Therapeutic effect of liposomal-N-acetylcysteine against acetaminophen-induced hepatotoxicity

Abstract

Background: Acetaminophen (APAP) is an antipyretic analgesic drug that when taken in overdose causes depletion of glutathione (GSH) and hepatotoxicity. N-acetylcysteine (NAC) is the antidote of choice for the treatment of APAP toxicity; however, due to its short-half-life repeated dosing of NAC is required.

Purpose: To determine whether a NAC-loaded liposomal formulation (Lipo-NAC) is more effective than the conventional NAC in protecting against acute APAP-induced hepatotoxicity.

Methods: Male Sprague–Dawley rats were challenged with an intragastric dose of APAP (850?mg/kg b.wt.); 4?h later, animals were administered saline, NAC, Lipo-NAC or empty liposomes and sacrificed 24?h post-APAP treatment.

Results: APAP administration resulted in hepatic injury as evidenced by increases in plasma bilirubin, alanine (AST) and aspartate (ALT) aminotransferase levels and tissue levels of lipid peroxidation and myeloperoxidase as well as decreases in hepatic levels of reduced GSH, GSH peroxidase and GSH reductase. Treatment of animals with Lipo-NAC was significantly more effective than free NAC in reducing APAP-induced hepatotoxicity. Histological evaluation showed that APAP caused periacinar hepatocellular apoptosis and/or necrosis of hepatocytes around the terminal hepatic venules which was reduced by NAC treatment, the degree of reduction being greater for Lipo-NAC.

Conclusion: These data suggest that administration of Lipo-NAC ameliorated the APAP-induced hepatotoxicity.     

Metabolic phenotyping applied to pre-clinical and clinical studies of acetaminophen metabolism and hepatotoxicity

Abstract

Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high-resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF.     

GC-MS analysis and hepatoprotective activity of the n-hexane extract of Acrocarpus fraxinifolius leaves against paracetamol-induced hepatotoxicity in male albino rats

Context: In Egypt, the burden of liver diseases is exceptionally high.

Objective: To investigate the components of the n-hexane extract of Acrocarpus fraxinifolius Arn. (Leguminosae) and its hepatoprotective activity against paracetamol (APAP)-induced hepatotoxicity in rats.

Material and methods: TRACE GC ultra gas chromatogaphic spectrometry was used for extract analysis. Thirty albino rats were divided into six groups (five rats in each). Group 1 was the healthy control; Groups 2 and 3 were healthy treated groups (250 and 500?mg/kg b.w. of the extract, respectively) for seven days. Group 4 was hepatotoxicity control (APAP intoxicated group). Groups 5 and 6 received APAP?+?extract 250 and APAP?+?extract 500, respectively.

Results: Chromatographic analysis revealed the presence of 36 components. Major compounds were α-tocopherol (18.23%), labda-8 (20)-13-dien-15-oic acid (13.15%), lupeol (11.93%), phytol (10.95%) and squalene (7.19%). In the acute oral toxicity study, the mortality rates and behavioural signs of toxicity were zero in all groups (doses from 0 to 5?g/kg b.w. of A. fraxinifolius). LD₅₀ was found to be greater than 5?g/kg of the extract. Only the high dose (500?mg/kg b.w.) of extract significantly alleviated the liver relative weight (4.01?±?0.06) and biomarkers, as serum aspartate aminotransferase (62.87?±?1.41), alanine aminotransferase (46.74?±?1.45), alkaline phosphatase (65.96?±?0.74), lipid profiles (180.39?±?3.51), bilirubin profiles (2.30?±?0.06) and hepatic lipid peroxidation (114.20?±?2.06), and increased body weight (11.58?±?0.20), serum protein profile (11.09?±?0.46) and hepatic total antioxidant capacity (23.78?±?0.66) in APAP-induced hepatotoxicity in rats.

Conclusion: Our study proves the antihepatotoxic/antioxidant efficacies of A. fraxinifolius hexane extract.     

Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats

Context: Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects.

Objective: The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated.

Materials and methods: Male Wistar rats were pretreated with RA (10, 50 and 100?mg/kg, i.g.) for one week. On day 7, rats received APAP (500?mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined.

Results: APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6?±?0.21?nmol/mg) as well as a decrease in the contents of TAC (1.75?±?0.14?μmol/g), GSH (1.9?±?0.22?μmol/g) and GST) 3.2?±?0.28?U/mg). RA treatment decreased MDA (4.32?±?0.35?nmol/mg) but increased the contents of TAC (3.51?±?0.34?μmol/g), GSH (3.42?±?0.16?μmol/g) and GST (5.71?±?0.71?μmol/g) in APAP group. RA 100?mg/kg decreased ALT (91.5?±?1.5?U/L), AST (169?±?8.8?U/L) and CYP450 (3?±?0.2?nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group.

Discussion and conclusions: This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.     

Therapeutic potential of Moringa oleifera extracts against acetaminophen-induced hepatotoxicity in rats

Context: Moringa oleifera Lam. (Moringaceae) is a rich source of essential minerals and antioxidants; it has been used in human and animal nutrition. The leaves and flowers are being used by the population with great dietary importance.

Objective: The present study was to investigate the therapeutic effects of the hydroethanolic extract of Moringa oleifera (MO) leaves and flowers against hepatotoxicity induced by acetaminophen (APAP) in rats.

Materials and methods: In the hepatoprotective study, either flowers or leaves of hydroethanolic extract (200 or 400?mg/kg bw through IP injection) were administered an hour after APAP administration. N-Acetylcysteine (NAC) was used as the positive control for this study. Liver and kidney function tests including lipid peroxidation levels were analyzed and histopathological changes of liver and kidney were also observed.

Results: Acetaminophen-induced hepatotoxicity increased the activities of liver marker enzymes. Histologically, the liver was observed to have inflammation and bridging necrosis. Liver marker enzymes were significantly reduced when treated with flower and leaf extracts of MO in animals with APAP induced toxicity. In addition, there were no significant changes observed in clinical markers of kidney function. Histological observation on liver tissue from the rats treated with MO flower and leaf extract showed reduction in the severity of the liver damage.

Discussion and conclusion: These results indicated the possible therapeutic action of flower and leaf extract from MO in protecting liver damage in rats given an over dosage of APAP.     

3,4-Dihydroxyphenylacetic acid,a microbiota-derived metabolite of quercetin,attenuates acetaminophen (APAP)-induced liver injury through activation of Nrf-2

1. Acetaminophen (APAP) overdose leads to severe hepatotoxicity. 3,4-dihydroxyphenylacetic acid (DOPAC) is a scarcely studied microbiota-derived metabolite of quercetin. The aim of this study was to determine the protective effect of DOPAC against APAP-induced liver injury.

2. Mice were treated intragastrically with DOPAC (10, 20 or 50?mg/kg) for 3 days before APAP (300?mg/kg) injection. APAP alone caused increase in serum aminotransferase levels and changes in hepatic histopathology. APAP also promoted oxidative stress by increasing lipid peroxidation and decreasing anti-oxidant enzyme activities. These events led to hepatocellular necrosis and reduced liver function. DOPAC increased nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation to the nucleus and enhanced the expression of phase II enzymes and anti-oxidant enzymes, and thereby reduced APAP hepatotoxicity and enhanced anti-oxidant ability.

3. Our data provide evidence that DOPAC protected the liver against APAP-induced injury, which is involved in Nrf-2 activation, implying that DOPAC can be considered as a potential natural hepatoprotective agent.     

Screening of herbal components for attenuating amiodarone-induced hepatotoxicity on gel-entrapped rat hepatocytes

Abstract

Amiodarone (AMD) is a hepatotoxic drug that has been widely used as a class III antiarrhythmic drug. Because, to date, only a few kinds of protectants are able to reduce AMD hepatotoxicity, this article utilized gel-entrapped rat hepatocytes to screen effective protectants from a series of herbal compounds for their effects against AMD-induced toxicity. Herbal compounds, including matrine, silibinin, glycyrrhizic acid, schisandrin B, epigallocatechin gallate and anisodamine, were cotreated with AMD to assess their protective effect, whereas vitamin E, which has been shown to be protective in rats, was selected as a control. It was found that vitamin E, as with its function in rats, provided the best protection in gel-entrapped rat hepatocytes, whereas silibinin, a major component of silymarin, could largely reduce AMD-induced hepatotoxicity, performing a similar function as silymarin in rats. The results illustrated that gel-entrapped hepatocytes may reflect the protective effects of drugs and serve as a reliable model for screening hepatoprotectants. Moreover, matrine, a widely used monomer of the traditional Chinese medicine, Sophora flavescens, for treatment of arrhythmia, was evidenced to show some effective protections against AMD hepatotoxicity. Taken together, gel-entrapped rat hepatocytes may provide a platform for screening effective candidates from the herbal component library.     

Changes in pharmacokinetic profiles of acetaminophen and its glucuronide after pretreatment with combinations of N-acetylcysteine and either glycyrrhizin,silibinin or spironolactone in rat

Abstract

1. The present study was to investigate the effects of giving N-acetylcysteine (NAC) alone and in combination with either glycyrrhizin (GL), silibinin (SIB) or spironolactone (SL) on the plasma pharmacokinetic (PK) profiles, hepatic exposure, biliary excretion and urinary excretion of acetaminophen (APAP) and its major metabolite, acetaminophen glucuronide (AG).

2. Groups of rats (n?=?5) were pretreated with oral doses of either NAC, NAC?+?GL, NAC?+?SIB or NAC?+?SL on five occasions every 12?h. At 1?h, after the last dose, they received APAP (200?mg/kg) by intraperitoneal injection. Blood, bile, liver and urine samples were collected at various times after APAP injection and analyzed for APAP and AG by HPLC. NAC alone and NAC?+?SIB did not significantly change the PK profiles of APAP and AG. In contrast, NAC?+?GL decreased the biliary excretion of APAP and AG leading to accumulation of APAP in the liver and systemic circulation whereas NAC?+?SL [multidrug resistance associated 2 (Mrp2) inducer] increased the biliary excretion of AG and decreased the hepatic exposure to APAP and AG.

3. Our results suggest that Mrp2 inhibitor GL should be discouraged with NAC to treat APAP hepatotoxicity. Such PK drug–drug interactions should be considered in the treatment of APAP-induced liver injury.     

Protective effects of exogenous glutathione and related thiol compounds against drug-induced liver injury

An overdose of acetaminophen (APAP) causes liver injury both in experimental animals and humans. N-acetylcysteine (NAC) is clinically used as an antidote for APAP intoxication, and it is thought to act by providing cysteine as a precursor of glutathione, which traps a reactive metabolite of APAP. Other hepatoprotective mechanisms of NAC have also been suggested. Here, we examined the effects of thiol compounds with different abilities to restore hepatic glutathione, on hepatotoxicity of APAP and furosemide in mice. Overnight-fasted male CD-1 mice were given APAP or furosemide intraperitoneally. NAC, cysteine, glutathione, or glutathione-monoethyl ester was administered concomitantly with APAP or furosemide. All thiol compounds used in this study effectively protected mice against APAP-induced liver injury. Only glutathione-monoethyl ester completely prevented APAP-induced early hepatic glutathione depletion. Cysteine also significantly restored hepatic glutathione levels. NAC partially restored glutathione levels. Exogenous glutathione had no effect on hepatic glutathione loss. NAC and glutathione highly stimulated the hepatic expression of cytokines, particularly interleukin-6, which might be involved in the alleviation of APAP hepatotoxicity. Furosemide-induced liver injury, which does not accompany hepatic glutathione depletion, was also attenuated by NAC and exogenous glutathione, supporting their protective mechanisms other than replenishment of glutathione. In conclusion, exogenous thiols could alleviate drug-induced liver injury. NAC and glutathione might exert their effects, at least partially, via mechanisms that are independent of increasing hepatic glutathione, but probably act through cytokine-mediated and anti-inflammatory mechanisms.     

Hepatoprotective effects of DL-α-lipoic acid and α-Tocopherol through amelioration of the mitochondrial oxidative stress in acetaminophen challenged rats

Abstract

Acetaminophen (APAP) is known to induce liver mitochondrial dysfunction leading to acute hepatotoxicity. Effect of DL-α-lipoic acid (LA) and α-tocopherol (α-Toc) against the APAP-induced liver mitochondrial damage was evaluated in rats. LA (100?mg/kg, p.o.) and α-Toc (100?mg/kg, p.o.) were given once daily for 15?d, prior to the APAP administration (3?g/kg, p.o). Hepatic damage was confirmed by determining the activities of serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase and alkaline phosphatase, 4?h after the single dose of APAP. To assess the mitochondrial damage, the activities of antioxidant enzymes, Krebs’ cycle dehydrogenases and mitochondrial electron transport chain complexes, and levels of reactive oxygen species (ROS), reduced glutathione, lipid peroxidation (malondialdehyde, MDA) as well as the mitochondrial membrane potential (Δψmt) were evaluated. The activities of mitochondrial enzymes and Δψmt were significantly (p?<?0.01) decreased and the level of ROS and MDA were significantly (p?<?0.01) increased due to APAP challenge. LA and α-Toc treatment significantly enhanced the activities of mitochondrial enzymes and Δψmt than that of control group; whereas the levels of ROS and MDA were decreased. The results of the study concluded that the liver damage induced by APAP was significantly ameliorated by LA and α-Toc. LA showed more protection than that of α-Toc. The protection can be partially ascribed to their mitochondrial protective effects through their antioxidant activity which could decrease the level of ROS and by direct enhancement of Δψmt.     

Cancer prevention and treatment using combination therapy with natural compounds

ABSTRACT

Introduction: Naturally occurring compounds play an essential role in the prevention and treatment of various cancers. There are more than 100 plant and animal based natural compounds currently in clinical use.

Areas covered: 1) The importance of natural products combinations in the prevention and treatment of cancer, 2) the need to maximize efficacy while minimizing side effects when using natural product combinations, and 3) specifics related to plant and animal derived natural products, as well as agents derived from natural products. Therapies using natural compounds that have been investigated, their rationale, mechanism of action and findings are reviewed. When the data warrant it, combined interventions that appear to increase efficacy (compared with monotherapy) while minimizing toxicity have been highlighted. Pubmed was used to search for relevant publications.

Expert opinion: Combination therapy with natural compounds has the potential to be more effective than single agent therapy. Similar to pharmacologic agents, the goal is to maximize efficacy while mimimizing potential side effects. There is an increasing research focus on the development of agents derived from natural products, with notable successes already achieved from the effort.     

Hospitalization costs and resource allocation in cholecystectomy with use of intravenous versus oral acetaminophen

Objective: To evaluate intravenous (IV) acetaminophen (APAP) vs oral APAP use as adjunctive analgesics in cholecystectomy patients by comparing associated hospital length of stay (LOS), hospital costs, opioid use, and rates of nausea/vomiting, respiratory depression, and bowel obstruction.

Methods: We conducted a retrospective analysis of the Premier Database (January 2012 to September 2015) including cholecystectomy patients who received either IV APAP or oral APAP. Differences in LOS, hospitalization costs, mean daily morphine equivalent dose (MED), and potential opioid-related adverse events were estimated. Multivariable logistic regression was performed for the binary outcomes and instrumental variable regressions, using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for continuous outcomes. Models were adjusted for patient demographics, clinical risk factors, and hospital characteristics.

Results: Among 61,017 cholecystectomy patients, 31,133 (51%) received IV APAP. Subjects averaged 51 and 57 years of age, respectively, in the IV and oral APAP cohorts. In the adjusted models, IV APAP was associated with 0.42 days shorter LOS (95% CI?=?–0.58 to –0.27; p?p?p?=?.0005), and lower rates of respiratory depression (odds ratio [OR]?=?0.89, 95% CI?=?0.82–0.97; p?=?.006), and nausea and vomiting (OR?=?0.86, 95% CI?=?0.86–0.86; p?Conclusions: In patients having cholecystectomy, the addition of IV APAP to perioperative pain management is associated with shorter LOS, lower costs, reduced opioid use, and less frequent nausea/vomiting and respiratory depression compared to oral APAP. These findings should be confirmed in a prospective study comparing IV and oral APAP.     

Combretastatin-based compounds with therapeutic characteristics: a patent review

ABSTRACT

Introduction: Combretastatins represent a potent class of phenolic-stilbene natural products that function as colchicine binding site inhibitors of tubulin polymerization and have been advanced as promising anticancer lead compounds. Among them, combretastatin A-4 is the most potent lead molecule due to its broad spectrum cytotoxicity against a variety of tumors. However, low water solubility due to its high lipophilic nature and inter-conversion of olefinic double bond from more active cis to less active trans-conformation poses limitations to its clinical utility. However, different approaches including prodrugs, salt formations, structural modifications, prevention of inter-conversion of the olefinic bond and changes to the substitution pattern on the rings of combretastatin A-4 were investigated and successfully resulted in different combretastatin-based molecules that demonstrated varying levels of potency against different types of tumors during their in-vitro and in-vivo studies.

Areas covered: This review covers the patents over a period of 2008–2018.

Expert opinion: Molecular hybridization and prodrug designing imparted multi-targeted actions to combretastatin derivatives. Currently, various combretastatin derivatives are under clinical trials. These derivatives could be used to treat disorders other than cancer, due to their vascular disrupting action.     

Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways

1. Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways.

2. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs.

3. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200?mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues.

4. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator.

     

Alleviation of doxorubicin-induced nephrotoxicity and hepatotoxicity by chrysin in Wistar rats

Abstract

Objective: Doxorubicin (DXR) is an anticancer drug used in the treatment of many human malignancies. However, its clinical use is limited because of several side effects like cardiotoxicity, nephrotoxicity and hepatotoxicity. In the present study, we investigated the protective efficacy of chrysin against DXR-induced oxidative stress, nephro- and hepatotoxicity in male Wistar rats using biochemical and histopathological approaches.

Methodology: Wistar rats were subjected to concomitant pre- and post-phylactic oral treatment of chrysin (40 and 80?mg/kg b.wt.) against nephro- and hepatotoxicity induced by single i.p. injection of DXR (40?mg/kg b.wt). Nephrotoxicity and hepatotoxicity were assessed by measuring the level of serum creatinine, BUN, AST, ALT and LDH. The level of antioxidant armory of kidney and liver tissue was also measured.

Key findings: Treatment with chrysin significantly decreased the levels of serum toxicity markers and additionally elevated antioxidant defense enzyme levels. Histopathological changes further confirmed the biochemical results showing that DXR caused significant structural damage to kidney and liver tissue architecture which were reversed with chrysin.

Conclusion: The results suggest that chrysin attenuated nephro and hepatic damage induced by DXR.     

Comparative analysis of length of stay,hospitalization costs,opioid use,and discharge status among spine surgery patients with postoperative pain management including intravenous versus oral acetaminophen

Background: Recovery from spine surgery is oriented toward restoring functional health outcomes while reducing resource use. Optimal pain management is a key to reaching these objectives. We compared outcomes of spine surgery patients who received standard pain management including intravenous (IV) acetaminophen (APAP) vs. oral APAP.

Methods: We performed a retrospective analysis of the Premier database (January 2012 to September 2015) comparing spine surgery patients who received pain management with IV APAP to those who received oral APAP, with no exclusions based on additional pain management. We performed multivariable logistic regression for the discharge and all cause 30-day readmission to the same hospital outcomes and instrumental variable regressions using the quarterly rate of IV APAP use for all hospitalizations by hospital as the instrument in two-stage least squares regressions for length of stay (LOS), hospitalization costs, and average daily morphine equivalent dose (MED) outcomes. Models adjusted for age, gender, race, admission type, 3M All Patient Refined Diagnosis Related Group severity of illness and risk of mortality, hospital size, and indicators for whether the hospital was an academic center and whether it was urban or rural.

Results: We identified 112,586 spine surgery patients with 51,835 (46%) having received IV APAP. Subjects averaged 57 and 59 years of age respectively in the IV APAP and oral APAP cohorts and were predominantly non-Hispanic Caucasians and female. In our adjusted models, IV APAP was associated with 0.68 days shorter LOS (95% CI: ?0.76 to ?0.59, p?p?p?p?Conclusions: Compared to oral APAP, managing post-spine-surgery pain with IV APAP is associated with less resource use, lower costs, lower doses of opioids, and improved discharge status.     

Hepatoprotection by chemical constituents of the marine brown alga Spatoglossum variabile: A relation to free radical scavenging potential

Context: In the course of searching hepatoprotective agents from natural sources, the protective effect of chemical constituents of the marine brown alga Spatoglossum variabile Figaro et DE Notar (Dictyoaceae) against CCl₄-induced liver damage in Wistar rats was investigated. The compounds were first investigated for in vitro radical scavenging potential and were also tested for β-glucuronidase inhibition to further explore the relationship between hepatoprotection and antiradical potential.

Methods: The compounds cinnamic acid esters 1 and 2 and aurone derivatives 3 and 4 were first investigated for in vitro radical scavenging potential against 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH), and superoxide anion radicals. In vivo hepatoprotective studies were performed in seven groups (n = 6) of Wistar rats. The test groups were pretreated with compounds (10?mg/kg body weight, po) orally for 30?min before the intraperitoneal administration of a dose of 20% CCl₄ diluted with dietary cooking oil. Moreover, compounds were also tested for β-glucuronidase inhibition to explore the relationship between hepatoprotection and radical scavenging potential.

Results: The test compounds 1–4 were found to exhibit antiradical activity against 1,1-diphenyl-2-picrylhydrazyl radicals with IC₅₀ values ranging between 54 and 138 µM, whereas aurone derivatives 3 and 4 additionally exhibited superoxide anion scavenging effects with IC₅₀ values of 95 and 87 µM, respectively. In addition, these compounds were found to be weak inhibitors of xanthine oxidase (IC₅₀ ≥1000 µM). In animal model, pretreatment with compounds 2–4 significantly blocked the CCl₄-induced increase in the levels of the serum biochemical markers.

Conclusion: It appears that the hepatoprotection afforded by these compounds was mainly due to their radical scavenging activity that protected the cells from the free radicals generated by CCl₄-induced hepatotoxicity.     

Synthesis and pharmacological activities of non-flavonoid chromones: a patent review (from 2005 to 2015)

Introduction: Chromones are one of the major classes of naturally occurring compounds. Their chemistry has been widely explored and extensively reviewed. The following review intends to give a broad overview of the patented chromones. Particular attention has been given to their synthesis, uses and applications in last 10 years.

Areas covered: The authors provide an overview of the recent scientific reports describing the obtaining and study of new chromones. The review emphasizes the rationale behind natural sources, synthesis, biological activities and structure–activity relationships of the new chromone derivatives. The article is based on the literature published from 2005 to 2015 related to the development of this family of compounds. The patents presented in this review have been collected from multiple electronic databases including SciFinder, Espacenet and Mendeley.

Expert opinion: Although a great number of chromones have been published in bibliographic sources in the last years, there is little innovation in the synthetic methodologies. Some natural sources and isolation techniques were described. Different pharmacological applications have also been claimed. Two of the most studied applications have been the use of these compounds as therapeutic agents for cancer and skin diseases. Some safety requirements need to be developed in order to find new chemical entities as new drugs.