Rabeprazole effective therapy versus GERD
Two experts cite better symptom control, unique metabolism
Gastroesophageal-reflux disease (GERD) is a difficult concept to grasp. As Dr. Irvin Modlin, professor at the Yale University School of Medicine, put it, "it has thorny problems," and physicians need to be very cautious when dealing with the it.
Together with Dr. Paul Lim, medical adviser of Eisai Co. Ltd., Modlin clarified issues surrounding GERD during a recent symposium organized by the Philippine Society of Gastroenterology.
Modlin defined GERD as a condition that occurs "when reflux of gastric juice into the esophagus or oropharynx causes symptoms, tissue injury, or both."
He explained that the "gastroesophageal junction is a very hostile place." It is exposed to-aside from Helicobacter pylori and trauma-a number of chemical substances such as acid, nitric oxide, N-nitroso compounds, and reactive oxygen species. "Since this area moves up and down two to three centimeters every time you swallow, it is traumatized, ending up with chronic inflammation," said Modlin.
Cardinal symptom
Modlin pointed out that there is a lot more to GERD than heartburn. "Heartburn is a symptom, and not a disease," he said. "You can have patients with severe heartburn without reflux esophagitis; you can have patients with severe reflux esophagitis without heartburn; and you can have patients with severe heartburn without GERD."
He noted that people with GERD have a constellation of different gastrointestinal symptom complexes-diarrhea, reflux, irritable- bowel syndrome, constipation, and dyspepsia-that sometimes overlap. He pointed to some extraesophageal manifestations aside from heartburn, such as asthma, chest pain, laryngitis, and sleep disturbance, that accompany GERD.
"Sleep disturbance is probably the most underrated big problem arising from GERD," Modlin said, citing a study which revealed that 63 percent of patients could not sleep well, 42 percent could not sleep through a full night, 39 percent took naps, and a third had to sleep seated.
As for medical therapy for GERD, antacids work very transiently while H2-receptor antagonists, according to Modlin, are outmoded. A far more effective option are the H+, K+-ATPase inhibitors or proton-pump inhibitors (PPIs).
Rabeprazole (Pariet) belongs to this class of drugs, which Lim said is effective in controlling nocturnal acid breakthrough (NAB), citing a study in which pH was significantly higher with 10-mg rabeprazole than 20-mg omeprazole and 40-mg pantoprazole. In another study of patients with nonerosive gastroesophageal-reflux disease at the Changi General Hospital, no difference was noted between 10-mg rabeprazole and 20-mg esomeprazole in the primary end point. However, in the secondary efficacy variable of daytime satisfactory relief of heartburn and regurgitation, rabeprazole was statistically superior to esomeprazole. Holtmann et al. also showed that 20-mg rabeprazole was superior to 40-mg omeprazole during the first three days of treatment in a subset of patients with severe heartburn.
Metabolism difference
Rabeprazole is metabolized differently from other PPIs. "The major metabolic pathway of most PPIs is the CYP2C19, while [that of] rabeprazole is nonenzymatic in nature, whose end product is the thioether metabolite," pointed out Lim. "For esomeprazole, which is an S-isomer of omeprazole, the major pathway is still the CYP2C19. More than 70 percent of it follows CYP2C19 hepatic metabolism, but when CYP2C19 is inhibited by their respective sulfone metabolites, accumulation of esomeprazole, omeprazole, and their sulfone metabolite takes place."
Lim noted that the ratio of the mean area under the plasma- concentration-time-curve values in poor metabolizers (PMs) versus extensive metabolizers (EMs) for rabeprazole is the smallest among all the PPIs. This gives patients a much more consistent inhibition of acid secretion and clinical response, regardless of whether they are extensive, intermediate, or poor metabolizers. In two separate but similarly designed studies, it was demonstrated that the therapeutic effects of rabeprazole 10-mg per day on reflux esophagitis was not influenced by the CYP2C19 polymorphism, unlike lansoprazole 30 mg per day. Lim summarized the distinct pharmacological features of rabeprazole-no inhibition of hepatic CYP2C19, consistent response across different CYP2C19 genotypes, and full bioavailability on the first day of dosing.
Among the PPIs, Modlin noted that "rabeprazole provided the highest gastric proton-pump inhibition, which means that it produces the fastest inhibition of the gastric H+, K+ -ATPase activity, and thus showing the fastest inhibition of acid secretion, leading, in turn, to earlier onset of symptom relief."
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