***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Abstract  Variability  in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size The aim of this study was to investigate the clinical efficacy of oral Pycnogenol ® ( Horphag Research Ltd , UK ) in patients with severe chronic venous insufficiency . Patients with severe venous hypertension ( chronic venous insufficiency , ankle swelling ) and history of venous ulcerations were treated with Pycnogenol . Patients received oral Pycnogenol ( 50 mg capsules , 3 times daily for a total of 150 mg daily ) for 8 weeks . A group of 21 patients was included in the treatment group and 18 equivalent patients were observed as controls ( no treatment during the observation period ) . All 21 patients ( age 53 years ; range , 42 - 60 years ; M : F=11:10 ) in the treatment group completed the 8-week study . Also the 18 controls completed the follow-up period . There were no drop-outs . The average ambulatory venous pressure was 59.3 ( SD 7.2 ; range 50 - 68 ) with a refilling time shorter than 10 seconds ( average 7.6 ; SD 3 ) . There were no differences in ambulatory venous pressure or refilling time between the treatment and control patients . The duration of the disease — from the first signs/symptoms — was on average 5.7 years ( SD 2.1 ) . At 4 and 8 weeks , in all Pycnogenol-treated subjects , microcirculatory and clinical evaluations indicated a progressive decrease in skin flux , indicating an improvement in the level of microangiopathy ; a significant decrease in capillary filtration ; a significant improvement in the symptomatic score ; and a reduction in edema . There were no visible effects in controls . In conclusion , this study confirms the fast clinical efficacy of Pycnogenol in patients with chronic venous insufficiency and venous microangiopathy . The study indicates the significant clinical role of Pycnogenol in the management , treatment and control of this common clinical problem . The treatment may be also useful to prevent ulcerations by controlling the level of venous microangiopathy The purpose of this r and omized , 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 ® 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 Melasma ( or chloasma ) is a common disorder of cutaneous hyperpigmentation predominantly affecting sun-exposed areas in women . The pathogenesis of melasma is not fully understood and treatments are frequently disappointing and often associated with side effects . Pycnogenol is a st and ardized extract of the bark of the French maritime pine ( Pinus pinaster ) , a well-known , potent antioxidant . Studies in vitro show that Pycnogenol is several times more powerful than vitamin E and vitamin C. In addition , it recycles vitamin C , regenerates vitamin E and increases the endogenous antioxidant enzyme system . Pycnogenol protects against ultraviolet ( UV ) radiation . Therefore its efficacy in the treatment of melasma was investigated . Thirty women with melasma completed a 30-day clinical trial in which they took one 25 mg tablet of Pycnogenol with meals three times daily , i.e. 75 mg Pycnogenol per day . These patients were evaluated clinical ly by parameters such as the melasma area index , pigmentary intensity index and by routine blood and urine tests . After a 30-day treatment , the average melasma area of the patients decreased by 25.86 + /- 20.39 mm(2 ) ( p < 0.001 ) and the average pigmentary intensity decreased by 0.47 + /- 0.51 unit ( p < 0.001 ) . The general effective rate was 80 % . No side effect was observed . The results of the blood and urine test parameters at baseline and at day 30 were within the normal range . Moreover , several other associated symptoms such as fatigue , constipation , pains in the body and anxiety were also improved . To conclude , Pycnogenol was shown to be therapeutically effective and safe in patients suffering from melasma Asthma is characterized as a chronic inflammatory process . Pycnogenol((R ) ) , a bioflavonoid mixture extracted from Pinus maritima , is known to scavenge free radicals while possessing antioxidant and antiinflammatory properties . The objective of this study was to evaluate the efficiency of this agent in a r and omized , double-blinded , placebo-controlled , crossover study in patients with varying asthma severity . Twenty-six patients who fulfilled the American Thoracic Society criteria for asthma were enrolled in the study . Medical history , physical examination , blood sample analyses , and spirometric values were obtained at baseline , 4 weeks , and 8 weeks . The patients were r and omly assigned to receive either 1 mg/lb/day ( maximum 200 mg/day ) Pycnogenol or placebo for the first period of 4 weeks and then crossed over to the alternate regimen for the next 4 weeks . No adverse effects were observed related to the study drug . Within the contingent of 22 patients who completed the study , almost all responded favorably to Pycnogenol in contrast to placebo . Pycnogenol treatment also significantly reduced serum leukotrienes compared with placebo . The results of this pilot study indicate that Pycnogenol may be a valuable nutraceutical in the management of chronic asthma . We recommend that further clinical trials be conducted in larger groups of asthmatics to establish its efficacy The aim of this study was to compare the efficacy of Venostasin ( horse chestnut seed extract ) and Pycnogenol ( French maritime pine bark extract ) in the treatment of chronic venous insufficiency ( CVI ) . In an open , controlled comparative study 40 patients with diagnosed CVI were treated either with 600 mg chestnut seed extract per day or 360 mg Pycnogenol per day over a period of 4 weeks . The following parameters were investigated before the start of treatment and after 2 and 4 weeks of treatment : circumference of the lower legs and rating of subjective symptoms ( scores ) of pain , cramps , night-time swelling , feeling of " heaviness " , and reddening of the skin . In addition , blood levels of cholesterol LDL and HDL were determined before and at the end of treatment . Pycnogenol significantly reduced the circumference of the lower limbs and significantly improved subjective symptoms . Furthermore , Pycnogenol significantly decreased cholesterol and LDL values in the blood , whereas HDL remained unaffected . Venostasin only moderately but not significantly , reduced the circumference of the lower limbs and marginally improved symptoms .  Venostasin had no influence on the determined lipid values . Both medications were equally well tolerated . In conclusion , Pycnogenol was found to be more efficacious than Venostasin for the treatment of CVI AIMS Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine . Pycnogenol is a proprietary bark extract of the French maritime pine tree ( Pinus pinaster ssp . atlantica ) that exerts antioxidative , anti-inflammatory , and anti-platelet effects . However , the effects of Pycnogenol on endothelial dysfunction , a precursor of atherosclerosis and cardiovascular events , remain still elusive . METHODS AND RESULTS Twenty-three patients with coronary artery disease ( CAD ) completed this r and omized , double-blind , placebo-controlled cross-over study . Patients received Pycnogenol ( 200 mg/day ) for 8 weeks followed by placebo or vice versa on top of st and ard cardiovascular therapy . Between the two treatment periods , a 2-week washout period was scheduled . At baseline and after each treatment period , endothelial function , non-invasively assessed by flow-mediated dilatation ( FMD ) of the brachial artery using high-resolution ultrasound , biomarkers of oxidative stress and inflammation , platelet adhesion , and 24 h blood pressure monitoring were evaluated . In CAD  patients , Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 ( P < 0.0001 ) , while no change was observed with placebo ( 5.4 ± 2.4 to 4.7 ± 2.0 ; P = 0.051 ) . This difference between study groups was significant [ estimated treatment effect 2.75 ; 95 % confidence interval ( CI ) : 1.75 , 3.75 , P < 0.0001 ] . 15-F(2t)-Isoprostane , an index of oxidative stress , significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment , while no change was observed in the placebo group ( mean difference 0.06 pg/mL with an associated 95 % CI ( 0.01 , 0.11 ) , P = 0.012 ] . Inflammation markers , platelet adhesion , and blood pressure did not change after treatment with Pycnogenol or placebo . CONCLUSION This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress The aim of this study was to investigate the clinical efficacy of oral Pycnogenol ® ( Horphag Research Ltd , United Kingdom ) in patients with diabetic microangiopathy . Patients without a history of diabetic ulcerations were treated with Pycnogenol . Patients received oral Pycnogenol ( 50 mg capsules , 3 times daily for a total of 150 mg daily for 4 weeks ) . A group of 30 patients was included ( severe microangiopathy ) ; 30 comparable patients were observed as controls ( no treatment during the observation period ) . All patients ( age , 59 years ; range , 55 - 68 years ; male : female = 18:12 ) included in the treatment group completed the 4-week study . Also , all controls completed the follow-up period . There were no drop-outs . All included subjects had signs and symptoms of diabetic microangiopathy . The duration of diabetes — from the first signs/symptoms — was on average 7.5 years ( SD = 3 ) . After 4 weeks , microcirculatory and clinical evaluations showed a progressive decrease in skin flux at rest in the foot ( indicating an improvement in the level of microangiopathy ) , a significant decrease in capillary filtration , and a significant improvement in the venoarteriolar response in all treated subjects . There were no visible effects in controls except a slight reduction in skin flux at rest in the foot . Treatment was well tolerated in both groups . In conclusion , this study confirms the clinical efficacy of Pycnogenol in patients with diabetic microangiopathy . The study indicates the clinical role of Pycnogenol in the management , treatment , and control of this common clinical problem . The treatment may be also useful to prevent diabetic ulcerations by controlling the 
    Output:
    
Current evidence is insufficient to support Pycnogenol ( ® ) use for the treatment of any chronic disorder .