Loading Dose In Patients Research Articles

Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting

Background Although patients undergoing coronary stenting routinely receive dual antiplatelet treatment to reduce the risk of stent thrombosis, this undesired event still occurs. A suboptimal response to clopidogrel treatment (low responders) has been suggested to contribute to stent thrombosis. In the present study, platelet function profiles were assessed in patients undergoing coronary stenting receiving a standard 300-mg clopidogrel loading dose with the aim to identify low clopidogrel responders. Materials and methods Platelet aggregation was assessed by light transmittance aggregometry following 6 μM ADP stimuli in 48 patients before and 10 min, 4 and 24 h after receiving clopidogrel front-loading. Patients having ≥40% inhibition of platelet aggregation 24 h after clopidogrel administration were defined as normal responders, whereas those having <40% inhibition were low responders. Glycoprotein (GP) IIb/IIIa activation and P-selectin expression were assessed by whole blood flow cytometry following 2 μM ADP stimuli at the same time points. Platelet function profiles were compared between normal and low clopidogrel responders. Results Twenty-seven patients (56%) were normal responders and 21 (44%) low responders. Baseline GP IIb/IIIa activation was higher in low responders (74.6±16.6% vs. 58.2±24.5%, p=0.03). Although GP IIb/IIIa activation reduced following clopidogrel front-loading in both groups, it remained increased among low responders at 24 h (58.6±21.3% vs. 40.2±28.7%, p=0.05) and during the overall study time course ( p=0.02). There were no differences in P-selectin expression. Conclusions A considerable proportion of patients have an early suboptimal response to a 300-mg clopidogrel loading dose. An increased GP IIb/IIIa activation before intervention may identify this group of patients suggesting the use of a more aggressive antithrombotic treatment in these individuals.

1159-190 Role of the 807 C/T polymorphism of glycoprotein Ia/IIa on platelet function following clopidogrel loading dose in patients undergoing coronary stenting

1159-190 Role of the 807 C/T polymorphism of glycoprotein Ia/IIa on platelet function following clopidogrel loading dose in patients undergoing coronary stenting

PlA polymorphism and platelet reactivity following clopidogrel loading dose in patients undergoing coronary stent implantation

The PlA polymorphism (Leu33Pro) of the platelet glycoprotein (GP) IIIa gene has been suggested to play an important role in coronary thrombosis. In vitro studies have shown differences for this polymorphism in platelet sensitivity towards antiplatelet drugs (aspirin and abciximab), suggesting a pharmacogenetic modulation. The aim of the study was to assess the modulatory effect of the PlA polymorphism on clopidogrel-induced antiplatelet effects in 38 patients undergoing coronary stent implantation receiving a 300 mg clopidogrel loading-dose. Platelet reactivity was assessed as GPIIb/IIIa activation and P-selectin expression in platelets stimulated with 2 micromol/l adenosine diphosphate using whole blood flow cytometry. The distribution of the homozygous PlA1/A1 and heterozygous PlA1/A2 genotypes were 74 and 26%, respectively. PlA2 carriers had a higher degree of GPIIb/IIIa activation (P = 0.05) and P-selectin expression (P = 0.02) during the overall study time course and a lower antiplatelet effect to a 300 mg clopidogrel loading-dose up to 24 h following intervention (P < 0.05). In conclusion, the Pl polymorphism of the GPIIIa gene modulates platelet reactivity towards clopidogrel front loading in patients undergoing coronary stenting. This suggests the need for individualized antithrombotic regimens to optimally inhibit platelet reactivity.

Effect of 300- and 450-mg clopidogrel loading doses on membrane and soluble P-selectin in patients undergoing coronary stent implantation

Background After coronary artery stent implantation patients are treated with the adenosine diphosphatase (ADP) receptor antagonist clopidogrel to prevent subacute stent thromboses. Today these patients initially receive a loading dose of 300 mg of clopidogrel to accelerate the complete drug effect. In the current study we investigated whether a higher loading dose can shorten the time until the maximum platelet inhibitory effect of clopidogrel is achieved. Methods P-selectin expression of nonstimulated and ADP-stimulated platelets was flow cytometrically measured before the clopidogrel loading dose and on 3 consecutive days in 52 patients with coronary artery disease: 21 patients in group 1 received 300 mg of clopidogrel after stent implantation and 11 patients in group 2 received the higher 450-mg clopidogrel loading dose followed by a daily dose of 75 mg of clopidogrel for both groups. The control group consisted of 20 patients who were monitored over 2 days before coronary intervention. Soluble P-selectin levels in plasma were determined by an enzyme-linked immunosorbent assay. Results Inducible P-selectin expression on ADP-stimulated platelets was significantly reduced (P =.05) on days 1 and 2 in patient group 2 (450-mg loading dose) compared with group 1 (300-mg loading dose). No influence of clopidogrel on the P-selectin levels in plasma was observed. Conclusions In our study the application of 450 mg of clopidogrel as the loading dose in patients undergoing coronary stenting shortens the period until the maximum effect of the ADP receptor antagonist is achieved and thus may lead to a more successful prevention of subacute coronary stent thromboses. (Am Heart J 2002;143:118-23.)

Volume of Distribution of Theophylline in Acute Exacerbations of Reversible Airway Disease: Effect of Body Weight

The literature is unclear as to whether theophylline loading doses should be based on total body weight (TBW) or ideal body weight (IBW). The objective of this study was to determine the most appropriate body weight for estimation of volume of distribution (Vd) in calculating theophylline loading dose in patients with acute bronchospasm. Fifty-four adult patients with acute bronchospasm requiring intravenous (IV) theophylline therapy were entered into the study. Patients were randomized into three theophylline loading dose groups based on (1) TBW, (2) IBW, and (3) adjusted body weight (ABW). Initial serum theophylline concentrations were used to determine an IV loading dose to reach a plasma concentration of 12 to 15 micrograms/ml. Percent prediction error was used to determine the appropriateness of each dosing group. Volumes of distribution were also determined for each group. There was a statistically significant difference at p less than 0.01 in the percent prediction error when patients in the TBW group were compared to the IBW and ABW groups. A statistically significant difference in the Vd was observed between the TBW and IBW group (p less than 0.01). We conclude that IBW is more appropriate than TBW or ABW for determining theophylline loading dose in patients with acute bronchospasm.