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Yakugaku Zasshi : Journal of the... 2024An aqueous solution of 2,3-cis gallate type catechin (-)-epigallocatechin-3-O-gallate (EGCg) and caffeine afforded a precipitate of Creaming-down Phenomenon, which... (Review)
Review
An aqueous solution of 2,3-cis gallate type catechin (-)-epigallocatechin-3-O-gallate (EGCg) and caffeine afforded a precipitate of Creaming-down Phenomenon, which crystallized slowly for about three months to give a colorless block crystal. By X-ray crystallographic analysis, the crystal was determined to be a 2 : 2 complex of EGCg and caffeine, in which caffeine molecules were captured in a hydrophobic space formed with three aromatic A, B, and B' rings of EGCg. It was considered that the solubility of the 2 : 2 complex in water rapidly decreased and the 2 : 2 complex precipitated from aqueous solution. The hydrophobic spaces of EGCg captured a variety of heterocyclic compounds, and the molecular capture abilities of heterocyclic compounds using EGCg from the aqueous solutions were evaluated. Since the C ring of EGCg has two chiral carbon atoms, C and C, the hydrophobic space of EGCg was a chiral space. EGCg captured diketopiperazine cyclo(Pro-Xxx) (Xxx=Phe, Tyr) and pharmaceuticals with a xanthine skeleton, proxyphylline and diprophylline, in the hydrophobic space, and recognized their chirality.
Topics: Catechin; Tea; Caffeine; Hydrophobic and Hydrophilic Interactions; Solubility; Crystallography, X-Ray; Stereoisomerism; Water; Crystallization; Solutions; Heterocyclic Compounds; Xanthines
PubMed: 38945846
DOI: 10.1248/yakushi.24-00086 -
Tierarztliche Praxis. Ausgabe K,... Apr 2024In 2023, 2 novel pharmaceutical agents for small animals were released on the German market: the structural but non-functional analog of the inhibitory neurotransmitter...
In 2023, 2 novel pharmaceutical agents for small animals were released on the German market: the structural but non-functional analog of the inhibitory neurotransmitter gamma-aminobutyric acid pregabalin with an anxiolytic active component and the dopamine agonist ropinirole in form of eye drops to induce vomiting. Two established active veterinary pharmaceutical ingredients became available for additional species: The phosphorus compound butafosfan was additionally approved for horses, dogs and cats and the mineral sodium chloride as an isotonic sodium chloride solution was also approved for rabbits and guinea pigs. In addition, for small animals, there were new releases of an agent (dexamethasone) in a novel pharmaceutical formulation, one drug with a new route of administration (hydrocortisone aceponate), one drug with a new content of the active ingredient (firocoxib) as well as one veterinary drug with a new combination of active ingredients in a novel pharmaceutical formulation (gentamicin+mometasone+posaconazole). Furthermore, one combination of active ingredients (diprophylline+heptaminol) is available on the market for small animals again.
Topics: Animals; Veterinary Drugs; Dogs; Cats; Horses; Germany; Rabbits
PubMed: 38701806
DOI: 10.1055/a-2291-7019 -
Tierarztliche Praxis. Ausgabe G,... Apr 2024In 2023, no new active pharmaceutical ingredients were released on the German market for horses and food-producing animals. Two established veterinary active...
In 2023, no new active pharmaceutical ingredients were released on the German market for horses and food-producing animals. Two established veterinary active pharmaceutical ingredients became available for additional species: The phosphorus compound butafosfan was also approved for horses, dogs, and cats and the mineral sodium chloride as an isotonic sodium chloride solution was also approved for rabbits and guinea pigs. In addition, for small animals, there were new releases of an agent (pergolidmesilate) in a novel pharmaceutical formulation and a lower content of the active ingredient, one drug (fluralaner) in a smaller package size as well as one drug (oxalic acid dehydrate) with a new route of administration. Furthermore, one combination of active ingredients (diprophylline+heptaminol) is available on the market for horses and food producing animals again.
Topics: Animals; Horses; Veterinary Drugs; Germany; Dogs; Cats; Guinea Pigs; Rabbits
PubMed: 38701800
DOI: 10.1055/a-2291-7062 -
Digestive Diseases and Sciences Apr 2024To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database.
OBJECTIVE
To describe hepatotoxicity due to amiodarone and dronedarone from the DILIN and the US FDA's surveillance database.
METHODS
Hepatotoxicity due to amiodarone and dronedarone enrolled in the U.S. Drug Induced Liver Injury Network (DILIN) from 2004 to 2020 are described. Dronedarone hepatotoxicity cases associated with liver biopsy results were obtained from the FDA Adverse Event Reporting System (FAERS) from 2009 to 2020.
RESULTS
Among DILIN's 10 amiodarone and 3 dronedarone DILIN cases, the latency for amiodarone was longer than with dronedarone (388 vs 119 days, p = 0.50) and the median ALT at DILI onset was significantly lower with amiodarone (118 vs 1191 U/L, p = 0.05). Liver biopsies in five amiodarone cases showed fibrosis, steatosis, and numerous Mallory-Denk bodies. Five patients died although only one from liver failure. One patient with dronedarone induced liver injury died of a non-liver related cause. Nine additional cases of DILI due to dronedarone requiring hospitalization were identified in the FAERS database. Three patients developed liver injury within a month of starting the medication. Two developed acute liver failure and underwent urgent liver transplant, one was evaluated for liver transplant but then recovered spontaneously, while one patient with cirrhosis died of liver related causes.
CONCLUSION
Amiodarone hepatotoxicity resembles that seen in alcohol related liver injury, with fatty infiltration and inflammation. Dronedarone is less predictable, typically without fat and with a shorter latency of use before presentation. These differences may be explained, in part, by the differing pharmacokinetics of the two drugs leading to different mechanisms of hepatotoxicity.
Topics: Humans; Dronedarone; Amiodarone; Anti-Arrhythmia Agents; Dyphylline; Chemical and Drug Induced Liver Injury
PubMed: 38416280
DOI: 10.1007/s10620-023-08251-2 -
Biomolecules Dec 2023Gout is characterized by the formation of monosodium urate crystals in peripheral joints. We carried out laboratory studies to investigate the effect of adding nine...
Gout is characterized by the formation of monosodium urate crystals in peripheral joints. We carried out laboratory studies to investigate the effect of adding nine different methylxanthines and two different methylated uric acid derivatives on the development of these crystals over the course of 96 h in a medium whose composition was similar to that of synovial fluid. Our results showed that 7-methylxanthine reduced or totally prevented crystal formation; 1-methylxanthine, 3-methylxanthine, 7-methyluric acid, and 1,3-dimethyluric acid had weaker effects, and the other molecules had no apparent effect. The presented results indicate that a 7-methylxanthine concentration of about 6 × 10 M (10 mg/L) prevented the formation of crystals for an initial urate concentration of 1.78 × 10 M (300 mg/L) in the presence of 0.4 M of Na for 96 h at 25 °C and a pH of 7.4. We attribute these results to alterations in thermodynamics, not kinetics. Our results suggest that prevention of crystallization in vivo could be achieved by direct oral administration of 7-methylxanthine or other methylxanthines that are metabolized to 7-methylxanthine. For example, the hepatic metabolism of theobromine leads to significant plasma levels of 7-methylxanthine (14% of the initial theobromine concentration) and 3-methylxanthine (6% of the initial theobromine concentration); however, 7-methyluric acid is present at very low concentrations in the plasma. It is important to consider that several of the specific molecules we examined (theobromine, caffeine, theophylline, dyphylline, etophylline, and pentoxifylline) did not directly affect crystallization.
Topics: Uric Acid; Theobromine; Solubility; Caffeine
PubMed: 38136640
DOI: 10.3390/biom13121769 -
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 -
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 -
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 -
The American Journal of Gastroenterology Sep 2022Hepatitis E virus (HEV) infection rarely causes icteric hepatitis, yet 10%-40% of adult Americans have serological evidence of previous infection. The aim of this study...
INTRODUCTION
Hepatitis E virus (HEV) infection rarely causes icteric hepatitis, yet 10%-40% of adult Americans have serological evidence of previous infection. The aim of this study was to investigate the incidence, presentation, and outcome of acute and previous HEV infection in a large cohort of patients with suspected drug-induced liver injury (DILI).
METHODS
Serum samples from 2012 patients enrolled in the DILI Network were tested for anti-HEV immunoglobulin G (IgG). Those with detectable anti-HEV IgG underwent testing for anti-HEV IgM; those with detectable anti-HEV immunoglobulin m (IgM) were tested for HEV RNA.
RESULTS
Anti-HEV IgG was detected in 407 (20%) patients and associated with increasing subject age and earlier year of enrollment. The median age of seropositive subjects was more than a decade higher than seronegative subjects (59.8 vs 48.7 years). The overall prevalence of anti-HEV declined from 22% (2004-2011) to 18% (2012-2019), suggestive of a cohort effect. The frequency of acute hepatitis E (median ALT = 1231 IU/L) also decreased from 3% (2004-2008) to 1.2% (2009-2013) to 0.6% (2014-2019). These results suggest that acute HEV infection is usually subclinical and was much more frequent in this cohort before 2004.
DISCUSSION
Acute HEV infection accounts for less than 1% of suspected American DILI cases and is more frequent in older men. Previous HEV infection is also most commonly seen in older individuals. Clinicians should consider testing for unsuspected acute HEV infection in older adult patients with acute hepatocellular DILI and jaundice.
Topics: Acute Disease; Aged; Chemical and Drug Induced Liver Injury; Dyphylline; Hepatitis Antibodies; Hepatitis E; Hepatitis E virus; Humans; Immunoglobulin G; Immunoglobulin M; Incidence; Male; Middle Aged; Prospective Studies; RNA, Viral; United States
PubMed: 35973149
DOI: 10.14309/ajg.0000000000001869 -
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