human
***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: AIMS Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John 's wort extract .  The aim of the present study was to investigate the effects of St John 's wort extract on oral contraceptive therapy with respect to ovarian activity , breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel .  METHODS Eighteen healthy females were treated with a low-dose oral contraceptive ( 0.02 mg ethinyloestradiol , 0.150 mg desogestrel ) alone ( control cycle ) or combined with 300 mg St John 's wort extract given twice daily ( cycle A ) or three times daily ( cycle B ) . Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations . The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel  were assessed under steady-state conditions . RESULTS During concomitant administration of low-dose oral contraceptive and St John 's wort , there was no significant change in follicle maturation , serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone . However , significantly more subjects reported intracyclic bleeding during cycles A ( 13/17 ( 77 % ) , P < 0.015 ) and cycle B ( 15/17 ( 88 % ) , P < 0.001 ) than with oral contraceptives alone ( 6/17 ( 35 % ) ) . The AUC(0,24 h ) and Cmax of ethinyloestradiol remained unchanged during all study cycles , whereas the AUC(0,24 h ) and Cmax of 3-ketodesogestrel  decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h ( 43.9 % ; 95 % confidence interval ( CI ) -49.3 , -38.5 , P = 0.001 ) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8 % ; CI -29.9 , -5.7 , P = 0.005 ) , respectively , during cycle A and by 41.7 % ( CI -47.9 , -35.6 ; P = 0.001 ) and by 22.8 % ( CI -31.2 , -13.3 ; P < 0.001 ) during cycle B respectively , compared with the control cycle . CONCLUSIONS There was no evidence of ovulation during low-dose oral contraceptive and St John 's wort extract combination therapy , but intracyclic bleeding episodes increased . Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John 's wort-induced decreases in serum 3-ketodesogestrel concentrations , enhance the risk of unintended pregnancies Many drugs are cosubstrates of cytochrome P450 ( CYP ) 3A and MDR1 ; furthermore , their disposition is markedly affected by pretreatment with inducing agents , including St John 's wort . Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor . However , the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown The popular herbal remedy St John 's wort is an inducer of cytochrome P450 ( CYP ) 3A enzymes and may reduce the efficacy of oral contraceptives . Therefore we evaluated the effect of St John 's wort on thedisposition and efficacy of Ortho‐Novum 1/35 ( Ortho‐McNeil Pharmaceutical , Inc , Raritan , NJ ) , a popular combination oral contraceptive pill containing ethinyl estradiol ( INN , ethinylestradiol ) and norethindrone ( INN , norethisterone ) The objective of this study was to investigate the effect of St. John 's wort ( SJW , Hypericum perforatum ) on the pharmacokinetics of theophylline in healthy volunteers . Twelve healthy Japanese male volunteers participated in this r and omized , open-labeled , crossover study . The subjects took an SJW caplet ( 300 mg ) three times a day for 15 days . On day 14 , they received a single oral dose of 400 mg of theophylline . They took the same dose of theophylline without SJW treatment on another occasion . Plasma and urine sample s were obtained during a 48-hour period after theophylline administration . Theophylline concentrations in plasma and urine , as well as the major metabolites ( 13U , 1U , 3X ) in urine , were measured . SJW caused no significant changes in the pharmacokinetics of theophylline in plasma . SJW administration tended to increase the ratio of 1U/the total amount excreted in urine . However , no changes in the ratio of unchanged theophylline , 13U , and 3X were observed . It is unlikely that the effect of 15 days of treatment with SJW on CYPs is sufficient to cause a change in plasma theophylline concentrations UNLABELLED M : The aim of this study was to investigate the effect of St John 's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin  . METHODS This was an open-label , three-way crossover r and omized study in 12 healthy male subjects , who received a single 25-mg dose of warfarin alone or after 14 days ' pretreatment with St John 's wort , or 7 days ' pretreatment with ginseng .  Dosing with St John 's wort or ginseng was continued for 7 days after administration of the warfarin dose . Platelet aggregation , international normalized ratio ( INR ) of prothrombin time , warfarin enantiomer protein binding , warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured . Statistical comparisons were made using anova and 90 % confidence intervals are reported . RESULTS INR and platelet aggregation were not affected by treatment with St John 's wort or ginseng . The apparent clearances of S-warfarin after warfarin alone or with St John 's wort or ginseng were , respectively , 198 + /- 38 ml h(-1 ) , 270 + /- 44 ml h(-1 ) and 220 + /- 29 ml h(-1 ) . The respective apparent clearances of R-warfarin were 110 + /- 25 ml h(-1 ) , 142 + /- 29 ml h(-1 ) and 119 + /- 20 ml h(-1 ) [ corrected ] . The mean ratio and 90 % confidence interval ( CI ) of apparent clearance for S-warfarin was 1.29 ( 1.16 , 1.46 ) and for R-warfarin it was 1.23 ( 1.11 , 1.37 ) when St John 's wort was coadministered . The mean ratio and 90 % CI of AUC(0 - 168 ) of INR was 0.79 ( 0.70 , 0.95 ) when St John 's wort was coadministered . St John 's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers . CONCLUSIONS St John 's wort significantly induced the apparent clearance of both S-warfarin and R-warfarin , which in turn result ed in a significant reduction in the pharmacological effect of rac-warfarin . Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin St John 's Wort , a widely used herbal product , is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates . The effects of St John 's Wort on the pharmacokinetics of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors simvastatin  ( an inactive lactone pro‐drug ) and pravastatin were determined in this study St John 's wort(Hypericum perforatum ) is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with substrates of several cytochrome P450 ( CYP ) isozymes . The effect of St John 's wort on CYP activity in vivo was examined with a probe drug cocktail St John 's wort is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with several substrates of P‐glycoprotein . The effect of St John 's wort on P‐glycoprotein activity in vivo was examined with use of fexofenadine as selective probe drug Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P-glycoprotein . A pharmacokinetic interaction between St. John 's wort ( antidepressant herbal product and inducer of CYP3A and P-glycoprotein ) and tacrolimus was evaluated in 10 healthy volunteers . The pharmacokinetics of tacrolimus were obtained from serial blood sample s collected following single oral doses ( 0.1 mg/kg ) prior to and during an 18-day concomitant St. John 's wort dosing phase ( 300 mg orally three times daily ) . Coadministration of St. John 's wort significantly decreased  tacrolimus AUC ( 306.9 microg.h/L + /- 175.8 microg.h/L vs. 198.7 microg.h/L + /- 139.6 microg.h/L ; p=0.004 ) and increased apparent oral clearance ( 349.0 mL/h/kg + /- 126.0 mL/h/kg vs. 586.4 mL/h/kg + /- 274.9 mL/h/kg ; p=0.01 ) and apparent oral volume of distribution at steady state ( 11.5 L/kg + /- 4.3 L/kg vs. 17.6 L/kg + /- 9.6 L/kg ; p=0.04 ) . St. John 's wort appears to induce  tacrolimus metabolism , most likely through induction of CYP3A and P-glycoprotein Extracts of St John 's wort ( Hypericum perforatum ) are widely used in the treatment of depression , often as an over‐the‐counter drug . In contrast to its frequent use , knowledge about the pharmacokinetics of ingredients and drug interactions of St John 's wort is poor . We studied the interaction between hypericum extract LI160 and digoxin OBJECTIVES Many cl aims are made that complementary medicine use is a substantial and growing part of health-care behaviour . Estimates of practitioner visits in the USA and Australia indicate high levels of use and expenditure . No reliable population -based estimates of practitioner use are available for the UK . METHODS In 1998 , a previously piloted postal question naire was sent to a geographically stratified , r and om sample of 5010 adults in Engl and . The question naire focuses on practitioner contacts , but also asked about the purchase of over-the-counter remedies . Additional information was requested on socio-demographic characteristics , perceived health , and recent NHS re source use . Information on use included reason for encounter , expenditure , insurance , and location of visit . MAIN OUTCOMES MEASURES Population estimates ( by age group and sex ) of lifetime use and use in the past 12 months for acupuncture , chiropractic , homoeopathy , hypnotherapy , medical herbalism , osteopathy . Estimates for two additional therapies ( reflexology and aromatherapy ) , and homoeopathic or herbal remedies purchased over-the-counter . Estimates of annual out-of-pocket expenditure on practitioner visits in 1998 . RESULTS A crude response rate of 60 % was achieved ( adjusted response rate 59 % ) . Responders were older and more likely to be female than non-responders . Usable responses ( n = 2669 ) were weighted using the age/sex profile of the sample frame . From these adjusted data we estimate that 10.6 % ( 95 % CI 9.4 to 11.7 ) of the adult population of Engl and had visited at least one therapist providing any one of the six more established therapies in the past 12 months ( 13.6 % for use of any of the eight named therapies , 95 % CI 12.3 to 14.9 ) . If all eight therapies , and self-care using remedies purchased over the counter are included , the estimated proportion rises to 28.3 % ( 95 % CI 26.6 to 30.0 ) for use in the past 12 months , and 46.6 % ( 95 % CI 44.6 to 48.5 ) for lifetime use . All types of use declined in older age groups , and were more commonly reported by women than men ( P < 0.01 for all comparisons ) . An estimated 22 million visits were made to practitioners of one of the six established therapies in 1998 . The NHS provided an estimated 10 % of these contacts . The majority of non-NHS visits were financed through 
    Output:
    
agent
Clinicians and patients should beware of possible decreases in the systemic bioavailability of conventional drugs when taken concomitantly with St John 's wort
***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: AIMS Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John 's wort extract .  The aim of the present study was to investigate the effects of St John 's wort extract on oral contraceptive therapy with respect to ovarian activity , breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel .  METHODS Eighteen healthy females were treated with a low-dose oral contraceptive ( 0.02 mg ethinyloestradiol , 0.150 mg desogestrel ) alone ( control cycle ) or combined with 300 mg St John 's wort extract given twice daily ( cycle A ) or three times daily ( cycle B ) . Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations . The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel  were assessed under steady-state conditions . RESULTS During concomitant administration of low-dose oral contraceptive and St John 's wort , there was no significant change in follicle maturation , serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone . However , significantly more subjects reported intracyclic bleeding during cycles A ( 13/17 ( 77 % ) , P < 0.015 ) and cycle B ( 15/17 ( 88 % ) , P < 0.001 ) than with oral contraceptives alone ( 6/17 ( 35 % ) ) . The AUC(0,24 h ) and Cmax of ethinyloestradiol remained unchanged during all study cycles , whereas the AUC(0,24 h ) and Cmax of 3-ketodesogestrel  decreased significantly from 31.2 ng ml-1 h to 17.7 ng x ml-1 h ( 43.9 % ; 95 % confidence interval ( CI ) -49.3 , -38.5 , P = 0.001 ) and from 3.6 ng x ml -1 to 3.0 ng x ml -1(17.8 % ; CI -29.9 , -5.7 , P = 0.005 ) , respectively , during cycle A and by 41.7 % ( CI -47.9 , -35.6 ; P = 0.001 ) and by 22.8 % ( CI -31.2 , -13.3 ; P < 0.001 ) during cycle B respectively , compared with the control cycle . CONCLUSIONS There was no evidence of ovulation during low-dose oral contraceptive and St John 's wort extract combination therapy , but intracyclic bleeding episodes increased . Bleeding irregularities may adversely effect compliance to oral contraceptives and together with St John 's wort-induced decreases in serum 3-ketodesogestrel concentrations , enhance the risk of unintended pregnancies Many drugs are cosubstrates of cytochrome P450 ( CYP ) 3A and MDR1 ; furthermore , their disposition is markedly affected by pretreatment with inducing agents , including St John 's wort . Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor . However , the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown The popular herbal remedy St John 's wort is an inducer of cytochrome P450 ( CYP ) 3A enzymes and may reduce the efficacy of oral contraceptives . Therefore we evaluated the effect of St John 's wort on thedisposition and efficacy of Ortho‐Novum 1/35 ( Ortho‐McNeil Pharmaceutical , Inc , Raritan , NJ ) , a popular combination oral contraceptive pill containing ethinyl estradiol ( INN , ethinylestradiol ) and norethindrone ( INN , norethisterone ) The objective of this study was to investigate the effect of St. John 's wort ( SJW , Hypericum perforatum ) on the pharmacokinetics of theophylline in healthy volunteers . Twelve healthy Japanese male volunteers participated in this r and omized , open-labeled , crossover study . The subjects took an SJW caplet ( 300 mg ) three times a day for 15 days . On day 14 , they received a single oral dose of 400 mg of theophylline . They took the same dose of theophylline without SJW treatment on another occasion . Plasma and urine sample s were obtained during a 48-hour period after theophylline administration . Theophylline concentrations in plasma and urine , as well as the major metabolites ( 13U , 1U , 3X ) in urine , were measured . SJW caused no significant changes in the pharmacokinetics of theophylline in plasma . SJW administration tended to increase the ratio of 1U/the total amount excreted in urine . However , no changes in the ratio of unchanged theophylline , 13U , and 3X were observed . It is unlikely that the effect of 15 days of treatment with SJW on CYPs is sufficient to cause a change in plasma theophylline concentrations UNLABELLED M : The aim of this study was to investigate the effect of St John 's wort and ginseng on the pharmacokinetics and pharmacodynamics of warfarin  . METHODS This was an open-label , three-way crossover r and omized study in 12 healthy male subjects , who received a single 25-mg dose of warfarin alone or after 14 days ' pretreatment with St John 's wort , or 7 days ' pretreatment with ginseng .  Dosing with St John 's wort or ginseng was continued for 7 days after administration of the warfarin dose . Platelet aggregation , international normalized ratio ( INR ) of prothrombin time , warfarin enantiomer protein binding , warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured . Statistical comparisons were made using anova and 90 % confidence intervals are reported . RESULTS INR and platelet aggregation were not affected by treatment with St John 's wort or ginseng . The apparent clearances of S-warfarin after warfarin alone or with St John 's wort or ginseng were , respectively , 198 + /- 38 ml h(-1 ) , 270 + /- 44 ml h(-1 ) and 220 + /- 29 ml h(-1 ) . The respective apparent clearances of R-warfarin were 110 + /- 25 ml h(-1 ) , 142 + /- 29 ml h(-1 ) and 119 + /- 20 ml h(-1 ) [ corrected ] . The mean ratio and 90 % confidence interval ( CI ) of apparent clearance for S-warfarin was 1.29 ( 1.16 , 1.46 ) and for R-warfarin it was 1.23 ( 1.11 , 1.37 ) when St John 's wort was coadministered . The mean ratio and 90 % CI of AUC(0 - 168 ) of INR was 0.79 ( 0.70 , 0.95 ) when St John 's wort was coadministered . St John 's wort and ginseng did not affect the apparent volumes of distribution or protein binding of warfarin enantiomers . CONCLUSIONS St John 's wort significantly induced the apparent clearance of both S-warfarin and R-warfarin , which in turn result ed in a significant reduction in the pharmacological effect of rac-warfarin . Coadministration of warfarin with ginseng did not affect the pharmacokinetics or pharmacodynamics of either S-warfarin or R-warfarin St John 's Wort , a widely used herbal product , is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates . The effects of St John 's Wort on the pharmacokinetics of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors simvastatin  ( an inactive lactone pro‐drug ) and pravastatin were determined in this study St John 's wort(Hypericum perforatum ) is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with substrates of several cytochrome P450 ( CYP ) isozymes . The effect of St John 's wort on CYP activity in vivo was examined with a probe drug cocktail St John 's wort is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with several substrates of P‐glycoprotein . The effect of St John 's wort on P‐glycoprotein activity in vivo was examined with use of fexofenadine as selective probe drug Tacrolimus is an immunosuppressant approved for the prevention of rejection following transplantation and is a substrate for CYP3A and P-glycoprotein . A pharmacokinetic interaction between St. John 's wort ( antidepressant herbal product and inducer of CYP3A and P-glycoprotein ) and tacrolimus was evaluated in 10 healthy volunteers . The pharmacokinetics of tacrolimus were obtained from serial blood sample s collected following single oral doses ( 0.1 mg/kg ) prior to and during an 18-day concomitant St. John 's wort dosing phase ( 300 mg orally three times daily ) . Coadministration of St. John 's wort significantly decreased  tacrolimus AUC ( 306.9 microg.h/L + /- 175.8 microg.h/L vs. 198.7 microg.h/L + /- 139.6 microg.h/L ; p=0.004 ) and increased apparent oral clearance ( 349.0 mL/h/kg + /- 126.0 mL/h/kg vs. 586.4 mL/h/kg + /- 274.9 mL/h/kg ; p=0.01 ) and apparent oral volume of distribution at steady state ( 11.5 L/kg + /- 4.3 L/kg vs. 17.6 L/kg + /- 9.6 L/kg ; p=0.04 ) . St. John 's wort appears to induce  tacrolimus metabolism , most likely through induction of CYP3A and P-glycoprotein Extracts of St John 's wort ( Hypericum perforatum ) are widely used in the treatment of depression , often as an over‐the‐counter drug . In contrast to its frequent use , knowledge about the pharmacokinetics of ingredients and drug interactions of St John 's wort is poor . We studied the interaction between hypericum extract LI160 and digoxin OBJECTIVES Many cl aims are made that complementary medicine use is a substantial and growing part of health-care behaviour . Estimates of practitioner visits in the USA and Australia indicate high levels of use and expenditure . No reliable population -based estimates of practitioner use are available for the UK . METHODS In 1998 , a previously piloted postal question naire was sent to a geographically stratified , r and om sample of 5010 adults in Engl and . The question naire focuses on practitioner contacts , but also asked about the purchase of over-the-counter remedies . Additional information was requested on socio-demographic characteristics , perceived health , and recent NHS re source use . Information on use included reason for encounter , expenditure , insurance , and location of visit . MAIN OUTCOMES MEASURES Population estimates ( by age group and sex ) of lifetime use and use in the past 12 months for acupuncture , chiropractic , homoeopathy , hypnotherapy , medical herbalism , osteopathy . Estimates for two additional therapies ( reflexology and aromatherapy ) , and homoeopathic or herbal remedies purchased over-the-counter . Estimates of annual out-of-pocket expenditure on practitioner visits in 1998 . RESULTS A crude response rate of 60 % was achieved ( adjusted response rate 59 % ) . Responders were older and more likely to be female than non-responders . Usable responses ( n = 2669 ) were weighted using the age/sex profile of the sample frame . From these adjusted data we estimate that 10.6 % ( 95 % CI 9.4 to 11.7 ) of the adult population of Engl and had visited at least one therapist providing any one of the six more established therapies in the past 12 months ( 13.6 % for use of any of the eight named therapies , 95 % CI 12.3 to 14.9 ) . If all eight therapies , and self-care using remedies purchased over the counter are included , the estimated proportion rises to 28.3 % ( 95 % CI 26.6 to 30.0 ) for use in the past 12 months , and 46.6 % ( 95 % CI 44.6 to 48.5 ) for lifetime use . All types of use declined in older age groups , and were more commonly reported by women than men ( P < 0.01 for all comparisons ) . An estimated 22 million visits were made to practitioners of one of the six established therapies in 1998 . The NHS provided an estimated 10 % of these contacts . The majority of non-NHS visits were financed through 
    Output:
    