Understanding cognitive frailty in aging adults: prevalence, risk factors, pathogenesis and non-pharmacological interventions.

The worldwide increase in the aged population raises health concerns for elderly individuals. Cognitive frailty of the elderly (apart from those suffering from Alzheimer´s disease or other type of dementia) is a complex construct associated with aging, which is composed of physical and cognitive components, while physical frailty and cognitive impairment mutually affect each other. Although the prevalence of cognitive frailty in community-dwelling older adults without neurodegenerative disease is low, it can rise dramatically in clinical settings. Early identification of this condition can contribute to delaying the adverse outcomes that lead to higher mortality rates. This review aims to define cognitive frailty, its prevalence, risk factors, and pathogenesis, while highlighting the need for further research on identification, prevention, and non-pharmacological management of cognitive frailty in older adults in view of promoting healthy aging and secondary prevention strategies for dementia (Fig. 1, Ref. 93). Keywords: cognitive frailty, older adults, risk factors, nutrition, exercise.

Improvement in cardiovascular risk markers by the combined effect of natural polyphenols and vitamins in patients after kidney transplantation.

OBJECTIVES: The aim of this study was to evaluate the potential of supportive therapy by natural polyphenols combined with vitamins C and E on kidney function and risk factors of cardiovascular diseases in renal transplant recipients (RTR). BACKGROUND: Transplant patients have an altered lipid profile associated with the development of cardiovascular disease, which is a major cause of graft loss and mortality in patients. METHODS: The study included 29 renal transplant recipients with mean graft function levels. The lipoprotein (atherogenic and non-atherogenic) subfractions were identified and quantified in plasma by polyacrylamide gel electrophoresis. RESULTS: After supplementation, glomerular filtration rate (GFR) was increased by 8 %, serum creatinine was decreased by 6.7 % and significant changes were found in atherogenic LDL subfractions. The effect of supplementation was observed in arylesterase and lactonase activities of paraoxonase 1 which increased by 9.3 % and 8.1 %, respectively. In addition, significantly decreased levels of neopterin (by 16 %) and asymmetric dimethylarginine (ADMA) (by 7.9 %) were found. CONCLUSION: We could summarize that supportive therapy improves the renal function (GFR, serum creatinine), and reduces the risk of cardiovascular disease by affecting important risk markers of atherosclerosis (lipid profile, paraoxonase 1 activity, neopterin and ADMA) in RTR (Tab. 4, Fig. 1, Ref. 53).

Rat liver intoxication with CCl4: biochemistry, histology, and mass spectrometry.

This work provides complex characterisation of cirrhotic rat liver tissue induced by carbon tetrachloride using biochemical and histopathological analyses, and also presents a novel approach, secondary ion mass spectrometry (SIMS). According to our knowledge, this is the first report that compares these three different approaches in study of liver damage. We observed increased levels of triacylglycerols and total cholesterol in the liver and decreased levels of those parameters in the plasma. Histopathological observations include fat accumulation in the cells and changes in internal configuration of cells such as shift of position of organelles from the centre to the edge. The damage to the rat tissue is additionally determined by SIMS analysis, which characterizes, among other substances, diacylglycerols, cholesterol and fatty acids, such as linoleic and oleic acids. Interestingly, unlike other observed particles, a marked difference in SIMS intensity for diacylglycerol C37H69O4 positive fragment at 575.5 m/u was observed. In fact, there was one order of magnitude difference between intoxicated liver samples and controls and this molecular signal seems to be a potential chemical indicator of the damage. The SIMS images are consistent with histopathological results and they additionally provide information about distribution of chemical compound which is a new potential tool for the liver disease characterisation on molecular level.

Therapeutic effects of N-acetyl-L-cysteine on liver damage induced by long-term CCl4 administration.

N-acetyl-L-cysteine (NAC) is a drug routinely used in several health problems, e.g. liver damage. There is some information emerged on its negative effects in certain situations. The aim of our study was to examine its ability to influence liver damage induced by long-term burden. We induced liver damage by CCl4 (10 weeks) and monitored the impact of parallel NAC administration (daily 150 mg/kg of b.w.) on liver morphology and some biochemical parameters (triacylglycerols, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, proteins, albumins and cholinesterase). NAC significantly decreased levels of bile acids and bilirubin in plasma and triacylglycerols in liver, all of them elevated by impairment with CCl4. Reduction of cholesterol induced by CCl4 was completely recovered in the presence of NAC as indicated by its elevation to control levels. NAC administration did not improve the histological parameters. Together with protective effects of NAC, we found also its deleterious properties: parallel administration of CCl4 and NAC increased triacylglycerols, ALT and AST activity and significantly increased plasma cholinesterase activity. We have observed nonsignificantly increased percentage of liver tissue fibrosis. Our results have shown that NAC administered simultaneously with liver damaging agent CCl4, exhibits not only protective, but also deleterious effects as indicated by several biochemical parameters.

Diabetes-induced abnormalities of mitochondrial function in rat brain cortex: the effect of n-3 fatty acid diet.

Diabetic encephalopathy, a proven complication of diabetes is associated with gradually developing end-organ damage in the CNS increasing the risk of stroke, cognitive dysfunction or Alzheimer's disease. This study investigated the response of rat cortical mitochondria to streptozotocin-induced diabetes and the potential for fish oil emulsion (FOE) to modulate mitochondrial function. Diabetes-induced deregulation of the respiratory chain function as a result of diminished complex I activity (CI) and cytochrome c oxidase hyperactivity was associated with attenuation of antioxidant defense of isolated cortical mitochondria, monitored by SOD activity, the thiol content, the dityrosine and protein-lipid peroxidation adduct formation. A parallel reduction in phosphorylation of the energy marker AMPK has pointed out to disrupted energy homeostasis. Dietary FOE administration partially preserved CI activity, restored AMPK phosphorylation, but was unable to attenuate oxidative stress and prevent the shift toward saturated fatty acids in the cardiolipin composition. Moreover, diabetes has induced alterations in the protein expression of the regulatory COX4 subunit of cytochrome c oxidase, in the inhibitory factor IF1 and ATP5A subunit of F0F1-ATP synthase, in the uncoupling protein UCP4 and supramolecular organization of the respiratory complexes. FOE administration to diabetic rats has partially reversed these alterations. This study suggests diabetes-induced dysfunction of brain cortical mitochondria and its modulation by FOE administration. The intricate diabetic milieu and the n-3 FA nutrigenomic strength, however require further investigations to be able to unequivocally evaluate neuroprotective and adverse effects of FOE supplementation on the diabetic brain function.

Influence of oak wood polyphenols on cysteine, homocysteine and glutathione total levels and PON1 activities in human adult volunteers - a pilot study.

Oxidative stress reflects an imbalance between antioxidants and pro-oxidants. Many diseases like atherosclerosis or heart failure are involved in oxidative stress. Increased oxidative stress is one of the potential contributing factors to aging. The aim of this study was to monitor the total thiol levels as markers of oxidative stress in 20 healthy volunteers after polyphenols intake (extract from the French oak wood Quercus robur - Robuvit® (300 mg/day)). Polyphenols are known as biomodulators with antioxidant activities. Homocysteine, cysteine and glutathione total levels were determined by using HPLC with electrochemical detection. The activity of the antioxidant enzyme paraoxonase-1 toward two substrates was determined by spectrophotometry. The level of thiol compounds and paraoxonase-1 activities were controlled after run-in (week 0), intervention (week 4) and washout (week 6) period. After the intervention period the results showed that Robuvit® had no significant influence on glutathione level (p = 0.382) and paraoxonase activities towards both, arylester and lactone substrates. On the other hand, homocysteine and cysteine levels decreased significantly (p = 0.029; p < 0.001, respectively). The negative correlation between paraoxonase lactonase activity and homocysteine level was noticed. This confirms that paraoxonase might play an important role in homocysteine-thiolactone metabolism.

The impact of probiotics and vitamin C on the prevention of upper respiratory tract symptoms in two preschool children cohorts.

BACKGROUND/OBJECTIVES: The efficacy of Lab4 probiotic and vitamin C combination on the prevention of upper respiratory tract infections (URTIs) was investigated in two studies with children. Our objective was to pool dataset of 57 preschool children from the PROCHILD study (ISRCTN28722693) and the dataset of 50 preschool matched cohort from the PROCHILD-2 study (ISRCTN26587549) to evaluate the impact of probiotic/vitamin C combination on the prevention of upper respiratory tract symptoms and provide a more robust assessment of effect using detailed individual level data. SUBJECTS/METHODS: The children were supplemented daily for 6 months with either the multistrain probiotic (1.25×1010 cfu/tablet consisting of two strains of Lactobacillus acidophilus CUL21 and CUL60, Bifidobacterium bifidum CUL20 and Bifidobacterium animalis subsp. lactis CUL34) plus 50 mg vitamin C or a placebo. RESULTS: In the pooled analysis of the individual participant data (per protocol population), significant reductions were observed for the incidence (-25%; 95% confidence interval [CI], 0.66, 0.85; P < 0.0001) and duration (-14.9 days; 95% CI, -24.8, -5.1; P = 0.0030) of typical URTI symptoms in the active group compared with the placebo. The incidence rates of absenteeism from preschool (IR ratio, 0.75; 95% CI, 0.66, 0.86; P < 0.0001), paediatric visits (IR ratio, 0.56; 95% CI, 0.47; 0.68; P < 0.0001) and antibiotic usage (IR ratio, 0.53; 95% CI, 0.39, 0.71; P < 0.0001) were also significantly reduced. CONCLUSION: The pooled analysis findings of comparable preschool cohorts from two studies indicate that the supplementation with probiotic and vitamin C combination is beneficial in the prevention and management of URTI symptoms.

The kynurenine and serotonin pathway, neopterin and biopterin in depressed children and adolescents: an impact of omega-3 fatty acids, and association with markers related to depressive disorder. A randomized, blinded, prospective study.

Depressive disorder is a severe mental condition. In addition to genetic factors, immunological-inflammatory factors, oxidative stress, and disturbances in neurotransmitter metabolism, kynurenine and serotonin pathways may play a role. The exact mechanisms, especially in depressed children and adolescents, are not fully understood. Our primary hypothesis was whether the metabolites of tryptophan degradation in children and adolescents with depressive disorder might be influenced by omega-3 FAs compared to omega-6 FAs during a 12-week supplementation. A secondary hypothesis was to investigate whether tryptophan metabolites in children and adolescents are associated with markers of inflammatory response, oxidative stress, cortisol, and the serum omega-6/omega-3 FA ratio. Metabolites of tryptophan degradation and pteridines, neopterin, and biopterin in urine were analyzed with an HPLC system. Surprisingly, omega-3 FAs stimulated both kynurenine (kynurenine/tryptophan ratio) and serotonin (5-hydroxytryptophan) pathways, whereas omega-6 FAs only increased the kynurenine/tryptophan ratio. Neopterin and biopterin were not different from the healthy controls. Biopterin increased after omega-3 FA supplementation. Serotonin was positively correlated with lipoperoxidation and a marker of oxidative protein damage. Of the monitored tryptophan metabolites, only 5-hydroxyindolacetic acid was positively correlated with the severity of depression, total cholesterol, and negatively with brain-derived neurotrophic factor and glutathione peroxidase. In conclusion, in children and adolescents, both supplemented FAs stimulated the kynurenine pathway (kynurenine/tryptophan ratio) and kynurenine formation. However, the serotonin pathway (5-hydroxytryptophan) was stimulated only by omega-3 FA. Tryptophan metabolism is associated with oxidative stress, inflammation, total cholesterol, and cortisol. We are the first to point out the association between the kynurenine pathway (KYN/TRP ratio) and the omega-6/omega-3 FA ratio. The metabolite 5-HIAA could play a role in the pathophysiology of depressive disorder in children and adolescents. Clinical Trial Registration: https://www.isrctn.com/ISRCTN81655012, identifier ISRCTN81655012.

Effect of a plant sterol, fish oil and B vitamin combination on cardiovascular risk factors in hypercholesterolemic children and adolescents: a pilot study.

BACKGROUND: Assessment of cardiovascular disease (CVD) risk factors can predict clinical manifestations of atherosclerosis in adulthood. In this pilot study with hypercholesterolemic children and adolescents, we investigated the effects of a combination of plant sterols, fish oil and B vitamins on the levels of four independent risk factors for CVD; LDL-cholesterol, triacylglycerols, C-reactive protein and homocysteine. METHODS: Twenty five participants (mean age 16 y, BMI 23 kg/m2) received daily for a period of 16 weeks an emulsified preparation comprising plant sterols esters (1300 mg), fish oil (providing 1000 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA)) and vitamins B12 (50 µg), B6 (2.5 mg), folic acid (800 µg) and coenzyme Q10 (3 mg). Atherogenic and inflammatory risk factors, plasma lipophilic vitamins, provitamins and fatty acids were measured at baseline, week 8 and 16. RESULTS: The serum total cholesterol, LDL- cholesterol, VLDL-cholesterol, subfractions LDL-2, IDL-1, IDL-2 and plasma homocysteine levels were significantly reduced at the end of the intervention period (p<0.05). The triacylglycerols levels decreased by 17.6%, but did not reach significance. No significant changes in high sensitivity C-reactive protein, HDL-cholesterol and apolipoprotein A-1 were observed during the study period. After standardisation for LDL cholesterol, there were no significant changes in the levels of plasma γ-tocopherol, ß-carotene and retinol, except for reduction in α-tocopherol levels. The plasma levels of n-3 fatty acids increased significantly with the dietary supplementation (p<0.05). CONCLUSIONS: Daily intake of a combination of plant sterols, fish oil and B vitamins may modulate the lipid profile of hypercholesterolemic children and adolescents. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89549017.

Oxidative Stress Markers and Antioxidant Enzymes in Children and Adolescents with Depressive Disorder and Impact of Omega-3 Fatty Acids in Randomised Clinical Trial.

Oxidative stress (OS) is thought to play a role in mental disorders. However, it is not clear whether the OS is the cause or consequence of the disorder. We investigated markers of oxidative stress (8-isoprostane (8-IsoP-U), lipoperoxides (LP), advanced oxidation protein products (AOPP) and nitrotyrosine (NT)) and antioxidant protection (Trolox equivalent antioxidant capacity (TEAC), activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) in 60 paediatric and adolescent patients with depressive disorder (DD) compared to healthy controls. The patients were divided into two groups (1:1). One group received an emulsion of omega-3 fatty acid (FA), and the other group an emulsion of sunflower oil with omega-6 FA for 12 weeks. The levels of 8-IsoP-U, AOPP and NT were increased, and GPx activity was decreased in patients compared to the controls. We found a significant positive correlation of the Children's Depression Inventory score with NT and a negative correlation with TEAC, SOD and GPx. NT correlated positively with the baseline omega-6/omega-3 FA ratio and a negatively with SOD. A supplementation with omega-3 FA, but not with omega-6 FA, decreased 8-IsoP-U, AOPP, NT levels and increased TEAC and SOD activity. Our results suggest that NT may play a role in the pathophysiology of DD, while elevated isoprostane is likely caused by the high omega-6/omega-3 FA ratio. Omega-3 FA supplementation reduces oxidative stress in patients with DD. This study was registered with the ISRCTN registry (ISRCTN81655012).

Gender differences in LDL and HDL subfractions in atherogenic and nonatherogenic phenotypes.

OBJECTIVES: The aim of our study was to examine the role of low density lipoprotein (LDL)-subfractions in individuals with the atherogenic and non-atherogenic phenotype and the gender differences in lipoprotein subfractions including small dense LDL (sdLDL) and small high density lipoprotein (sHDL) subfractions representing the most atherogenic lipoprotein subfractions. DESIGN & METHODS: 35 persons in the atherogenic group (AG) (with sdLDL3-7 subfractions ≥6 mg/dl) and 104 individuals in the non-atherogenic group (NAG) (sdLDL3-7 subfractions <6 mg/dl) were included in our study. To analyze plasma lipoprotein subfractions, a polyacrylamide gel electrophoresis-the Lipoprint system was used. RESULTS: Males compared to females in the AG had significantly higher levels of atherogenic lipoprotein subfractions such as HDL8, HDL9 and HDL10. All participants in AG had significantly lower levels of intermediate density lipoprotein IDL-A than those in NAG but significantly higher levels of IDL-B and IDL-C. Males in the AG compared to NAG had significantly lower levels of LDL1 and higher levels of LDL2 and LDL3-7 subfractions. In the NAG LDL2 positively correlated with sHDL subfractions while in the AG with the large HDL subfraction. CONCLUSION: Results of our study demonstrate more atherogenic profile in males compared to females and a double role of LDL2 subfraction in the atherogenic process depending on the phenotype (atherogenic/non-atherogenic) of individuals.

The Oak-wood Extract Robuvit® Improves Recovery and Oxidative Stress after Hysterectomy: A Randomized, Double-blind, Placebo-controlled Pilot Study.

Hysterectomy has a variety of medical indications and improves pre-operative symptoms but might compromise the quality of life during recovery due to symptoms such as fatigue, headache, nausea, depression, or pain. The aim of the present study was to determine the effect of a standardized extract from French oak wood (Quercus robur) containing at least 40% polyphenols of the ellagitannins class, Robuvit®, on convalescence and oxidative stress of women after hysterectomy. Recovery status was monitored with the SF-36 questionnaire. The supplementation with Robuvit® (300 mg/day) during 4 weeks significantly improved general and mental health, while under placebo some items significantly deteriorated. Oxidative stress and enhancement of MMP-9 activity was significantly reduced by Robuvit® versus placebo. After 8 weeks of intervention, the patients' condition improved independently of the intervention. Our results suggest that the use of Robuvit® as a natural supplement relieves post-operative symptoms of patients after hysterectomy and reduces oxidative stress. The study was registered with ID ISRCTN 11457040 (13/09/2019).

Influence of pyridoxylidene aminoguanidine on biomarkers of the oxidative stress and selected metabolic parameters of rats with diabetes mellitus.

Oxidative damage is considered to play an important role in the pathogenesis of several diseases, such as diabetes mellitus (DM), atherosclerosis, cardiovascular complications and chronic renal failure. DM is associated with the oxidative stress and formation of advanced glycation end products (AGEs). Different drugs inhibit oxidative stress and formation of advanced glycation end products. Aminoguanidine (AG) has been proposed as a drug of potential benefit in prophylaxis of the complications of DM. Recent reports show a pro-oxidant activity of AG. Therefore we examined the effect of structural analogue of AG, its Schiff base with pyridoxal-pyridoxylidene aminoguanidine (PAG) on the level of selected markers of oxidative stress. We found that PAG decreased total damage to DNA in controls as well as in diabetic group of rats. However, we also found that PAG supplementation increases susceptibility of lipoproteins to oxidation and formation of conjugated dienes in both, diabetic as well as control animals. Its administration to diabetic rats decreases antioxidant capacity of plasma. Therefore, it is necessary to search for other structural modifications of AG that would combine its higher anti-diabetic activity with less toxicity.

French maritime pine bark extract Pycnogenol reduces thromboxane generation in blood from diabetic male rats.

The protective effect of Pycnogenol against cardiovascular diseases was clearly demonstrated. Nevertheless, little is known about its antithrombotic effect, especially in diabetes associated with enhanced thromboxane synthesis leading to severe vascular complications. Therefore, the main purpose of our study was to evaluate the effect of long-term Pycnogenol intake on synthesis of prothrombotic thromboxane A(2) (TXA(2)) in animal model of insulin-dependent diabetes. The levels of main plasma TXA(2) metabolite, thromboxane B(2) (TXB(2)), were assessed by enzyme-linked immunosorbent assay. Diabetes was induced in Wistar male rats by single injection of streptozotocin, resulting after 8 weeks in significant body weight reduction, increased plasma glucose concentrations, and decreased plasma C-peptide levels, compared to non-diabetic animals. There was no significant reduction of plasma glucose concentrations after Pycnogenol ingestion. It was found, however, that daily administration of either Pycnogenol (5mg/kg b.wt.) or acetylsalicylic acid (ASA, 10mg/kg b.wt.) significantly reduced plasma TXB(2) concentrations, and this inhibitory effect was higher in the latter case. Nonetheless, simultaneous administration of Pycnogenol and ASA did not improve effectiveness of ASA-mediated decrease in TXB(2) generation. The results of the present study suggest that Pycnogenol might have a beneficial antithrombotic effect when administered alone or as a supplementation of standard antiplatelet therapy in diabetic patients.

Effect of pine bark extract (Pycnogenol) on symptoms of knee osteoarthritis.

OBJECTIVE: The safe and efficacious use of Pycnogenol (French maritime pine bark extract) in other inflammatory diseases prompted this study of its antiinflammatory effects in patients with osteoarthritis (OA). The aim of the study was to evaluate whether Pycnogenol reduces the symptoms of OA in a double-blind, placebo-controlled, randomly allocated trial with patients suffering from knee osteoarthritis stages I and II. METHODS: 100 patients were treated for 3 months either by 150 mg Pycnogenol per day at meals or by placebo. Patients had to report any change of use of previously prescribed antiinflammatory medication during the study period. Patients filled the Western Ontario and Mc Masters University (WOMAC) questionnaire for osteoarthritis every 2 weeks and evaluated weekly pain symptoms using a visual analogue scale for pain intensity. RESULTS: Following treatment with Pycnogenol patients reported an improvement of WOMAC index (p < 0.05), and a significant alleviation of pain by visual analogue scale (p < 0.04), the placebo had no effect. The use of analgesics diminished in the verum group but increased under the placebo. Treatment with Pycnogenol was well tolerated. CONCLUSION: Results show that Pycnogenol in patients with mild to moderate OA improves symptoms and is able to spare NSAIDs.

Fish oil emulsion supplementation might improve quality of life of diabetic patients due to its antioxidant and anti-inflammatory properties.

Diabetes-related complications, including cardiovascular disease, retinopathy, nephropathy, and neuropathy, are a significant cause of increased morbidity and mortality among people with diabetes. Previous studies have confirmed that hyperglycemia has pro-oxidative and proinflammatory properties which cause diabetic complications. We hypothesized that supplementation of fish oil emulsion (FOE), rich in omega-3 polyunsaturated fatty acids, to diabetic patients might reduce hyperglycemia-induced pathological changes due to specific properties of FOE. Omega-3 polyunsaturated fatty acids have a wide range of biological effects. In this project, we have examined the potential protective effect of the FOE on hyperglycemia-induced oxidative stress and cytokine generation in monocytes/macrophages U937 system in vitro. The monocytes/macrophages U937 were cultivated under normal or hyperglycemic (35 mmol/L glucose) conditions with/without FOE for 72 hours. We have focused on specific markers of oxidative stress (antioxidant capacity; superoxide dismutase activity; oxidative damage to DNA, proteins, and lipids) and inflammation (tumor necrosis factor, interleukin-6, interleukin-8, monocytic chemotactic protein-1). Hyperglycemia caused reduction of antioxidant capacity, induction of DNA damage, and proinflammatory cytokine secretion. FOE significantly increased antioxidant capacity of cells as well as superoxide dismutase activity and significantly reduced tumor necrosis factor, interleukin-6, interleukin-8, and monocytic chemotactic protein-1 release. No effect was observed on oxidative damage to DNA, proteins, and lipids. Our results indicate that FOE can reduce hyperglycemia-induced pathological mechanisms by its antioxidant and anti-inflammatory properties.

Acute dark chocolate ingestion is beneficial for hemodynamics via enhancement of erythrocyte deformability in healthy humans.

Erythrocyte deformability is an important property of erythrocytes that considerably affects blood flow and hemodynamics. The high content of polyphenols present in dark chocolate has been reported to play a protective role in functionality of erythrocytes. We hypothesized that chocolate might influence erythrocytes not only after repeated chronic intake, but also immediately after its ingestion. Thus, we determined the acute effect of dark chocolate and milk (with lower content of biologically active substances) chocolate intake on erythrocyte deformability. We also focused on selected factors that may affect erythrocyte deformability, specifically nitric oxide production in erythrocytes and total antioxidant capacity of plasma. We determined posttreatment changes in the mentioned parameters 2hours after consumption of chocolate compared with their levels before consumption of chocolate. In contrast to milk chocolate intake, the dark chocolate led to a significantly higher increase in erythrocyte deformability. Nitric oxide production in erythrocytes was not changed after dark chocolate intake, but significantly decreased after milk chocolate. The plasma total antioxidant capacity remained unaffected after ingestion of both chocolates. We conclude that our hypothesis was confirmed. Single ingestion of dark chocolate improved erythrocyte deformability despite unchanged nitric oxide production and antioxidant capacity of plasma. Increased deformability of erythrocytes may considerably improve rheological properties of blood and thus hemodynamics in humans, resulting in better tissue oxygenation.

Effect of polyphenolic extract, Pycnogenol, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder.

The purpose of this randomized, double-blind and placebo controlled study was to test the effect of polyphenolic extract of pine bark Pycnogenol (Pyc) on the level of oxidized purines represented by 8-oxo-7,8-dihydroguanine (8-oxoG) and on the total antioxidant status (TAS) in children with attention deficit/hyperactivity disorder (ADHD).We have found significantly increased damage to DNA in ADHD children when compared to controls. 8-oxoG was significantly lower after 1 month of Pyc administration in comparison to the beginning state and to placebo group. TAS in ADHD children was lower in comparison to controls. After Pyc administration, TAS was elevated but statistically significant increase was recorded after 1 month of termination of Pyc application. Improvement of DNA damage and TAS after Pyc administration is associated with the improvement of attention in ADHD children. In conclusion, Pycnogenol(R) administration reduces oxidative damage to DNA, normalizes TAS and improves attention of ADHD children. Explanation of mutual relation between oxidative damage to DNA, TAS and symptoms of ADHD and mechanism of Pyc's action needs further investigations.

Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol).

There is evidence from several studies that supplementation with French maritime pine bark extract (Pycnogenol) improves inflammatory symptoms in vivo. However, the molecular pharmacological basis for the observed effects has not been fully uncovered yet. Direct inhibitory effects of plant extracts or components upon cyclooxygenase (COX) activity have been repeatedly reported, but the question remained whether sufficiently high in vivo concentrations of bioactive compounds could be achieved in humans. The purpose of the present study was to determine a possible inhibition of the enzymatic activity of COX-1 and COX-2 by serum samples of human volunteers after intake of French maritime pine bark extract. This methodology considered that the serum samples would contain any bioavailable active principle. Therefore, we obtained blood samples before and after 5 days administration of 200 mg Pycnogenol to five healthy humans. The plasma moderately inhibited both COX-1 and COX-2 activities ex vivo. In a second approach, 10 volunteers received a single dose of 300 mg Pycnogenol. Only 30 min after ingestion of the pine bark extract the serum samples induced a statistically significant increase in the inhibition of both COX-1 (P < 0.02) and COX-2 (P < 0.002). This suggests a strikingly rapid bioavailability of bioeffective compounds after oral intake of the extract. Thus, we provide evidence that Pycnogenol exerts effects by inhibition of eicosanoid generating enzymes which is consistent with reported clinical anti-inflammatory and platelet inhibitory effects in vivo. The next challenge is to identify the active principle(s) that are rapidly bioavailable in human plasma.

Single and multiple dose pharmacokinetics of maritime pine bark extract (pycnogenol) after oral administration to healthy volunteers.

BACKGROUND: Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers. METHODS: Eleven volunteers received a single dose of 300 mg pine bark extract, five volunteers ingested 200 mg daily for five days to reach steady state concentrations. Plasma samples were obtained before and at defined time points after intake of the extract. Samples were analyzed by HPLC with ion-pair reagents and simultaneous UV and electrochemical detection. RESULTS: We quantified total plasma concentrations of catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (delta-(3,4-dihydroxy-phenyl)-gamma-valerolactone). Additionally, we describe plasma time courses and steady state appearance of ten so far unknown compounds, U1 to U10. After single ingestion, compounds derived from the extract were rapidly absorbed and the majority of them were detectable over whole experimental period of 14 h. The analysis of steady state plasma samples revealed significant phase II metabolism. CONCLUSION: We present the first systematic pharmacokinetic analysis of compounds derived from maritime pine bark extract. Beyond the known constituents and metabolites we uncovered the plasma time courses of ten unknown compounds. In concert with our previous detection of anti-inflammatory bioefficacy of these plasma samples ex vivo we suggest that constituents and metabolites of Pycnogenol bear potential for disclosure of novel active principles.