|
|
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result sql = An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study.
An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study.char = <;code = 60
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char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = h;code = 104
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = .;code = 46
char = ;code = 32
char = D;code = 68
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = i;code = 105
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = I;code = 73
char = M;code = 77
char = S;code = 83
char = ;code = 32
char = T;code = 84
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = i;code = 105
char = s;code = 115
char = h;code = 104
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = h;code = 104
char = i;code = 105
char = p;code = 112
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = t;code = 116
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = a;code = 97
char = f;code = 102
char = e;code = 101
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = M;code = 77
char = E;code = 69
char = T;code = 84
char = H;code = 72
char = O;code = 79
char = D;code = 68
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = S;code = 83
char = i;code = 105
char = x;code = 120
char = t;code = 116
char = y;code = 121
char = -;code = 45
char = s;code = 115
char = i;code = 105
char = x;code = 120
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 1;code = 49
char = 0;code = 48
char = ,;code = 44
char = ;code = 32
char = 5;code = 53
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = k;code = 107
char = g;code = 103
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = -;code = 45
char = l;code = 108
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = f;code = 102
char = u;code = 117
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = 3;code = 51
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = p;code = 112
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = o;code = 111
char = p;code = 112
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = N;code = 78
char = O;code = 79
char = N;code = 78
char = M;code = 77
char = E;code = 69
char = M;code = 77
char = .;code = 46
char = ;code = 32
char = B;code = 66
char = a;code = 97
char = y;code = 121
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = u;code = 117
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = ;code = 32
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = I;code = 73
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = -;code = 45
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
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char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = e;code = 101
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = p;code = 112
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = j;code = 106
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = b;code = 98
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = %;code = 37
char = );code = 41
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = :;code = 58
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = C;code = 67
char = L;code = 76
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 9;code = 57
char = .;code = 46
char = 4;code = 52
char = 9;code = 57
char = ;code = 32
char = m;code = 109
char = l;code = 108
char = ;code = 32
char = h;code = 104
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = (;code = 40
char = 6;code = 54
char = 2;code = 50
char = %;code = 37
char = );code = 41
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = v;code = 118
char = o;code = 111
char = l;code = 108
char = u;code = 117
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = V;code = 86
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 3;code = 51
char = 7;code = 55
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = l;code = 108
char = ;code = 32
char = (;code = 40
char = 7;code = 55
char = 2;code = 50
char = %;code = 37
char = );code = 41
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = C;code = 67
char = L;code = 76
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = N;code = 78
char = A;code = 65
char = );code = 41
char = :;code = 58
char = ;code = 32
char = C;code = 67
char = L;code = 76
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 9;code = 57
char = .;code = 46
char = 4;code = 52
char = 9;code = 57
char = *;code = 42
char = (;code = 40
char = P;code = 80
char = N;code = 78
char = A;code = 65
char = /;code = 47
char = 9;code = 57
char = 6;code = 54
char = .;code = 46
char = 3;code = 51
char = );code = 41
char = (;code = 40
char = 1;code = 49
char = .;code = 46
char = 4;code = 52
char = 9;code = 57
char = );code = 41
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = r;code = 114
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 1;code = 49
char = D;code = 68
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = m;code = 109
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 3;code = 51
char = D;code = 68
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
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char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
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char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = 5;code = 53
char = 7;code = 55
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = a;code = 97
char = n;code = 110
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = n;code = 110
char = i;code = 105
char = n;code = 110
char = e;code = 101
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char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 0;code = 48
char = .;code = 46
char = 0;code = 48
char = 2;code = 50
char = );code = 41
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = 5;code = 53
char = 0;code = 48
char = %;code = 37
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
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char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 1;code = 49
char = D;code = 68
char = ;code = 32
char = <;code = 60
char = ;code = 32
char = 6;code = 54
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
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char = ;code = 32
char = h;code = 104
char = ;code = 32
char = (;code = 40
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 3;code = 51
char = D;code = 68
char = ;code = 32
char = <;code = 60
char = ;code = 32
char = 9;code = 57
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = h;code = 104
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char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
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char = 9;code = 57
char = 1;code = 49
char = %;code = 37
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
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char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 1;code = 49
char = D;code = 68
char = ;code = 32
char = >;code = 62
char = ;code = 32
char = 6;code = 54
char = 0;code = 48
char = 0;code = 48
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char = m;code = 109
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
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char = ;code = 32
char = h;code = 104
char = ;code = 32
char = (;code = 40
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 3;code = 51
char = D;code = 68
char = ;code = 32
char = >;code = 62
char = ;code = 32
char = 9;code = 57
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char = 0;code = 48
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char = m;code = 109
char = g;code = 103
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char = l;code = 108
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char = -;code = 45
char = 1;code = 49
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char = ;code = 32
char = h;code = 104
char = );code = 41
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = ;code = 32
char = =;code = 61
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char = 0;code = 48
char = .;code = 46
char = 0;code = 48
char = 0;code = 48
char = 6;code = 54
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char = .;code = 46
char = ;code = 32
char = N;code = 78
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
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char = b;code = 98
char = e;code = 101
char = t;code = 116
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = n;code = 110
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char = A;code = 65
char = U;code = 85
char = C;code = 67
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char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = s;code = 115
char = i;code = 105
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char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = u;code = 117
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = e;code = 101
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char = d;code = 100
char = e;code = 101
char = m;code = 109
char = o;code = 111
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char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
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char = e;code = 101
char = d;code = 100
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = C;code = 67
char = O;code = 79
char = N;code = 78
char = C;code = 67
char = L;code = 76
char = U;code = 85
char = S;code = 83
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = T;code = 84
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = i;code = 105
char = e;code = 101
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char = e;code = 101
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char = t;code = 116
char = h;code = 104
char = e;code = 101
char = s;code = 115
char = e;code = 101
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char = o;code = 111
char = p;code = 112
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
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char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = i;code = 105
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
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char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = d;code = 100
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = 2;code = 50
char = 4;code = 52
char = ;code = 32
char = h;code = 104
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char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = v;code = 118
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = m;code = 109
char = e;code = 101
char = n;code = 110
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result sql = WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT : Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.
WHAT THIS STUDY ADDS : A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.
METHODS : Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.
RESULTS : Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.
CONCLUSIONS : To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.
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result sql = An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study.
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char = o;code = 111
char = n;code = 110
char = -;code = 45
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = u;code = 117
char = r;code = 114
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = f;code = 102
char = r;code = 114
char = o;code = 111
char = m;code = 109
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = 1;code = 49
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = ;code = 32
char = 8;code = 56
char = ,;code = 44
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = n;code = 110
char = o;code = 111
char = t;code = 116
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = h;code = 104
char = i;code = 105
char = p;code = 112
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = s;code = 115
char = h;code = 104
char = o;code = 111
char = w;code = 119
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = t;code = 116
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = ;code = 32
char = u;code = 117
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = h;code = 104
char = o;code = 111
char = l;code = 108
char = d;code = 100
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = e;code = 101
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = e;code = 101
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = d;code = 100
char = .;code = 46
char = ;code = 32
char = D;code = 68
char = o;code = 111
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = s;code = 115
char = c;code = 99
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = f;code = 102
char = u;code = 117
char = n;code = 110
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = h;code = 104
char = i;code = 105
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = i;code = 105
char = s;code = 115
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = I;code = 73
char = M;code = 77
char = S;code = 83
char = ;code = 32
char = T;code = 84
char = o;code = 111
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = e;code = 101
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = m;code = 109
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = p;code = 112
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = u;code = 117
char = c;code = 99
char = t;code = 116
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = i;code = 105
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = b;code = 98
char = l;code = 108
char = i;code = 105
char = s;code = 115
char = h;code = 104
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = h;code = 104
char = i;code = 105
char = p;code = 112
char = s;code = 115
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = t;code = 116
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = m;code = 109
char = a;code = 97
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = e;code = 101
char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = c;code = 99
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = a;code = 97
char = f;code = 102
char = e;code = 101
char = t;code = 116
char = y;code = 121
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = M;code = 77
char = E;code = 69
char = T;code = 84
char = H;code = 72
char = O;code = 79
char = D;code = 68
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = S;code = 83
char = i;code = 105
char = x;code = 120
char = t;code = 116
char = y;code = 121
char = -;code = 45
char = s;code = 115
char = i;code = 105
char = x;code = 120
char = ;code = 32
char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
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char = t;code = 116
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = 1;code = 49
char = 0;code = 48
char = ,;code = 44
char = ;code = 32
char = 5;code = 53
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = k;code = 107
char = g;code = 103
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = -;code = 45
char = l;code = 108
char = y;code = 121
char = s;code = 115
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = v;code = 118
char = e;code = 101
char = n;code = 110
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = f;code = 102
char = u;code = 117
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = 3;code = 51
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = s;code = 115
char = e;code = 101
char = c;code = 99
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = a;code = 97
char = y;code = 121
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = p;code = 112
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = v;code = 118
char = e;code = 101
char = l;code = 108
char = o;code = 111
char = p;code = 112
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = N;code = 78
char = O;code = 79
char = N;code = 78
char = M;code = 77
char = E;code = 69
char = M;code = 77
char = .;code = 46
char = ;code = 32
char = B;code = 66
char = a;code = 97
char = y;code = 121
char = e;code = 101
char = s;code = 115
char = i;code = 105
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = d;code = 100
char = u;code = 117
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = c;code = 99
char = a;code = 97
char = l;code = 108
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = u;code = 117
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = ;code = 32
char = l;code = 108
char = o;code = 111
char = g;code = 103
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = g;code = 103
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = s;code = 115
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = e;code = 101
char = r;code = 114
char = f;code = 102
char = o;code = 111
char = r;code = 114
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = R;code = 82
char = E;code = 69
char = S;code = 83
char = U;code = 85
char = L;code = 76
char = T;code = 84
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = I;code = 73
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = e;code = 101
char = s;code = 115
char = c;code = 99
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = a;code = 97
char = ;code = 32
char = o;code = 111
char = n;code = 110
char = e;code = 101
char = -;code = 45
char = c;code = 99
char = o;code = 111
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = e;code = 101
char = l;code = 108
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = l;code = 108
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = .;code = 46
char = ;code = 32
char = M;code = 77
char = e;code = 101
char = a;code = 97
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = p;code = 112
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = a;code = 97
char = r;code = 114
char = m;code = 109
char = a;code = 97
char = c;code = 99
char = o;code = 111
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = r;code = 114
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = d;code = 100
char = i;code = 105
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = s;code = 115
char = u;code = 117
char = b;code = 98
char = j;code = 106
char = e;code = 101
char = c;code = 99
char = t;code = 116
char = ;code = 32
char = v;code = 118
char = a;code = 97
char = r;code = 114
char = i;code = 105
char = a;code = 97
char = b;code = 98
char = i;code = 105
char = l;code = 108
char = i;code = 105
char = t;code = 116
char = i;code = 105
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = %;code = 37
char = );code = 41
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = :;code = 58
char = ;code = 32
char = e;code = 101
char = l;code = 108
char = i;code = 105
char = m;code = 109
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = a;code = 97
char = n;code = 110
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = C;code = 67
char = L;code = 76
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 9;code = 57
char = .;code = 46
char = 4;code = 52
char = 9;code = 57
char = ;code = 32
char = m;code = 109
char = l;code = 108
char = ;code = 32
char = h;code = 104
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = (;code = 40
char = 6;code = 54
char = 2;code = 50
char = %;code = 37
char = );code = 41
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = v;code = 118
char = o;code = 111
char = l;code = 108
char = u;code = 117
char = m;code = 109
char = e;code = 101
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = s;code = 115
char = t;code = 116
char = r;code = 114
char = i;code = 105
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = V;code = 86
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 3;code = 51
char = 7;code = 55
char = 5;code = 53
char = ;code = 32
char = m;code = 109
char = l;code = 108
char = ;code = 32
char = (;code = 40
char = 7;code = 55
char = 2;code = 50
char = %;code = 37
char = );code = 41
char = .;code = 46
char = ;code = 32
char = I;code = 73
char = b;code = 98
char = u;code = 117
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = f;code = 102
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = C;code = 67
char = L;code = 76
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = c;code = 99
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = s;code = 115
char = t;code = 116
char = n;code = 110
char = a;code = 97
char = t;code = 116
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = N;code = 78
char = A;code = 65
char = );code = 41
char = :;code = 58
char = ;code = 32
char = C;code = 67
char = L;code = 76
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 9;code = 57
char = .;code = 46
char = 4;code = 52
char = 9;code = 57
char = *;code = 42
char = (;code = 40
char = P;code = 80
char = N;code = 78
char = A;code = 65
char = /;code = 47
char = 9;code = 57
char = 6;code = 54
char = .;code = 46
char = 3;code = 51
char = );code = 41
char = (;code = 40
char = 1;code = 49
char = .;code = 46
char = 4;code = 52
char = 9;code = 57
char = );code = 41
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = f;code = 102
char = i;code = 105
char = r;code = 114
char = s;code = 115
char = t;code = 116
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 1;code = 49
char = D;code = 68
char = );code = 41
char = ,;code = 44
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = m;code = 109
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = ;code = 32
char = a;code = 97
char = f;code = 102
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = r;code = 114
char = e;code = 101
char = e;code = 101
char = ;code = 32
char = d;code = 100
char = o;code = 111
char = s;code = 115
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 3;code = 51
char = D;code = 68
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = g;code = 103
char = e;code = 101
char = s;code = 115
char = t;code = 116
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = a;code = 97
char = l;code = 108
char = ;code = 32
char = a;code = 97
char = g;code = 103
char = e;code = 101
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char = w;code = 119
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = i;code = 105
char = g;code = 103
char = n;code = 110
char = i;code = 105
char = f;code = 102
char = i;code = 105
char = c;code = 99
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = l;code = 108
char = y;code = 121
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char = h;code = 104
char = i;code = 105
char = g;code = 103
char = h;code = 104
char = e;code = 101
char = r;code = 114
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char = i;code = 105
char = n;code = 110
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char = 5;code = 53
char = 7;code = 55
char = ;code = 32
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char = o;code = 111
char = n;code = 110
char = a;code = 97
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char = e;code = 101
char = s;code = 115
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char = w;code = 119
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char = c;code = 99
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char = o;code = 111
char = s;code = 115
char = i;code = 105
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char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
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char = t;code = 116
char = h;code = 104
char = a;code = 97
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char = i;code = 105
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char = ;code = 32
char = n;code = 110
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char = n;code = 110
char = e;code = 101
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char = n;code = 110
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char = o;code = 111
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char = a;code = 97
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char = e;code = 101
char = s;code = 115
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char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = c;code = 99
char = l;code = 108
char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = ;code = 32
char = =;code = 61
char = ;code = 32
char = 0;code = 48
char = .;code = 46
char = 0;code = 48
char = 2;code = 50
char = );code = 41
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = D;code = 68
char = A;code = 65
char = ;code = 32
char = c;code = 99
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char = o;code = 111
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = w;code = 119
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = o;code = 111
char = b;code = 98
char = s;code = 115
char = e;code = 101
char = r;code = 114
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = 5;code = 53
char = 0;code = 48
char = %;code = 37
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = e;code = 101
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char = n;code = 110
char = e;code = 101
char = o;code = 111
char = n;code = 110
char = a;code = 97
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char = e;code = 101
char = s;code = 115
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 1;code = 49
char = D;code = 68
char = ;code = 32
char = <;code = 60
char = ;code = 32
char = 6;code = 54
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
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char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
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char = ;code = 32
char = h;code = 104
char = ;code = 32
char = (;code = 40
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 3;code = 51
char = D;code = 68
char = ;code = 32
char = <;code = 60
char = ;code = 32
char = 9;code = 57
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
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char = ;code = 32
char = h;code = 104
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char = ;code = 32
char = a;code = 97
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char = d;code = 100
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char = i;code = 105
char = n;code = 110
char = ;code = 32
char = 9;code = 57
char = 1;code = 49
char = %;code = 37
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = n;code = 110
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 1;code = 49
char = D;code = 68
char = ;code = 32
char = >;code = 62
char = ;code = 32
char = 6;code = 54
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = (;code = 40
char = -;code = 45
char = 1;code = 49
char = );code = 41
char = ;code = 32
char = h;code = 104
char = ;code = 32
char = (;code = 40
char = o;code = 111
char = r;code = 114
char = ;code = 32
char = A;code = 65
char = U;code = 85
char = C;code = 67
char = 3;code = 51
char = D;code = 68
char = ;code = 32
char = >;code = 62
char = ;code = 32
char = 9;code = 57
char = 0;code = 48
char = 0;code = 48
char = ;code = 32
char = m;code = 109
char = g;code = 103
char = ;code = 32
char = l;code = 108
char = (;code = 40
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result sql = WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT : Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.
WHAT THIS STUDY ADDS : A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.
METHODS : Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.
RESULTS : Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.
CONCLUSIONS : To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.
Publication: Br J Clin Pharmacol 2008 May ;65(5)::629-36. :doi: 10.1111/j.1365-2125.2008.03118.x.
Publication Date: 2008 May
Study Author(s): Hirt, Déborah;Van Overmeire, Bart;Treluyer, Jean-Marc;Langhendries, Jean-Paul;Marguglio, Arnaud;Eisinger, Mark J;Schepens, Paul;Urien, Saïk;
Institution: EA3620, Université Paris - Descartes, Paris, France. [email protected]
Shortcut link to this study:
Publication Date: 2008 May
Study Author(s): Hirt, Déborah;Van Overmeire, Bart;Treluyer, Jean-Marc;Langhendries, Jean-Paul;Marguglio, Arnaud;Eisinger, Mark J;Schepens, Paul;Urien, Saïk;
Institution: EA3620, Université Paris - Descartes, Paris, France. [email protected]
Shortcut link to this study:
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT : Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates. Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.
WHAT THIS STUDY ADDS : A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.
METHODS : Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.
RESULTS : Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.
CONCLUSIONS : To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.
WHAT THIS STUDY ADDS : A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen. Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age. A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced. Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates. AIMS To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.
METHODS : Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg(-1) of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.
RESULTS : Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h(-1) (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)(1.49). AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l(-1) h (or AUC3D < 900 mg l(-1) h) and in 91% when AUC1D > 600 mg l(-1) h (or AUC3D > 900 mg l(-1) h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.
CONCLUSIONS : To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg(-1) for neonates younger than 70 h, 14, 7, 7 mg kg(-1) for neonates between 70 and 108 h and 18, 9, 9 mg kg(-1) for neonates between 108 and 180 h.
PMID: 18307541
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