Prevacid
Potent inhibitory action of the gastric proton pump inhibitor lansoprazole against urease activity of Helicobacter pylori: unique action selective for H. pylori cells.

Nagata K, Satoh H, Iwahi T, Shimoyama T, Tamura T.

Department of Bacteriology, Hyogo College of Medicine, Japan.

The gastric proton pump inhibitor lansoprazole, its active analog AG-2000, and omeprazole dose dependently inhibited urease activity extracted with distilled water from Helicobacter pylori cells; the 50% inhibitory concentrations were between 3.6 and 9.5 microM, which were more potent than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. These compounds also inhibited urease activity in intact cells of H. pylori and Helicobacter mustelae but did not inhibit ureases from other bacteria, such as Proteus vulgaris, Proteus mirabilis, and Providencia rettgeri. The mechanism of urease inhibition was considered to be blockage of the SH groups of H. pylori urease, since SH residues in the enzyme decreased after preincubation with lansoprazole and glutathione or dithiothreitol completely abolished the inhibitory action. The SH-blocking reagents N-ethylmaleimide and idoacetamide were also examined for their inhibition of the urease activity; their 50% inhibitory concentrations were 100- to 1,000-fold higher than those of lansoprazole. These results suggest that lansoprazole and omeprazole can potently and selectively inhibit H. pylori urease and that inhibition may be related to earlier findings indicating that these compounds have selective activity against HP growth.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8494373&dopt=Abstract lansoprazole Prevacid



Prevacid
Pharmacokinetics of lansoprazole in hemodialysis patients.

Karol MD, Machinist JM, Cavanaugh JM.

Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.

The pharmacokinetics of the new benzimidazole proton pump inhibitor lansoprazole and five of its metabolites were assessed after single oral dose administration to five hemodialysis patients. Patients were studied on dialysis and nondialysis days. Multiple blood and dialysate samples were collected after dosing and were assayed for lansoprazole and metabolite content via high-performance liquid chromatography. The degree of lansoprazole plasma protein binding was lower in hemodialysis patients than in subjects with normal renal function or patients with renal impairment not requiring dialytic therapy, although this tended to moderate when assessed immediately after dialysis. Examination of venous plasma concentration, paired arterial-venous concentration, and dialysate data revealed that lansoprazole and its metabolites were poorly dialyzable. No dosage adjustment of lansoprazole is necessary in hemodialysis patients nor is supplementation after hemodialysis sessions necessary.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8522639&dopt=Abstract lansoprazole Prevacid



Prevacid
Duodenal ulcer healing after 7-day treatment: a pilot study with lansoprazole, amoxicillin and clarithromycin.

Schutze K, Hentschel E.

Medical Department I, Hanusch Hospital, Vienna, Austria.

OBJECTIVE: To evaluate the efficacy and safety of a one-week triple therapy without bismuth and metronidazole in duodenal ulcer healing and symptom relief. PATIENTS AND METHODS: Forty-five patients with duodenal ulcers and Helicobacter pylori (H. pylori) infections were given a 7-day treatment with lansoprazole 30 mg bid, amoxicillin 1.000 mg bid, and clarithromycin 500 mg bid. Endoscopies with urease tests and histologic examinations were performed before initiation and four weeks after cessation of therapy. RESULTS: Using efficacy analysis, 41 of 42 duodenal ulcers (98%; 95% CI 0.87-1.00) were healed after one week of treatment. H. pylori was eradicated in 40 of 42 patients (95%; 95% CI 0.84-1.00). Two patients with healed ulcers showed a persistent infection, whereas H. pylori was eradicated in the one patient with persisting ulcer. Using intention-to-treat analysis, ulcer healing was achieved in 41 of 45 (91%; 95% CI 0.79-0.98) and H. pylori eradication in 40 of 45 patients (89%; 95% CI 0.76-0.96). After a mean of five days, 40 of 41 patients (98%; 95% CI 0.87-1.00) with ulcer healing became completely pain-free. CONCLUSIONS: One-week therapy with lansoprazole, amoxicillin and clarithromycin is highly effective in duodenal ulcer healing and symptom improvement. Prolonged acid suppression does not seem to be essential for duodenal ulcer treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8600661&dopt=Abstract lansoprazole Prevacid



Prevacid
Growth inhibition of Ureaplasma urealyticum by the proton pump inhibitor lansoprazole: direct attribution to inhibition by lansoprazole of urease activity and urea-induced ATP synthesis in U. urealyticum.

Nagata K, Takagi E, Satoh H, Okamura H, Tamura T.

Department of Bacteriology Hyogo College of Medicine, Japan.

The proton pump inhibitors (PPIs) omeprazole and lansoprazole and the acid-activated analog of lansoprazole AG-2000, which potently inhibit the urease of Helicobacter pylori (K. Nagata, H. Satoh, T. Iwahi, T. Shimoyama, and T. Tamura, Antimicrob. Agents Chemother. 37:769-774, 1993), also inhibited the urease activities of cell-free extracts as well as intact cells of Ureaplasma urealyticum. The 50% inhibitory concentrations were between 1 and 25 microM. These compounds also inhibited the ATP synthesis induced by urea in ureaplasma cells. The 50% inhibitory concentrations for ATP synthesis were close to those for urease activity, but they were lower than those of urease inhibitors, such as acetohydroxamic acid, hydroxyurea, and thiourea. In addition, one of the metabolites of lansoprazole found in human urine, M-VI, also inhibited ureaplasmal urease activity and the ATP synthesis induced by urea at almost the same concentrations as those of lansoprazole. The inhibition of PPIs against ureaplasma urease was very similar to those against H. pylori urease, suggesting that the inhibitory mechanism against these ureases was due to the blockage of the SH residues on the cysteine of the enzyme. Omeprazole, lansoprazole, AG-2000, and M-VI inhibited the growth of U. urealyticum. Since ureaplasma urease is thought to be involved in the pathogenicity of this organism in the urogenital tract, PPIs and their analogs may be useful as chemotherapeutic agents against diseases caused by U. urealyticum.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8619564&dopt=Abstract lansoprazole Prevacid



Prevacid
Identification of the human P450 enzymes involved in lansoprazole metabolism.

Pearce RE, Rodrigues AD, Goldstein JA, Parkinson A.

Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, USA.

The aim of this study was to identify which human P450 enzymes are involved in the metabolism of lansoprazole. In the presence of NADPH and oxygen, human liver microsomes converted lansoprazole to lansoprazole sulfide, lansoprazole sulfone and 5-hydroxylansoprazole. Formation of lansoprazole sulfide occurred nonenzymatically. The formation of lansoprazole sulfone appeared to be catalyzed by a single, low-affinity enzyme (apparent Km approximately 100 microM). In contrast, lansoprazole 5-hydroxylation appeared to be catalyzed by two kinetically distinct enzymes (apparent Km approximately 100 microM and approximately 15 microM). When human liver microsomes (n = 16) were incubated with 100 microM lansoprazole, both the 5-hydroxylation and sulfoxidation of lansoprazole appeared to be catalyzed by CYP3A4/5 (based on correlation analyses). Antibodies against rat CYP3A enzymes inhibited the rate of both 5-hydroxylation (approximately 55%) and sulfoxidation (approximately 70%) and cDNA-expressed CYP3A4 catalyzed both the 5-hydroxylation and sulfoxidation of lansoprazole (apparent Km approximately 100 microM). However, at the pharmacologically relevant substrate concentration of 1 microM, lansoprazole sulfoxidation was still highly correlated with CYP3A4/5 activity (r2 = .905), but lansoprazole 5-hydroxylation appeared to be catalyzed by CYP2C19 (r2 = .875) rather than CYP3A4/5 (r2 = .113). Antibodies and chemical inhibitors of CYP2C enzymes preferentially inhibited the 5-hydroxylation of lansoprazole, whereas lansoprazole sulfoxidation was preferentially inhibited by antibodies and chemical inhibitors of CYP3A4/5. The cDNA expressed enzymes CYP2C8, CYP2C9 and CYP2C19 catalyzed varying rates of lansoprazole 5-hydroxylation at a substrate concentration of 50 microM, but only CYPC19 catalyzed this reaction at 1 microM. These results suggest that at pharmacologically relevant concentrations, the 5-hydroxylation of lansoprazole is primarily catalyzed by CYP2C19, whereas the sulfoxidation of lansoprazole is primarily catalyzed by CYP3A4/5. It is possible that individuals lacking CYP2C19 will be poor metabolizers of lansoprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8627562&dopt=Abstract lansoprazole Prevacid