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: Iloprost , a stable prostacyclin analogue , was given by intravenous infusion to 29 patients with severe Raynaud 's phenomenon , 26 of whom had systemic sclerosis ( SS ) , and compared with placebo infusion in a double blind crossover trial . Iloprost significantly lessened the number and the severity of attacks compared with placebo . Nine patients expressed a preference for effectiveness of treatment , eight of these in favour of Iloprost .  Thermography failed to show any long term effect of Iloprost . Side effects of headache , flushing , nausea , and vomiting were common , and the inconvenience of intravenous administration may limit its routine use OBJECTIVE To investigate the efficacy of the endothelin receptor antagonist , bosentan , in patients with RP secondary to SSc without pre-existing digital ulcers . METHODS Single-centre , r and omized , prospect i ve , double-blinded comparison of bosentan and placebo . Patients received either 62.5 mg bosentan twice daily for 4 weeks , followed by 125 mg twice daily for 12 weeks or matching doses of placebo . RESULTS Of the 17 patients enrolled , 16 completed the study and 1 withdrew from the study due to the reversible development of peripheral oedema .  Compared with placebo , bosentan did not improve the frequency , duration , pain or severity of RP attacks . However , in contrast to placebo , bosentan significantly improved the functional scores . With respect to baseline , the scleroderma HAQ disability index changes were in favour of bosentan at Weeks 12 ( P = 0.03 ) and 20 ( P = 0.01 ) , and the United Kingdom functional score changes at Weeks 8 ( P = 0.038 ) and 16 ( P = 0.039 ) . CONCLUSIONS Bosentan is not effective in SSc-related RP without pre-existing digital ulcers , but it might benefit functional impairment in those patients . TRIAL REGISTRATION European Union Drug Regulating Authorities Clinical Trials , https://eudract.emea.europa.eu , EudraCT-Nr 2004 - 002686 - 21 OBJECTIVE --To compare the efficacy , tolerance and safety of 50 - 150 micrograms orally administered iloprost given twice a day versus placebo in patients with Raynaud 's syndrome . METHODS --The study was multicentre ( n = 3 ) , double blind and placebo controlled . Sixty three patients who had eight or more vasospastic attacks per week were enrolled . After a one week run-in period , all patients received either iloprost or placebo treatment to a maximum tolerated dose of 150 micrograms twice a day for 10 days . Diary cards assessed the duration and severity of the vasospastic attacks . Side effects were monitored by direct question ing . A global assessment of treatment efficacy was made by the patient at the end of treatment and two weeks later . RESULTS --Patient opinion tended to favour iloprost at the end of the 10 day treatment phase ( p = 0.09 ) and this was significant at day 24 ( the follow up visit ) ( p = 0.011 ) . Although the duration and severity of attacks tended to decrease in the iloprost treated group , these results tended not to reach statistical significance ( for severity p = 0.06 at end of treatment , p = 0.09 on day 24 ) . CONCLUSION --Iloprost administered intravenously has been shown to be of benefit in the treatment of the Raynaud 's syndrome associated with systemic sclerosis , but this route of administration is inconvenient . This study evaluated the use of iloprost administered orally to patients with Raynaud 's syndrome . Patient documented improvement was significantly improved by iloprost . Diary card analysis showed a trend in favour of iloprost , but these results did not reach statistical significance Summary Oral and sublingual isoxsuprine 20 mg were compared with placebo in a double blind r and omised cross over trial in 7 patients with Raynaud 's phenomenon .  Skin thermography , plethysmography of the finger tips and direct temperature measurements showed that sublingual isoxsuprine was slightly but consistently superior to the oral form and to placebo ; no significant difference was observed between the latter two treatments . It is concluded that sublingual administration of isoxsuprine has advantages over other routes of administration , and that thermography is a suitable technique for qualitative , but less appropriate for quantitative , measurement of drug effects in patients with Raynaud 's phenomenon There is evidence to suggest that platelet activation occurs in Raynaud 's syndrome . We evaluated the effect of prostacyclin ( PGI2 ) a potent antiplatelet and vasodilator agent in 5 female patients with Raynaud 's syndrome . Outpatient visits were made at weekly intervals for 4 weeks . At the first visit buffer solution ( Wellcome Laboratories ) was infused intravenously for 5 hrs , thereafter three five hr infusions of PGI2 at a peak dose of 10 ng/Kg/min were given . Six weeks after the infusions patients were review ed . Symptomatic improvement , including healing of ischaemic ulcers , occurred in 4 out of 5 patients . Thermography confirmed an increase in h and temperature after PCI2 . Subjective and objective improvement has persisted for at least 6 weeks after the last treatment OBJECTIVE To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud 's phenomenon secondary to systemic sclerosis . DESIGN Multicentre , r and omized , parallel-group comparison of two different doses of oral iloprost and placebo . SETTING European university hospitals . PATIENTS A total of 103 patients with Raynaud 's phenomenon secondary to systemic sclerosis . INTERVENTION Patients received one of three treatments for 6 weeks : placebo , oral iloprost 50 microg or oral iloprost 100 microg . Each treatment was taken twice daily , giving total daily doses of iloprost of 100 and 200 microg . MEASUREMENTS The frequency , total daily duration and severity of Raynaud 's attacks were recorded in a specially design ed patient diary ; physician 's global assessment and adverse events were recorded at visits to the clinic . Analysis was performed on an intention-to-treat population . RESULTS A total of 103 patients were recruited , 89 completed the assessment s throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment . Thirty-five patients received placebo , 33 received iloprost 50 microg and 35 received iloprost 100 microg . The mean percentage reductions in the frequency , total daily duration and severity of Raynaud 's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up . At the end of treatment ( 6 weeks ) , there were significant treatment differences in the total daily duration of attacks ( P = 0.03 ) , but not in the severity ( P = 0.07 ) or the frequency of attacks ( P = 0.37 ) . At the end of follow-up ( 12 weeks ) , there were significant treatment differences in the total daily duration of attacks ( P = 0.001 ) and in the severity of attacks ( P = 0.007 ) , but not in the frequency of attacks ( P = 0.07 ) . Percentages of patients improved at the end of treatment as assessed by the physician were 44 % placebo , 57 % iloprost 50 microg and 64 % iloprost 100 microg ( not significant ) . Side-effects were reported by 80 % of patients on placebo , 85 % on oral iloprost 50 microg and 97 % on oral iloprost 100 microg . Premature discontinuations of treatment in each group were 9 , 30 and 51 % , respectively , with 6 , 27 and 51 % being due to adverse events . CONCLUSION The results on the daily duration of Raynaud 's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud 's phenomenon secondary to systemic sclerosis . The 50 microg iloprost dose was better tolerated in this patient group OBJECTIVE To compare fluoxetine , a selective serotonin reuptake inhibitor , with nifedipine as treatment for primary or secondary Raynaud 's phenomenon . METHODS Twenty-six patients with primary and 27 patients with secondary Raynaud 's phenomenon were assigned r and omly to receive 6 weeks of treatment with fluoxetine ( 20 mg daily ) or nifedipine ( 40 mg daily ) . Following a 2-week washout period , each group was crossed over to the other treatment arm . The primary outcome variable was the frequency of attacks of Raynaud 's phenomenon . Self-reported attack severity , thermographic recovery from cold challenge and plasma levels of von Willebr and factor and soluble P-selectin were also measured . RESULTS There was a reduction in attack frequency and severity of Raynaud 's phenomenon in patients treated with either fluoxetine or nifedipine , but the effect was statistically significant only in the fluoxetine-treated group ( P=0.0002 for attack severity and P=0.003 for attack frequency ) . Subgroup analysis showed that the greatest response was seen in females and in patients with primary Raynaud 's phenomenon . A significant improvement in the thermographic response to cold challenge was also seen in female patients with primary Raynaud 's phenomenon treated with fluoxetine but not in those treated with nifedipine . There was no significant treatment effect on von Willebr and factor or soluble P-selectin . No significant adverse effects occurred in the fluoxetine-treated group . CONCLUSION This pilot study confirms the tolerability of fluoxetine and suggests that it would be effective as a novel treatment for Raynaud 's phenomenon . Larger and placebo-controlled trials are warranted to assess fluoxetine 's therapeutic potential further in this vasospastic condition OBJECTIVE To determine the effect of re-injection of small sample s of autologous blood , pretreated with heat , ozone and ultraviolet light ( H-O-U therapy ) in patients with severe Raynaud 's syndrome . EXPERIMENTAL DESIGN Open trial in 4 patients . SETTING Temperature/humidity controlled vascular laboratory . PATIENTS Severe Raynaud 's syndrome of more than 5 years duration and defined as more than 5 attacks daily or 10 attacks in one week , at least half of which were painful and lasting for more than 30 minutes . Three patients were refractory to infusions of Iloprost . INTERVENTIONS Patients were treated daily or on alternate days for a two to three weeks period by re-injection of citrated autologous blood pre-treated with heat , ozone and ultraviolet light ( H-O-U therapy ) . MEASURES Clinical observations ; mean equilibrated h and temperature ( infrared thermography ) ; distributive and microcirculatory blood-flow ( venous occlusion strain-gauge plethysmography , infrared photoplethysmography , laser Doppler flowmetry ) iontophoresis of acetylcholine and sodium nitroprusside ; estimations : serum levels of 6-keto-PGF1alpha and serum levels of anti-hsp65 antibody . RESULTS Reduction or abolition of Raynaud 's attacks for at least three months after treatment . Mean equilibrated h and temperature increased but did not normalise . Blood flow parameters improved but did not reach statistical significance . Iontophoresis of acetylcholine showed an increase in laser Doppler flowmetry which was statistically significant . Serum levels of 6-keto-PGF1alpha , fell significantly in three patients . Serum levels of anti-hsp65 antibody fell in the one patient which was followed sequentially . CONCLUSIONS H-O-U therapy may prove useful in patients with severe Raynaud 's syndrome OBJECTIVE --To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud 's phenomenon associated with systemic sclerosis . DESIGN --Double blind , placebo controlled , r and omised group comparison . SETTING --Dermatology outpatient clinic . PATIENTS --Twenty three patients with Raynaud 's phenomenon associated with well documented systemic sclerosis ( American Rheumatism Association criteria ) and with typical abnormalities in fingernail folds on capillaroscopy . INTERVENTIONS --Twelve patients were r and omised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8 . Placebo capsules were given concurrently . Eleven patients were r and omised to receive nifedipine , starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks . Infusions of placebo were given in the same manner as the infusions of iloprost . One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects . END POINT -- Reduction in number , duration , and severity of attacks of Raynaud 's phenomenon , reduction in number of digital lesions , increase in digital blood flow . MEASUREMENTS AND MAIN RESULTS -- Measurements were taken at 0 , 4 , 8 , 12 , and 16 weeks . Both regimens produced a reduction in the number , duration , and severity of attacks of Raynaud 's phenomenon . The mean ( SE ) number of digital lesions was reduced with iloprost ( from 3.5 ( 1 
    Output:
    
agent
***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: Iloprost , a stable prostacyclin analogue , was given by intravenous infusion to 29 patients with severe Raynaud 's phenomenon , 26 of whom had systemic sclerosis ( SS ) , and compared with placebo infusion in a double blind crossover trial . Iloprost significantly lessened the number and the severity of attacks compared with placebo . Nine patients expressed a preference for effectiveness of treatment , eight of these in favour of Iloprost .  Thermography failed to show any long term effect of Iloprost . Side effects of headache , flushing , nausea , and vomiting were common , and the inconvenience of intravenous administration may limit its routine use OBJECTIVE To investigate the efficacy of the endothelin receptor antagonist , bosentan , in patients with RP secondary to SSc without pre-existing digital ulcers . METHODS Single-centre , r and omized , prospect i ve , double-blinded comparison of bosentan and placebo . Patients received either 62.5 mg bosentan twice daily for 4 weeks , followed by 125 mg twice daily for 12 weeks or matching doses of placebo . RESULTS Of the 17 patients enrolled , 16 completed the study and 1 withdrew from the study due to the reversible development of peripheral oedema .  Compared with placebo , bosentan did not improve the frequency , duration , pain or severity of RP attacks . However , in contrast to placebo , bosentan significantly improved the functional scores . With respect to baseline , the scleroderma HAQ disability index changes were in favour of bosentan at Weeks 12 ( P = 0.03 ) and 20 ( P = 0.01 ) , and the United Kingdom functional score changes at Weeks 8 ( P = 0.038 ) and 16 ( P = 0.039 ) . CONCLUSIONS Bosentan is not effective in SSc-related RP without pre-existing digital ulcers , but it might benefit functional impairment in those patients . TRIAL REGISTRATION European Union Drug Regulating Authorities Clinical Trials , https://eudract.emea.europa.eu , EudraCT-Nr 2004 - 002686 - 21 OBJECTIVE --To compare the efficacy , tolerance and safety of 50 - 150 micrograms orally administered iloprost given twice a day versus placebo in patients with Raynaud 's syndrome . METHODS --The study was multicentre ( n = 3 ) , double blind and placebo controlled . Sixty three patients who had eight or more vasospastic attacks per week were enrolled . After a one week run-in period , all patients received either iloprost or placebo treatment to a maximum tolerated dose of 150 micrograms twice a day for 10 days . Diary cards assessed the duration and severity of the vasospastic attacks . Side effects were monitored by direct question ing . A global assessment of treatment efficacy was made by the patient at the end of treatment and two weeks later . RESULTS --Patient opinion tended to favour iloprost at the end of the 10 day treatment phase ( p = 0.09 ) and this was significant at day 24 ( the follow up visit ) ( p = 0.011 ) . Although the duration and severity of attacks tended to decrease in the iloprost treated group , these results tended not to reach statistical significance ( for severity p = 0.06 at end of treatment , p = 0.09 on day 24 ) . CONCLUSION --Iloprost administered intravenously has been shown to be of benefit in the treatment of the Raynaud 's syndrome associated with systemic sclerosis , but this route of administration is inconvenient . This study evaluated the use of iloprost administered orally to patients with Raynaud 's syndrome . Patient documented improvement was significantly improved by iloprost . Diary card analysis showed a trend in favour of iloprost , but these results did not reach statistical significance Summary Oral and sublingual isoxsuprine 20 mg were compared with placebo in a double blind r and omised cross over trial in 7 patients with Raynaud 's phenomenon .  Skin thermography , plethysmography of the finger tips and direct temperature measurements showed that sublingual isoxsuprine was slightly but consistently superior to the oral form and to placebo ; no significant difference was observed between the latter two treatments . It is concluded that sublingual administration of isoxsuprine has advantages over other routes of administration , and that thermography is a suitable technique for qualitative , but less appropriate for quantitative , measurement of drug effects in patients with Raynaud 's phenomenon There is evidence to suggest that platelet activation occurs in Raynaud 's syndrome . We evaluated the effect of prostacyclin ( PGI2 ) a potent antiplatelet and vasodilator agent in 5 female patients with Raynaud 's syndrome . Outpatient visits were made at weekly intervals for 4 weeks . At the first visit buffer solution ( Wellcome Laboratories ) was infused intravenously for 5 hrs , thereafter three five hr infusions of PGI2 at a peak dose of 10 ng/Kg/min were given . Six weeks after the infusions patients were review ed . Symptomatic improvement , including healing of ischaemic ulcers , occurred in 4 out of 5 patients . Thermography confirmed an increase in h and temperature after PCI2 . Subjective and objective improvement has persisted for at least 6 weeks after the last treatment OBJECTIVE To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud 's phenomenon secondary to systemic sclerosis . DESIGN Multicentre , r and omized , parallel-group comparison of two different doses of oral iloprost and placebo . SETTING European university hospitals . PATIENTS A total of 103 patients with Raynaud 's phenomenon secondary to systemic sclerosis . INTERVENTION Patients received one of three treatments for 6 weeks : placebo , oral iloprost 50 microg or oral iloprost 100 microg . Each treatment was taken twice daily , giving total daily doses of iloprost of 100 and 200 microg . MEASUREMENTS The frequency , total daily duration and severity of Raynaud 's attacks were recorded in a specially design ed patient diary ; physician 's global assessment and adverse events were recorded at visits to the clinic . Analysis was performed on an intention-to-treat population . RESULTS A total of 103 patients were recruited , 89 completed the assessment s throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment . Thirty-five patients received placebo , 33 received iloprost 50 microg and 35 received iloprost 100 microg . The mean percentage reductions in the frequency , total daily duration and severity of Raynaud 's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up . At the end of treatment ( 6 weeks ) , there were significant treatment differences in the total daily duration of attacks ( P = 0.03 ) , but not in the severity ( P = 0.07 ) or the frequency of attacks ( P = 0.37 ) . At the end of follow-up ( 12 weeks ) , there were significant treatment differences in the total daily duration of attacks ( P = 0.001 ) and in the severity of attacks ( P = 0.007 ) , but not in the frequency of attacks ( P = 0.07 ) . Percentages of patients improved at the end of treatment as assessed by the physician were 44 % placebo , 57 % iloprost 50 microg and 64 % iloprost 100 microg ( not significant ) . Side-effects were reported by 80 % of patients on placebo , 85 % on oral iloprost 50 microg and 97 % on oral iloprost 100 microg . Premature discontinuations of treatment in each group were 9 , 30 and 51 % , respectively , with 6 , 27 and 51 % being due to adverse events . CONCLUSION The results on the daily duration of Raynaud 's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud 's phenomenon secondary to systemic sclerosis . The 50 microg iloprost dose was better tolerated in this patient group OBJECTIVE To compare fluoxetine , a selective serotonin reuptake inhibitor , with nifedipine as treatment for primary or secondary Raynaud 's phenomenon . METHODS Twenty-six patients with primary and 27 patients with secondary Raynaud 's phenomenon were assigned r and omly to receive 6 weeks of treatment with fluoxetine ( 20 mg daily ) or nifedipine ( 40 mg daily ) . Following a 2-week washout period , each group was crossed over to the other treatment arm . The primary outcome variable was the frequency of attacks of Raynaud 's phenomenon . Self-reported attack severity , thermographic recovery from cold challenge and plasma levels of von Willebr and factor and soluble P-selectin were also measured . RESULTS There was a reduction in attack frequency and severity of Raynaud 's phenomenon in patients treated with either fluoxetine or nifedipine , but the effect was statistically significant only in the fluoxetine-treated group ( P=0.0002 for attack severity and P=0.003 for attack frequency ) . Subgroup analysis showed that the greatest response was seen in females and in patients with primary Raynaud 's phenomenon . A significant improvement in the thermographic response to cold challenge was also seen in female patients with primary Raynaud 's phenomenon treated with fluoxetine but not in those treated with nifedipine . There was no significant treatment effect on von Willebr and factor or soluble P-selectin . No significant adverse effects occurred in the fluoxetine-treated group . CONCLUSION This pilot study confirms the tolerability of fluoxetine and suggests that it would be effective as a novel treatment for Raynaud 's phenomenon . Larger and placebo-controlled trials are warranted to assess fluoxetine 's therapeutic potential further in this vasospastic condition OBJECTIVE To determine the effect of re-injection of small sample s of autologous blood , pretreated with heat , ozone and ultraviolet light ( H-O-U therapy ) in patients with severe Raynaud 's syndrome . EXPERIMENTAL DESIGN Open trial in 4 patients . SETTING Temperature/humidity controlled vascular laboratory . PATIENTS Severe Raynaud 's syndrome of more than 5 years duration and defined as more than 5 attacks daily or 10 attacks in one week , at least half of which were painful and lasting for more than 30 minutes . Three patients were refractory to infusions of Iloprost . INTERVENTIONS Patients were treated daily or on alternate days for a two to three weeks period by re-injection of citrated autologous blood pre-treated with heat , ozone and ultraviolet light ( H-O-U therapy ) . MEASURES Clinical observations ; mean equilibrated h and temperature ( infrared thermography ) ; distributive and microcirculatory blood-flow ( venous occlusion strain-gauge plethysmography , infrared photoplethysmography , laser Doppler flowmetry ) iontophoresis of acetylcholine and sodium nitroprusside ; estimations : serum levels of 6-keto-PGF1alpha and serum levels of anti-hsp65 antibody . RESULTS Reduction or abolition of Raynaud 's attacks for at least three months after treatment . Mean equilibrated h and temperature increased but did not normalise . Blood flow parameters improved but did not reach statistical significance . Iontophoresis of acetylcholine showed an increase in laser Doppler flowmetry which was statistically significant . Serum levels of 6-keto-PGF1alpha , fell significantly in three patients . Serum levels of anti-hsp65 antibody fell in the one patient which was followed sequentially . CONCLUSIONS H-O-U therapy may prove useful in patients with severe Raynaud 's syndrome OBJECTIVE --To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud 's phenomenon associated with systemic sclerosis . DESIGN --Double blind , placebo controlled , r and omised group comparison . SETTING --Dermatology outpatient clinic . PATIENTS --Twenty three patients with Raynaud 's phenomenon associated with well documented systemic sclerosis ( American Rheumatism Association criteria ) and with typical abnormalities in fingernail folds on capillaroscopy . INTERVENTIONS --Twelve patients were r and omised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8 . Placebo capsules were given concurrently . Eleven patients were r and omised to receive nifedipine , starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks . Infusions of placebo were given in the same manner as the infusions of iloprost . One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects . END POINT -- Reduction in number , duration , and severity of attacks of Raynaud 's phenomenon , reduction in number of digital lesions , increase in digital blood flow . MEASUREMENTS AND MAIN RESULTS -- Measurements were taken at 0 , 4 , 8 , 12 , and 16 weeks . Both regimens produced a reduction in the number , duration , and severity of attacks of Raynaud 's phenomenon . The mean ( SE ) number of digital lesions was reduced with iloprost ( from 3.5 ( 1 
    Output:
    