Are Observational Studies More Informative Than Randomized Controlled Trials in Hypertension?: Con Side of the Argument Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. A systematic review of randomized controlled trials on curative and health enhancement effects of forest therapy Daily Nighttime Melatonin Reduces Blood Pressure in Male Patients With Essential Hypertension Tianma Gouteng Yin as Adjunctive Treatment for Essential Hypertension: A Systematic Review of Randomized Controlled Trials Melatonin for nondippers with coronary artery disease: assessment of blood pressure profile and heart rate variability Efficacy of Melatonin on Serum Pro-inflammatory Cytokines and Oxidative Stress Markers in Relapsing Remitting Multiple Sclerosis. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. The role of cardiac registries in evidence-based medicine. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. Effects of antihypertensive agents on circadian blood pressure in hypertensive patients with previous brain infarction Review: E-health interventions improve blood pressure level and control in hypertension Prevention of cytokine-induced hypotension in cancer patients by the pineal hormone melatonin A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results Lessons from a pilot and feasibility randomised trial in depression (Blood pressure Rapid Intensive Lowering And Normal Treatment for Mood and cognition in persistent depression (BRILiANT mood study))
The very first rigorously design ed , r and omized controlled trial ( RCT ) in the history of modern medicine was published in 1948 . The study , design ed and carried out by the Streptomycin in Tuberculosis Trials Committee of the Medical Research Council , demonstrated the efficacy of streptomycin in treating pulmonary tuberculosis on top of bed rest , which was the best available treatment at that time.1 In the field of hypertension treatment and cardiovascular prevention , the history of event-based RCTs began in 1967 , when the cardiovascular benefits and risks of antihypertensive drug treatment were evaluated in the setting of the Veterans Administration Cooperative Study in Hypertension.2 In that trial , 143 patients with severe hypertension were r and omized to receive blood pressure (BP)–lowering drug treatment or matched placebo for 11 months . A major morbid or fatal event was observed in 26 of 70 patients who received placebo ( 37 % ) and in only 1 of 73 patients under active treatment ( 1 % ) . The amazing results of this l and mark trial established beyond any doubt the striking cardiovascular benefits of antihypertensive drug treatment of hypertension at a time when controversy still persisted regarding the supposedly deleterious effects of BP reduction on organ perfusion.3 Ever since , RCTs have represented a formidable tool for evaluating risks and benefits of hypertension treatment . Over the past 50 years , the remarkable progress in treatment and control of high BP , one of the most outst and ing achievements of modern medicine , has been driven by the results of many large , event-based RCTs . The influential position of RCTs in clinical and therapeutic research as opposed to real-world observational studies ( surveys , registries , and retrospective analyses of existing data bases ) originates from their high internal validity ( ie , the power to address clinical questions with a low level of internal bias ) . A list of strengths and weaknesses of RCTs and observational studies is AIMS As melatonin has been found to play a role in the mechanisms of cardiovascular regulation , we design ed the present study to evaluate whether the evening ingestion of the pineal hormone might interfere with the antihypertensive therapy in hypertensive patients well-controlled by nifedipine monotherapy . METHODS Forty-seven mild to moderate essential hypertensive out patients taking nifedipine GITS 30 or 60 mg monotherapy at 08.30 h for at least 3 months , were given placebo or melatonin  5  mg at 22.30 h for 4 weeks according to a double-blind cross-over study . At the end of each treatment period patients underwent a 24 h noninvasive ambulatory blood pressure monitoring  ( ABPM ) during usual working days ; sleeping period was scheduled to last from 23.00 to 07.00 h. RESULTS The evening administration of melatonin induced an increase of blood pressure and heart rate throughout the 24 h period ( DeltaSBP = + 6.5 mmHg , P < 0.001 ; DeltaDBP = + 4.9 mmHg , P < 0.01 ; DeltaHR = + 3.9 beats min-1 , P < 0.01 ) . The DBP as well as the HR increase were particularly evident during the morning and the afternoon hours . CONCLUSIONS We hypothesize that competition between melatonin and nifedipine , is able to impair the antihypertensive efficacy of the calcium channel blocker . This suggests caution in uncontrolled use of melatonin in hypertensive patients . As the pineal hormone might interfere with calcium channel blocker therapy , it can not be considered simply a dietary supplement Objective To summarize the evidence for curative and health enhancement effects through  forest therapy  and to assess the quality of studies based on a review of r and omized controlled trials ( RCTs ) . Study design A systematic review based on RCTs . Methods Studies were eligible if they were RCTs . Studies included one treatment group in which forest therapy was applied .  The following data bases – from 1990 to November 9 , 2010 – were search ed : MEDLINE via PubMed , CINAHL , Web of Science , and Ichushi- Web . All Cochrane data bases and Campbell Systematic Review s were also search ed up to November 9 , 2010 . Results Two trials met all inclusion criteria . No specific diseases were evaluated , and both studies reported significant effectiveness in one or more outcomes for health enhancement . However , the results of evaluations with the CONSORT ( Consoli date d St and ards of Reporting Trials ) 2010 and CLEAR NPT ( A Checklist to Evaluate a Report of a Nonpharmacological Trial ) checklists generally showed a remarkable lack of description in the studies . Furthermore , there was a problem of heterogeneity , thus a meta- analysis was unable to be performed . Conclusion Because there was insufficient evidence on forest therapy due to poor method ological and reporting quality and heterogeneity of RCTs , it was not possible to offer any conclusions about the effects of this intervention . However , it was possible to identify problems with current RCTs of forest therapy , and to propose a strategy for strengthening study quality and stressing the importance of study feasibility and original check items based on characteristics of forest therapy as a future research agenda Abstract — Patients with essential hypertension have disturbed autonomic cardiovascular regulation and circadian pacemaker function . Recently , the biological clock was shown to be involved in autonomic cardiovascular regulation . Our objective was to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in patients with essential hypertension . We conducted a r and omized , double-blind , placebo-controlled , crossover trial in 16 men with untreated essential hypertension to investigate the influence of acute ( single ) and repeated ( daily for 3 weeks ) oral melatonin ( 2.5 mg ) intake 1 hour before sleep on 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality . Repeated melatonin intake reduced systolic and diastolic blood pressure during sleep by 6 and 4 mm Hg , respectively . The treatment did not affect heart rate . The day – night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15 % and 25 % , respectively . A single dose of melatonin had no effect on blood pressure . Repeated ( but not acute ) melatonin also improved sleep . Improvements in blood pressure and sleep were statistically unrelated . In patients with essential hypertension , repeated bedtime melatonin intake significantly reduced nocturnal blood pressure . Future studies in larger patient group should be performed to define the characteristics of the patients who would benefit most from melatonin intake . The present study suggests that support of circadian pacemaker function may provide a new strategy in the treatment of essential hypertension Background . Tianma Gouteng Yin ( TGY ) is widely used for essential hypertension ( EH ) as adjunctive treatment . Many r and omized clinical trials ( RCTs ) of TGY for EH have been published . However , it has not been evaluated to justify their clinical use and recommendation based on TCM zheng classification . Objectives . To assess the current clinical evidence of TGY as adjunctive treatment for EH with liver yang hyperactivity syndrome ( LYHS ) and liver-kidney yin deficiency syndrome ( LKYDS ) . Search Strategy . 7 electronic data bases were search ed until November 20 , 2012 . Inclusion Criteria . RCTs testing TGY combined with antihypertensive drugs versus antihypertensive drugs were included . Data Extraction and Analyses . Study selection , data extraction , quality assessment , and data analyses were conducted according to the Cochrane st and ards . Results . 22 RCTs were included . Method ological quality was generally low . Except diuretics treatment group , blood pressure was improved in the other 5 subgroups ; zheng was improved in angiotensin converting enzyme inhibitors ( ACEIs ) , calcium channel blockers ( CCBs ) , and “ CCB + ACEI ” treatment groups . The safety of TGY is still uncertain . Conclusions . No confirmed conclusion about the effectiveness and safety of TGY as adjunctive treatment for EH with LYHS and LKYDS could be made . More rigorous trials are needed to confirm the results The aim of this study was to assess the effects of 5 mg melatonin before sleep in patients with coronary artery disease ( CAD ) and with an abnormal circadian pattern of blood pressure ( BP ) on changes in circadian BP profile and heart rate variability ( HRV ) . Sixty patients with CAD , nondippers aged 48–80 years ( male 75 % ) , were included . In addition to previous treatment , they were r and omly allocated to melatonin or placebo . After 90 days , a second 24-h BP monitoring was carried out . Each patient had two sessions ( before r and omization and at the end of study ) of 24-h ECG monitoring to assess the changes in HRV . Inclusion of melatonin led to BP pattern normalization in 35 % of patients in the melatonin group and in 15 % of controls ( P=0.609 ) . This effect was reached not only by a decrease in nighttime BP , but also by an increase in daytime BP ( significant in the melatonin group ) . A nonoptimal effect for BP profile was observed in 12.5 % of patients : extreme- or reverse dippers . In patients with conversion from nondippers to dippers ( responders ) , an increase in st and ard deviation of normal-to-normal intervals between initial and final HRV analyses was observed . Nonresponders represented an increase in the mean circadian heart rate . To avoid nonoptimal effects , the inclusion of melatonin in pharmacotherapy of patients with CAD should be based on monitoring of circadian BP profile , before and during treatment . As melatonin caused not only a nocturnal decrease in BP but also a daytime increase , it should not be recommended in patients with ‘ high normal ’ values of BP because of the danger of induction of arterial hypertension Multiple sclerosis ( MS ) is a chronic inflammatory disease , which leads to focal plaques of demyelination and tissue injury in the central nervous system ( CNS ) . Neuroinflammation and oxidative stress are involved in the pathogenesis of MS , promoting tissue damage and demielinization . Current research findings suggest that melatonin has antioxidant and neuroprotective effects . The aim of this study was to evaluate the efficacy of melatonin on serum pro-inflammatory cytokines and oxidative stress markers in relapsing-remitting multiple sclerosis ( RRMS ) . 36 patients diagnose with RRMS treated with Interferon β-1b ( IFNβ-1b ) were enrolled in a double bind , r and omized , placebo controlled trial . The experimental group received orally 25 mg/d of melatonin for 6 months . After melatonin administration , we observed a significant decrease in serum concentration of pro-inflammatory cytokines and oxidative stress markers ; 18 % for TNF-α ( p < 0.05 ) , 34.8 % for IL-1β ( p < 0.05 ) , 34.7 % for IL-6 ( p < 0.05 ) , 39.9 % for lipoperoxides ( LPO ) ( p < 0.05 ) and 24 % for nitric oxide catabolites ( NOC ) levels ( p < 0.05 ) , compared with placebo group . No significant difference in clinical efficacy outcomes were found between groups . Melatonin treatment was well tolerated and we did not observe significant differences in rates of side effects between the two groups . We concluded that melatonin administration during 6 months period is effective in reducing levels of serum pro-inflammatory cytokines and oxidative stress markers in patients with RRMS . These data support future studies evaluating the safety and effectiveness of melatonin supplementation in RRMS patients PURPOSE Nocturnal hypertension is associated with a high risk of morbidity and mortality . A blunted nocturnal surge in melatonin excretion has been described in nondipping hypertensive patients . We therefore studied the potency of melatonin to reduce nighttime blood pressure ( BP ) in treated hypertensive patients with nocturnal hypertension . PATIENTS AND METHODS Thirty-eight treated hypertensive patients ( 22 males , mean age 64+/-11 years ) with confirmed nocturnal hypertension ( mean nighttime systolic BP > 125 mm Hg ) , according to repeated 24-hour ambulatory blood pressure monitoring ( ABPM ) , were r and omized in a double-blind fashion to receive either controlled release (CR)-melatonin 2 mg or placebo 2 hours before bedtime for 4 weeks . A 24-hour ABPM was then performed . RESULTS Melatonin treatment reduced nocturnal systolic BP significantly from 136+/-9 to 130+/-10 mm Hg ( P=.011 ) , and diastolic BP from 72+/-11 to 69+/-9 mm Hg ( P=.002 ) , whereas placebo had no effect on nocturnal BP . The reduction in nocturnal systolic BP was significantly greater with melatonin than with placebo ( P=.01 ) , and was most prominent between 2:00 AM and 5:00 AM ( P=.002 ) . CONCLUSIONS Evening CR-melatonin 2 mg treatment for 4 weeks significantly reduced nocturnal systolic BP in patients with nocturnal hypertension . Thus , an addition of melatonin 2 mg at night to stable antihypertensive treatment may improve nocturnal BP control in treated patients with nocturnal hypertension The objective of the present study was to assess the toxicology of melatonin ( 10 mg ) , administered for 28 days to 40 volunteers r and omly assigned to groups receiving either melatonin ( N = 30 ) or placebo  ( N = 10 ) in a double-blind fashion . The following measurements were performed : polysomnography ( PSG ) , laboratory examinations , including complete blood count , urinalysis , sodium , potassium and calcium levels , total protein levels , albumin , blood glucose , triglycerides , total cholesterol , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) , and very low-density lipoprotein ( VLDL ) , urea , creatinine , uric acid , glutamic-oxalacetic transaminase ( GOT ) , glutamic-pyruvate transaminase ( GPT ) , bilirubin , alkaline phosphatase , gama-glutamic transaminase ( GGT ) , T3 , T4 , TSH , LH/FSH , cortisol , and melatonin serum concentrations . In addition , the Epworth Somnolence Scale ( ESS ) and a sleep diary ( SD ) were also applied to the volunteers 1 wk before each PSG . In addition , the volunteers were asked about possible side effects ( SE ) that appeared during the treatment . The study was carried out according to the following timetable : Visit 0 , filling out the term of consent and inclusion criteria ; Visit 1 , PSG , laboratory examinations , ESS , SD ,  melatonin serum concentrations ; Visit 2 , SD ,  melatonin serum concentrations , SE ; Visit 3 ,  melatonin serum concentrations , PSG , ESS , SE ; Visit 4 , laboratory examinations , SE , melatonin serum concentrations , SD ; and Visit 5 , PSG , ESS , SE . Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group . No other differences between the placebo and melatonin groups were obtained . In the present study we did not observe , according to the parameters analyzed , any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study Cardiovascular disease remains the primary cause of mortality , and a major cause of disability in the developed world.1 This significant burden necessitates ongoing improvements in patient management , to minimize the impact of cardiovascular conditions on both patients and healthcare systems . These improvements in cardiovascular care are promoted by an evidence -based approach , shaped by comprehensive clinical guidelines . The scientific basis of recommendations is an important feature of clinical guidelines , and influences the degree to which they are followed in clinical practice .2 Recent studies have assigned the highest evidence grading to r and omized controlled trials ( RCTs ) that are clinical ly important , and representative of the clinical population covered by the guideline recommendation .3 For example , this highest grading was assigned to a recommendation based on a meta- analysis of RCTs showing low-dose diuretics to be the most effective first-line treatment for cardiovascular event prevention in hypertensive patients . This study review ed data from 42 RCTs which were , crucially , representative of the population that the recommendation was made for ( i.e. hypertensive patients ) .3,4 The importance of the applicability of evidence to recommendations highlights the need to consider evidence from clinical ly relevant situations , not all of which have been assessed by RCTs . This evidence can originate from expert consensus , as well as non-r and omized prospect i ve studies . Although generally providing a lower evidence -level than RCTs , 3,5 observational studies can make an important contribution to the evidence base when the study outcomes are clinical ly important , and the population s involved are representative . Indeed , information from several registries was considered in the recent American Heart Association Acute Coronary Care in the Elderly Scientific Statement.6 Non-r and omized prospect i ve registries document the treatment and outcomes for consecutive patients in clinical practice . Therefore , data are gained from a ‘ real-world ’ selection of patients , many of whom would be excluded from RCTs , In this study it was investigated whether the oral administration of melatonin ( 1 mg ) in comparison to placebo was able to reduce blood pressure , vascular reactivity , and catecholamines  in men , as previously reported in young women . The administration of melatonin significantly reduced blood pressure , the pulsatility index in the internal carotid artery , and catecholamines levels within 90 minutes . The effect of melatonin on the artery pulsatility index was related to baseline values , being greater in men with higher baseline values . The present data indicate that melatonin may blunt the activity of the cardiovascular system and may have both physiopathologic and clinical implication Several experimental studies have shown that melatonin has an oncostatic action , either by stimulating host antitumor immune defenses or by directly inhibiting the growth of some cancer histotypes , including melanoma . Our previous clinical studies demonstrated that melatonin may induce stabilization of the disease in untreatable metastatic solid tumor patients , and these results have been confirmed by others , at least in patients with metastatic melanoma . On the contrary , at present there are no data related to the possible efficacy of melatonin as an adjuvant endocrine therapy . This study was performed to investigate the impact of melatonin therapy on the disease-free survival ( DFS ) in melanoma patients surgically treated for regional node recurrence . The study included 30 node-relapsed melanoma patients , who were r and omized to receive no treatment or adjuvant therapy of melatonin  ( 20 mg/day orally in the evening ) every day until disease progression . After a median follow up of 31 months , the percent of DFS was significantly higher in melatonin-treated individuals than in controls . The DFS curve was also significantly longer in melatonin group than in controls . No melatonin-related toxicity was observed . This preliminary study suggests that an adjuvant endocrine therapy with melatonin may be effective in preventing disease progression in node-relapsed melanoma patients To evaluate the effects of antihypertensive agents on the circadian blood pressure ( BP )  of patients with previous brain infa rct ion , the ambulatory BP was measured non-invasively for 24 h before and after administration of antihypertensive agents . One hundred milligrams of acebutolol twice daily ( n = 15 ) is effective in lowering the BP during the daytime , but has little effect during the night and the morning . Twenty milligrams of slow-release nifedipine twice daily ( n = 14 ) produced a consistent reduction in the BP over the entire 24-h period and effectively blunted the rise in BP in the morning . Captopril ( 12.5 mg ) twice daily ( n = 15 ) produced a mild reduction in BP with little change in the circadian pattern . The slow-release nifedipine group had the greatest decrease in mean systolic and diastolic BP . The heart rate significantly increased after administration of slow-release nifedipine and decreased after administration of acebutolol . To reduce stroke recurrence , we should consider the effects of antihypertensive agents on circadian BP in hypertensive patients with previous brain infa rct ion Question In patients with hypertension , do electronic health ( e-health ) interventions improve blood pressure ( BP ) control and other outcomes ? Review scope Included studies compared e-health interventions with usual or st and ard care or attention control in patients with adequately or inadequately controlled hypertension .  E-health interventions had to use portable , Web-based , interactive wireless communication devices and focus on self-care , self-management , self-care behavior change , or education . Studies of interventions that only displayed information ( not interactive ) , were only used for follow-up , or that mostly benefitted health care providers were excluded . Outcomes included physical outcomes ( inadequate BP control , systolic [ SBP ] and diastolic BP [ DBP ] , body mass index [ BMI ] , body weight , and cholesterol levels ) , and self-care behavioral outcomes ( sodium and alcohol intake , smoking , and physical activities ) . Review methods MEDLINE , EMBASE /Excerpta Medica , Cochrane Data base of Systematic Review s , Cochrane Central Register of Controlled Trials , CINAHL Plus , PsycINFO , SCOPUS , Web of Science , Joanna Briggs Institute EBP Data base , INSPEC , China Journal Net , and WanFang Data ( all 2000 to Nov 2017 ) were search ed for English- and Chinese- language r and omized controlled trials ( RCTs ) . 14 RCTs ( n = 3998 , mean age 50 to 68 y ) , ranging in size from 44 to 778 patients , met the selection criteria . Follow-up ranged from 3 to 24 months . Studies were conducted in various setting s , including primary care clinics , community health centers , and hospitals . Intervention strategies included BP monitoring , lifestyle modification techniques , and motivation and maintenance . 9 RCTs had adequate r and omization sequence generation , 6 concealed allocation , 4 blinded outcome assessors , and none adequately reported blinding participants . Main results Results for inadequate BP control , SPB , DBP , BMI , body weight , and sodium intake are in the Table . E-health interventions did not improve total cholesterol levels at 3 to 6 months after the intervention ( 3 RCTs ) ; or alcohol intake , smoking , or physical activity at 6 months after the intervention ( 3 RCTs ) . Conclusion In patients with hypertension , electronic health interventions reduce blood pressure levels and increase likelihood of blood pressure control .  Electronic health interventions vs control in patients with hypertension * Outcomes Assessment times ( after intervention ) Number of trials ( n ) RRR ( 95 % CI ) NNT ( CI ) Inadequate BP control 3 to 12 mo 5 ( 1518 ) 31 % ( 16 to 43 ) 6 ( 4 to 11 ) Mean between-group difference ( CI ) Change in systolic BP ( mm Hg ) 6 mo 12 ( 3171 ) 5.50 ( 9.85 to 1.16 ) 12 mo 3 ( 1272 ) 7.68 ( 9.95 to 5.41 ) 18 mo 2 ( 735 ) 6.26 ( 9.29 to 3.23 ) Change in diastolic BP ( mm Hg ) 6 mo 12 ( 3171 ) 3.40 ( 7.79 to 0.99 ) 12 mo 3 ( 1272 ) 3.36 ( 4.80 to 1.92 ) 18 mo 2 ( 735 ) 2.53 ( 4.72 to 0.34 ) Change in body mass index ( kg/m2 ) 6 mo 5 ( 1486 ) 0.22 ( 0.46 to 0.02 ) 12 mo 3 ( 1272 ) 0.24 ( 0.82 to 0.33 ) 18 mo 2 ( 735 ) 0.07 ( 0.77 to 0.91 ) Change in body weight ( kg ) 3 to 6 mo 3 ( 517 ) 1.08 ( 2.04 to 0.13 ) Change in sodium intake ( SMD ) 6 mo 2 ( 768 ) 0.34 ( 0.49 to 0.20 ) 12 mo 2 ( 753 ) 0.39 ( 0.54 to 0.25 ) 18 mo 2 ( 735 ) 0.30 ( 0.45 to 0.16 ) * BP = blood pressure ; SMD = st and ardized mean difference ; other abbreviations defined in Glossary . Weighted electronic health intervention event rate , RRR , NNT , and CI calculated using control event rate and relative risk in article . Blood pressure 140/90 mm Hg . Weighted event rates 42 % vs 60 % . Commentary The systematic review and meta- analysis by Ma and colleagues showed a small but clinical ly meaningful reduction in SBP and DBP  in patients who received e-health re sources . However , some health outcomes , including BMI and cholesterol levels , were not improved . Despite a risk for selection bias in some of the studies and substantial heterogeneity between studies , the meta- analysis is of high quality . The interventions in the included studies varied greatly and included use of telephone calls , Web sites , and smartphone applications . The comparison treatments were either attention control or usual care , and trials did not directly compare e-health interventions . The outcomes measured also varied among studies . Because clinic BP measurements may overestimate the degree of elevation and ambulatory monitoring is costly and limited to brief periods of measurement , home BP monitoring using newer e-health re sources may provide a cost-effective alternative ( 1 ) . This is an exciting new avenue for improving BP control by allowing for more accurate and streamlined monitoring , leading to more precise and timely interventions . However , based on the heterogeneity of intervention types , the optimum method is unknown . Further studies should directly compare e-health platforms and assess patient-centered outcomes , including usability , satisfaction , affordability , and quality of life as well as BP . Although the evidence indicates that these interventions are not yet ready for routine clinical practice , there is a promising signal that they could be useful for BP management Hypotension is a frequent side-effect of cancer biotherapies with cytokines .  Cytokine-induced hypotension would mainly depend on the stimulation of nitric oxide ( NO ) production , which represents the most effective endogenous vasodilator . Moreover , it has been proven that both biological activity and toxicity of cytokines are influenced by the psychoneuroendocrine system , in particular by the pineal hormone melatonin . To investigate the possible modulatory effect of melatonin on cytokine cardiovascular toxicity , we evaluated the influence of a concomitant melatonin administration on interleukin-2(IL-2)- and tumour-necrosis-factor-α(TNF)-induced hypotension in advanced cancer patients . The study included 116 patients with advanced solid tumour , for whom no effective st and ard anticancer therapy was available , who underwent  cancer biotherapy with IL-2 ( 3 × 106 IU/day s.c . every day , 6 days/week for 4 weeks ) or with TNF ( 0.75 mg/day i.v . for 5 days ) as compassionate treatment for their disease . Patients were r and omized to be treated with or without a concomitant melatonin administration ( 40 mg/day orally in the evening , starting 7 days prior to cytokine injection ) . The occurrence of hypotension was significantly less frequent in patients concomitantly treated by melatonin than in those who received the cytokine alone , during either IL-2 or TNF immunotherapy ( IL-2 : 11/45 versus 2/46,P<0.05 ; TNF : 10/23 versus 1/12,P<0.01 ) . This study shows that melatonin may prevent hypotension occurring during cancer immunotherapy with IL-2 or TNF . Since the pineal hormone has appeared to inhibit the activity of NO synthase from the endothelial cells , we suggest that melatonin may prevent cytokine-induced hypotension by inhibiting NO production , which plays an essential role in inducing hypotension during IL-2 and TNF biotherapies R and omized controlled trials ( RCTs ) are conducted under idealized and rigorously controlled conditions that may compromise their external validity . A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice . The review focused on publications in the fields of cardiology , mental health , and oncology . A range of data bases were interrogated ( MEDLINE ; EMBASE ; Science Citation Index ; Cochrane Methodology Register ) . Double- abstract review and data extraction were performed as per protocol specifications . Out of 5,456 de-duplicated abstract s , 52 studies met the inclusion criteria ( cardiology , n = 20 ; mental health , n = 17 ; oncology , n = 15 ) . Studies either performed an analysis of the baseline characteristics ( demographic , socioeconomic , and clinical parameters ) of RCT -enrolled patients compared with a real-world population , or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion /exclusion criteria . Many of the included studies concluded that RCT sample s are highly selected and have a lower risk profile than real-world population s , with the frequent exclusion of elderly patients and patients with co-morbidities . Calculation of in eligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials . The majority of studies ( n = 37 [ 71.2 % ] ) explicitly concluded that RCT sample s were not broadly representative of real-world patients and that this may limit the external validity of the RCT . Authors made a number of recommendations to improve external validity . Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world setting s have the appropriate evidence on which to base their clinical decisions . This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies . In general , a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner Background The blood pressure rapid intensive lowering and normal treatment for mood and cognition in persistent depression ( BRILiANT mood study ) was devised as a pilot study to investigate the feasibility and safety of intensive blood pressure lowering as treatment for persistent mood and cognitive symptoms in older adults with major depressive disorder and to assess the availability of this population for recruitment . In addition , the relationship between reduced blood pressure and the change in cerebral blood flow and mood was to be investigated . Methods A single centre pilot r and omised controlled trial ( RCT ) , with two parallel groups of intensive or normal treatment for hypertension , recruiting from primary and secondary care and newspaper advert , with an aim of recruiting 66 participants , was observed in this study . At the end of the recruitment period , in order to explore the reasons for failure to recruit to target , surveys were developed and issued to those involved in recruitment . Results Recruitment rates were lower than expected which led to the study being exp and ed to further areas and opened to self-referral via advertisement . However , because of better management of hypertension due to changes in the UK Quality and Outcomes Framework guidelines for blood pressure treatment , few eligible patients were identified and the study closed at the end of the recruitment period , with 13 participants consenting , but 12 failing screening result ing in one recruited participant . Conclusions Overall , the BRILiANT mood study was found not to be feasible , and results suggest that the expected patient population no longer exists . To overcome such recruitment difficulties , a prompt commencement of a study after funding so no relevant care changes occur might help prevent similar problems in future studies . In addition , self-referral , in this case via advertisement in papers , may be a useful tool to increase response rate . When recruiting in primary care , direct access to primary care data bases , in a secure and anonymised way , may enable more effective screening . Ultimately , the BRILiANT mood study was shown not to be feasible ; this was a useful conclusion from this pilot study .Trial Registration IS RCT N 64524251 ; UKCRN Portfolio No :
In summary , the current meta- analysis demonstrated that melatonin supplementation  significantly decreased SBP and DBP in patients with metabolic disorders .
The current systematic review and meta- analysis of r and omized controlled trials ( RCTs ) was conducted to evaluate the potential effect of melatonin supplementation on  blood pressure in patients with metabolic disorders .