Extract from Aronia melanocarpa, Lonicera caerulea, and Vaccinium myrtillus Improves near Visual Acuity in People with Presbyopia.

Presbyopia is a global problem with an estimated 1.3 billion patients worldwide. In the area of functional food applications, dietary supplements or herbs, there are very few reports describing the positive effects of their use. In the available literature, there is a lack of studies in humans as well as on an animal model of extracts containing, simultaneously, compounds from the polyphenol group (in particular, anthocyanins) and iridoids, so we undertook a study of the effects of a preparation composed of these compounds on a condition of the organ of vision. Our previous experience on a rabbit model proved the positive effect of taking an oral extract of Cornus mas in stabilizing the intraocular pressure of the eye. The purpose of this study was to evaluate the effect of an orally administered ternary compound preparation on the status of physiological parameters of the ocular organ. The preparation contained an extract of the chokeberry Aronia melanocarpa, the honeysuckle berry Lonicera caerulea L., and the bilberry Vaccinium myrtillus (hereafter AKB) standardized for anthocyanins and iridoids, as bioactive compounds known from the literature. A randomized, double-blind, cross-over study lasting with a "wash-out" period of 17 weeks evaluated a group of 23 people over the age of 50, who were subjects with presbyopia and burdened by prolonged work in front of screen monitors. The group of volunteers was recruited from people who perform white-collar jobs on a daily basis. The effects of the test substances contained in the preparation on visual acuity for distance and near, sense of contrast for distance and near, intraocular pressure, and conjunctival lubrication, tested by Schirmer test, LIPCOF index and TBUT test, and visual field test were evaluated. Anthocyanins (including cyanidin 3-O-galactoside, delphinidin 3-O-arabinoside, cyanidin 3-O-glucoside, cyanidin 3-O-rutinoside, cyanidin 3-O-arabinoside) and iridoids (including loganin, sweroside, loganic acid) were identified as substances present in the extract obtained by HPLC-MS. The preliminary results showed that the composition of AKB applied orally does not change visual acuity in the first 6 weeks of administration. Only in the next cycle of the study was an improvement in near visual acuity observed in 92.3% of the patients. This may indicate potential to correct near vision in presbyopic patients. On the other hand, an improvement in conjunctival wetting was observed in the Schirmer test at the beginning of week 6 of administration in 80% of patients. This effect was weakened in subsequent weeks of conducting the experiment to 61.5%. The improvement in conjunctival hydration in the Schirmer test shows the potential beneficial effect of the AKB formulation in a group of patients with dry eye syndrome. This is the first study of a preparation based on natural, standardized extracts of chokeberry, honeysuckle berry, and bilberry. Preliminary studies show an improvement in near visual acuity and conjunctival hydration on the Schirmer test, but this needs to be confirmed in further studies.

Cornelian Cherry (Cornus mas L.) Iridoid and Anthocyanin Extract Enhances PPAR-α, PPAR-γ Expression and Reduces I/M Ratio in Aorta, Increases LXR-α Expression and Alters Adipokines and Triglycerides Levels in Cholesterol-Rich Diet Rabbit Model.

Cornelian cherry (Cornus mas L.) fruits possess potential cardiovascular, lipid-lowering and hypoglycemic bioactivities. The aim of this study is to evaluate the influence of resin-purified cornelian cherry extract rich in iridoids and anthocyanins on several transcription factors, intima/media ratio in aorta and serum parameters, which determine or are valuable indicators of the adverse changes observed in the course of atherosclerosis, cardiovascular disease, and metabolic syndrome. For this purpose, male New Zealand rabbits were fed a diet enriched in 1% cholesterol for 60 days. Additionally, one group received 10 mg/kg b.w. of cornelian cherry extract and the second group 50 mg/kg b.w. of cornelian cherry extract. PPAR-α and PPAR-γ expression in the aorta, LXR-α expression in the liver; cholesterol, triglycerides, adipokines, apolipoproteins, glucose and insulin levels in serum; the intima and media diameter in the thoracic and abdominal aorta were determined. Administration of cornelian cherry extract resulted in an enhancement in the expression of all tested transcription factors, a decrease in triglycerides, leptin and resistin, and an increase in adiponectin levels. In addition, a significant reduction in the I/M ratio was observed for both the thoracic and abdominal aorta. The results we have obtained confirm the potential contribution of cornelian cherry extract to mitigation of the risk of developing and the intensity of symptoms of obesity-related cardiovascular diseases and metabolic disorders such as atherosclerosis or metabolic syndrome.

Acute intranasal intoxication with mercuric chloride taken accidently instead of cocaine - A case report.

CONTEXT: Mercuric chloride (mercury (II) chloride) belongs to inorganic mercury compounds characterized by good water solubility and associated high toxicity. The paper describes an unusual case of intranasal intoxication with corrosive sublimate confused with cocaine by a young male. CASE REPORT: Intranasal administration of corrosive sublimate caused severe local symptoms of chemical burn within the nasal cavity. From the 2nd day the patient developed symptoms of renal dysfunction with transient polyuria and serum retention of nitrogen metabolites. The patient was undergoing chelation therapy with DMPS, N-acetylcysteine and d-penicyllamine. Four procedures of haemodialysis were performed with simultaneous DMPS and N-acetylcysteine treatment. The urine mercury level on the first day of hospitalization was 1989 µg/L, and after 26 days of treatment returned to the physiological level. During treatment renal function was normalized, the patient was discharged in general good condition. DISCUSSION: Mercuric chloride is readily absorbed from the nasal cavity. Its administration may cause intoxication manifested by both chemical burn at the exposure site and systemic symptoms, particularly renal impairment. Even in case of renal dysfunction the use of DMPS seems safe, if haemodialysis is performed at the same time. Simultaneous haemodialysis and chelation therapy may accelerate elimination of mercury from the organism.

The iridoid loganic acid and anthocyanins from the cornelian cherry (Cornus mas L.) fruit increase the plasma l-arginine/ADMA ratio and decrease levels of ADMA in rabbits fed a high-cholesterol diet.

BACKGROUND: Although fruit and vegetable-rich diets have beneficial effects on cardiovascular diseases, we have little knowledge of the impact of fruits and their constituents, iridoids and anthocyanins, on the l-arginine-ADMA-DDAH pathway. Our previous study demonstrated the modulation of those factors by the oral administration of the cornelian cherry fruit. HYPOTHESIS/PURPOSE: We have assessed the effects of the oral administration of two main constituents isolated from the cornelian cherry fruit, iridoid loganic acid and anthocyanins, on l-arginine, its derivatives (ADMA, SDMA), metabolites (DMA, l-citrulline), and the hepatic DDAH activity and its isoform expression in rabbits fed a high-cholesterol diet. We have also analyzed eNOS expression in the thoracic aorta as well as the redox status in blood. STUDY DESIGN: In the present study, we used an animal model of diet induced atherosclerosis. For 60 days, white New Zealand rabbits were fed a standard diet, a 1% cholesterol enriched diet, or concomitantly with the investigated substances. l-arginine, ADMA, SDMA, DMA, and l-citrulline were assessed using the LC-MS/MS method. DDAH activity and redox parameters were analyzed spectrophotometrically. DDAH1 and DDAH2 isoform expressions were assessed by western blotting, mRNA expression of eNOS was quantified by real-time PCR. RESULTS: We demonstrated that the administration of loganic acid (20 mg/kg b.w.), and to a lesser extent of anthocyanins (10 mg/kg b.w.), caused an increase in the l-arginine level and the l-arginine/ADMA ratio. Also, both substances decreased ADMA, DMA, and l-citrulline, but not SDMA levels. Anthocyanins, but not loganic acid, enhanced the activity of DDAH in the liver. Anthocyanins also significantly enhanced both DDAH1 and DDAH2 expression, while loganic acid to a lesser extent enhanced DDAH1 but not DDAH2 expression. Both loganic acid and anthocyanins pronouncedly increased mRNA expression of eNOS in thoracic aortas. Both loganic acid and anthocyanins reversed the blood glutathione level depleted by dietary cholesterol. Cholesterol feeding decreased the blood GPx level, and the change was not reversed by anthocyanins or loganic acid. We did not observe any significant differences in the blood levels of MDA or SOD among the groups. CONCLUSION: Iridoids and anthocyanins may modulate the l-arginine-ADMA pathway in subjects fed a high-cholesterol diet.

Loganic acid and anthocyanins from cornelian cherry (Cornus mas L.) fruits modulate diet-induced atherosclerosis and redox status in rabbits.

BACKGROUND: Cornelian cherry (Cornus mas L.) is a plant growing in southeast Europe, in the past used in folk medicine. There are many previous publications showing the preventive effects of (poly)phenolic compounds, especially anthocyanins, on cardiovascular diseases, but there is a lack of studies comparing the effects of (poly)phenolics and other constituents of fruits. OBJECTIVES: We have attempted to determine if iridoids and anthocyanins from cornelian cherry fruits may affect the formation of atherosclerotic plaques in the aorta as well as lipid peroxidation and oxidative stress in the livers of cholesterol-fed rabbits. MATERIAL AND METHODS: Fractions of iridoids and anthocyanins were analyzed using the high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) methods. Loganic acid (20 mg/kg b.w.) and a mixture of anthocyanins (10 mg/kg b.w.) were administered orally for 60 days to rabbits fed with 1% cholesterol. Histopathological samples of the aortas and the livers were stained with hematoxylin and eosin. Lipid peroxidation (malondialdehyde - MDA) and redox status (glutathione - GSH, glutathione peroxidase - Gpx and superoxide dismutase - SOD) were analyzed using spectrophotometrical methods. RESULTS: Both loganic acid (an iridoid) and a mixture of anthocyanins diminished the formation of atherosclerotic plaques in the aorta. Both substances also diminished lipid peroxidation, measured as a decrease of MDA, and attenuated oxidative stress, measured as an increase of GSH in the livers depleted by cholesterol feeding. Unexpectedly, cholesterol feeding decreased the Gpx activity in the liver, which was reversed by both investigated substances. CONCLUSIONS: We have shown that both iridoids and anthocyanins help prevent fed-induced atherosclerosis, and the consumption of fruits rich in these substances may elicit beneficial effects on the cardiovascular system.

Iridoid-loganic acid versus anthocyanins from the Cornus mas fruits (cornelian cherry): Common and different effects on diet-induced atherosclerosis, PPARs expression and inflammation.

BACKGROUND AND AIMS: Cardiovascular benefits of fruits are attributed mainly to their (poly)phenolic constituents, especially anthocyanins. The main aim of our study is to compare effects of iridoids and anthocyanins from one fruit on diet-induced atherosclerosis. The cornelian cherry is a native or cultivated plant that grows in many European countries, used in cuisine and folk medicine. In our previous study, we showed its constituents and proved that oral administration of lyophilized fruits to hypercholesterolemic rabbits had preventive effects on atherosclerosis through the activation of PPARα expression. In this study, we have compared the effects of the main constituents of the cornelian cherry:iridoid loganic acid and anthocyanins. METHODS: Our experiment followed the model used in our previous study, in which rabbits were fed 1% cholesterol. RESULTS: We showed that both loganic acid (20 mg/kg b.w.) and a mixture of anthocyanins (10 mg/kg b.w.) administered orally for 60 days had a positive impact on dyslipidemia caused by cholesterol-rich diet, although the effects of anthocyanins were more pronounced. Anthocyanins decreased total and LDL-cholesterol and triglycerides and increased HDL-cholesterol. Loganic acid showed similar effects, but only the triglycerides and HDL-cholesterol changes achieved statistical significance. Anthocyanins, and to a lesser extent loganic acid, significantly decreased intima thickness and intima/media ratio in the thoracic aorta. Both substances decrease ox-LDL in the plasma. Anthocyanins significantly increased expression of PPARγ and α in the liver. Loganic acid also increased their expression, but to a lesser extent. Conversely, loganic acid showed pronounced anti-inflammatory effects, decreasing TNF-α and IL-6 activity. CONCLUSIONS: Our results imply that both substances have a positive effect on factors contributing to the development of diet-induced atherosclerosis. Our results also indicate the potential health benefits of fruits containing anthocyanins and iridoids, and support the idea of creating composed phytopharmaceuticals containing both groups of substances.

Application of Cornelian Cherry Iridoid-Polyphenolic Fraction and Loganic Acid to Reduce Intraocular Pressure.

One of the most common diseases of old age in modern societies is glaucoma. It is strongly connected with increased intraocular pressure (IOP) and could permanently damage vision in the affected eye. As there are only a limited number of chemical compounds that can decrease IOP as well as blood flow in eye vessels, the up-to-date investigation of new molecules is important. The chemical composition of the dried Cornelian cherry (Cornus mas L.) polar, iridoid-polyphenol-rich fraction was investigated. Loganic acid (50%) and pelargonidin-3-galactoside (7%) were found as the main components. Among the other constituents, iridoid compound cornuside and the anthocyans cyanidin 3-O-galactoside, cyanidin 3-O-robinobioside, and pelargonidin 3-O-robinobioside were quantified in the fraction. In an animal model (New Zealand rabbits), the influence of loganic acid and the polyphenolic fraction isolated from Cornelian cherry fruit was investigated. We found a strong IOP-hypotensive effect for a 0.7% solution of loganic acid, which could be compared with the widely ophthalmologically used timolol. About a 25% decrease in IOP was observed within the first 3 hours of use.

Fulminant hepatic failure in woman with iron and non-steroidal anti-inflammatory drug intoxication.

A 17-year-old, previously healthy female ingested 16,000 mg iron sulphate (96.15 mg of iron ions per kg of b.wt.) with a suicidal intent. The patient was admitted to a toxicology unit 10 hours after the drug ingestion. Serum iron concentration at admission was 2351 µg% (421.0 µmol/L). In the course of the intoxication, hemorrhagic gastritis, renal insufficiency and increasing signs of fulminant hepatic failure complicated with coagulopathy and encephalopathy were observed. Treatment with deferoxamine was started immediately after admission to the hospital and continued for 15 hours until the serum concentration of iron decreased to 145 µg% (25.9 µmol/L). Patient was qualified for liver transplant, therefore albumin dialysis as a bridge to liver transplantation was performed. In spite of two procedures of albumin dialysis using the Prometheus system, deep coma, shock and respiratory insufficiency developed. The patient died 80 hours after iron ingestion. In the presented case, the ingestion of a very high dose of iron and late introduction of deferoxamine treatment contributed to fulminant liver failure and fatal outcome of the intoxication.

Failure of benzylpenicillin, N-acetylcysteine and silibinin to reduce alpha-amanitin hepatotoxicity.

BACKGROUND: Intoxications caused by amanitin-containing mushrooms represent an unresolved problem in clinical toxicology. The objective of this study was a comparative evaluation of benzylpenicillin (Bp), acetylcysteine (ACC) and silibinin (Sil) efficacy as antidotes in hepatocytes intoxicated with alpha-amanitin (alpha-AMA). MATERIALS AND METHODS: All experiments were performed on cultured canine hepatocytes. Cytotoxicity evaluation of cultured cells (MTT assay, extracellular lactate dehydrogenase activity) was performed at 12, 24 and 48 h of exposure to alpha-AMA and/or antidotes. RESULTS: Following 24 and 48 h exposure there was a significant decline of hepatocyte viability and an increase of lactate dehydrogenase activity in groups exposed to alpha-AMA and in groups exposed simultaneously to alpha-AMA and antidotes. Moreover, hepatocyte viability and lactate dehydrogenase activity in all these groups were similar. Administration of studied antidotes without alpha-AMA, was not associated with any adverse effects in hepatocytes. CONCLUSION: All antidotes tested in this study against alpha-AMA were not effective in canine hepatocyte cultures.

[Successful treatment by 4--aminopyridine of three cases of severe verapamil poisoning]. / Skuteczna terapia 4-aminopirydyna trzech przypadków ciezkiego zatrucia werapamilem.

Three cases of verapamil intoxication were presented. In all cases shock and circulatory insufficiency were observed. In case no. 1 respiratory insufficiency and confusion were observed, in case no. 3 second-degree atrioventricular block was noted. The protracted hypotension (shock), circulatory insufficiency and atrioventricular block did not respond to calcium therapy, high dose of vasopressor amines and atropine. The addition of 4-aminopyridine (4-AP) infusion resulted in fast receding of poisoning symptoms; receding of atrioventricular block, cardiogenic shock and circulatory insufficiency. These cases suggest the usefulness of 4-AP in the treatment of verapamil poisoning. However, confirmation of the effectiveness of this substance for pharmacotherapy of calcium antagonists poisoning requires further clinical research. The influence of 4-AP on calcium channels is indirect. It blocks potassium channels K1 in cytoplasm side which makes potassium to stay inside the cell leading to depolarisation and opening of voltage-dependent calcium channels.

New treatment methods in verapamil poisoning: experimental studies.

The aim of this study was to evaluate the effectiveness of the treatment with 4-aminopyridine (4-AP, potassium channel inhibitor) and Bay K 8644 (calcium channel activator) in experimentally evoked verapamil poisoning in rats and to compare the results of this treatment with the effectiveness of widely accepted methods (adrenaline, calcium compounds). The experiment was carried out on male and female Wistar rats which were divided into 4 experimental (A, B, C, D) and a control (K) groups. Rats were anesthetized and the abdominal aorta was cannulated for mean arterial pressure and heart rate measurements while caudal vein was cannulated for drug administration. All animals were infused with verapamil (150 mg/kg/h) until 50% reduction of mean arterial pressure and/or heart rate was observed. After verapamil, control animals were given 0.9% NaCl solution and the other groups received 687.5 mg/kg/h of calcium glucolactobionicum (group A), 0.3 mg/kg/h of adrenaline (group B), 2 mg/kg/h of 4-AP (group C) or 2 mg/kg/h of Bay K 8644 (group D). The mean blood pressure and heart rate was checked and ECG was recorded every 10 min. A statistically significant decrease in mortality compared with the control group was observed in animals treated with adrenaline (p < or = 0.05), Bay K 8644 (p < or = 0.01) and 4-AP (p < or = 0.005). The treatment of experimentally evoked poisoning in rats using 4-AP or Bay K 8644 resulted in fast receding of poisoning symptoms: increase in blood pressure and heart rate, receding of bradyarrhythmia and return of sinus rhythm. The results of the study suggest the usefulness of 4-AP and Bay K 8644 in the treatment of verapamil poisoning.

Influence of nifedipine, nitrendipine and verapamil at low concentration on antipyrine metabolism examined by extracorporeal rat liver perfusion.

An increase in calcium ion concentration in the cytoplasm due to the influence of various toxic agents causes disturbances in the structure and function of hepatocytes, leading to their damage and even death. Calcium ions enter the cell mostly through calcium channels, therefore, it has been suggested that calcium channel inhibitors (CCI) could protect hepatocytes from the action of toxic substances. The present study investigated the effect of the selected CCI (nifedipine, nitrendipine and verapamil) on liver function, measured by the efficiency of oxidation reaction, in this case by determination of the rate of antipyrine metabolism. The experiment was carried out using the method of extracorporeal liver perfusion (ELP). None of the studied CCI applied at a concentration of 50 micromol/l increased the rate of antipyrine metabolism over the whole period of ELP. However, supplementation of perfusion fluid with nifedipine, nitrendipine or verapamil at a concentration of 20 micromol/l considerably improved metabolic liver efficiency during the second hour of perfusion, i.e. at the time, when large number of hepatocytes started to perish, which could indicate protective action of the tested CCI. However, the CCI-induced acceleration of antipyrine metabolism was not a result of their influence on calcium channels, since these drugs block calcium channels, when given at the concentrations as high as 100-400 micromol/l. Moreover, it seems that facilitation of antipyrine metabolism during ELP was not due to their action on microsomal enzymes because CCI were administered at very low concentrations, besides, they are metabolic inhibitors, and not inducers. The present experiment suggests that low concentrations of CCI can exert hepatoprotective effect. However, confirmation of this conclusion requires further studies using other experimental methods.