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Angewandte Chemie (International Ed. in... Oct 2019Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally... (Review)
Review
Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH-sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. A highly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, which also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy-amino-λ -sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles.
Topics: Alcohols; Amines; Molecular Structure; Nitriles; Sulfamerazine; Sulfonamides
PubMed: 31390133
DOI: 10.1002/anie.201906001 -
Viruses Mar 2022Viral replication and transmissibility are the principal causes of endemic and pandemic disease threats. There remains a need for broad-spectrum antiviral agents. The... (Review)
Review
Viral replication and transmissibility are the principal causes of endemic and pandemic disease threats. There remains a need for broad-spectrum antiviral agents. The most common respiratory viruses are endemic agents such as coronaviruses, respiratory syncytial viruses, and influenza viruses. Although vaccines are available for SARS-CoV-2 and some influenza viruses, there is a paucity of effective antiviral drugs, while for RSV there is no vaccine available, and therapeutic treatments are very limited. We have previously shown that probenecid is safe and effective in limiting influenza A virus replication and SARS-CoV-2 replication, along with strong evidence showing inhibition of RSV replication in vitro and in vivo. This review article will describe the antiviral activity profile of probenecid against these three viruses.
Topics: Drug Repositioning; Humans; Orthomyxoviridae; Probenecid; Respiratory Syncytial Virus, Human; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35337018
DOI: 10.3390/v14030612 -
The Journal of General Physiology Apr 2023Tight control of skeletal muscle contractile activation is secured by the excitation-contraction (EC) coupling protein complex, a molecular machinery allowing the plasma...
Tight control of skeletal muscle contractile activation is secured by the excitation-contraction (EC) coupling protein complex, a molecular machinery allowing the plasma membrane voltage to control the activity of the ryanodine receptor Ca2+ release channel in the sarcoplasmic reticulum (SR) membrane. This machinery has been shown to be intimately linked to the plasma membrane protein pannexin-1 (Panx1). We investigated whether the prescription drug probenecid, a widely used Panx1 blocker, affects Ca2+ signaling, EC coupling, and muscle force. The effect of probenecid was tested on membrane current, resting Ca2+, and SR Ca2+ release in isolated mouse muscle fibers, using a combination of whole-cell voltage-clamp and Ca2+ imaging, and on electrically triggered contraction of isolated muscles. Probenecid (1 mM) induces SR Ca2+ leak at rest and reduces peak voltage-activated SR Ca2+ release and contractile force by 40%. Carbenoxolone, another Panx1 blocker, also reduces Ca2+ release, but neither a Panx1 channel inhibitory peptide nor a purinergic antagonist affected Ca2+ release, suggesting that probenecid and carbenoxolone do not act through inhibition of Panx1-mediated ATP release and consequently altered purinergic signaling. Probenecid may act by altering Panx1 interaction with the EC coupling machinery, yet the implication of another molecular target cannot be excluded. Since probenecid has been used both in the clinic and as a masking agent for doping in sports, these results should encourage evaluation of possible effects on muscle function in treated individuals. In addition, they also raise the question of whether probenecid-induced altered Ca2+ homeostasis may be shared by other tissues.
Topics: Mice; Animals; Probenecid; Calcium; Carbenoxolone; Muscle Fibers, Skeletal; Muscle Contraction; Muscle, Skeletal; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Nerve Tissue Proteins; Connexins
PubMed: 36820799
DOI: 10.1085/jgp.202213203 -
Mediators of Inflammation 2023Neuropathic pain is a complex sort of pain that is detrimental to individuals' health, both physically and mentally, but merely a small portion of them could witness... (Review)
Review
BACKGROUND
Neuropathic pain is a complex sort of pain that is detrimental to individuals' health, both physically and mentally, but merely a small portion of them could witness pain alleviation. Mirogabalin, by distinctive binding characteristics of voltage-gated calcium channels, has won approval from the Japanese authority as a third member of gabapentinoids in Japan. Our review was aimed at encompassing the bulk of clinical research on mirogabalin, which included clinical trials, special considerations, coadministration studies, case reports, and cost-effectiveness studies.
METHODS
A review was carried out on a series of platforms, such as PubMed, MEDLINE, and Scopus, up to December 2021 using the keywords as follows: "mirogabalin OR mirogabalin besylate OR Tarlige OR DS-5565" AND "neuropathic pain OR Neuropathy."
RESULTS
Mirogabalin demonstrated analgesic activity and manageable adverse reactions and provides a new alternative for individuals with PHN or DPNP in 3 phase II and 4 III trials. Mirogabalin alleviated pain markedly in comparison with placebo. Administration of mirogabalin on a long-term basis is a flexible dosage regimen for patients with PHN. It is noteworthy that mirogabalin should be administrated cautiously when combined with probenecid and cimetidine on account of a slight increase in pharmacodynamics effects of mirogabalin.
CONCLUSION
The development of mirogabalin allows further optimization of individual treatment strategies so as to provide more therapeutic choices in this medical domain.
Topics: Humans; Neuralgia; Bridged Bicyclo Compounds; Analgesics; Cimetidine
PubMed: 37152369
DOI: 10.1155/2023/4893436 -
Nature Structural & Molecular Biology Nov 2023In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites....
In mammals, the kidney plays an essential role in maintaining blood homeostasis through the selective uptake, retention or elimination of toxins, drugs and metabolites. Organic anion transporters (OATs) are responsible for the recognition of metabolites and toxins in the nephron and their eventual urinary excretion. Inhibition of OATs is used therapeutically to improve drug efficacy and reduce nephrotoxicity. The founding member of the renal organic anion transporter family, OAT1 (also known as SLC22A6), uses the export of α-ketoglutarate (α-KG), a key intermediate in the Krebs cycle, to drive selective transport and is allosterically regulated by intracellular chloride. However, the mechanisms linking metabolite cycling, drug transport and intracellular chloride remain obscure. Here, we present cryogenic-electron microscopy structures of OAT1 bound to α-KG, the antiviral tenofovir and clinical inhibitor probenecid, used in the treatment of Gout. Complementary in vivo cellular assays explain the molecular basis for α-KG driven drug elimination and the allosteric regulation of organic anion transport in the kidney by chloride.
Topics: Animals; Organic Anion Transport Protein 1; Chlorides; Kidney; Biological Transport; Anions; Ketoglutaric Acids; Mammals
PubMed: 37482561
DOI: 10.1038/s41594-023-01039-y -
Antimicrobial Agents and Chemotherapy Apr 2022In this study, we explored clofazimine (CFZ) as a potential substrate of uptake and efflux transporters that might be involved in CFZ disposition, using transporter gene...
In this study, we explored clofazimine (CFZ) as a potential substrate of uptake and efflux transporters that might be involved in CFZ disposition, using transporter gene overexpressing cell lines . The intracellular concentrations of CFZ were significantly increased in the presence of selective inhibitors of P-gp and BCRP, which include verapamil, cyclosporine-A, PSC-833, quinidine, Ko143, and daunorubicin. In a bidirectional transport assay using transwell cultures of cell lines overexpressing P-gp and BCRP, the mean efflux ratios of CFZ were found to be 4.17 ± 0.63 and 3.37 ± 1.2, respectively. The and maximum rate of uptake () were estimated to be 223.3 ± 14.73 μM and 548.8 ± 87.15 pmol/min/mg protein for P-gp and 381.9 ± 25.07 μM and 5.8 ± 1.22 pmol/min/mg protein for BCRP, respectively. Among the uptake transporters screened, the CFZ uptake rate was increased 1.93 and 3.09-fold in HEK293 cell lines overexpressing OAT1 and OAT3, respectively, compared to the control cell lines, but no significant uptake was observed in cell lines overexpressing OCT1, OCT2, OATP1B1, OATP1B3, OATP2B1, or NTCP. Both OAT1- and OAT3-mediated uptake was inhibited by the selective inhibitors diclofenac, probenecid, and butanesulfonic acid. The and values of CFZ were estimated to be 0.63 ± 0.15 M and 8.23 ± 1.03 pmol/min/mg protein, respectively, for OAT1 and 0.47 ± 0.1 μM and 17.81 ± 2.19 pmol/min/mg protein, respectively, for OAT3. These findings suggest that CFZ is a novel substrate of BCRP, OAT1, and OAT3 and a known substrate of P-gp .
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Clofazimine; Drug Interactions; HEK293 Cells; Humans; Membrane Transport Proteins; Neoplasm Proteins
PubMed: 35254089
DOI: 10.1128/aac.02158-21 -
Pharmaceutics Aug 2020Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases...
Prior studies have demonstrated an organic anion transporter 6 (OAT6)-mediated accumulation of sorafenib in keratinocytes. The OAT6 inhibitor probenecid decreases sorafenib uptake in skin and might, therefore, decrease sorafenib-induced cutaneous adverse events. Here, the influence of probenecid on sorafenib pharmacokinetics and toxicity was investigated. Pharmacokinetic sampling was performed in 16 patients on steady-state sorafenib treatment at days 1 and 15 of the study. Patients received sorafenib (200-800 mg daily) in combination with probenecid (500 mg two times daily (b.i.d.)) on days 2-15. This study was designed to determine bioequivalence with geometric mean Area under the curve from zero to twelve hours (AUC) as primary endpoint. During concomitant probenecid, sorafenib plasma AUC decreased by 27% (90% CI: -38% to -14%; < 0.01). Furthermore, peak and trough levels of sorafenib, as well as sorafenib concentrations in skin, decreased to a similar extent in the presence of probenecid. The metabolic ratio of sorafenib-glucuronide to parent drug increased (+29%) in the presence of probenecid. A decrease in systemic sorafenib concentrations during probenecid administration seems to have influenced cutaneous concentrations. Since sorafenib-glucuronide concentrations increased compared with sorafenib and sorafenib--oxide, probenecid may have interrupted enterohepatic circulation of sorafenib by inhibition of the organic anion transporting polypeptides 1B1 (OATP1B1). Sorafenib treatment with probenecid is, therefore, not bioequivalent to sorafenib monotherapy. A clear effect of probenecid on sorafenib toxicity could not be identified in this study.
PubMed: 32825359
DOI: 10.3390/pharmaceutics12090788 -
The Journal of Antimicrobial... Aug 2022To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral β-lactams. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral β-lactams.
METHODS
Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral β-lactam [flucloxacillin, penicillin V, amoxicillin (± clavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes, plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed.
RESULTS
Overall, 18/295 (6%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral β-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (6/8; 75%). Probenecid improved PTA (2/2; 100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random-effects model of 0.33 (95% CI 0.20-0.55; I2 = 7%), favouring probenecid.
CONCLUSIONS
Probenecid-boosted β-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral β-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.
Topics: Amoxicillin; Anti-Bacterial Agents; Gonorrhea; Humans; Monobactams; Probenecid; beta-Lactams
PubMed: 35726853
DOI: 10.1093/jac/dkac200 -
Artificial Intelligence in Medicine Sep 2022In health-care, there is a need to quantify medical errors. Among these errors, we observe wrong dose prescriptions. Drug dose titration (DT) is the process by which...
In health-care, there is a need to quantify medical errors. Among these errors, we observe wrong dose prescriptions. Drug dose titration (DT) is the process by which dosage is progressively adjusted to the patient till a steady dose is reached. Depending on the clinical disease, drug, and patient condition, dose titration can follow different procedures. Once modeled, these procedures can serve for clinical homogenization, standardization, decision support and retrospective analysis. Here, we propose a language to model dose titration procedures. The language was used to formalize one- and two-drug titration of chronic and acute cases, and to perform retrospective analysis of the drug titration processes on 253 patients diagnosed of diabetes mellitus type 2 and treated with metformin, 321 patients treated of chonic heart failure with furosemide, 155 patients with hyperuricemia treated with allopurinol as initial drug and febuxostat as alternative drug, and 187 hyperuricemia patients with primary drug allopurinol and supplementary drug probenecid, in order to identify different types of drug titration deviations from standard DT methods.
Topics: Allopurinol; Gout; Gout Suppressants; Humans; Hyperuricemia; Retrospective Studies; Uric Acid
PubMed: 36100337
DOI: 10.1016/j.artmed.2022.102343 -
International Journal of Molecular... Sep 2020Interaction between umami and bitter taste has long been observed in human sensory studies and in neural responses in animal models, however, the molecular mechanism for...
Interaction between umami and bitter taste has long been observed in human sensory studies and in neural responses in animal models, however, the molecular mechanism for their action has not been delineated. Humans detect diverse bitter compounds using 25-30 members of the type 2 taste receptor (TAS2R) family of G protein-coupled receptor. In this study, we investigated the putative mechanism of antagonism by umami substances using HEK293T cells expressing hTAS2R16 and two known probenecid-insensitive mutant receptors, hTAS2R16 N96T and P44T. In wild type receptor, Glu-Glu, inosine monophosphate (IMP), and l-theanine behave as partial insurmountable antagonists, and monosodium glutamate (MSG) acts as a surmountable antagonist in comparison with probenecid as a full insurmountable antagonist. The synergism with IMP of umami substances still stands in the suppression of hTAS2R16 signaling. In mutagenesis analysis, we found that Glu-Glu, MSG, and l-theanine share at least one critical binding site on N96 and P44 with probenecid. These results provide the first evidence for a direct binding of umami substances to the hTAS2R16 through the probenecid binding pocket on the receptor, resulting in the suppression of bitterness.
Topics: Benzyl Alcohols; Cyclooxygenase Inhibitors; Dipeptides; Glucosides; Glutamates; HEK293 Cells; Humans; Inosine Monophosphate; Protein Binding; Receptors, G-Protein-Coupled; Sodium Glutamate
PubMed: 32987926
DOI: 10.3390/ijms21197045