Br. J. clin. Pharmac. (1990), 29, 120-122
Effects of aspirin upon the flushing reaction induced by niceritrol R. H. JAY, A. C. DICKSON & D. J. BETTERIDGE Department of Medicine, University College and Middlesex School of Medicine, The Rayne Institute, University Street, London WC1E 6JJ
The usefulness of niceritrol as a lipid-lowering agent is limited by a prostaglandinmediated flushing reaction after each dose occurring in the early stages of treatment. We have tested the effect of premedication with aspirin on the reaction to 250 mg niceritrol in 30 healthy male volunteers using both subjective and observed assessments of severity. Both 300 mg and 600 mg of aspirin significantly reduced the. severity of flushing when compared with placebo. No significant difference was seen between the two dose levels. Prior dosing with aspirin may increase acceptability of niceritrol and hence improve compliance. Keywords niceritrol flushing aspirin Introduction
Niceritrol (pentaerythritol tetranicotinate) is an effective lipid-lowering agent (Hamazaki et al., 1985; Olsson et al., 1974; Sigroth, 1968) which has been in use in Scandinavia for some years. The clinical efficacy and unwanted effects of niceritrol are similar to those of its parent compound, nicotinic acid (Olsson et al., 1974), and in particular its acceptability to patients is limited by a common post dose flushing reaction maximally affecting the blush area of the face. A gradual reduction in the severity of this reaction is seen with continued dosing of nicotinic acid and its derivatives over a period of days, and the reaction is usually eliminated in long-term
after breakfast. Severity of flushing was recorded every 15 min for 3 h and every 30 min for a further hour. Assessment was made on a six point analogue scale (0 to 5 ranging from no flush to severe flushing) both subjectively and also visually by an independent observer. Subjects were also asked to report any other symptoms during the period of assessment. Fifty-eight subjects were screened in order to find thirty who experienced a grade 2 to 5 response to proceed to the trial phase.
treatment.
The thirty subjects were restudied on a separate day, being randomised to three equal groups receiving a fruit flavoured drink containing either no medication, 300 mg or 600 mg aspirin (Aspro Clear, Nicholas Laboratories) 15 min before the niceritrol. Both subject and observer were unaware of the contents of the drink. Subjects gave written informed consent and the protocol was approved by the ethics committee of University College and Middlesex School of Medicine. Statistical significance of the differences between the three treatment groups at screening and during the study was tested by the KruskalWallis test. Significance of differences between
Inhibitors of prostaglandin synthesis have been shown to ameliorate the flushing after nicotinic acid (Phillips & Lightman, 1981; Wilkin et al., 1982). This study assesses the effect of premedication with two doses of aspirin upon the flush caused by niceritrol using a double-
blind, placebo-controlled design. Methods
Screening Healthy male subjects aged between 18 and 60 years were given 250 mg niceritrol orally 1.5-2 h
Trial
120
121
R. H. Jay et al.
the screening and trial assessments for each tested by the Wilcoxon matched pairs
Discussion
test.
We have shown that the flushing reaction experienced after niceritrol may be reduced by prior dosing with 300 mg of aspirin, but have not demonstrated a clear benefit from increasing the dose to 600 mg. The higher frequency of complete abolition of flushing after 600 mg aspirin than after 300 mg may suggest the presence of a dose related response. However sample sizes were not selected to test the frequency of complete abolition and this could have occurred by chance. The fact that all six subjects experiencing reactions other than flushing had not taken aspirin at the time is consistent with the possibility that gastrointestinal adverse effects and headache may also be prostaglandin-mediated and similarly amenable to prevention. This again is not statistically testable in a study of this size. The additional protective effect of aspirin against cardiovascular events is particularly desirable in subjects with hyperlipidaemia, who are at higher than normal risk. The optimal dose of aspirin for primary or secondary prevention of vascular events is uncertain, but appears to be 300 mg daily or less (Orme, 1988). It has been suggested that 162 mg aspirin given once daily may abolish the flushing caused by
group was
Results There were no significant differences between the three treatment groups before screening in height, weight, heart rate or blood pressure. Flushing responses to niceritrol at initial screening and during the trial phase are shown in Table 1. There were no significant differences between groups at screening or between initial response and that during the trial period in the placebo group. Mean (s.e. mean) time to the peak flushing response was 41 (4.8) min at screening and was not significantly changed by aspirin. In one subject taking 300 mg aspirin and four taking 600 mg the flush was completely abolished by aspirin. Both maximum severity (Cmax) of flushing and area under the severity-time curve (AUC), calculated using the trapezium rule, were significantly reduced by aspirin in comparison with both placebo and baseline, but no difference was seen between the two dose levels. Other side effects were reported by six subjects (Table 2). None occurred after premedication with aspirin.
Table 1 Mean (s.e. mean) severity of flushing Aspirin dose (mg) 300 600 0
Screening AUC
Cmax Trial AUC
S 0 S O
166 (32) 164 (34) 3.3 (0.3) 3.2 (0.4)
167 (27) 174 (28) 3.1 (0.3) 3.0 (0.4)
157 (24) 150 (28) 3.4 (0.4) 3.3 (0.3)
136 (27) 65 (17)*t 64 (25)*t 140 (25) 69 (18)*t 63 (24)*t 2.9 (0.4) 1.7 (0.4)*t Cmax 1.5 (0.5)*t O 2.7 (0.3) 1.5 (0.3)*t 1.5 (0.5)t S = subject's assessment; 0 = observer's assessment; AUC = area under severity/time curve; Cmax = maximum intensity of flush. * P
Effects of aspirin upon the flushing reaction induced by niceritrol R. H. JAY, A. C. DICKSON & D. J. BETTERIDGE Department of Medicine, University College and Middlesex School of Medicine, The Rayne Institute, University Street, London WC1E 6JJ
The usefulness of niceritrol as a lipid-lowering agent is limited by a prostaglandinmediated flushing reaction after each dose occurring in the early stages of treatment. We have tested the effect of premedication with aspirin on the reaction to 250 mg niceritrol in 30 healthy male volunteers using both subjective and observed assessments of severity. Both 300 mg and 600 mg of aspirin significantly reduced the. severity of flushing when compared with placebo. No significant difference was seen between the two dose levels. Prior dosing with aspirin may increase acceptability of niceritrol and hence improve compliance. Keywords niceritrol flushing aspirin Introduction
Niceritrol (pentaerythritol tetranicotinate) is an effective lipid-lowering agent (Hamazaki et al., 1985; Olsson et al., 1974; Sigroth, 1968) which has been in use in Scandinavia for some years. The clinical efficacy and unwanted effects of niceritrol are similar to those of its parent compound, nicotinic acid (Olsson et al., 1974), and in particular its acceptability to patients is limited by a common post dose flushing reaction maximally affecting the blush area of the face. A gradual reduction in the severity of this reaction is seen with continued dosing of nicotinic acid and its derivatives over a period of days, and the reaction is usually eliminated in long-term
after breakfast. Severity of flushing was recorded every 15 min for 3 h and every 30 min for a further hour. Assessment was made on a six point analogue scale (0 to 5 ranging from no flush to severe flushing) both subjectively and also visually by an independent observer. Subjects were also asked to report any other symptoms during the period of assessment. Fifty-eight subjects were screened in order to find thirty who experienced a grade 2 to 5 response to proceed to the trial phase.
treatment.
The thirty subjects were restudied on a separate day, being randomised to three equal groups receiving a fruit flavoured drink containing either no medication, 300 mg or 600 mg aspirin (Aspro Clear, Nicholas Laboratories) 15 min before the niceritrol. Both subject and observer were unaware of the contents of the drink. Subjects gave written informed consent and the protocol was approved by the ethics committee of University College and Middlesex School of Medicine. Statistical significance of the differences between the three treatment groups at screening and during the study was tested by the KruskalWallis test. Significance of differences between
Inhibitors of prostaglandin synthesis have been shown to ameliorate the flushing after nicotinic acid (Phillips & Lightman, 1981; Wilkin et al., 1982). This study assesses the effect of premedication with two doses of aspirin upon the flush caused by niceritrol using a double-
blind, placebo-controlled design. Methods
Screening Healthy male subjects aged between 18 and 60 years were given 250 mg niceritrol orally 1.5-2 h
Trial
120
121
R. H. Jay et al.
the screening and trial assessments for each tested by the Wilcoxon matched pairs
Discussion
test.
We have shown that the flushing reaction experienced after niceritrol may be reduced by prior dosing with 300 mg of aspirin, but have not demonstrated a clear benefit from increasing the dose to 600 mg. The higher frequency of complete abolition of flushing after 600 mg aspirin than after 300 mg may suggest the presence of a dose related response. However sample sizes were not selected to test the frequency of complete abolition and this could have occurred by chance. The fact that all six subjects experiencing reactions other than flushing had not taken aspirin at the time is consistent with the possibility that gastrointestinal adverse effects and headache may also be prostaglandin-mediated and similarly amenable to prevention. This again is not statistically testable in a study of this size. The additional protective effect of aspirin against cardiovascular events is particularly desirable in subjects with hyperlipidaemia, who are at higher than normal risk. The optimal dose of aspirin for primary or secondary prevention of vascular events is uncertain, but appears to be 300 mg daily or less (Orme, 1988). It has been suggested that 162 mg aspirin given once daily may abolish the flushing caused by
group was
Results There were no significant differences between the three treatment groups before screening in height, weight, heart rate or blood pressure. Flushing responses to niceritrol at initial screening and during the trial phase are shown in Table 1. There were no significant differences between groups at screening or between initial response and that during the trial period in the placebo group. Mean (s.e. mean) time to the peak flushing response was 41 (4.8) min at screening and was not significantly changed by aspirin. In one subject taking 300 mg aspirin and four taking 600 mg the flush was completely abolished by aspirin. Both maximum severity (Cmax) of flushing and area under the severity-time curve (AUC), calculated using the trapezium rule, were significantly reduced by aspirin in comparison with both placebo and baseline, but no difference was seen between the two dose levels. Other side effects were reported by six subjects (Table 2). None occurred after premedication with aspirin.
Table 1 Mean (s.e. mean) severity of flushing Aspirin dose (mg) 300 600 0
Screening AUC
Cmax Trial AUC
S 0 S O
166 (32) 164 (34) 3.3 (0.3) 3.2 (0.4)
167 (27) 174 (28) 3.1 (0.3) 3.0 (0.4)
157 (24) 150 (28) 3.4 (0.4) 3.3 (0.3)
136 (27) 65 (17)*t 64 (25)*t 140 (25) 69 (18)*t 63 (24)*t 2.9 (0.4) 1.7 (0.4)*t Cmax 1.5 (0.5)*t O 2.7 (0.3) 1.5 (0.3)*t 1.5 (0.5)t S = subject's assessment; 0 = observer's assessment; AUC = area under severity/time curve; Cmax = maximum intensity of flush. * P
