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Alimentary Pharmacology & Therapeutics Oct 2022Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The induction dose is 10 mg twice daily (b.d.), whilst for... (Review)
Review
BACKGROUND
Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The induction dose is 10 mg twice daily (b.d.), whilst for maintenance therapy, the lowest effective dose should be used.
AIM
To examine published evidence on the two tofacitinib dosing strategies used in UC treatment, including expert interpretation of the data and how they could inform clinical practice.
METHODS
The use of tofacitinib 5 or 10 mg b.d. was assessed using data from the tofacitinib UC clinical programme in the context of different clinical scenarios. We include experts' opinions on the clinical implications of dose adjustment to inform the benefit/risk of using tofacitinib 5 or 10 mg b.d., based on clinical scenarios and real-world data.
RESULTS
Factors to consider when adjusting the tofacitinib dose include disease severity, comorbidities and previous biological exposure. The endoscopic subscore can determine whether a patient is a good candidate for dose reduction. Following disease relapse, the response can be recaptured in a substantial number of patients with a dose increase. Furthermore, data are now published showing real-world use of tofacitinib and, so far, these are consistent with data from the clinical trials.
CONCLUSION
Clinicians must consider the benefit/risk balance of tofacitinib 10 versus 5 mg b.d. in terms of dose-related side effects, as well as the safety implications of undertreating active disease. All patients should be closely monitored for disease relapse following dose reduction or interruption for early recapture of response.
Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Pyrroles; Recurrence
PubMed: 35993338
DOI: 10.1111/apt.17185 -
Pharmaceutical Biology Dec 2020Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on...
Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats. Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 μL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS. Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant ( < 0.05). Compared with the control group, the was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h ( < 0.05), and the MRT was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h ( < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg ( < 0.05) in experimental group. Although the and of tofacitinib were increased, there were no significant differences ( > 0.05). This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Area Under Curve; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Drug Interactions; Female; Flavanones; Piperidines; Pyrimidines; Pyrroles; Rats, Sprague-Dawley; Signal-To-Noise Ratio
PubMed: 32202190
DOI: 10.1080/13880209.2020.1738504 -
Microbiology Spectrum Apr 2022Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at...
Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase of (CgHMGR), Thus Decreasing Yeast Viability and Ergosterol Synthesis.
Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of three different series of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase and thus affect ergosterol synthesis and yeast viability. Compounds 1c (α-asarone-related) and 5b (with a pyrrolic core) were selected as the best antifungal candidates among over 20 synthetic compounds studied. Both inhibited the growth of fluconazole-resistant and fluconazole-susceptible C. glabrata strains. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 fluconazole-resistant (versus fluconazole-susceptible) strain and after treatment with 1c (versus 5b). Given that the compounds decreased the concentration of ergosterol in the yeast strains, they probably target ergosterol synthesis. According to the docking analysis, the inhibitory effect of 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of the enzyme. Since 1c displayed higher binding energy than α-asarone and 5b, it is the best candidate for further research, which should include structural modifications to increase its specificity and potency. The derivatives could then be examined with animal models using a therapeutic dose. Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris, Candida glabrata, and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals. The three series of synthetic compounds herein designed and synthesized are inhibitors of ergosterol synthesis in yeasts. Of the more than 20 compounds studied, two were selected as the best antifungal candidates. These compounds were able to inhibit the growth and synthesis of ergosterol in C. glabrata strains, whether susceptible or resistant to fluconazole. The rational design of antifungal compounds derived from clinical drugs (statins, fibrates, etc.) has many advantages. Future studies are needed to modify the structure of the two present test compounds to obtain safer and less toxic antifungals. Moreover, it is important to carry out a more in-depth mechanistic approach.
Topics: Acyl Coenzyme A; Animals; Antifungal Agents; COVID-19; Candida glabrata; Drug Resistance, Fungal; Ergosterol; Fibric Acids; Fluconazole; Humans; Hydroxymethylglutaryl CoA Reductases; Microbial Sensitivity Tests; Pandemics; Pyrroles
PubMed: 35377226
DOI: 10.1128/spectrum.01642-21 -
Internal Medicine (Tokyo, Japan) Apr 2024Objective The use of a proton pump inhibitor (PPI) reduces rebleeding and mortality in patients with upper gastrointestinal bleeding (UGIB). Vonoprazan is a novel oral...
Objective The use of a proton pump inhibitor (PPI) reduces rebleeding and mortality in patients with upper gastrointestinal bleeding (UGIB). Vonoprazan is a novel oral agent with strong and sustained acid-inhibitory activity. We clarified the effect of vonoprazan compared with oral PPIs in such patients. Methods We analyzed the Diagnosis Procedure Combination database. The primary outcome was rebleeding, and secondary outcomes were in-hospital mortality and in-hospital mortality after rebleeding. Propensity score matching was performed to balance the comparison groups, and logistic regression analyses were used to compare the outcomes between vonoprazan and oral PPIs. Patients Patients on vonoprazan or oral PPIs who underwent endoscopic hemostasis for UGIB between 2014 and 2019 were included. Results We enrolled 78,964 patients, of whom 27,101 and 51,863 were prescribed vonoprazan and a PPI, respectively. After propensity score matching, the rebleeding rate of vonoprazan did not significantly differ from that of oral PPIs [6.4% vs. 6.1%; odds ratio (OR), 1.05; 95% confidence interval (CI), 0.98-1.13]; similarly, the in-hospital mortality rate (1.4% vs. 1.5%; OR, 0.91; 95% CI, 0.79-1.05) and in-hospital mortality after rebleeding (0.3% vs. 0.2%; OR, 1.09; 95% CI, 0.78-1.54) also did not significantly differ between the groups. The acquired findings were robust across dose-restricted analyses and several sensitivity analyses. Conclusion Rebleeding and in-hospital mortality risks in patients on vonoprazan were similar to those in patients on oral PPIs. Considering the higher cost of vonoprazan, oral PPIs might be an optimal oral agent as an acid-suppressive therapy in such patients.
Topics: Humans; Proton Pump Inhibitors; Gastrointestinal Hemorrhage; Pyrroles; Sulfonamides
PubMed: 37558479
DOI: 10.2169/internalmedicine.2211-23 -
Chemical Record (New York, N.Y.) Jun 2021To maintain the functions of living organisms, cells have developed complex gene regulatory networks. Transcription factors have a central role in spatiotemporal control... (Review)
Review
To maintain the functions of living organisms, cells have developed complex gene regulatory networks. Transcription factors have a central role in spatiotemporal control of gene expression and this has motivated us to develop artificial transcription factors that mimic their function. We found that three functions could be mimicked by applying our chemical approaches: i) efficient delivery into organelles that contain target DNA, ii) specific DNA binding to the target genomic region, and iii) regulation of gene expression by interaction with other transcription coregulators. We chose pyrrole-imidazole polyamides (PIPs), sequence-selective DNA binding molecules, as DNA binding domains, and have achieved each of the required functions by introducing other functional moieties. The developed artificial transcription factors have potential as chemical tools that can be used to artificially modulate gene expression to enable cell fate control and to correct abnormal gene regulation for therapeutic purposes.
Topics: DNA; Humans; Imidazoles; Nylons; Pyrroles; Transcription Factors
PubMed: 33332727
DOI: 10.1002/tcr.202000158 -
Drugs in R&D Sep 2020Tenosynovial giant cell tumor is a rare proliferative tumor that arises from the synovium, bursae, or tendon sheaths due to an overproduction of colony-stimulating... (Review)
Review
Tenosynovial giant cell tumor is a rare proliferative tumor that arises from the synovium, bursae, or tendon sheaths due to an overproduction of colony-stimulating factor 1. Historically, treatment options for patients with local or diffuse tenosynovial giant cell tumor have been limited to surgical interventions. However, for some patients, surgical resection could worsen functional limitations and/or morbidity. In August 2019, the FDA approved pexidartinib (TURALIO™, Daiichi Sankyo), the first systemic treatment option for adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations that were not amenable to improvement with surgery. Pexidartinib is an oral tyrosine kinase inhibitor with selective inhibition of colony-stimulating factor 1 receptor and is the first systemic therapy to show significant improvement in overall response rates when compared with placebo. Clinicians using pexidartinib should monitor for liver-related adverse events, which may require treatment interruption, dose reduction, or treatment discontinuation. Pexidartinib provides a novel non-surgical treatment option for patients with tenosynovial giant cell tumor that may significantly improve patients' overall response, range of motion, physical function, tumor volume, and stiffness.
Topics: Administration, Oral; Adult; Aminopyridines; Antineoplastic Agents; Clinical Trials as Topic; Contraindications, Drug; Drug Approval; Drug Interactions; Female; Giant Cell Tumor of Tendon Sheath; Humans; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Protein Kinase Inhibitors; Pyrroles; United States; United States Food and Drug Administration
PubMed: 32617868
DOI: 10.1007/s40268-020-00314-3 -
Accounts of Chemical Research Feb 2021Macrocyclic natural products are plentiful in the bacteria, archaea, and eukaryote domains of life. For the significant advantages that they provide to the producing...
Macrocyclic natural products are plentiful in the bacteria, archaea, and eukaryote domains of life. For the significant advantages that they provide to the producing organisms, evolution has learned how to implement various types of macrocyclization reactions into the different biosynthetic pathways and how to effect them with remarkable ease. Mankind greatly benefits from nature's pool, not least because naturally occurring macrocycles or derivatives thereof serve as important drugs for the treatment of many serious ailments.In stark contrast, macrocyclization reactions are usually perceived as difficult to accomplish by purely chemical means. While it is true that ring closure necessarily entails an entropic loss and may result in the buildup of (considerable) ring strain that must be compensated for in one way or the other, it is also fair to note tremendous methodological advances during the last decades that greatly alleviated this traditional "macrocycle challenge". It is therefore increasingly possible to explore the advantages provided by large as well as medium-size ring systems in a more systematic manner. This venture also holds the promise of increasing the "chemical space" amenable to drug development to a considerable extent.In consideration of this and other important long-term perspectives, it is appropriate to revisit the current state of the art. To this end, a number of vignettes are presented, each of which summarizes a total synthesis project targeting macrocyclic natural products of greatly different chemotypes using a variety of transformations to reach these goals. Although we were occasionally facing "dead ends", which are also delineated for the sake of a complete picture, these case studies illustrate the notion that the formation of a certain macrocyclic perimeter is (usually) no longer seriously limiting. In addition to substantial progress in the "classical" repertoire (macrolactonization and macrolactamization (pateamine A, spirastrellolide, and belizentrin)), various metal-catalyzed reactions have arguably led to the greatest leaps forward. Among them, palladium-catalyzed C-C bond formation (roseophilin and nominal xestocyclamine A) and, in particular, alkene and alkyne metathesis stand out (iejimalide, spirastrellolide, enigmazole, ingenamine, and sinulariadiolide). In some cases, different methods were pursued in parallel, thus allowing for a critical assessment and comparison.To the extent that the macrocyclic challenge is vanishing, the opportunity arises to focus attention on the postmacrocyclization phase. One may stipulate that a well-designed cyclization precursor does not only ensure efficient ring closure but also fosters and streamlines the steps that come after the event. One way to do so is dual (multiple) use in that the functional groups serving the actual cyclization reaction also find productive applications downstream from it rather than being subject to simple defunctionalization. In this context, better insight into the conformational peculiarities of large rings and the growing confidence in their accessibility in a stereochemically well defined format rejuvenate the implementation of transannular reactions or reaction cascades that can lead to rapid and substantial increases in molecular complexity. The examples summarized herein showcase such possibilities, with special emphasis on tranannular gold catalysis and the emerging ruthenium-catalyzed -hydrometalation chemistry for the selective functionalization of alkynes.
Topics: Alkenes; Alkynes; Biological Products; Catalysis; Cyclization; Heterocyclic Compounds, 3-Ring; Lactams, Macrocyclic; Macrolides; Metals; Pyrroles; Spiro Compounds
PubMed: 33507727
DOI: 10.1021/acs.accounts.0c00759 -
ACS Nano Sep 2023Experimental studies and clinical trials of nanoparticles for treating diseases are increasing continuously. However, the reach to the market does not correlate with...
Experimental studies and clinical trials of nanoparticles for treating diseases are increasing continuously. However, the reach to the market does not correlate with these efforts due to the enormous cost, several years of development, and off-target effects like cardiotoxicity. Multicellular organisms such as the () can bridge the gap between and vertebrate testing as they can provide extensive information on systemic toxicity and specific harmful effects through facile experimentation following 3R EU directives on animal use. Since the nematodes' pharynx shares similarities with the human heart, we assessed the general and pharyngeal effects of drugs and polypyrrole nanoparticles (Ppy NPs) using . The evaluation of FDA-approved drugs, such as Propranolol and Racepinephrine reproduced the arrhythmic behavior reported in humans and supported the use of this small animal model. Consequently, Ppy NPs were evaluated due to their research interest in cardiac arrhythmia treatments. The NPs' biocompatibility was confirmed by assessing survival, growth and development, reproduction, and transgenerational toxicity in . Interestingly, the NPs increased the pharyngeal pumping rate of in two slow-pumping mutant strains, JD21 and DA464. Moreover, the NPs increased the pumping rate over time, which sustained up to a day post-excretion. By measuring pharyngeal calcium levels, we found that the impact of Ppy NPs on the pumping rate could be mediated through calcium signaling. Thus, evaluating arrhythmic effects in offers a simple system to test drugs and nanoparticles, as elucidated through Ppy NPs.
Topics: Animals; Humans; Caenorhabditis elegans; Polymers; Pyrroles; Nanoparticles
PubMed: 37624669
DOI: 10.1021/acsnano.3c05245 -
Molecules (Basel, Switzerland) Apr 20221-pyrrole-2,5-dione derivatives are known for their wide range of pharmacological properties, including anti-inflammatory and antimicrobial activities. This study aimed...
1-pyrrole-2,5-dione derivatives are known for their wide range of pharmacological properties, including anti-inflammatory and antimicrobial activities. This study aimed to synthesize new 3,4-dimethyl--pyrrole-2,5-dione derivatives - in the reaction of -substituted amidrazones with 2,3-dimethylmaleic anhydride and evaluate their structural and biological properties. Compounds - were studied by the H-C NMR two-dimensional techniques (HMQC, HMBC) and single-crystal X-ray diffraction (derivatives and ). The anti-inflammatory activity of compounds - was examined by both an anti-proliferative study and a production study on the inhibition of pro-inflammatory cytokines (IL-6 and TNF-α) in anti-CD3 antibody- or lipopolysaccharide-stimulated human peripheral blood mononuclear cell (PBMC) cultures. The antibacterial activity of compounds against , , , , , , and strains was determined using the broth microdilution method. Structural studies of - revealed the presence of distinct and stereoisomers in the solid state and the solution. All compounds significantly inhibited the proliferation of PBMCs in anti-CD3-stimulated cultures. The strongest effect was observed for derivatives -. The strongest inhibition of pro-inflammatory cytokine production was observed for the most promising anti-inflammatory compound .
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Humans; Leukocytes, Mononuclear; Microbial Sensitivity Tests; Pyrroles; Staphylococcus aureus
PubMed: 35566243
DOI: 10.3390/molecules27092891 -
Journal of Enzyme Inhibition and... Dec 2022In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of...
In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found possessed high potency (IC = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner. Also, in response to STING pathway activation, cytokines such as IFN- and IP-10 were induced by in a concentration dependent manner. Finally, we discovered that causes inhibition of tumour growth in 4T1 syngeneic mouse model. This study provides new insight into the designing of novel ENPP1 inhibitors and warrants further development of small molecule immune modulators for cancer immunotherapy.
Topics: Animals; Mice; Phosphoric Diester Hydrolases; Pyrimidines; Pyrophosphatases; Pyrroles; Structure-Activity Relationship
PubMed: 36069240
DOI: 10.1080/14756366.2022.2119566