***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: Objective Polycyclic aromatic hydrocarbons in cigarette smoke induce cytochrome P450(CYP)1A2 , which is involved in the hepatic metabolism of melatonin ( MT ) . This suggests that habitual smokers may have low serum MT levels during smoking compared with a non-smoking period . We decided to investigate whether this suggestion is correct . Methods Eight habitual smokers were tested on two occasions . They had smoked prior to the first occasion but had not smoked for 7 days prior to the second . Each test was divided into two parts . The first part spanned the night between 2000 hours and 0800 hours .  Venous blood sample s were collected every second hour during this period for analysis of  endogenous serum MT . The second part was performed the subsequent day . At 0930 hours , 25 mg MT was ingested orally , and blood sample s for  exogenous serum MT analysis were collected every hour between 1000 hours and 1600 hours . Endogenous and exogenous areas under the serum MT – time curve ( MT-AUCs ) were calculated . Results Endogenous serum MT-AUCs were similar during the two periods . Oral administration of MT induced supraphysiological levels of serum MT . Moreover , exogenous serum MT-AUCs were significantly smaller before than after smoking abstinence ( 7.34±1.85 versus 21.07±7.28 nmol/l × h ; P<0.02 ; means±SEM ) . Conclusion This investigation shows that exogenous , but not endogenous ( at night ) , serum MT levels are influenced by cigarette smoking . When the MT levels are low , the influence of CYP1A2 levels appears to be less pronounced than when they are high , and the enzyme capacity hugely utilized . These findings implicate that interactions between exogenous MT , and substrates metabolized by CYP1A2 , may differ in individuals before and after smoking abstinence Purpose Our intention was to assess the effectiveness of preoperative oral melatonin medication on sedation , sleep quality , and postoperative analgesia in patients undergoing elective prostatectomy . Methods Fifty-two ASA I – II patients undergoing elective prostatectomy were included in this study , r and omly divided into two groups . Patients received an oral placebo ( n = 26 ) or 6 mg melatonin ( n = 26 ) the night before and 1 h before surgery . All patients received a st and ard anesthetic protocol . At the end of surgery , all patients received tramadol i.v . via a PCA device . Extubation time , intraoperative fentanyl consumption , and recovery time were assessed at the end of the operation . Pain scores , tramadol consumption , and sedation scores were assessed at 1 , 2 , 4 , 6 , 12 , 18 , and 24 h postoperatively , and sleep quality and subjective analgesic efficacy were assessed at 24 h after surgery . Results There were no significant differences in demographic data between the groups . Extubation time and recovery time from anesthesia were significantly longer in the melatonin group ( P < 0.05 ) . Intraoperative fentanyl usage , pain scores , and tramadol consumption were significantly lower in the melatonin group ( P < 0.05 ) . The postoperative sleep quality of patients was significantly better in the melatonin group than in the control group ( P < 0.05 ) . Postoperative VAS of pain was significantly lower in the melatonin group compared with the control group at 1 , 2 , 4 , 6 , 12 , 18 , and 24 h postoperatively ( P < 0.05 ) . Subjective analgesic efficacy of patients was significantly different between groups ( P < 0.05 ) . The sedation scores were significantly higher in the melatonin group than in the control group at 1 h and 2 h after surgery ( P < 0.05 ) . Conclusions Preoperative oral melatonin administration decreased pain scores and tramadol consumption and enhanced sleep quality , sedation scores , and subjective analgesic efficacy during the postoperative period Melatonin is increasingly used for the treatment of sleep disorders . Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile . However , relatively little is known about the pharmacokinetic properties of low-dose ( < 0.5 mg ) and high-dose ( > 2 mg ) melatonin in a combined immediate release/controlled release dose , especially in older adults who may also exhibit altered melatonin disposition . To assess this , we conducted a r and omized , double-blind , placebo-controlled study of low-dose ( 0.4 mg ) and high-dose ( 4.0 mg ) melatonin ( 25 % immediate release+75 % controlled release ) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses . The time to maximum level ( 1.3hrs versus 1.5hrs ) , elimination half-life ( 1.8hrs versus 2.1hrs ) , and apparent total clearance ( 379L/hr versus 478L/hr ) did not differ significantly between the low- and high-dose arms , respectively . The maximum concentration was 405 ±93pg/mL for the low-dose arm and 3999±700pg/mL for the high-dose arm , both of which are substantially higher than physiologic melatonin levels for this age group . In addition , subjects in the high-dose arm maintained melatonin levels > 50pg/mL for an average of 10hrs , which could result in elevated melatonin levels beyond the typical sleep period . Renal and liver function parameters remained stable after 6wks of treatment . The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes Introduction Sleep disturbances are common in critically ill patients and when sleep does occur it traverses the day-night periods . The reduction in plasma melatonin levels and loss of circadian rhythm observed in critically ill patients receiving mechanical ventilation may contribute to this irregular sleep-wake pattern . We sought to evaluate the effect of exogenous melatonin on nocturnal sleep quantity in these patients and , furthermore , to describe the kinetics of melatonin after oral administration in this patient population , thereby guiding future dosing schedules . Methods We conducted a r and omised double-blind placebo-controlled trial in 24 patients who had undergone a tracheostomy to aid weaning from mechanical ventilation .  Oral melatonin 10 mg or placebo was administered at 9 p.m. for four nights . Nocturnal sleep was monitored using the bispectral index ( BIS ) and was expressed in terms of sleep efficiency index ( SEI ) and area under the curve ( AUC ) . Secondary endpoints were SEI measured by actigraphy and nurse and patient assessment s. Plasma melatonin concentrations were measured in nine patients in the melatonin group on the first night . Results Nocturnal sleep time was 2.5 hours in the placebo group ( mean SEI = 0.26 , 95 % confidence interval [ CI ] 0.17 to 0.36 ) . Melatonin use was associated with a 1-hour increase in nocturnal sleep ( SEI difference = 0.12 , 95 % CI -0.02 to 0.27 ; P = 0.09 ) and a decrease in BIS AUC indicating ' better ' sleep ( AUC difference = -54.23 , 95 % CI -104.47 to -3.98 ; P = 0.04 ) . Results from the additional sleep measurement methods were inconclusive . Melatonin appeared to be rapidly absorbed from the oral solution , producing higher plasma concentrations relative to similar doses reported in healthy individuals . Plasma concentrations declined biexponentially , but morning ( 8 a.m. ) plasma levels remained supraphysiological . Conclusion In our patients , nocturnal sleep quantity was severely compromised and melatonin use was associated with increased nocturnal sleep efficiency . Although these promising findings need to be confirmed by a larger r and omised clinical trial , they do suggest a possible future role for melatonin in the routine care of critically ill patients . Our pharmacokinetic analysis suggests that the 10-mg dose used in this study is too high in these patients and may lead to carryover of effects into the next morning . Reduced doses of 1 to 2 mg could be used in future studies .Trial registration Current Controlled Trials IS RCT N47578325 AIMS The aim of this study was to assess the influence of concomitant caffeine intake on the pharmacokinetics of oral melatonin  , a probe drug for CYP1A2 activity . METHODS Twelve healthy subjects , six smokers and six nonsmokers , were given melatonin ( 6 mg ) either alone or in combination with caffeine ( 3 x 200 mg ) . Blood sample s for the analysis of melatonin or caffeine and paraxanthine were taken from 1 h before until 6 h after intake of melatonin . Subjects were genotyped with respect to the CYP1A2 * 1F ( C734A ) polymorphism . RESULTS When caffeine was coadministered the Cmax and AUC of melatonin  were increased on average by 142 % ( P = 0.001 , confidence interval on the difference 44 , 80 % ) and 120 % ( P < 0.001 , confidence interval on the difference 63 , 178 % ) , respectively . The inhibitory effect of caffeine was more pronounced in nonsmokers and in individuals with the * 1F/*1F genotype . CONCLUSION The results of this study revealed a pronounced effect of caffeine on the bioavailability of orally given melatonin , most probably due to inhibition of CYP1A2 activity Using melatonin ( MT ) as a circadian synchroniser in humans to treat a variety of rhythm disorders , it is desirable to develop controlled-release dosage forms that deliver MT in accordance with its endogenous secretory pattern as well as preparations that release MT in a pulsatile way . In this paper we describe two oral pulsatile dosage forms containing 10 mg MT each ( capsules B and C ) and a fast-release form containing 5 mg MT ( capsule A ) studied in a r and omised single-dose , threefold cross-over study in 15 healthy male volunteers . The concentrations of both MT in serum and its main metabolite 6-sulfatoxymelatonin ( aMT6s ) in urine were analysed by means of specific radioimmunoassays up to 10 h p.a . of the MT preparations . Mean peak concentrations of MT in serum were reached between 0.5 h and 0.75 h ( Cmax[1 ] pmol/ml ) : 20.7 ( A ) , 16.4 ( B ) , 9.7 ( C ) . The capsules B and C released a second MT pulse after about 3.5 h with Cmax[2 ] of 13.0 and 17.5 pmol/ml , respectively . Dose proportionality for the MT preparations studied was calculated by determining the AUC0-infinity ( pmol/ml.h ) : 18.4 ( A ) , 36.1 ( B ) , 42.4 ( C ) . The terminal serum half-lives of MT ranged between 0.64 and 0.84 h. The time course of the renally excreted aMT6s correlated with that of changes in MT serum concentrations Fluvoxamine , a selective serotonin reuptake inhibitor , is known to elevate melatonin serum concentrations . It has not been clear whether these effects might be attributed to an increased melatonin production or to an decreased elimination of melatonin . The latter hypothesis was tested by this study Surgery for abdominal aortic aneurysm is associated with elevated oxidative stress . As an antioxidant in animal and human studies , melatonin has the potential of ameliorating some of this oxidative stress , but melatonin has never been administered to adults during surgery for the purpose of reducing oxidative damage . The aim of this pilot study was to evaluate the safety of various doses of melatonin administered during or after surgery and to monitor the changes in biomarkers of oxidative stress and inflammation during the pre- , intra- , and postoperative period . Six patients undergoing aortic surgery received 10 ( n = 2 ) , 30 ( n = 2 ) or 60 ( n = 2 ) mg melatonin intravenously in the intraoperative phase and 10 mg orally for three nights after surgery . Patients were monitored for hemodynamic parameters during and after surgery . Any unexpected events during the hospitalization were registered . Blood sample s were collected preoperatively and at 5 min , 6 hr and 24 hr after clamp removal or after re-circulation of the first leg and the sample s were analyzed for malondialdehyde ( MDA ) , ascorbic acid ( AA ) , dehydroascorbic acid ( DHA ) , and interleukin-6 ( IL-6 ) . Troponin I ( TpI ) and C-reactive protein ( CRP ) were also measured for 4 days after surgery . Melatonin administration did not change hemodynamic parameters ( mean arterial pressure or pulse rate ) during surgery ( P = 0.499 and 0.149 , respectively ) , but oxidative stress parameters ( MDA and AA ) decreased significantly ( P = 0.01 
    Output:
    
Pharmacokinetics was affected by age , caffeine , smoking , oral contraceptives , feeding status , and fluvoxamine .
Critically ill patients displayed accelerated absorption and compromised elimination .