid PBPK model was adapted from the Simcyp database and re-verified to capture its dose-dependent pharmacokinetics (n = 9 studies). The PBPK model successfully predicted the PDA plasma concentrations, area under the curve, and renal clearance in healthy subjects at baseline and after single/multiple probenecid doses. Prospective simulations in severe CKD predicted successfully the increase in PDA plasma concentration relative to healthy (within 2-fold of observed data) after accounting for 60% increase in fraction unbound in plasma and additional 50% decline in OAT1/3 activity beyond the decrease in glomerular filtration rate. The verified PDA PBPK model supports future robust evaluation of OAT1/3 DDI in drug development and increases our confidence in predicting exposure and renal secretion in patients with CKD.
Topics: Humans; Pyridoxic Acid; Probenecid; Renal Insufficiency, Chronic; Kidney; Drug Interactions; Biomarkers; Models, Biological
PubMed: 37620246
DOI: 10.1002/cpt.3029 -
Neurotherapeutics : the Journal of the... Oct 2023N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to... (Review)
Review
N-Acetylcysteine (NAC) has shown promise as a putative neurotherapeutic for traumatic brain injury (TBI). Yet, many such promising compounds have limited ability to cross the blood-brain barrier (BBB), achieve therapeutic concentrations in brain, demonstrate target engagement, among other things, that have hampered successful translation. A pharmacologic strategy for overcoming poor BBB permeability and/or efflux out of the brain of organic acid-based, small molecule therapeutics such as NAC is co-administration with a targeted or nonselective membrane transporter inhibitor. Probenecid is a classic ATP-binding cassette and solute carrier inhibitor that blocks transport of organic acids, including NAC. Accordingly, combination therapy using probenecid as an adjuvant with NAC represents a logical neurotherapeutic strategy for treatment of TBI (and other CNS diseases). We have completed a proof-of-concept pilot study using this drug combination in children with severe TBI-the Pro-NAC Trial (ClinicalTrials.gov NCT01322009). In this review, we will discuss the background and rationale for combination therapy with probenecid and NAC in TBI, providing justification for further clinical investigation.
Topics: Child; Humans; Probenecid; Acetylcysteine; Pilot Projects; Brain Injuries, Traumatic; Brain; Blood-Brain Barrier
PubMed: 37596428
DOI: 10.1007/s13311-023-01422-z -
Therapeutic Advances in Infectious... 2023Standard therapy for early syphilis involves intramuscular injections of penicillin G, which frequently faces shortages in several countries. Fourteen-day amoxicillin...
BACKGROUND
Standard therapy for early syphilis involves intramuscular injections of penicillin G, which frequently faces shortages in several countries. Fourteen-day amoxicillin therapy has been suggested as an alternative to benzathine penicillin G, but the optimal duration of amoxicillin therapy remains unclear and could theoretically be shortened to less than 14 days. The aim of this study was to explore the effectiveness of short-term amoxicillin therapy for early syphilis.
METHODS
We retrospectively explored the effectiveness of short-term amoxicillin therapy for early syphilis. The treatment data of patients who had received amoxicillin therapy for less than 14 days for unintended reasons were reviewed. Diagnosis was confirmed based on either the physician's description or clinical presentation. Successful treatment was defined as a fourfold or greater decline in the rapid plasma reagin titer or sero-reversion to negative within 12 months.
RESULTS
Of 295 patients, 8 received short-term amoxicillin treatment. All were men who had sex with men and people living with human immunodeficiency virus. Their median age, CD4 count, and treatment duration were 34 years (range, 26-40), 258/mL (range, 112-930), and 9.5 days (range, 5-11), respectively. One patient had primary syphilis, six had secondary syphilis, and one had early latent syphilis. All patients, except one who showed reinfection, demonstrated a serological response within 4 months. The median time for serological response was 112 days.
CONCLUSION
The results indicate that early syphilis could potentially be treated with 5-11 days of amoxicillin therapy combined with probenecid. This suggests that short-term amoxicillin therapy might be a sufficient treatment for early syphilis instead of the standard 14-day course.
PubMed: 37581104
DOI: 10.1177/20499361231192777 -
Clinical Pharmacology and Therapeutics Nov 2023Endogenous biomarkers are discussed as tools for detection of drug-drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2...
Endogenous biomarkers are discussed as tools for detection of drug-drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2-K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intra-study comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of 10 previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with 4 inhibitors of transport proteins [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N-oxide were both sensitive and specific (median log2-fold changes -1.18 in estimated renal elimination and -0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2-fold changes -3.77 and -2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid, and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE- and OAT-mediated DDIs.
PubMed: 37540045
DOI: 10.1002/cpt.3017