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Hepatology (Baltimore, Md.) Jul 2022Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the...
BACKGROUND AND AIMS
Roussel Uclaf Causality Assessment Method (RUCAM) for DILI has been hindered by subjectivity and poor reliability. We sought to improve the RUCAM using data from the Drug-Induced Liver Injury Network (DILIN) and the Spanish DILI Registry, published literature, and iterative computer modeling.
APPROACH AND RESULTS
RUCAM criteria were updated, clarified, and computerized. We removed criteria 3 (risk factors) for lack of added value and criteria 4 because we felt it more useful to assess each drug separately. Criteria 6 (drug-specific risk) was anchored to LiverTox likelihood scores. Iterative testing in subsets of 50-100 single-agent, nonherbal cases from both registries was done to optimize performance. We used classification tree analysis to establish diagnostic cutoffs for this revised electronic causality assessment method (RECAM) and compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 DILIN, 96 Spanish DILI). Area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for RECAM and RUCAM. However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, p = 0.14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, p = 0.02; 65 vs. 48 for unlikely/excluded, p = 0.08) than RUCAM diagnostic categories.
CONCLUSIONS
RECAM is an evidence-based update that is at least as capable as RUCAM in diagnosing DILI compared with expert opinion but is better than RUCAM at the diagnostic extremes. RECAM's increased objectivity and clarity will improve precision, reliability, and standardization of DILI diagnosis, but further refinement and validation in other cohorts are needed.
Topics: Causality; Chemical and Drug Induced Liver Injury; Dyphylline; Electronics; Humans; Reproducibility of Results
PubMed: 35014066
DOI: 10.1002/hep.32327 -
The American Journal of Medicine Feb 2023Turmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic, and...
BACKGROUND
Turmeric is a commonly used herbal product that has been implicated in causing liver injury. The aim of this case series is to describe the clinical, histologic, and human leukocyte antigen (HLA) associations of turmeric-associated liver injury cases enrolled the in US Drug-Induced Liver Injury Network (DILIN).
METHODS
All adjudicated cases enrolled in DILIN between 2004 and 2022 in which turmeric was an implicated product were reviewed. Causality was assessed using a 5-point expert opinion score. Available products were analyzed for the presence of turmeric using ultra-high-performance liquid chromatography. Genetic analyses included HLA sequencing.
RESULTS
Ten cases of turmeric-associated liver injury were found, all enrolled since 2011, and 6 since 2017. Of the 10 cases, 8 were women, 9 were White, and median age was 56 years (range 35-71). Liver injury was hepatocellular in 9 patients and mixed in 1. Liver biopsies in 4 patients showed acute hepatitis or mixed cholestatic-hepatic injury with eosinophils. Five patients were hospitalized, and 1 patient died of acute liver failure. Chemical analysis confirmed the presence of turmeric in all 7 products tested; 3 also contained piperine (black pepper). HLA typing demonstrated that 7 patients carried HLA-B*35:01, 2 of whom were homozygous, yielding an allele frequency of 0.450 compared with population controls of 0.056-0.069.
CONCLUSION
Liver injury due to turmeric appears to be increasing in the United States, perhaps reflecting usage patterns or increased combination with black pepper. Turmeric causes potentially severe liver injury that is typically hepatocellular, with a latency of 1 to 4 months and strong linkage to HLA-B*35:01.
Topics: Humans; Female; United States; Adult; Middle Aged; Aged; Male; Curcuma; Dyphylline; Chemical and Drug Induced Liver Injury; Hepatitis
PubMed: 36252717
DOI: 10.1016/j.amjmed.2022.09.026 -
Future Medicinal Chemistry May 2022In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human...
In the last two decades, the world has witnessed the emergence of zoonotic corona viruses (CoVs), which cause mild to severe respiratory diseases in humans. Human coronaviruses (HCoVs), mainly from the alpha-CoV and beta-CoV genera, have evolved to be highly pathogenic, such as SARS-CoV-2 causing the COVID-19 pandemic. These coronaviruses carry functional enzymes necessary for the virus life cycle, which represent attractive antiviral targets. We aimed to therapeutically target the main protease (Mpro) of HCoV-NL63 and HCoV-229E (from alpha-CoV genus) and HCoV-OC43 and SARS-CoV-2 (from beta-CoV genus). Through virtual screening, we identified an FDA-approved drug dyphylline, a xanthine derivate, that binds to the catalytic dyad residues; histidine and cystine of the Mpro structures. Importantly, dyphylline dose-dependently inhibited the viral replication in cell culture models infected with the viruses. Our findings support the repurposing of dyphylline as a pan-coronavirus antiviral agent.
Topics: Antiviral Agents; Drug Repositioning; Dyphylline; Humans; Pandemics; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35387498
DOI: 10.4155/fmc-2021-0311 -
Canadian Medical Association Journal Sep 1981
PubMed: 20313615
DOI: No ID Found -
Chemical Science Aug 2022The development of chemoselective C(sp)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective,...
The development of chemoselective C(sp)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen(H)/deuterium(D) isotope exchange of alcohols using deuterium oxide (DO) as the primary deuterium source. This method enables the direct, chemoselective deuteration of primary and secondary alcohols under basic or neutral conditions without being affected by coordinative functional groups such as imidazole and tetrazole. Successful substrates for deuterium labelling include the pharmaceuticals losartan potassium, rapidosept, guaifenesin, and diprophylline. The deuterated losartan potassium shows higher stability towards the metabolism by CYP2C9 than the protiated analogue. Kinetic and DFT studies indicate that the direct deuteration proceeds through dehydrogenation of alcohol to the carbonyl intermediate, conversion of [Ir-H] to [Ir-D] with DO, and deuteration of the carbonyl intermediate to give the α-deuterated product.
PubMed: 35975159
DOI: 10.1039/d2sc01805e -
ACS Omega Aug 2022The assembly of an inclusion complex in an aqueous medium using a metabolizer drug (dyphylline) as guest and β-cyclodextrin as host has been established, which is...
Probing the Molecular Assembly of a Metabolizer Drug with β-Cyclodextrin and Its Binding with CT-DNA in Augmenting Antibacterial Activity and Photostability by Physicochemical and Computational Methodologies.
The assembly of an inclusion complex in an aqueous medium using a metabolizer drug (dyphylline) as guest and β-cyclodextrin as host has been established, which is extremely appropriate for a variety of applications in modern biomedical sciences. The formation of the inclusion complex is established by H NMR, and surface tension and conductivity measurements demonstrate that the inclusion complex was produced with 1:1 stoichiometry. The thermodynamic parameters based on density, viscosity, and refractive index measurements were used to determine the nature of the complex. This research also forecasts how dyphylline will release in the presence of CT-DNA without any chemical modifications. The produced insertion complex (IC) has a higher photostability due to the drug dyphylline being protected by β-CD. The antibacterial activity of dyphylline greatly improved after complexation and exhibited higher toxicity against Gram-negative (highest against ) in comparison to Gram-positive bacteria. The encapsulation mode of the dyphylline molecule into the cavity of the β-CD was also investigated using DFT to confirm preliminary results.
PubMed: 35936474
DOI: 10.1021/acsomega.2c01902 -
Journal of Biomolecular Structure &... Mar 2022In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which...
In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which killed thousands of people worldwide. Therefore, the necessity to find out the potential therapeutic pharmaceuticals is imperious. This study investigates the inhibitory effect of SARS-CoV-2 3-chymotrypsin-like protease (3CL) using caffeine and caffeine-containing pharmaceuticals (3CPs) based on molecular dynamics simulations and free energy calculations by means of molecular mechanics-Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics-generalized-Born surface area (MMGBSA). Of these 3CPs, seven drugs approved by the US-Food and Drug Administration have shown a good binding affinity to the catalytic residues of 3CL of His and Cys: caffeine, theophylline, dyphylline, pentoxifylline, linagliptin, bromotheophylline and istradefylline. Their binding affinity score ranged from -4.9 to -8.6 kcal/mol. The molecular dynamic simulation in an aqueous solution of docked complexes demonstrated that the 3CPs conformations bound to the active sites of 3CL during 200 ns molecular dynamics simulations. The free energy of binding also confirms the stability of the 3CPs-3CL complexes. To our knowledge, this study shows for the first time very inexpensive drugs available in large quantities that can be potential inhibitors against 3CL. In particular, the repurposing of linagliptin, and caffeine are recommended for COVID-19 treatment after and clinical trial validation.Communicated by Ramaswamy H. Sarma.
Topics: Caffeine; Chymases; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 33094705
DOI: 10.1080/07391102.2020.1835732 -
Bioorganic Chemistry Oct 2022Alcohol dehydrogenases (ADHs; EC 1.1.1.1) have been widely used for the reversible redox reactions of carbonyl compounds (i.e., aldehydes and ketones) and primary or...
Alcohol dehydrogenases (ADHs; EC 1.1.1.1) have been widely used for the reversible redox reactions of carbonyl compounds (i.e., aldehydes and ketones) and primary or secondary alcohols, often resulting in optically pure hydroxyl products with high added value. In this work, we report a concise chemoenzymatic route toward xanthine-based enantiomerically pure active pharmaceutical ingredients (API) - proxyphylline, xanthinol, and diprophylline employing various recombinant short-chain ADHs with (R)- or (S)-selectivity as key biocatalysts. By choosing the appropriate ADH, the (R)- as well as the (S)-enantiomer of proxyphylline was prepared in excellent enantiomeric excess (99-99.9% ee), >99% conversion, and the isolated yield ranging from 65% to 74%, depending on the used biocatalyst (ADH-A from Rhodococcus ruber or a variant derived from Lactobacillus kefir, Lk-ADH-Lica). In turn, E. coli/ADH-catalyzed bioreduction of the carbonylic precursor of xanthinol and diprophylline furnished the corresponding (S)-chlorohydrin in >99% ee, >99% conversion, and 80% yield (in the case of Lk-ADH-Lica); while the (R)-counterpart was afforded in 94% ee, 64% conversion, and 41% yield (in the case of SyADH from Sphingobium yanoikuyae). After further chemical functionalization of the key (S)-chlorohydrin intermediate, the desired homochiral (R)-xanthinol (>99% ee) was obtained in 97% yield and (S)-diprophylline (>99% ee) in 90% yield. The devised biocatalytic method is straightforward and thus might be considered practical in the manufacturing of title pharmaceuticals.
Topics: Biocatalysis; Chlorohydrins; Dyphylline; Escherichia coli; Hydrogen; Stereoisomerism; Theophylline
PubMed: 35777234
DOI: 10.1016/j.bioorg.2022.105967 -
Journal of Hepatology Feb 2023Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical...
BACKGROUND & AIMS
Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN).
METHODS
Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661).
RESULTS
Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10), and non-NTF DILI (OR 3.34, p = 0.003).
CONCLUSION
NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies.
IMPACT AND IMPLICATIONS
Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin.
Topics: Humans; Nitrofurantoin; Hepatitis, Autoimmune; Chemical and Drug Induced Liver Injury, Chronic; HLA-DRB1 Chains; Dyphylline; Chemical and Drug Induced Liver Injury; Risk Factors; HLA Antigens; Fibrosis; Necrosis
PubMed: 36152763
DOI: 10.1016/j.jhep.2022.09.010