Hemodynamic efficacy of sequential hemoclip application using the Olympus HX-110/610 reloadable clipping device in spurting bleedings.

BACKGROUND: Hemoclip application in GI-hemorrhage has proven to be effective. Clinical experience shows that multiple clips are frequently necessary. In 2005, an easily reloadable clip-applicator was introduced. We evaluated the hemodynamic efficacy of this new device. MATERIAL/METHODS: We prospectively compared the new clipping device (Olympus HX 110/610) in a validated experimental setting using the compactEASIE®-simulator for GI bleeding. The artificial blood circulation system in the simulator was connected to a pressure transducer. Four investigators of different endoscopic experience (1000-6000 endoscopies) treated 12 bleeding sources each, with up to 6 clips for each bleeding location. Pressures were recorded to objectify the additive effects of sequential clip application on the reduction in vessel diameter. The intervention was abandoned if a maximum measurable pressure of 300 mmHg was achieved. RESULTS: Hemoclip application led to a significant increase of peak pressure (91±100 mmHg, p<0.001) and mean pressure (95±99 mmHg, p<0.001), representing a significant reduction in vessel diameter. Pooled data showed a significant stepwise increase in mean and maximum system pressure, resulting in reduction of vessel diameter up to the fifth hemoclip. On average, 5 clips (range 1-6) were used. More experienced endoscopists achieved a higher increase in mean pressure (167 and 118 mmHg vs 72 and 23 mmHg, p<0.05). Mean reloading time was 39 seconds (19-49 sec). CONCLUSIONS: Sequential application of multiple hemoclips led to an increasing effect, comparable to the results of previous clinical trials. The number of hemoclips applied correlated inversely, but not significantly, with the endoscopist´s experience. Expensive single-use clips appear dispensable in view of the short reloading time.

Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects.

OBJECTIVE: The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance. Cytochrome P450 2D6 (CYP2D6) poor metabolizers exhibit 3- to 10-fold higher plasma concentrations after administration of metoprolol than extensive metabolizers. However, the impact of the CYP2D6 genotype on the occurrence of adverse effects of metoprolol remains controversial. This study addressed whether the incidence of poor metabolizers was higher in patients with metoprolol-associated adverse effects than in the German population at large. METHODS: Approximately 1200 German physicians were asked to report on patients who had experienced pronounced adverse effects in association with administration of metoprolol. CYP2D6 genotypes were determined with a combination of allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. The adverse effects, consisting of symptoms related to beta-adrenergic receptor blockade and nonspecific symptoms, were recorded by use of a standardized questionnaire. RESULTS: Twenty-four patients were included in the study. Nine patients had 2 null alleles (poor metabolizer genotype; 38%); the remaining 15 had either 1 null allele (n = 7) or no null alleles (n = 8). Therefore the occurrences of poor metabolizer genotypes in the study population were 4.9- and 5.2-fold more frequent, respectively, than that found in unselected members of the German population in two large studies (P <.0001; chi(2) test). CONCLUSIONS: These data showed that CYP2D6 poor metabolizers had a 5-fold higher risk for development of adverse effects during metoprolol treatment than patients who were not poor metabolizers. Because the absolute risk of adverse effects of metoprolol is unknown, the clinical relevance of the CYP2D6 genotype for metoprolol therapy has to be determined in a prospective manner.

Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment.

The beta1 selective beta-blocker metoprolol is metabolized predominantly but not exclusively by CYP2D6. Due to the polymorphism of the CYP2D6 gene, CYP2D6 activity varies markedly between individuals. Consequently, after short-term administration metoprolol plasma concentrations were found to be several fold higher in poor metabolizers than in extensive metabolizers. However, it is currently not known, whether the impact of the CYP2D6 polymorphism persists during long-term therapy, since alternate mechanisms of elimination or metabolism could be effective in this setting. The study comprised 91 Caucasian patients on long-term treatment with metoprolol (median duration of treatment 12.6 months; median daily drug dose: 47.5 mg/day). Metoprolol and alpha-OH-metoprolol plasma concentrations were assessed by HPLC. Genotyping detected the null alleles (*0): *3, *4, *5, *6, *7, *8, *12, *14, *15, the alleles *9, *10 and *41 associated with reduced enzymatic activity as well as the fully functional alleles *1 and *2. Genotype and allele frequencies were in accordance with published frequencies for the German population. The plasma metabolic ratio of metoprolol/alpha-OH-metoprolol was markedly affected by the genotype (P < 0.0001). In accordance, median adjusted metoprolol plasma concentrations were 6.2- and 3.9-fold higher in patients with *0/*0 genotypes (n = 8) and intermediate genotypes (n = 10), respectively, as compared to those with two fully functional alleles (n = 31; P < 0.01). In summary, the pronounced effect of the CYP2D6 genotype persists during long-term therapy, affecting both metabolic ratio and metoprolol plasma concentration.